New compounds and pharmaceutical compositions for treating diseases

Abstract

The present invention discloses a compound of formula (I), wherein R 1a , R 1b , R 1c , R 2a , W 1 , W 2 , X 1 , X 2 , X 3 , Y and Z are as defined herein. The present invention relates to compounds, methods for preparing compounds of the present invention, pharmaceutical compositions comprising compounds of the present invention, and methods of treating the following diseases by administering compounds of the present invention: inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases involving abnormal cartilage turnover, congenital cartilage malformations, diseases involving abnormal 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. #imgabs0#

Description

Technical Field

[0001] The present invention relates to compounds, methods for preparing the compounds of the present invention, pharmaceutical compositions comprising the compounds of the present invention, uses and methods for preventing and / or treating the following diseases by administering the compounds of the present invention: inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases involving abnormal cartilage turnover, congenital cartilage malformations, diseases involving abnormal 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. Specifically, the compounds of the present invention can inhibit salt-inducible kinase ("SIK" kinase). Background of the Invention

[0003] Protein kinases belong to a large family of structurally related enzymes responsible for controlling a variety of cellular signaling processes. Specifically, they have been shown to be key regulators of cellular functions including, for example, proliferation, metabolism, and apoptosis. Consequently, defects in the control of protein phosphorylation leading to uncontrolled signaling are associated with a variety of diseases including, for example, inflammation, allergies, cancer, autoimmune diseases, CNS disorders, and angiogenesis.

[0004] In healthy individuals, inflammation is self-limited, its resolution being controlled by the release of anti-inflammatory mediators and cytokines such as interleukin-10 (IL-10), produced as part of a negative feedback loop, by so-called "suppressor" or "regulatory" cells.

[0005] Indeed, in the body's normal inflammatory process, an initial proinflammatory response is followed by a pro-resolving response that resolves the inflammation after the damage has resolved, leading to a decrease in pro-inflammatory cytokines such as TNFα and IL-12 and an increase in the levels of anti-inflammatory cytokines such as IL-10 and TGF-β, thereby creating a so-called tolerogenic environment.

[0006] 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, designated SIK1 (also known as SNFI-like kinase (SNF1LK) or cardiac Snf1-like kinase (MSK)), SIK2 (SNF1LK2 or KIAA0781), and SIK3 (KIAA0999) (Katoh et al., 2004).

[0007] SIKs play a variety of roles in different cell types. They have been found to phosphorylate a variety of substrates, including CREB-responsive transcriptional coactivator (CRTC) proteins and histone deacetylase (HDAC) proteins, thereby regulating the transcription of a variety of different genes. One of the effects of CRTC signaling involves controlling the phenotype of macrophages, particularly macrophage polarization through CRTC3 phosphorylation, as measured by reduced secretion of the pro-inflammatory cytokine IL-12 and concomitant increased secretion of the pro-resolving cytokine IL-10 (Clark et al., 2012; Ozanne et al., 2015).

[0008] SIK1 has recently been shown to be associated with skeletal muscle sensitivity in obese mice and may be an interesting target for preventing type 2 diabetes (Nixon et al., 2016) and diabetic nephropathy (Yu et al., 2013).

[0009] 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 that SIK proteins play a role in fibrotic diseases.

[0010] SIK2 and SIK3 have recently been identified to play a role in inflammation by secreting high levels of anti-inflammatory cytokines, particularly interleukin-10 (IL-10), and very low levels of pro-inflammatory cytokines such as TNF-α (Darling et al., 2017).

[0011] A role for SIK2 in T helper (Th) 1 cell differentiation through regulation of IFNγ and IL-12 signaling has recently been described, suggesting that SIK2 may be an interesting target for inflammatory diseases (Yao et al., 2013).

[0012] It has also been recently demonstrated that, similar to PTH, small molecule SIK inhibitors cause reduced phosphorylation and increased nuclear translocation of HDAC4 / 5 and CRTC2. Treatment with the small molecule SIK inhibitor YKL-05-099 increased bone formation and bone mass in mice (Wein et al., 2016), confirming the relevance of SIK inhibition in the treatment of bone turnover diseases.

[0013] In addition, it has been demonstrated that inhibition of SIK2 enhances neuronal survival after oxygen-glucose deprivation (Sasaki et al., 2011) or promotes melanin production in melanoma cells (Kumagai et al., 2011). In this context, since therapeutic strategies are needed to regulate stress cellular responses (e.g., during ischemia and after tissue reperfusion, in the chronic phase of cardiac remodeling, in diabetes and neurodegenerative disorders), the rapid activation or degradation of SIK proteins after a variety of stresses makes them a target of interest in inflammatory, cardiac or metabolic diseases and neurodegenerative diseases. SIK inhibition may also be applied to cosmetology or pigmentation-related diseases to induce melanin production.

[0014] 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 that SIK proteins play a role in fibrotic diseases.

[0015] In addition to their important role in cellular energy homeostasis, SIK proteins are also involved in cell cycle regulation. Higher SIK2 expression is significantly associated with poor survival in patients with high-grade serous ovarian cancer (Ashour Ahmed et al., 2010). Furthermore, SIK3 expression is elevated in ovarian cancer, particularly in the serous subtype and in advanced ovarian cancer (Charoenfuprasert et al., 2011). Therefore, SIK inhibition could be used to treat cancer.

[0016] Despite significant progress in the past two decades in treating patients with autoimmune diseases based on antibodies targeting proinflammatory cytokines, such as anti-TNFα, a large proportion of patients do not respond to these therapies or experience serious adverse events such as opportunistic infections. Therefore, there remains a large unmet medical need for the treatment of these diseases, and new drugs are needed for the prevention and / or treatment of the above-mentioned diseases. SUMMARY OF THE INVENTION

[0018] The present invention is based on the identification of novel compounds and their use in preventing and / or treating inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases involving abnormal cartilage turnover, congenital cartilage malformations, diseases involving abnormal 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, in particular SIK1, SIK2 and / or SIK3 inhibitors. The present invention also provides methods for preparing these compounds, pharmaceutical compositions containing these compounds, and methods for preventing and / or treating the following diseases by administering the compounds of the present invention: inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases involving abnormal cartilage turnover, congenital cartilage malformations, diseases involving abnormal 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] Thus, in a first aspect of the present invention, there is provided a compound of the present invention having formula I:

[0020]

[0021] in,

[0022] W1 is N or CR 3 and W2 is N or CH, provided that W1 and W2 cannot be N at the same time;

[0023] One of X1, X2 and X3 is N and the other two are C;

[0024] Y is N or CR 2b ;

[0025] Z is

[0026] --NR 4a R 4b ,

[0027] --NR 4c -, wherein the N atom and R 2a together with the atoms to which it is attached, form a fused 5-6 membered heterocycloalkenyl containing one double bond, or

[0028] -N-linked 4-7 membered monocyclic or spirocyclic heterocycloalkyl, further comprising zero, one or two additional heteroatoms independently selected from N, O and S, optionally replaced by one or more independently selected R 5 group substitution;

[0029] R 1a Selected from

[0030] -H,

[0031] -halogen,

[0032] --OH,

[0033] --CN,

[0034] -C 1-6 Alkyl, which is optionally replaced by one or more independently selected R 6 replace,

[0035] -C 1-4 alkoxy, which is optionally substituted by one or more -OH or a 5-6 membered monocyclic heterocycloalkyl group containing one, two or three heteroatoms independently selected from N, O and S,

[0036] --C(=O)-R 7 ,

[0037] --NR 8a R 8b ,

[0038] --S(=O)2-C 1-4 alkyl,

[0039] -5-6 membered monocyclic heteroaryl, comprising one, two or three heteroatoms independently selected from N, O and S, the heteroaryl being optionally substituted by one or more independently selected C 1-4 alkyl substituted, and

[0040] -4-6 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S;

[0041] R 1b and R 1c Independently selected from

[0042] -halogen,

[0043] --OH,

[0044] --CN,

[0045] -C 1-4 Alkyl, which is optionally replaced by one or more independently selected -OH, -CN or C 2-4 Alkenyl substitution,

[0046] -C 3-7 Cycloalkyl,

[0047] -4-8 membered monocyclic or spirocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S, the heterocycloalkyl optionally being replaced by one or more independently selected R 9 group substitution, and

[0048] --NR 10a R 10b ,

[0049] or R 1b and R 1c Together with the atoms to which it is attached, it forms C 3-6 Cycloalkyl,

[0050] or R 1b and R 1c Together with the atoms to which they are attached, they form a 4-6 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S, which heterocycloalkyl is optionally replaced by one or more independently selected R 11 group substitution;

[0051] R 2a and R 2b Independently selected from

[0052] -halogen,

[0053] -C 1-4 alkyl,

[0054] -C 1-4 Alkoxy, which is optionally substituted by one or more independently selected halogen, -OH or C 1-4 Alkoxy substitution,

[0055] --NR 12a R 12b ,and

[0056] --OH;

[0057] R 3 is H, halogen or optionally one or more independently selected -OH or C 1-4 Alkoxy-substituted C 1-4 alkoxy;

[0058] R 4a H or C 1-4 alkyl;

[0059] R 4b Selected from

[0060] -C 1-6 Alkyl, which is optionally replaced by one or more independently selected R13 replace,

[0061] -C 3-7 Cycloalkyl, which is optionally substituted with one or more independently selected R 14a replace,

[0062] -4-7 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S, the heterocycloalkyl optionally being replaced by one or more independently selected R 14b Replace, and

[0063] -5-6 membered monocyclic heteroaryl, comprising one, two or three heteroatoms independently selected from N, O and S, the heteroaryl being optionally substituted by one or more independently selected C 1-4 Alkyl substitution;

[0064] R 4c H, C 3-7 Cycloalkyl or C optionally substituted by one or more independently selected halogen or -CN 1-6 alkyl;

[0065] Each R 5 Independently selected from:

[0066] -oxo,

[0067] -halogen,

[0068] --CN,

[0069] --OH,

[0070] --NR 15a R 15b ,

[0071] -phenyl,

[0072] -C 3-7 Cycloalkyl,

[0073] -C 2-4 Alkynyl,

[0074] --C(=O)-C 1-4 Alkoxy,

[0075] -C 1-4 alkoxy, which is optionally substituted with one or more independently selected halogen or phenyl,

[0076] -C 1-4 Alkyl, which is optionally substituted by one or more independently selected halogen, -OH or C 1-4 Alkoxy substitution, and

[0077] -4-7 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S;

[0078] Each R 6 Independently selected from

[0079] -halogen,

[0080] --OR 16 ,

[0081] --NR 17a R 17b ,

[0082] - a 5-6 membered monocyclic heteroaryl group containing one, two or three heteroatoms independently selected from N, O and S, and

[0083] - 4-6 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S, which heterocycloalkyl is optionally substituted with one or more independently selected halogens;

[0084] R 7 -OH, C 1-4 Alkyl, C 1-4 Alkoxy, -NR 18a R 18b or a 4-6 membered monocyclic heterocycloalkyl group containing one, two or three heteroatoms independently selected from N, O and S, which is optionally substituted with one or more -OH groups;

[0085] R 8a and R 8b are independently H, -C(=O)-C 1-4 Alkoxy or C optionally substituted with one or more independently selected halogen, -CN or -OH 1-4 alkyl;

[0086] Each R 9 is independently halogen, -OH or C optionally substituted with one or more -OH 1-4 alkyl;

[0087] Each R 10a and R 10b is independently H or C optionally substituted with one or more -OH 1-4 alkyl;

[0088] Each R 11 Independently selected from

[0089] -C 1-4 Alkyl, which is optionally replaced by one or more independently selected -CN or C 1-4 Alkoxy substitution,

[0090] --C(=O)-C 1-6 Alkyl, and

[0091] --C(=O)-C 1-6 alkoxy;

[0092] Each R 12a and R 12b is independently H or optionally replaced by a -OH or C 1-4 Alkoxy-substituted C 1-4 alkyl;

[0093] Each R 13 Independently selected from

[0094] -halogen,

[0095] --CN,

[0096] --NR 19a R 19b ,

[0097] --OH,

[0098] -C 1-4 Alkoxy,

[0099] -C 3-7 Cycloalkyl,

[0100] --S(=O)2-C 1-4 alkyl,

[0101] - a 4-7 membered monocyclic heterocycloalkyl group containing one, two or three heteroatoms independently selected from N, O and S, and

[0102] -5-6 membered monocyclic heteroaryl, comprising one, two or three heteroatoms independently selected from N, O and S, the heteroaryl being optionally substituted by one or more independently selected C 1-4 Alkyl substitution;

[0103] Each R 14a and R 14b Independently selected from

[0104] -halogen,

[0105] -oxo,

[0106] -C 1-4 Alkyl, which is optionally substituted by one or more independently selected halogen, -OH or C 1-4 Alkoxy substitution,

[0107] --OH,

[0108] -C 1-4 alkoxy, and

[0109] --NR 20a R 20b ;

[0110] Each R 15a and R 15b Independently H, C 1-4 Alkyl or -C(=O)-C 1-4 alkoxy;

[0111] Each R 16 Independently selected from

[0112] -H,

[0113] --S(=O)2-C 1-4 alkyl,

[0114] -C 1-4 Alkyl, which is optionally substituted with one or more -C(=O)-NR 21a R 21b or substituted by a 4-6 membered monocyclic heterocycloalkyl group containing one, two or three heteroatoms independently selected from N, O and S, and

[0115] -4-6 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S;

[0116] Each R 17a and R 17b is independently H or optionally one or more independently selected -OH or C 1-4 Alkoxy-substituted C 1-4 alkyl;

[0117] R 18a and R 18b is independently H or optionally one or more independently selected -OH or C 1-4 Alkoxy-substituted C 1-4 alkyl;

[0118] Each R 19a 、R 19b 、R 20a 、R 20b 、R 21a and R 21b are independently H or C 1-4 alkyl.

[0119] In a specific aspect, the compounds of the present invention are provided for use in preventing and / or treating inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases involving abnormal cartilage turnover, congenital cartilage malformations, diseases involving abnormal 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.

[0120] Furthermore, it was unexpectedly demonstrated that the compounds of the present invention exhibit potency against SIK (particularly SIK1, SIK2 and / or SIK3, more particularly SIK3), which can result in tolerogenic therapy (i.e., reducing the levels of pro-inflammatory cytokines such as TNFα and IL-12 and increasing the levels of anti-inflammatory cytokines such as IL-10 and TGF-β).

[0121] On the other hand, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutical carrier, excipient or diluent. In a specific aspect, the pharmaceutical composition may further comprise other therapeutically active ingredients suitable for use in combination with the compounds of the present invention. In a more specific aspect, the other therapeutically active ingredients are agents for the treatment of the following diseases: inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases involving abnormal 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 abnormal angiogenesis-related diseases.

[0122] Furthermore, the compounds of the invention useful in the pharmaceutical compositions and methods of treatment disclosed herein are pharmaceutically acceptable at the time of preparation and use.

[0123] In another aspect of the present invention, the present invention provides a method for treating a mammal, particularly a human, having a disease selected from those listed herein, particularly inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases involving abnormal cartilage turnover, congenital cartilage malformations, diseases involving abnormal 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, which method comprises administering an effective amount of a pharmaceutical composition or compound of the present invention as described herein.

[0124] 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 a pharmaceutical. In one specific aspect, the pharmaceutical composition is used to prevent and / or treat inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases involving abnormal cartilage turnover, congenital cartilage malformations, diseases involving abnormal 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.

[0125] In another aspect, the present invention provides methods for synthesizing the compounds of the present invention, representative synthetic schemes and routes are disclosed later herein.

[0126] Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing detailed description.

[0127] It will be appreciated that the compounds of the present invention may be metabolized to produce biologically active metabolites. Detailed Description of the Invention

[0129] definition

[0130] The following terms have the meanings provided below and are useful in understanding the description and intended scope of the present invention.

[0131] When describing the present invention (which may include compounds, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions), the following terms (if any) have the following meanings, unless otherwise indicated. It is also understood that when described herein, any moiety defined below may be substituted with a variety of substituents, and each definition is intended to include such substituted moieties within its scope, as given below. Unless otherwise indicated, the term "substituted" is defined as described below. It is also understood that the terms "group" and "radical" are interchangeable when used herein.

[0132] The articles "a" and "an" herein may be used to refer to one or more than one (ie, to at least one) of the grammatical object of the article. For example, "an analogue" refers to one or more analogues.

[0133] "Alkyl" refers to a straight or branched aliphatic hydrocarbon having the specified number of carbon atoms. Specific alkyl groups have 1 to 6 carbon atoms or 1 to 4 carbon atoms. Branched refers to one or more alkyl groups (e.g., methyl, ethyl, or propyl) attached to a straight alkyl chain. Specific alkyl groups include methyl (-CH3), ethyl (-CH2-CH3), n-propyl (-CH2-CH2-CH3), isopropyl (-CH(CH3)2), n-butyl (-CH2-CH2-CH2-CH3), tert-butyl (-C(CH3)3), sec-butyl (-CH(CH3)-CH2CH3), isobutyl (-CH2-CH(CH3)2), n-pentyl (-CH2-CH2-CH2-CH2-CH3), n-hexyl (-CH2-CH2-CH2-CH2-CH2-CH3), and 1,2-dimethylbutyl (-CHCH3)-C(CH3)H2-CH2-CH3). Particular alkyl groups have 1 to 4 carbon atoms.

[0134] "Alkenyl" refers to a monovalent olefinic (unsaturated) hydrocarbon radical having the specified number of carbon atoms. Specific alkenyl groups have 2 to 8 carbon atoms, more specifically 2 to 6 carbon atoms, can be straight or branched, and have at least one, and specifically 1 to 2, sites of olefinic unsaturation. Specific alkenyl groups include ethenyl (-CH=CH), n-propenyl (-CHCH=CH), isopropenyl (-C(CH)=CH), and the like.

[0135] "Alkylene" refers to a divalent hydrocarbon radical having the specified number of carbon atoms, particularly 1 to 6 carbon atoms, more particularly 1 to 4 carbon atoms, which may be straight or branched. Examples of this term include methylene (-CH2-), ethylene (-CH2-CH2-), or -CH(CH3)-.

[0136] "Alkynylene" refers to a divalent alkynyl group having the specified number of carbon atoms and triple bonds, specifically 2 to 6 carbon atoms, more specifically 2 to 4 carbon atoms, which may be straight or branched. Examples of this term include -C≡C-, -CH2-C≡C-, and -C(CH3)HC≡CH-.

[0137] "Alkoxy" refers to the group O-alkyl, wherein the alkyl group has the specified number of carbon atoms. In particular, the term refers to the group -OC 1-6 Alkyl. Specific alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Specific alkoxy groups are lower alkoxy groups, i.e., having 1 to 6 carbon atoms. Other specific alkoxy groups have 1 to 4 carbon atoms.

[0138] "Amino" refers to the group -NH2.

[0139] "Aryl" refers to a monovalent aromatic hydrocarbon radical derived by removing one hydrogen atom from a single carbon atom of a parent aromatic ring system. In particular, aryl refers to an aromatic ring structure (monocyclic or fused polycyclic) having the specified number of ring atoms. Specifically, the term includes radicals containing 6 to 10 ring members. Specific aryl groups include phenyl and naphthyl.

[0140] "Cycloalkyl" refers to a non-aromatic hydrocarbon ring structure (monocyclic, fused polycyclic, bridged polycyclic, or spirocyclic) having the specified number of ring atoms. A cycloalkyl group can have 3 to 12 carbon atoms, specifically 3 to 10, more specifically 3 to 7 carbon atoms. Such cycloalkyl groups include, for example, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0141] "Cyano" refers to the radical -CN.

[0142] "Halogen" or "halo" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). Specific halogen groups are fluorine or chlorine.

[0143] The term "polycyclic" as used herein refers to a chemical group having a plurality of atoms in a closed ring. Specifically, it refers to a group having two, three or four atom rings, more particularly two or three atom rings, most particularly two atom rings.

[0144] When used to describe a compound or a group present on a compound, "hetero" means that one or more carbon atoms in the compound or group have been replaced by nitrogen, oxygen or sulfur heteroatoms. Hetero can be applied to any of the above-mentioned hydrocarbon groups, such as alkyl (e.g., heteroalkyl), cycloalkyl (e.g., heterocycloalkyl), aryl (e.g., heteroaryl), etc., which have 1 to 4, particularly 1 to 3 heteroatoms, more typically 1 or 2 heteroatoms, such as a single heteroatom.

[0145] "Heteroaryl" refers to a monocyclic or fused polycyclic aromatic ring structure comprising one or more heteroatoms independently selected from O, N, and S and a specified number of ring atoms. Specifically, the aromatic ring structure may have 5 to 9 ring members. The heteroaryl group may, for example, be a five-membered or six-membered monocyclic ring or a fused bicyclic structure formed by a fused five-membered ring and a six-membered ring or two fused six-membered rings or, as a further example, two fused five-membered rings. Each ring may contain up to four heteroatoms, typically selected from nitrogen, sulfur, and oxygen. Typically, the heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, and more often up to 2, for example, a single heteroatom. In particular, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atom in the heteroaryl ring may be basic (as in the case of imidazole or pyridine) or substantially non-basic (as in the case of indole or pyrrole nitrogen). Typically, the number of basic nitrogen atoms present in the heteroaryl group (including any amino substituents of the ring) is less than five.

[0146] Examples of five-membered monocyclic heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl groups.

[0147] Examples of six-membered monocyclic heteroaryl groups include, but are not limited to, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl.

[0148] Specific examples of bicyclic heteroaryl groups containing a five-membered ring fused to another five-membered ring include, but are not limited to, imidazothiazolyl and imidazoimidazolyl.

[0149] Specific examples of bicyclic heteroaryl groups containing a six-membered ring fused to a five-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.

[0150] The specific example of the bicyclic heteroaryl group containing two fused six-membered rings includes but is not limited to quinolyl, isoquinolyl, pyridopyridyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl and pteridinyl groups.Specific heteroaryl groups are those derived from thienyl, pyrrolyl, benzothienyl, benzofuranyl, indolyl, pyridyl, quinolyl, imidazolyl, oxazolyl and pyrazinyl.

[0151] Representative examples of heteroaryl groups include the following:

[0152]

[0153] wherein each Y is selected from >C═O, NH, O, and S.

[0154] "Heterocycloalkyl" refers to 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. The heterocycloalkyl ring structure may have 4 to 12 ring members, particularly 4 to 10 ring members, more particularly 4 to 7 ring members. Each ring may contain up to four heteroatoms, typically selected from nitrogen, sulfur, and oxygen. Typically, the heterocycloalkyl ring contains up to 4 heteroatoms, more typically up to 3 heteroatoms, more typically up to 2, for example, a single heteroatom. Examples of heterocycles 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.

[0155] As used herein, the term "heterocycloalkenyl" refers to a "heterocycloalkyl" group containing at least one double bond. Specific examples of heterocycloalkenyl groups are shown in the following illustrative examples:

[0156]

[0157] wherein each W is selected from CH2, NH, O, and S; each Y is selected from NH, O, C(=O), SO2, and S; and each Z is selected from N or CH.

[0158] Specific examples of monocyclic rings are shown in the following illustrative examples:

[0159]

[0160] wherein each W and Y is independently selected from -CH2-, -NH-, -O- and -S-.

[0161] Specific examples of fused bicyclic rings are shown in the following illustrative examples:

[0162]

[0163] wherein each W and Y is independently selected from -CH2-, -NH-, -O- and -S-.

[0164] Specific examples of bridged bicyclic rings are shown in the following illustrative examples:

[0165]

[0166] wherein each W and Y is independently selected from -CH2-, -NH-, -O- and -S-.

[0167] Specific examples of spiro rings are shown in the following illustrative examples:

[0168]

[0169] wherein each Y is selected from -CH2-, -NH-, -O- and -S-.

[0170] "Hydroxy" refers to the radical -OH.

[0171] "Oxo" refers to the group =0.

[0172] "Substituted" refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituents.

[0173] "Sulfo" or "sulfonic acid" refers to, for example, a -SO3H group.

[0174] "Thiol" refers to the group -SH.

[0175] As used herein, the term "substituted with one or more" refers to one to four substituents. Specifically, it refers to one to three substituents. More specifically, it refers to one or two substituents. In particular, it refers to one substituent.

[0176] Those skilled in the art of organic synthesis will appreciate that the maximum number of heteroatoms in a stable, chemically feasible heterocycle (whether aromatic or non-aromatic) is determined by the ring size, degree of unsaturation, and heteroatom valence. Typically, a heterocycle may contain from one to four heteroatoms, as long as the heteroaromatic ring is chemically feasible and stable.

[0177] "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or a state government, or equivalent agency in a country outside the United States, or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0178] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention that are pharmaceutically acceptable and possess the intended pharmacological activity of the parent compound. In particular, such salts are non-toxic and may be inorganic acid addition salts or organic acid addition salts and base addition salts. In particular, such salts include: (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or acid addition salts formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chloro- benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptanoic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc.; or (2) salts formed when the acidic proton present in the parent compound is replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth metal ion, or an aluminum ion) or coordinated with an organic base (e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc.). Salts also include, by way of example only, sodium salts, potassium salts, calcium salts, magnesium salts, ammonium salts, tetraalkylammonium salts, etc.; when the compound contains a basic functional group, salts of non-toxic organic or inorganic acids, such as hydrochlorides, hydrobromides, tartrates, methanesulfonates, acetates, maleates, oxalates, etc., are also included. The term "pharmaceutically acceptable cation" refers to an acceptable positively charged counterion of an acidic functional group. Examples of such cations include sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.

[0179] "Pharmaceutically acceptable excipient" refers to a diluent, adjuvant, excipient, or carrier with which a compound of the present invention is administered.

[0180] "Prodrugs" refer to compounds, including derivatives of compounds of the present invention, that have a cleavable group and become pharmaceutically active in vivo through solvolysis or under physiological conditions. Examples include, but are not limited to, choline ester derivatives, N-alkylmorpholine esters, and the like.

[0181] "Solvate" refers to a form of a compound that is associated with a solvent, typically by a solvolysis reaction. This physical association includes hydrogen bonding. Conventional solvents include water, EtOH, acetic acid, and the like. The compounds of the present invention can, for example, be prepared in crystalline form and can be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and also include both stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate will be capable of separation, for example when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0182] "Subject" includes humans. The terms "human," "patient," and "subject" are used interchangeably herein.

[0183] "Effective amount" refers to the amount of a compound of the invention that, when administered to a subject for treating a disease, is sufficient to achieve such treatment for the disease. "Effective amount" varies depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.

[0184] "Prevent" refers to reducing the risk of acquiring or developing a disease or condition (ie, preventing the appearance of at least one clinical symptom of a disease in an individual who may be exposed to a disease-causing agent or who is susceptible to the disease before onset of the disease).

[0185] The term "prevent" is related to "prevent" and refers to measures or procedures whose purpose is to prevent, rather than to treat or cure, a disease. Non-limiting examples of preventive measures may include administering vaccines; administering low molecular weight heparin to hospitalized patients at risk due to, for example, fixed thrombosis; and administering antimalarial agents, such as chloroquine, before visiting geographic areas where malaria is endemic or the risk of contracting malaria is high.

[0186] In one embodiment, "treating" any disease or condition refers to ameliorating the disease or condition (i.e., arresting the disease or reducing the manifestation, extent, or severity of at least one clinical symptom thereof). In another embodiment, "treating" refers to improving at least one physical parameter that cannot be discerned by the individual. In another embodiment, "treating" refers to modulating the disease or condition physically (e.g., stabilizing a discernible symptom), physiologically (e.g., stabilizing a physical parameter), or both. In another embodiment, "treating" involves slowing the progression of a disease.

[0187] As used herein, the term "inflammatory disorder" refers to a group of disorders 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 disease states (e.g., post-bypass surgery complications or chronic endotoxin conditions that contribute to, for example, chronic heart failure), and related diseases involving cartilage, such as articular cartilage. 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.

[0188] As used herein, the term "autoinflammatory disease" refers to the group of disorders that includes: cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), and tumor necrosis factor receptor-associated periodic syndromes (TRAPS), Behçet's disease Systemic-onset juvenile idiopathic arthritis (SJIA) or Still's disease.

[0189] As used herein, the term "autoimmune disease" refers to the group of conditions that includes the following: obstructive airway diseases, including conditions such as COPD, asthma (e.g., intrinsic asthma, extrinsic asthma, dust asthma, infantile asthma), particularly chronic or inveterate asthma (e.g., late-stage asthma and airway hyperresponsiveness), bronchitis (including bronchial asthma), systemic lupus erythematosus (SLE), cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, autoimmune liver diseases (e.g., autoimmune hepatitis, primary sclerosing cholangitis and primary biliary cirrhosis), Sjögren's disease, The term includes, but is not limited to, COPD, asthma, systemic lupus erythematosus, type 1 diabetes, and inflammatory bowel disease.

[0190] As used herein, the term "proliferative disease" refers to conditions such as cancer (e.g., uterine leiomyosarcoma or prostate cancer), myeloproliferative diseases (e.g., polycythemia vera, essential thrombocythemia, and myelofibrosis), leukemias (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.

[0191] The term "cancer" as used herein refers to a malignant or benign growth of cells in the skin or body organs (such as, but not limited to, breast, prostate, lung, kidney, pancreas, stomach, or intestine). Cancer tends to infiltrate adjacent tissues and spread (metastasise) to distant organs such as bone, liver, lung, or brain. The term cancer as used herein includes metastatic tumor cell types (such as, but not limited to, melanoma, lymphoma, leukemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma) and tissue cancer types (such as, but not limited to, colorectal cancer, prostate cancer, small cell lung cancer, and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, kidney cancer, gastric cancer, glioblastoma, primary liver cancer, ovarian cancer, and uterine leiomyosarcoma). In particular, the term "cancer" refers to acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytoma, atypical teratoid / rhabdoid tumor, 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, Embryonic tumor, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, Ewing sarcoma family of tumors, eye cancer, retinoblastoma, gallbladder cancer, 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 sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, hairy cell leukemia, liver cancer, non-small cell lung cancer, small cell lung cancer , cutaneous T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoma, Waldenstrom's macroglobulinemia, medulloblastoma, medullary epithelioma, melanoma, mesothelioma, oral cancer, myeloid leukemia, multiple myeloma, nasopharyngeal cancer, neuroblastoma, oral cancer, oropharyngeal cancer, osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian tumor of low malignant potential, pancreatic cancer, papillomatosis, parathyroid cancer, penile cancer, pharyngeal cancer, moderately differentiated pineal parenchymal tumor, pineoblastoma, and supratentorial primitive Neuroectodermal tumors, pituitary tumors, plasmacytoma / multiple myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcomas, the Ewing sarcoma family of tumors, Sezary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcomas, squamous cell carcinoma, gastric cancer, supratentorial primitive neuroectodermal tumor, testicular cancer, laryngeal cancer, thymoma and thymic cancer, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms' tumor.

[0192] As used herein, the term "leukemia" refers to neoplastic diseases of the blood and hematopoietic organs. Such diseases can cause bone marrow and immune system dysfunction, rendering the host highly susceptible to infection and bleeding. In particular, the term leukemia refers to acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic lymphoblastic leukemia (CLL).

[0193] As used herein, the term "fibrotic disease" refers to diseases characterized by excessive scarring due to overproduction, deposition, and contraction of the extracellular matrix, and those accompanied by abnormal accumulation of cells and / or fibronectin and / or collagen and / or increased recruitment of fibroblasts, including but not limited to fibrosis of an individual's organs or tissues, such as the heart, kidneys, liver, joints, lungs, pleural tissue, peritoneal tissue, skin, cornea, retina, muscle bone, and digestive tract. In particular, the term fibrotic disease refers to idiopathic pulmonary fibrosis (IPF); cystic fibrosis, other diffuse parenchymal lung diseases of varying etiology, including iatrogenic drug-induced fibrosis, occupational and / or environmentally induced fibrosis, granulomatous diseases (sarcoidosis, hypersensitivity pneumonitis), collagen vascular diseases, pulmonary alveolar proteinosis, Langerhans cell granulomatosis, lymphangioleiomyomatosis, genetic diseases (Herbert-Prague syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage disorders, familial interstitial lung disease); radiation-induced fibrosis; chronic obstructive pulmonary disease (COPD); scleroderma; bleomycin-induced pulmonary fibrosis; chronic asthma; silicosis; Asbestos-induced pulmonary fibrosis; acute respiratory distress syndrome (ARDS); renal fibrosis; tubulointerstitial fibrosis; glomerulonephritis; diabetic nephropathy, focal segmental glomerulosclerosis; IgA nephropathy; hypertension; Allport syndrome; intestinal fibrosis; hepatic fibrosis; cirrhosis; alcohol-induced hepatic fibrosis; toxin / drug-induced hepatic fibrosis; hemochromatosis; nonalcoholic steatohepatitis (NASH); bile duct injury; primary biliary cirrhosis; infection-induced hepatic fibrosis; viral-induced hepatic fibrosis; and autoimmune hepatitis; corneal scarring; hypertrophic scarring; Dupuytren's disease, keloids, cutaneous fibrosis; cutaneous scleroderma; systemic sclerosis, spinal cord injury / fibrosis; myelofibrosis; Duchenne muscular dystrophy (DMD)-related musculoskeletal fibrosis, vascular restenosis; atherosclerosis; arteriosclerosis; Wegener's granulomatosis; Peyronie's disease or chronic lymphocytic leukoderma. More particularly, the term "fibrotic disease" refers to idiopathic pulmonary fibrosis (IPF), Dupuytren's disease, nonalcoholic steatohepatitis (NASH), systemic sclerosis, renal fibrosis and skin fibrosis.

[0194] As used herein, the term "transplant rejection" refers to acute or chronic rejection or graft-versus-host disease of an allogeneic or xenogeneic transplant of cells, tissues, or solid organs (e.g., pancreatic islets, stem cells, bone marrow, skin, muscle, corneal tissue, neuronal tissue, heart, lung, combined heart-lung, kidney, liver, intestine, pancreas, trachea, or esophagus).

[0195] As used herein, the term "disease involving abnormal cartilage turnover" includes conditions such as osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, dystrophy of pain, Tietze syndrome or costochondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, endemic arthritis such as endemic osteoarthritis deformans, Mseleni's disease and Handigodu's disease); degeneration caused by fibromyalgia, systemic lupus erythematosus, scleroderma and ankylosing spondylitis.

[0196] As used herein, the term "congenital cartilage malformations" includes conditions such as hereditary chondrolysis, achondroplasias and pseudoachondroplasias, particularly but not limited to microtia, anotia, metaphyseal chondrodysplasia and related conditions.

[0197] As used herein, the term "diseases involving abnormal bone turnover" includes disorders such as osteoporosis (including postmenopausal osteoporosis, male osteoporosis, glucocorticoid-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, excess glucocorticoids, hyperthyroidism, hyperparathyroidism), Paget's disease, osteoarthritis, renal bone disease, osteogenesis imperfecta, and hypophosphatasia.

[0198] As used herein, the term "diseases associated with excessive secretion of IL-6" includes disorders such as Castleman's disease, multiple myeloma, psoriasis, Kaposi's sarcoma, and / or mesangial proliferative glomerulonephritis.

[0199] As used herein, the term "diseases associated with excessive secretion of TNFα, interferon, IL-12 and / or IL-23" includes conditions such as 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.

[0200] As used herein, the term "respiratory disease" refers to diseases affecting organs involved in breathing, such as the nose, pharynx, larynx, Eustachian tube, trachea, bronchi, lungs, related muscles (e.g., diaphragm and intercostal space), and nerves. In particular, examples of respiratory diseases include asthma, adult respiratory distress syndrome, and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, isocapnic hyperventilation, 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 lung fibrosis and / or airway inflammation, cystic fibrosis, and hypoxia.

[0201] As used herein, the term "endocrine and / or metabolic disease" refers to a group of conditions involving the body's production of too much or too little of a certain hormone or hormones, while metabolic conditions affect the body's ability to process certain nutrients and vitamins. Endocrine conditions include, among others, 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 conditions include cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets. Specific examples of metabolic conditions are obesity and / or type II diabetes.

[0202] As used herein, the term "cardiovascular disease" refers to a disease that affects the heart or blood vessels, or both. In particular, cardiovascular disease includes arrhythmias (atrial or ventricular or both); atherosclerosis and its sequelae; angina pectoris; heart rhythm disturbances; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysms; vasculitis (e.g., giant cell arteritis (GCA), retinal vasculitis, rheumatoid vasculitis); stroke; peripheral occlusive arterial disease of a limb, organ, or tissue; ischemic reperfusion injury to the brain, heart, kidney, or other organs or tissues; endotoxic, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; vasoconstriction (including vasoconstriction associated with migraine); vascular abnormalities, inflammation, or dysfunction limited to a single organ or tissue. More particularly, cardiovascular disease refers to atherosclerosis or giant cell arteritis.

[0203] As used herein, the term "dermatological disease" refers to a skin disorder. In particular, dermatological disorders include proliferative or inflammatory disorders of the skin, such as atopic dermatitis, bullous diseases, collagen diseases, psoriasis, psoriatic lesions, dermatitis, contact dermatitis, eczema, vitiligo, pruritus, scleroderma, wound healing, scarring, hypertrophic scarring, keloids, Kawasaki disease, rosacea, Sjögren-Larsen disease, dermatitis ... -Larsson syndrome or urticaria. More specifically, the term dermatological disease refers to vitiligo.

[0204] As used herein, the term "abnormal angiogenesis-related disease" refers to a disease caused by dysregulation of the process regulating angiogenesis. In particular, abnormal angiogenesis-related diseases refer to atherosclerosis, hypertension, tumor growth, inflammation, rheumatoid arthritis, wet macular degeneration, choroidal neovascularization, retinal neovascularization, and diabetic retinopathy.

[0205] "Compounds of the present invention" and equivalent expressions are intended to encompass compounds of the general formula as described herein, including pharmaceutically acceptable salts and solvates (e.g., hydrates) and solvates of pharmaceutically acceptable salts where the context permits. Similarly, references to intermediates, whether or not required per se, are intended to encompass their salts and solvates where the context permits.

[0206] When referring to a range, for example but not limited to C 1-8 When alkyl is present, the reference to a range should be considered as giving each member of that range.

[0207] Other derivatives of the compounds of the invention are active in both their acid and acid derivative forms, but the acid-sensitive forms generally provide advantages in solubility, tissue compatibility, or delayed release in mammalian organisms (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 compound with a substituted or unsubstituted amine, or anhydrides or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acid groups pendant from the compounds of the invention are particularly useful prodrugs. In some cases, it is desirable to prepare diester-type prodrugs, such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. Specific prodrugs of this type include C 1-8 Alkyl, C 2-8 Alkenyl, C 6-10 Optionally substituted aryl and (C 6-10 Aryl)-(C 1-4 alkyl) esters.

[0208] The present disclosure includes all isotopic forms of the compounds of the invention provided herein, whether (i) in which all atoms of a given atomic number have a mass number (or mixture of mass numbers) predominant in nature (referred to herein as a "natural isotopic form") or (ii) in which one or more atoms are replaced by atoms having the same atomic number, but a mass number different from the mass number of atoms predominant in nature (referred to herein as a "non-natural variant isotopic form"). It is understood that atoms can 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 a mass number less commonly found in nature (referred to herein as an "uncommon isotope") is increased relative to the naturally occurring amount, for example, to a level of >20%, >50%, >75%, >90%, >95%, or >99% based on the number of atoms of that atomic number (the latter embodiment being referred to as an "isotopically enriched variant form"). The term "non-natural variant isotopic form" also includes embodiments in which the proportion of the uncommon isotope is reduced relative to the naturally occurring amount. Isotopic forms may include radioactive forms (ie, they incorporate a radioactive isotope) and non-radioactive forms. Radioactive forms will generally be isotopically enriched variants.

[0209] Thus, an unnatural variant isotopic form of a compound may contain one or more artificial or unusual isotopes, such as deuterium ( 2 H or D), carbon-11 ( 11 C), carbon-13 ( 13 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), nitrogen-15 ( 15 N), oxygen-15 ( 15 O), oxygen-17 ( 17 O), oxygen-18 ( 18 O), phosphorus-32 ( 32 P), sulfur-35( 35 S), chlorine-36 ( 36 Cl), chlorine-37( 37 Cl), fluorine-18 ( 18 F), iodine-123 ( 123 I), iodine-125( 125 I), or may contain in one or more atoms an increased proportion of said isotope compared to the ratio prevalent in nature.

[0210] Isotopic forms containing non-natural variants of radioactive isotopes can be used, for example, in drug and / or substrate tissue distribution studies. 3 H) and carbon-14 (i.e. 14C) are particularly suitable for this purpose due to their ease of incorporation and readily available means of detection. 2 Unnatural variant isotopic forms of 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 some circumstances. In addition, it is possible to prepare 11 C. 18 F. 15 O and 13 Unnatural variant isotopic forms of N that can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy.

[0211] It is also 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."

[0212] Stereoisomers that are not mirror images of each other are termed "diastereomers", and those that are non-superimposable mirror images of each other are termed "enantiomers". When a compound has an asymmetric center, for example, it is bonded to four different groups, then a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center, described by the R- and S-sequencing rules of Cahn and Prelog or in terms of how the molecule rotates the plane of polarized light and is designated as right- or left-handed (i.e., a (+) or (-) isomer, respectively). A chiral compound can exist as an individual enantiomer or as a mixture thereof. A mixture containing equal ratios of enantiomers is termed a "racemic mixture".

[0213] "Tautomers" refer to compounds that are interchangeable forms of a particular compound structure with varying displacements of hydrogen atoms and electrons. Thus, the two structures can be in equilibrium through the movement of π electrons and atoms (usually H). For example, enols and ketones are tautomers because they rapidly interconvert upon treatment with acid or base. Another example of tautomerism is the acid and nitro forms of phenylnitromethane, which are also formed upon treatment with acid or base.

[0214] Tautomeric forms can be relevant to achieving optimal chemical reactivity and biological activity of a compound of interest.

[0215] The compounds of the present invention may possess one or more asymmetric centers; therefore, such compounds can be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof.

[0216] 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 (racemic or otherwise) thereof.Methods for determining stereochemistry and separating stereoisomers are well known in the art.

[0217] It will be appreciated that the compounds of the present invention may be metabolized to produce biologically active metabolites.

[0218] The present invention

[0219] The present invention is based on the identification of novel compounds and their use in preventing and / or treating inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases involving abnormal cartilage turnover, congenital cartilage malformations, diseases involving abnormal 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, in particular SIK1, SIK2 and / or SIK3 inhibitors.

[0220] The present invention also provides methods for preparing these compounds, pharmaceutical compositions containing these compounds, and methods for preventing and / or treating the following diseases by administering the compounds of the present invention: inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases involving abnormal cartilage turnover, congenital cartilage malformations, diseases involving abnormal 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.

[0221] Thus, in a first aspect of the present invention, there is provided a compound of the present invention having formula I:

[0222]

[0223] in,

[0224] W1 is N or CR 3 and W2 is N or CH, provided that W1 and W2 cannot be N at the same time;

[0225] One of X1, X2 and X3 is N and the other two are C;

[0226] Y is N or CR 2b ;

[0227] Z is

[0228] --NR 4a R 4b ,

[0229] --NR 4c -, wherein the N atom and R 2a together with the atoms to which it is attached, form a fused 5-6 membered heterocycloalkenyl containing one double bond, or

[0230] -N-linked 4-7 membered monocyclic or spirocyclic heterocycloalkyl, further comprising zero, one or two additional heteroatoms independently selected from N, O and S, optionally replaced by one or more independently selected R 5 group substitution;

[0231] R 1a Selected from

[0232] -H,

[0233] -halogen,

[0234] --OH,

[0235] -CN,

[0236] -C 1-6 Alkyl, which is optionally replaced by one or more independently selected R 6 replace,

[0237] -C 1-4 alkoxy, which is optionally substituted by one or more -OH or a 5-6 membered monocyclic heterocycloalkyl group containing one, two or three heteroatoms independently selected from N, O and S,

[0238] --C(=O)-R 7 ,

[0239] --NR 8a R 8b ,

[0240] --S(=O)2-C 1-4 alkyl,

[0241] -5-6 membered monocyclic heteroaryl, comprising one, two or three heteroatoms independently selected from N, O and S, the heteroaryl being optionally substituted by one or more independently selected C 1-4 alkyl substituted, and

[0242] -4-6 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S;

[0243] R 1b and R 1c Independently selected from

[0244] -halogen,

[0245] --OH,

[0246] --CN,

[0247] -C 1-4 Alkyl, which is optionally replaced by one or more independently selected -OH, -CN or C 2-4 Alkenyl substitution,

[0248] -C 3-7 Cycloalkyl,

[0249] -4-8 membered monocyclic or spirocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S, the heterocycloalkyl optionally being replaced by one or more independently selected R 9 group substitution, and

[0250] --NR 10a R 10b ,

[0251] or R 1b and R 1c Together with the atoms to which it is attached, it forms C 3-6 Cycloalkyl,

[0252] or R 1b and R 1c Together with the atoms to which they are attached, they form a 4-6 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S, which heterocycloalkyl is optionally replaced by one or more independently selected R 11 group substitution;

[0253] R 2a and R 2b Independently selected from

[0254] -halogen,

[0255] -C 1-4 alkyl,

[0256] -C 1-4 Alkoxy, which is optionally substituted by one or more independently selected halogen, -OH or C 1-4 Alkoxy substitution,

[0257] --NR 12a R 12b ,and

[0258] --OH;

[0259] R 3 is H, halogen or optionally one or more independently selected -OH or C 1-4 Alkoxy-substituted C 1-4 alkoxy;

[0260] R 4a H or C 1-4 alkyl;

[0261] R 4b Selected from

[0262] -C 1-6 Alkyl, which is optionally replaced by one or more independently selected R 13 replace,

[0263] -C 3-7 Cycloalkyl, which is optionally substituted with one or more independently selected R 14a replace,

[0264] -4-7 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S, the heterocycloalkyl optionally being replaced by one or more independently selected R 14b Replace, and

[0265] -5-6 membered monocyclic heteroaryl, comprising one, two or three heteroatoms independently selected from N, O and S, the heteroaryl being optionally substituted by one or more independently selected C 1-4 Alkyl substitution;

[0266] R 4c H, C 3-7 Cycloalkyl or C optionally substituted by one or more independently selected halogen or -CN 1-6 alkyl,;

[0267] Each R 5 Independently selected from

[0268] -oxo,

[0269] -halogen,

[0270] --CN,

[0271] --OH,

[0272] --NR 15a R 15b ,

[0273] -phenyl,

[0274] -C 3-7 Cycloalkyl,

[0275] -C 2-4 Alkynyl,

[0276] --C(=O)-C 1-4 Alkoxy,

[0277] -C 1-4alkoxy, which is optionally substituted with one or more independently selected halogen or phenyl,

[0278] -C 1-4 Alkyl, which is optionally substituted by one or more independently selected halogen, -OH or C 1-4 Alkoxy substitution, and

[0279] -4-7 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S;

[0280] Each R 6 Independently selected from

[0281] -halogen,

[0282] --OR 16 ,

[0283] --NR 17a R 17b ,

[0284] - a 5-6 membered monocyclic heteroaryl group containing one, two or three heteroatoms independently selected from N, O and S, and

[0285] - 4-6 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S, which heterocycloalkyl is optionally substituted with one or more independently selected halogens;

[0286] R 7 -OH, C 1-4 Alkyl, C 1-4 Alkoxy, -NR 18a R 18b or a 4-6 membered monocyclic heterocycloalkyl group containing one, two or three heteroatoms independently selected from N, O and S, which is optionally substituted with one or more -OH groups;

[0287] R 8a and R 8b are independently H, -C(=O)-C 1-4 Alkoxy or C optionally substituted with one or more independently selected halogen, -CN or -OH 1-4 alkyl;

[0288] Each R 9 is independently halogen, -OH or C optionally substituted with one or more -OH 1-4 alkyl;

[0289] Each R 10a and R 10b is independently H or C optionally substituted with one or more -OH 1-4 alkyl;

[0290] Each R 11 Independently selected from

[0291] -C 1-4 Alkyl, which is optionally replaced by one or more independently selected -CN or C 1-4 Alkoxy substitution,

[0292] --C(=O)-C 1-6 Alkyl, and

[0293] --C(=O)-C 1-6 alkoxy;

[0294] Each R 12a and R 12b is independently H or optionally replaced by a -OH or C 1-4 Alkoxy-substituted C 1-4 alkyl;

[0295] Each R 13 Independently selected from

[0296] -halogen,

[0297] --CN,

[0298] --NR 19a R 19b ,

[0299] --OH,

[0300] -C 1-4 Alkoxy,

[0301] -C 3-7 Cycloalkyl,

[0302] --S(=O)2-C 1-4 alkyl,

[0303] - a 4-7 membered monocyclic heterocycloalkyl group containing one, two or three heteroatoms independently selected from N, O and S, and

[0304] -5-6 membered monocyclic heteroaryl, comprising one, two or three heteroatoms independently selected from N, O and S, the heteroaryl being optionally substituted by one or more independently selected C 1-4 Alkyl substitution;

[0305] Each R 14a and R 14b Independently selected from

[0306] -halogen,

[0307] -oxo,

[0308] -C 1-4Alkyl, which is optionally substituted by one or more independently selected halogen, -OH or C 1-4 Alkoxy substitution,

[0309] --OH,

[0310] -C 1-4 alkoxy, and

[0311] --NR 20a R 20b ;

[0312] Each R 15a and R 15b Independently H, C 1-4 Alkyl or -C(=O)-C 1-4 alkoxy;

[0313] Each R 16 Independently selected from

[0314] -H,

[0315] --S(=O)2-C 1-4 alkyl,

[0316] -C 1-4 Alkyl, which is optionally substituted with one or more -C(=O)-NR 21a R 21b or substituted by a 4-6 membered monocyclic heterocycloalkyl group containing one, two or three heteroatoms independently selected from N, O and S, and

[0317] -4-6 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S;

[0318] Each R 17a and R 17b is independently H or optionally one or more independently selected -OH or C 1-4 Alkoxy-substituted C 1-4 alkyl;

[0319] R 18a and R 18b is independently H or optionally one or more independently selected -OH or C 1-4 Alkoxy-substituted C 1-4 alkyl;

[0320] Each R 19a 、R 19b 、R 20a 、R 20b 、R 21a and R 21b are independently H or C 1-4 alkyl.

[0321] In one embodiment, the compound of the invention is according to formula I, wherein W2 is N.

[0322] In one embodiment, the compound of the invention is according to Formula I, wherein W2 is CH.

[0323] In one embodiment, the compound of the invention is according to Formula I, wherein W1 is N.

[0324] In one embodiment, the compound of the invention is a compound of formula I, wherein W1 is CR 3 , and R 3 For H.

[0325] In one embodiment, the compound of the invention is a compound of formula I, wherein W1 is CR 3 , and R 3 In a specific embodiment, R 3 is F, Cl or Br. In a more specific embodiment, R 3 For F.

[0326] In one embodiment, the compound of the invention is a compound of formula I, wherein W1 is CR 3 , and R 3 C 1-4 In a specific embodiment, R 3 In a more specific embodiment, R 3 In a most specific embodiment, R 3 is -O-CH3.

[0327] In one embodiment, the compound of the invention is a compound of formula I, wherein W1 is CR 3 , and R 3 is one or more independently selected -OH or C 1-4 Alkoxy-substituted C 1-4 In a specific embodiment, R 3 is -O-CH2CH3 or -O-CH(CH3)2, each of which is replaced by one or more independently selected -OH or C 1-4 In another specific embodiment, R 3 is one, two or three independently selected -OH or C 1-4 Alkoxy-substituted C 1-4 In another specific embodiment, R 3is C substituted by one or more independently selected -OH, -O-CH3, -O-CH2CH3 or -O-CH(CH3)2 1-4 In a more specific embodiment, R 3 is -O-CH2CH3 or -O-CH(CH3)2, each of which is replaced by one, two or three independently selected -OH or C 1-4 In another more specific embodiment, R 3 is C substituted by one, two or three independently selected -OH, -O-CH3, -O-CH2CH3 or -O-CH(CH3)2 1-4 In another more specific embodiment, R 3 is one, two or three independently selected -OH or C 1-4 In a most specific embodiment, R 3 It is -O-CH2CH2-OH.

[0328] In one embodiment, the compound of the invention is a compound of Formula I, wherein R 2a In a specific embodiment, R 2a In a more specific embodiment, R 2a For F.

[0329] In one embodiment, the compound of the invention is a compound of Formula I, wherein R 2a C 1-4 In a specific embodiment, R 2a In a more specific embodiment, R 2a is -CH3.

[0330] In one embodiment, the compound of the invention is a compound of Formula I, wherein R 2a C 1-4 In a specific embodiment, R 2a In a more specific embodiment, R 2a In a most specific embodiment, R 2a is -O-CH3.

[0331] In one embodiment, the compound of the invention is a compound of Formula I, wherein R 2a is one or more independently selected halogen, -OH or C 1-4 Alkoxy-substituted C1-4 In a specific embodiment, R 2a is -O-CH3, -O-CH2CH3 or -O-CH(CH3)2, each of which is replaced by one or more independently selected halogens, -OH or C 1-4 In another specific embodiment, R 2a is one, two or three independently selected halogen, -OH or C 1-4 Alkoxy-substituted C 1-4 In another specific embodiment, R 2a is C optionally substituted with one or more independently selected F, Cl, Br, -OH, -O-CH3, -O-CH2CH3 or -O-CH(CH3)2 1-4 In a more specific embodiment, R 2a is -O-CH3, -O-CH2CH3 or -O-CH(CH3)2, each of which is replaced by one, two or three independently selected halogens, -OH or C 1-4 In another more specific embodiment, R 2a is C substituted by one, two or three independently selected F, Cl, Br, -OH, -O-CH3, -O-CH2CH3 or -O-CH(CH3)2 1-4 In another more specific embodiment, R 2a In another more specific embodiment, R 2a is one, two or three independently selected halogen, -OH or C 1-4 In a most specific embodiment, R 2a It is -O-CHF2, -O-CH2CH2-OH or -O-CH2CH2-O-CH3.

[0332] In one embodiment, the compound of the invention is a compound of Formula I, wherein R 2a -NR 12a R 6b , and R 12a and R 12b is independently H or optionally replaced by a -OH or C 1-4 Alkoxy-substituted C 1-4 In a specific embodiment, R 12a and R 12b In another specific embodiment, R 12a and R 12b One of them is H, and the other is optionally substituted by a -OH or C1-4 Alkoxy-substituted C 1-4 In another specific embodiment, R 12a and R 12b are optionally replaced by a -OH or C 1-4 Alkoxy-substituted C 1-4 In a more specific embodiment, R 12a and R 12b One of them is H, and the other is -CH3, -CH2CH3 or -CH(CH3)2. In another more specific embodiment, R 12a and R 12b One of them is H, and the other is -CH3, -CH2CH3 or -CH(CH3)2, each of which is substituted with one -OH, -O-CH3, -O-CH2CH3 or -O-CH(CH3)2. In a most specific embodiment, R 2a It is -NH-CH3, -NH-CH(CH3)2 or -NH-CH2CH2-OH.

[0333] In one embodiment, the compound of the invention is a compound of formula I, wherein Z is -NR 4c -, where N atoms and R 2a Together with the atoms to which they are attached, they form a 5-6 membered heterocycloalkenyl containing one double bond, and R 4c As previously described. In a specific embodiment, Z is -NR 4c -, where N atoms and R 2a Together with the atoms to which it is attached, it forms a fused 3-pyrroline or 1,2,3,6-tetrahydropyridine. In a more specific embodiment, Z is -NR 4c -, where N atoms and R 2a Together with the atoms to which it is attached, it forms a fused 1,2,3,6-tetrahydropyridine.

[0334] In one embodiment, the compound of the invention is a compound of Formula IIa, IIb, IIc, IId, IIe, IIf, IIg, or IIh:

[0335]

[0336] where R 1a 、R 1b 、R 1c 、R 4c and Y as described above.

[0337] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IIh, wherein R 4c For H.

[0338] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IIh, wherein R 4c C 3-7 In a specific embodiment, R 4c In a more specific embodiment, R 4c It is cyclopropyl.

[0339] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IIh, wherein R 4c C 1-6 In a specific embodiment, R 4c In a more specific embodiment, R 4c It is -CH2CH3.

[0340] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IIh, wherein R 4c is C substituted by one or more independently selected halogens or -CN 1-6 In a specific embodiment, R 4c is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2 or -C(CH3)3, each of which is substituted by one or more independently selected halogens or -CN. In another specific embodiment, R 4c is C substituted by one, two or three independently selected halogens or -CN 1-6 In another specific embodiment, R 4c is C substituted by one or more independently selected F, Cl or -CN 1-6 In a more specific embodiment, R 4c is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2 or -C(CH3)3, each of which is substituted by one, two or three independently selected halogens or -CN. In another more specific embodiment, R 4c is C substituted with one, two or three independently selected F, Cl or -CN 1-6 In another more specific embodiment, R 4c is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2 or -C(CH3)3, each of which is substituted by one or more independently selected F, Cl or -CN. In another more specific embodiment, R 4cis -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2 or -C(CH3)3, each of which is substituted by one, two or three independently selected F, Cl or -CN. In another more specific embodiment, R 4c is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2 or -C(CH3)3, each of which is substituted with one or more F or -CN. In yet another more specific embodiment, R 4c is C substituted with one, two or three independently selected F or -CN 1-6 In a most specific embodiment, R 4c is -CH2CH3 substituted by one, two or three F. In another most specific embodiment, R 4c In another most specific embodiment, R 4c is -CH2CF3.

[0341] In one embodiment, the compound of the invention is a compound of Formula I, wherein Z is a monocyclic or spirocyclic N-linked 4-7 membered heterocycloalkyl further comprising zero, one or two additional heteroatoms independently selected from N, O and S. In a specific embodiment, Z is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 2-azaspiro[3.3]heptyl, 1,6-diazaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 1-oxa-6-azaspiro[3.3]heptyl, 2-oxa-6-azaspiro[3.3]heptyl, 1-thia-6-azaspiro[3.3]heptyl or 2-thia-6-azaspiro[3.3]heptyl. In a more specific embodiment, Z is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 2-oxa-6-azaspiro[3.3]heptyl or 2-thia-6-azaspiro[3.3]heptyl.

[0342] In one embodiment, the compound of the invention is a compound of formula I, wherein Z is one or more independently selected R 5or 2-oxa-6-azaspiro[3.3]heptyl, 1-thia-6-azaspiro[3.3]heptyl, 2-oxa-6-azaspiro[3.3]heptyl, 1-thia-6-azaspiro[3.3]heptyl, or 2-thia-6-azaspiro[3.3]heptyl, each of which is replaced by one, two, or three independently selected R 5 In a more specific embodiment, Z is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, thiomorpholinyl or 2-thia-6-azaspiro[3.3]heptyl, each of which is replaced by one, two or three independently selected R 5 Group substitution.

[0343] In one embodiment, the compound of the invention is a compound of formula I, wherein Z is one or more independently selected R 5 a substituted N-linked 4-7 membered monocyclic or spirocyclic heterocycloalkyl group further comprising zero, one or two additional heteroatoms independently selected from N, O and S, and R 5 For oxo, halogen, -CN, -OH, phenyl, C 3-7 Cycloalkyl, C 2-4 Alkynyl or -C(=O)-C 1-4 In a specific embodiment, R 5 is oxo, F, Cl, -CN, -OH, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, -C≡CH, -C(=O)-O-CH3, -C(=O)-O-CH2CH3 or -C(=O)-O-CH(CH3)2. In a more specific embodiment, R 5 It is oxo, F, -CN, -OH, phenyl, cyclopropyl or -C≡CH.

[0344] In one embodiment, the compound of the invention is a compound of formula I, wherein Z is one or more independently selected R 5 a substituted N-linked 4-7 membered monocyclic or spirocyclic heterocycloalkyl group further comprising zero, one or two additional heteroatoms independently selected from N, O and S, and R 5 -NR 15a R 15b , and each R 15a and R 15b As previously described. In a specific embodiment, R 15a and R 15bIn another specific embodiment, R 15a and R 15b One is H and the other is C 1-4 Alkyl or -C(=O)-C 1-4 In another specific embodiment, R 15a and R 15b All C 1-4 In a more specific embodiment, R 15a and R 15b One is H, and the other is -CH3, -CH2CH3, -CH(CH3)2, -C(=O)-O-CH3, -C(=O)-O-CH2CH3, -C(=O)-O-CH(CH3)2, or -C(=O)-OC(CH3)3. In another more specific embodiment, R 15a and R 15b In a most specific embodiment, R 15a and R 15b One is H, and the other is -C(=O)-OC(CH3)3.

[0345] In one embodiment, the compound of the invention is a compound of formula I, wherein Z is one or more independently selected R 5 a substituted N-linked 4-7 membered monocyclic or spirocyclic heterocycloalkyl group further comprising zero, one or two additional heteroatoms independently selected from N, O and S, and R 5 C 1-4 In a specific embodiment, R 5 In a more specific embodiment, R 5 is -O-CH3.

[0346] In one embodiment, the compound of the invention is a compound of formula I, wherein Z is one or more independently selected R 5 a substituted N-linked 4-7 membered monocyclic or spirocyclic heterocycloalkyl group further comprising zero, one or two additional heteroatoms independently selected from N, O and S, and R 5 is C substituted by one or more halogen or phenyl groups 1-4 In a specific embodiment, R 5 is -O-CH3, -O-CH2CH3 or -O-CH(CH3)2, each of which is substituted by one or more halogen or phenyl. In another specific embodiment, R 5 is C substituted by one, two or three halogen or phenyl groups1-4 In another specific embodiment, R 5 is C substituted by one or more F, Cl or phenyl 1-4 In a more specific embodiment, R 5 is -O-CH3, -O-CH2CH3 or -O-CH(CH3)2, each of which is substituted with one or more F, Cl or phenyl. In another more specific embodiment, R 5 is C substituted by one, two or three F, Cl or phenyl groups 1-4 In another more specific embodiment, R 5 is -O-CH 3 substituted by one, two or three halogen or phenyl groups. In a most specific embodiment, R 5 is -O-CH 3 substituted by one, two or three F. In another most specific embodiment, R 5 It is -O-CH3 substituted by a phenyl group.

[0347] In one embodiment, the compound of the invention is a compound of formula I, wherein Z is one or more independently selected R 5 a substituted N-linked 4-7 membered monocyclic or spirocyclic heterocycloalkyl group further comprising zero, one or two additional heteroatoms independently selected from N, O and S, and R 5 C 1-4 In a specific embodiment, R 5 In a more specific embodiment, R 5 is -CH3.

[0348] In one embodiment, the compound of the invention is a compound of formula I, wherein Z is one or more independently selected R 5 a substituted N-linked 4-7 membered monocyclic or spirocyclic heterocycloalkyl group further comprising zero, one or two additional heteroatoms independently selected from N, O and S, and R 5 is replaced by one or more halogens, -OH or C 1-4 Alkoxy-substituted C 1-4 In a specific embodiment, R 5 is replaced by one or more halogens, -OH or C 1-4 In another specific embodiment, R 5 is replaced by one, two or three halogens, -OH or C 1-4 Alkoxy-substituted C 1-4 In another specific embodiment, R 5C substituted by one or more F, Cl, -OH, -O-CH3, -O-CH2CH3 or -O-CH(CH3)2 1-4 In a more specific embodiment, R 5 is replaced by one, two or three halogens, -OH or C 1-4 In another more specific embodiment, R 5 C substituted by one, two or three F, Cl, -OH, -O-CH3, -O-CH2CH3 or -O-CH(CH3)2 1-4 In another more specific embodiment, R 5 is -CH3, -CH2CH3 or -CH(CH3)2, each of which is substituted by one, two or three F, Cl, -OH, -O-CH3, -O-CH2CH3 or -O-CH(CH3)2. In a most specific embodiment, R 5 It is -CH3 substituted by one, two or three F or -OH.

[0349] In one embodiment, the compound of the invention is a compound of formula I, wherein Z is one or more independently selected R 5 a substituted N-linked 4-7 membered monocyclic or spirocyclic heterocycloalkyl group further comprising zero, one or two additional heteroatoms independently selected from N, O and S, and R 5 is a 4-7 membered monocyclic heterocycloalkyl group containing one, two or three heteroatoms independently selected from N, O and S. In a specific embodiment, R 5 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl or piperazinyl.

[0350] In one embodiment, the compound of the invention is according to any one of Formulas I-IIh, wherein Y is N.

[0351] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IIh, wherein Y is CR 2b , and R 2b In a specific embodiment, R 2b In a more specific embodiment, R 2b For F.

[0352] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IIh, wherein Y is CR 2b , and R 2b C 1-4In a specific embodiment, R 2b In a more specific embodiment, R 2b is -CH3.

[0353] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IIh, wherein Y is CR 2b , and R 2b C 1-4 In a specific embodiment, R 2b In a more specific embodiment, R 2b In a most specific embodiment, R 2b is -O-CH3.

[0354] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IIh, wherein Y is CR 2b , and R 2b is one or more independently selected halogen, -OH or C 1-4 Alkoxy-substituted C 1-4 In a specific embodiment, R 2b is -O-CH3, -O-CH2CH3 or -O-CH(CH3)2, each of which is replaced by one or more independently selected halogens, -OH or C 1-4 In another specific embodiment, R 2b is one, two or three independently selected halogen, -OH or C 1-4 Alkoxy-substituted C 1-4 In another specific embodiment, R 2b is C substituted by one or more independently selected F, Cl, Br, -OH, -O-CH3, -O-CH2CH3 or -O-CH(CH3)2 1-4 In a more specific embodiment, R 2b is -O-CH3, -O-CH2CH3 or -O-CH(CH3)2, each of which is replaced by one, two or three independently selected halogens, -OH or C 1-4 In another more specific embodiment, R 2b is C substituted by one, two or three independently selected F, Cl, Br, -OH, -O-CH3, -O-CH2CH3 or -O-CH(CH3)2 1-4 In another more specific embodiment, R 2bIn another more specific embodiment, R 2b is one, two or three independently selected halogen, -OH or C 1-4 In a most specific embodiment, R 2b It is -O-CHF2, -O-CH2CH2-OH or -O-CH2CH2-O-CH2CH3.

[0355] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IIh, wherein Y is CR 2b , R 2b -NR 12a R 12b , and R 12a and R 12b is independently H or optionally replaced by a -OH or C 1-4 Alkoxy-substituted C 1-4 In a specific embodiment, R 12a and R 12b In another specific embodiment, R 12a and R 12b One of them is H, and the other is optionally substituted by a -OH or C 1-4 Alkoxy-substituted C 1-4 In another specific embodiment, R 12a and R 12b are optionally replaced by a -OH or C 1-4 Alkoxy-substituted C 1-4 In a more specific embodiment, R 12a and R 12b One of them is H, and the other is -CH3, -CH2CH3 or -CH(CH3)2. In another more specific embodiment, R 12a and R 12b One of them is H, and the other is -CH3, -CH2CH3 or -CH(CH3)2, each of which is substituted with one -OH, -O-CH3, -O-CH2CH3 or -O-CH(CH3)2. In a most specific embodiment, R 2b It is -NH-CH3, -NH-CH(CH3)2 or -NH-CH2CH2-OH.

[0356] In one embodiment, the compound of the invention is a compound of formula I, wherein Z is -NR 4a R 4b , and R 4a and R 4bAs previously described. In a specific embodiment, R 4a is H. In another specific embodiment, R 4a C 1-4 In a more specific embodiment, R 4a In a most specific embodiment, R 4a is -CH3.

[0357] In one embodiment, the compound of the invention is a compound of Formula IIIa, IIIb, IIIc or IIId:

[0358]

[0359] where R 1a 、R 1b 、R 1c and R 4b As described above.

[0360] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IIId, wherein R 1b is halogen, -OH, -CN or C 3-7 In a specific embodiment, R 1b In a more specific embodiment, R 1b is F, -OH, -CN, cyclopropyl or cyclobutyl.

[0361] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IIId, wherein R 1b C 1-4 In a specific embodiment, R 1b It is -CH3, -CH2CH3 or -CH(CH3)2.

[0362] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IIId, wherein R 1b is one or more independently selected -OH, -CN or C 2-4 Alkenyl substituted C 1-4 In a specific embodiment, R 1b is -CH3, -CH2CH3 or -CH(CH3)2, each of which is substituted by one, two or three independently selected -OH, -CN, -CH=CH2, -CH2CH=CH2, -C(CH3)=CH2 or -CH2C(CH3)=CH2. In a more specific embodiment, R 1bIt is -CH2-OH, -CH2-CN or -CH2-CH=CH2.

[0363] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IIId, wherein R 1b is a 4-8 membered monocyclic or spirocyclic heterocycloalkyl group containing one, two or three heteroatoms independently selected from N, O and S. In a specific embodiment, R 1b is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, 2-azaspiro[3.3]heptyl, 1,6-diazaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 1-oxa-6-azaspiro[3.3]heptyl, 2-oxa-6-azaspiro[3.3]heptyl, 1-thia-6-azaspiro[3.3]heptyl or 2-thia-6-azaspiro[3.3]heptyl. In a more specific embodiment, R 1b is azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, morpholinyl or 2-oxa-6-azaspiro[3.3]heptyl.

[0364] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IIId, wherein R 1b is a 4-8 membered monocyclic or spirocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S, the heterocycloalkyl being replaced by one or more independently selected R 9 In a specific embodiment, R 1b is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, 2-azaspiro[3.3]heptyl, 1,6-diazaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 1-oxa-6-azaspiro[3.3]heptyl, 2-oxa-6-azaspiro[3.3]heptyl, 1-thia-6-azaspiro[3.3]heptyl or 2-thia-6-azaspiro[3.3]heptyl, each of which is replaced by one, two or three independently selected R 9 In a more specific embodiment, R 1b is azetidinyl, oxetanyl or morpholinyl, each of which is replaced by one, two or three independently selected R 9 Group substitution.

[0365] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IIId, wherein R 1bis a 4-8 membered monocyclic or spirocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S, the heterocycloalkyl being replaced by one or more independently selected R 9 Group substituted, and R 9 In a specific embodiment, R 9 In a more specific embodiment, R 9 It is F or -OH.

[0366] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IIId, wherein R 1b is a 4-8 membered monocyclic or spirocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S, the heterocycloalkyl being replaced by one or more independently selected R 9 Group substituted, and R 9 C 1-4 In a specific embodiment, R 9 In a more specific embodiment, R 9 is -CH3.

[0367] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IIId, wherein R 1b is a 4-8 membered monocyclic or spirocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S, the heterocycloalkyl being replaced by one or more independently selected R 9 Group substituted, and R 9 C substituted by one or more -OH 1-4 In a specific embodiment, R 9 is -CH3, -CH2CH3 or -CH(CH3)2, each of which is substituted by one, two or three -OH groups. In a more specific embodiment, R 9 It is -CH2-OH.

[0368] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IIId, wherein R 1b -NR 10a R 10b , and each R 10a and R 10b As previously described. In a specific embodiment, R 10a and R 10b In another specific embodiment, R 10a and R 10b One of them is H, and the other is C optionally substituted with one or more -OH 1-4In another specific embodiment, R 10a and R 10b are C optionally substituted with one or more -OH 1-4 In a more specific embodiment, R 10a and R 10b One of them is H, and the other is -CH3, -CH2CH3 or -CH(CH3)2. In another more specific embodiment, R 10a and R 10b One of them is H, and the other is -CH3, -CH2CH3 or -CH(CH3)2, each of which is substituted with one or more -OH. In another more specific embodiment, R 10a and R 10b are -CH3, -CH2CH3 or -CH(CH3)2, each of which is optionally substituted with one or more -OH. In a most specific embodiment, R 1b It is -NH-CH(CH3)2, -NH-CH2CH2-OH, -N(CH2CH3)2 or -N(CH3)-CH2CH2-OH.

[0369] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IIId, wherein R 1c is halogen, -OH, -CN or C 3-7 In a specific embodiment, R 1c In a more specific embodiment, R 1c is F, -OH, -CN, cyclopropyl or cyclobutyl.

[0370] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IIId, wherein R 1c C 1-4 In a specific embodiment, R 1c It is -CH3, -CH2CH3 or -CH(CH3)2.

[0371] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IIId, wherein R 1c is one or more independently selected -OH, -CN or C 2-4 Alkenyl substituted C 1-4 In a specific embodiment, R 1cis -CH3, -CH2CH3 or -CH(CH3)2, each of which is substituted by one, two or three independently selected -OH, -CN, -CH=CH2, -CH2CH=CH2, -C(CH3)=CH2 or -CH2C(CH3)=CH2. In a more specific embodiment, R 1c It is -CH2-OH, -CH2-CN or -CH2-CH=CH2.

[0372] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IIId, wherein R 1c is a 4-8 membered monocyclic or spirocyclic heterocycloalkyl group containing one, two or three heteroatoms independently selected from N, O and S. In a specific embodiment, R 1c is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, 2-azaspiro[3.3]heptyl, 1,6-diazaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 1-oxa-6-azaspiro[3.3]heptyl, 2-oxa-6-azaspiro[3.3]heptyl, 1-thia-6-azaspiro[3.3]heptyl or 2-thia-6-azaspiro[3.3]heptyl. In a more specific embodiment, R 1c is azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, morpholinyl or 2-oxa-6-azaspiro[3.3]heptyl.

[0373] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IIId, wherein R 1c is a 4-8 membered monocyclic or spirocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S, the heterocycloalkyl being replaced by one or more independently selected R 9 In a specific embodiment, R 1c is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, 2-azaspiro[3.3]heptyl, 1,6-diazaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 1-oxa-6-azaspiro[3.3]heptyl, 2-oxa-6-azaspiro[3.3]heptyl, 1-thia-6-azaspiro[3.3]heptyl or 2-thia-6-azaspiro[3.3]heptyl, each of which is replaced by one, two or three independently selected R 9 In a more specific embodiment, R 1cis azetidinyl, oxetanyl or morpholinyl, each of which is replaced by one, two or three independently selected R 9 Group substitution.

[0374] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IIId, wherein R 1c is a 4-8 membered monocyclic or spirocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S, the heterocycloalkyl being replaced by one or more independently selected R 9 Group substituted, and R 9 In a specific embodiment, R 9 In a more specific embodiment, R 9 It is F or -OH.

[0375] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IIId, wherein R 1c is a 4-8 membered monocyclic or spirocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S, the heterocycloalkyl being replaced by one or more independently selected R 9 Group substituted, and R 9 C 1-4 In a specific embodiment, R 9 In a more specific embodiment, R 9 is -CH3.

[0376] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IIId, wherein R 1c is a 4-8 membered monocyclic or spirocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S, the heterocycloalkyl being replaced by one or more independently selected R 9 Group substituted, and R 9 C substituted by one or more -OH 1-4 In a specific embodiment, R 9 is -CH3, -CH2CH3 or -CH(CH3)2, each of which is substituted by one, two or three -OH groups. In a more specific embodiment, R 9 It is -CH2-OH.

[0377] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IIId, wherein R 1c -NR 10a R 10b , and each R 10a and R 10bis independently H or C optionally substituted with one or more -OH 1-4 In a specific embodiment, R 10a and R 10b In another specific embodiment, R 10a and R 10b One of them is H, and the other is C optionally substituted with one or more -OH 1-4 In another specific embodiment, R 10a and R 10b are C optionally substituted with one or more -OH 1-4 In a more specific embodiment, R 10a and R 10b One of them is H, and the other is -CH3, -CH2CH3 or -CH(CH3)2. In another more specific embodiment, R 10a and R 10b One of them is H, and the other is -CH3, -CH2CH3 or -CH(CH3)2, each of which is substituted with one or more -OH. In another more specific embodiment, R 10a and R 10b are -CH3, -CH2CH3 or -CH(CH3)2, each of which is optionally substituted with one or more -OH. In a most specific embodiment, R 1c It is -NH-CH(CH3)2, -NH-CH2CH2-OH, -N(CH2CH3)2 or -N(CH3)-CH2CH2-OH.

[0378] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IIId, wherein R 1b and R 1c Together with the atoms to which it is attached, it forms C 3-6 In a specific embodiment, R 1b and R 1c Together with the atoms to which they are attached, they form a cyclopropyl, cyclobutyl or cyclopentyl group. In a more specific embodiment, R 1b and R 1c Together with the atoms to which it is attached, it forms a cyclobutyl group.

[0379] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IIId, wherein R 1b and R 1c Together with the atoms to which they are attached, they form a 4-6 membered monocyclic heterocycloalkyl group containing one, two or three heteroatoms independently selected from N, O and S. In a specific embodiment, R 1b and R 1cand the atoms to which they are attached form azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl or piperazinyl. In a more specific embodiment, R 1b and R 1c Together with the atoms to which they are attached, they form an azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl, or 1,4-dioxanyl group.

[0380] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IIId, wherein R 1b and R 1c Together with the atoms to which they are attached, they form a 4-6 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S, the heterocycloalkyl being replaced by one or more independently selected R 11 In a specific embodiment, R 1b and R 1c together with the atoms to which they are attached form an azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl, each of which is replaced by one, two, or three independently selected R 11 In a more specific embodiment, R 1b and R 1c Together with the atoms to which they are attached, they form an azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl, or 1,4-dioxanyl, each of which is replaced by one, two, or three independently selected R 11 Group substitution.

[0381] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IIId, wherein R 1b and R 1c Together with the atoms to which they are attached, they form a 4-6 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S, the heterocycloalkyl being replaced by one or more independently selected R 11 Group substituted, and R 11 C 1-4 In a specific embodiment, R 11 In a more specific embodiment, R 11 It is -CH3 or -CH(CH3)2.

[0382] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IIId, wherein R1b and R 1c Together with the atoms to which they are attached, they form a 4-6 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S, the heterocycloalkyl being replaced by one or more independently selected R 11 Group substituted, and R 11 is one or more independently selected -CN or C 1-4 Alkoxy-substituted C 1-4 In a specific embodiment, R 11 is -CH3, -CH2CH3 or -CH(CH3)2, each of which is substituted by one, two or three independently selected -CN, -O-CH3, -O-CH2CH3 or -O-CH(CH3)2. In a more specific embodiment, R 11 It is -CH2-CN or -CH2CH2-O-CH3.

[0383] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IIId, wherein R 1b and R 1c Together with the atoms to which they are attached, they form a 4-6 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S, the heterocycloalkyl being replaced by one or more independently selected R 11 Group substituted, and R 11 -C(=O)-C 1-6 In a specific embodiment, R 11 In a more specific embodiment, R 11 It is -C(=O)-CH3.

[0384] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IIId, wherein R 1b and R 1c Together with the atoms to which they are attached, they form a 4-6 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S, the heterocycloalkyl being replaced by one or more independently selected R 11 Group substituted, and R11 -C(=O)-C 1-6 In a specific embodiment, R 11 In a more specific embodiment, R 11 It is -C(=O)-OC(CH3)3.

[0385] In one embodiment, the compound of the invention is a compound of Formula IVa, IVb, IVc, IVd, IVe, IVf, IVg, IVh, IVi, IVj, IVk, IVl, IVm, IVn, IVo, or IVp:

[0386]

[0387]

[0388] where R 1a and R 4b As described above.

[0389] In one embodiment, the compound of the invention is a compound of formula I, wherein Z is -NR 4a R 4b And R 4a As previously described, or a compound of any one of Formulas IIIa-IVp, wherein R 4b C 1-6 In a specific embodiment, R 4b In a more specific embodiment, R 4b In a most specific embodiment, R 4bIt is -CH2CH3, -CH(CH3)2 or -CH2CH(CH3)2.

[0390] In one embodiment, the compound of the invention is a compound of formula I, wherein Z is -NR 4a R 4b And R 4a As previously described, or a compound of any one of Formulas IIIa-IVp, wherein R 4b is one or more independently selected R 13 Substituted C 1-6 In a specific embodiment, R 4b is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -C(CH3)3, -CH(CH3)CH2CH3 or -CH(CH3)CH(CH3)2, each of which is replaced by one or more independently selected R 13 In another specific embodiment, R 4b is one, two or three independently selected R 13 Substituted C 1-6 In a more specific embodiment, R 4b is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3 or -CH(CH3)CH(CH3)2, each of which is replaced by one or more independently selected R 13 In another more specific embodiment, R 4b is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -C(CH3)3, -CH(CH3)CH2CH3 or -CH(CH3)CH(CH3)2, each of which is replaced by one, two or three independently selected R 13 In another more specific embodiment, R 4b To be an R 13 Substituted C 1-6 In a more specific embodiment, R 4b is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3 or -CH(CH3)CH(CH3)2, each of which is replaced by one, two or three independently selected R 13 In another more specific embodiment, R 4bis -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -C(CH3)3, -CH(CH3)CH2CH3 or -CH(CH3)CH(CH3)2, each of which is separated by an R 13 In a most specific embodiment, R 4b is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3 or -CH(CH3)CH(CH3)2, each of which is separated by an R 13 replace.

[0391] In one embodiment, the compound of the invention is a compound of formula I, wherein Z is -NR 4a R 4b And R 4a As previously described, or a compound of any one of Formulas IIIa-IVp, wherein R 4b is one or more independently selected R 13 Substituted C 1-6 Alkyl, and R 13 Halogen, -CN, -OH, C 1-4 Alkoxy, C 3-7 Cycloalkyl or -S(=O)2-C 1-4 In a specific embodiment, each R 13 is independently F, Cl, -CN, -OH, -O-CH3, -O-CH2CH3, -O-CH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -S(=O)2-CH3, -S(=O)2-CH2CH3 or -S(=O)2-CH(CH3)2. In a more specific embodiment, each R 13 is independently F, -CN, -OH, -O-CH3, cyclopropyl, cyclobutyl or -S(=O)2-CH3.

[0392] In one embodiment, the compound of the invention is a compound of formula I, wherein Z is -NR 4a R 4b And R 4a As previously described, or a compound of any one of Formulas IIIa-IVp, wherein R 4b is one or more independently selected R 13 Substituted C 1-6 Alkyl, and R 13 -NR 19a R 19b , and each R 19a and R 19b As previously described. In a specific embodiment, R 19a and R19b In another specific embodiment, R 19a and R 19b One is H and the other is C 1-4 In another specific embodiment, R 19a and R 19b All C 1-4 In a more specific embodiment, R 19a and R 19b One of them is H, and the other is -CH3, -CH2CH3 or -CH(CH3)2. In another more specific embodiment, R 19a and R 19b It is -CH3, -CH2CH3 or -CH(CH3)2.

[0393] In one embodiment, the compound of the invention is a compound of formula I, wherein Z is -NR 4a R 4b And R 4a As previously described, or a compound of any one of Formulas IIIa-IVp, wherein R 4b is one or more independently selected R 13 Substituted C 1-6 Alkyl, and R 13 is a 4-7 membered monocyclic heterocycloalkyl group containing one, two or three heteroatoms independently selected from N, O and S. In a specific embodiment, R 13 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl or piperazinyl. In a more specific embodiment, R 13 is oxetanyl, tetrahydrofuranyl or morpholinyl.

[0394] In one embodiment, the compound of the invention is a compound of formula I, wherein Z is -NR 4a R 4b And R 4a As previously described, or a compound of any one of Formulas IIIa-IVp, wherein R 4b is one or more independently selected R 13 Substituted C 1-6 Alkyl, and R 13 is a 5-6 membered monocyclic heteroaryl group containing one, two or three heteroatoms independently selected from N, O and S. In a specific embodiment, R 13is pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl or pyrimidinyl. In a more specific embodiment, R 13 is imidazolyl, pyrazolyl or pyridinyl.

[0395] In one embodiment, the compound of the invention is a compound of formula I, wherein Z is -NR 4a R 4b And R 4a As previously described, or a compound of any one of Formulas IIIa-IVp, wherein R 4b is one or more independently selected R 13 Substituted C 1-6 Alkyl, and R 13 is a 5-6 membered monocyclic heteroaryl group containing one, two or three heteroatoms independently selected from N, O and S, the heteroaryl group being replaced by one or more independently selected C 1-4 In a specific embodiment, R 13 is pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl or pyrimidinyl, each of which is replaced by one or more independently selected C 1-4 In another specific embodiment, R 13 is a 5-6 membered monocyclic heteroaryl group containing one, two or three heteroatoms independently selected from N, O and S, the heteroaryl group being separated by a C 1-4 In another specific embodiment, R 13 is a 5-6 membered monocyclic heteroaryl group containing one, two or three heteroatoms independently selected from N, O and S, which is substituted by one or more independently selected -CH3, -CH2CH3 or -CH(CH3)2. In a more specific embodiment, R 13 is imidazolyl or pyrazolyl, each of which is replaced by one or more independently selected C 1-4 In another more specific embodiment, R 13 is pyrrolyl, furyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl or pyrimidinyl, each of which is replaced by a C 1-4 In another more specific embodiment, R 13is pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl or pyrimidinyl, each of which is substituted with one or more independently selected -CH3, -CH2CH3 or -CH(CH3)2. In another more specific embodiment, R 13 is a 5-6 membered monocyclic heteroaryl group containing one, two or three heteroatoms independently selected from N, O and S, which is substituted with one -CH3, -CH2CH3 or -CH(CH3)2. In another more specific embodiment, R 13 is a 5-6 membered monocyclic heteroaryl group containing one, two or three heteroatoms independently selected from N, O and S, which is substituted with one or more -CH3. In a more specific embodiment, R 13 is imidazolyl or pyrazolyl, each of which is replaced by a C 1-4 In another more specific embodiment, R 13 is pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl or pyrimidinyl, each of which is substituted with one -CH3, -CH2CH3 or -CH(CH3)2. In another more specific embodiment, R 13 is a 5-6 membered monocyclic heteroaryl group containing one, two or three heteroatoms independently selected from N, O and S, which is substituted with one -CH3. In a most specific embodiment, R 13 for

[0396] In one embodiment, the compound of the invention is a compound of formula I, wherein Z is -NR 4a R 4b And R 4a As previously described, or a compound of any one of Formulas IIIa-IVp, wherein R 4b C 3-7 In a specific embodiment, R 4b In a more specific embodiment, R 4b In a most specific embodiment, R 4b It is cyclopropyl.

[0397] In one embodiment, the compound of the invention is a compound of formula I, wherein Z is -NR 4a R 4b And R 4aAs previously described, or a compound of any one of Formulas IIIa-IVp, wherein R 4b is one or more independently selected R 14a Substituted C 3-7 In a specific embodiment, R 4b is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is replaced by one or more independently selected R 14a In another specific embodiment, R 4b is one, two or three independently selected R 14a Substituted C 3-7 In a more specific embodiment, R 4b is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is replaced by one, two or three independently selected R 14a In another more specific embodiment, R 4b To be an R 14a Substituted C 3-7 In a most specific embodiment, R 4b is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is replaced by an R 14a replace.

[0398] In one embodiment, the compound of the invention is a compound of formula I, wherein Z is -NR 4a R 4b And R 4a As previously described, or a compound of any one of Formulas IIIa-IVp, wherein R 4b is one or more independently selected R 14a Substituted C 3-7 Cycloalkyl, and R 14a Halogen, -OH or C 1-4 In a specific embodiment, R 14a is F, Cl, -OH, -O-CH3, -O-CH2CH3 or -O-CH(CH3)2. In a more specific embodiment, R 14a In another more specific embodiment, R 4b for In a most specific embodiment, R 4b for

[0399] In one embodiment, the compound of the invention is a compound of formula I, wherein Z is -NR 4a R 4b And R 4aAs previously described, or a compound of any one of Formulas IIIa-IVp, wherein R 4b is one or more independently selected R 14a Substituted C 3-7 Cycloalkyl, and R 14a C 1-4 In a specific embodiment, R 14a In a more specific embodiment, R 14a It is -CH2CH3 or -CH(CH3)2.

[0400] In one embodiment, the compound of the invention is a compound of formula I, wherein Z is -NR 4a R 4b And R 4a As previously described, or a compound of any one of Formulas IIIa-IVp, wherein R 4b is one or more independently selected R 14a Substituted C 3-7 Cycloalkyl, and R 14a is one or more independently selected halogen, -OH or C 1-4 Alkoxy-substituted C 1-4 In a specific embodiment, R 14a is -CH3, -CH2CH3 or -CH(CH3)2, each of which is replaced by one or more independently selected halogen, -OH or C 1-4 In another specific embodiment, R 14a is one, two or three independently selected halogen, -OH or C 1-4 Alkoxy-substituted C 1-4 In another specific embodiment, R 14a C substituted by one or more F, Cl, -OH, -O-CH3, -O-CH2CH3 or -O-CH(CH3)2 1-4 In a more specific embodiment, R 14a is one or more independently selected halogen, -OH or C 1-4 In another more specific embodiment, R 14a For a halogen, -OH or C 1-4 Alkoxy-substituted C 1-4 In another more specific embodiment, R 14a is C substituted with one or more independently selected F or -OH 1-4 In another more specific embodiment, R 14ais -CH3, -CH2CH3 or -CH(CH3)2, each of which is replaced by one, two or three independently selected halogens, -OH or C 1-4 In another more specific embodiment, R 14a is C substituted by one, two or three independently selected F, Cl, -OH, -O-CH3-O-CH2CH3 or -O-CH(CH3)2 1-4 In a most specific embodiment, R 14a It is -CH2-O-CH3.

[0401] In one embodiment, the compound of the invention is a compound of formula I, wherein Z is -NR 4a R 4b And R 4a As previously described, or a compound of any one of Formulas IIIa-IVp, wherein R 4b is one or more independently selected R 14a Substituted C 3-7 Cycloalkyl, and R 14a -NR 20a R 20b , and each R 20a and R 20b As previously described. In a specific embodiment, R 20a and R 20b In another specific embodiment, R 20a and R 20b One is H and the other is C 1-4 In another specific embodiment, R 20a and R 20b All C 1-4 In a more specific embodiment, R 20a and R 20b One of them is H, and the other is -CH3, -CH2CH3 or -CH(CH3)2. In another more specific embodiment, R 20a and R 20b It is -CH3, -CH2CH3 or -CH(CH3)2.

[0402] In one embodiment, the compound of the invention is a compound of formula I, wherein Z is -NR 4a R 4b And R 4a As previously described, or a compound of any one of Formulas IIIa-IVp, wherein R 4b is a 4-7 membered monocyclic heterocycloalkyl group containing one, two or three heteroatoms independently selected from N, O and S. In a specific embodiment, R 4bis azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxane or piperazinyl. In a more specific embodiment, R 4b In a most specific embodiment, R 4b It is oxetanyl or tetrahydrofuranyl.

[0403] In one embodiment, the compound of the invention is a compound of formula I, wherein Z is -NR 4a R 4b And R 4a As previously described, or a compound of any one of Formulas IIIa-IVp, wherein R 4b is a 4-7 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S, the heterocycloalkyl being replaced by one or more independently selected R 14b In a specific embodiment, R 4b is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl or piperazinyl, each of which is replaced by one or more independently selected R 14b In another specific embodiment, R 4b is a 4-7 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S, the heterocycloalkyl being replaced by one, two or three independently selected R 14b In a more specific embodiment, R 4b is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl or piperazinyl, each of which is replaced by one, two or three independently selected R 14b In another more specific embodiment, R 4b is a 4-7 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S, the heterocycloalkyl being separated by one R 14b In a most specific embodiment, R 4b To be two R 14b Substituted thietanyl.

[0404] In one embodiment, the compound of the invention is a compound of formula I, wherein Z is -NR 4a R 4b And R 4aAs previously described, or a compound of any one of Formulas IIIa-IVp, wherein R 4b is a 4-7 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S, the heterocycloalkyl being replaced by one or more independently selected R 14b Replace, and R 14b is halogen, oxo, -OH or C 1-4 In a specific embodiment, R 14b is F, Cl, oxo, -OH, -O-CH3, -O-CH2CH3 or -O-CH(CH3)2. In a more specific embodiment, R 14b is F, oxo, -OH or -O-CH3. In a most specific embodiment, R 14b For oxygen.

[0405] In one embodiment, the compound of the invention is a compound of formula I, wherein Z is -NR 4a R 4b And R 4a As previously described, or a compound of any one of Formulas IIIa-IVp, wherein R 4b is a 4-7 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S, the heterocycloalkyl being replaced by one or more independently selected R 14b Replace, and R 14b C 1-4 In a specific embodiment, R 14b In a more specific embodiment, R 14b is -CH3.

[0406] In one embodiment, the compound of the invention is a compound of formula I, wherein Z is -NR 4a R 4b And R 4a As previously described, or a compound of any one of Formulas IIIa-IVp, wherein R 4b is a 4-7 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S, the heterocycloalkyl being replaced by one or more independently selected R 14b Replace, and R 14b is one or more independently selected halogen, -OH or C 1-4 Alkoxy-substituted C 1-4 In a specific embodiment, R 14b is -CH3, -CH2CH3 or -CH(CH3)2, each of which is replaced by one or more independently selected halogen, -OH or C 1-4In another specific embodiment, R 14b is one, two or three independently selected halogen, -OH or C 1-4 Alkoxy-substituted C 1-4 In another specific embodiment, R 14b C substituted by one or more F, Cl, -OH, -O-CH3, -O-CH2CH3 or -O-CH(CH3)2 1-4 In a more specific embodiment, R 14b is one or more independently selected halogen, -OH or C 1-4 In another more specific embodiment, R 14b For a halogen, -OH or C 1-4 Alkoxy-substituted C 1-4 In another more specific embodiment, R 14b is C substituted with one or more independently selected F or -OH 1-4 In another more specific embodiment, R 14b is -CH3, -CH2CH3 or -CH(CH3)2, each of which is replaced by one, two or three independently selected halogens, -OH or C 1-4 In another more specific embodiment, R 14b is C substituted by one, two or three independently selected F, Cl, -OH, -O-CH3, -O-CH2CH3 or -O-CH(CH3)2 1-4 In a most specific embodiment, R 14b It is -CH2F, -CHF2, -CF3 or -CH2-OH.

[0407] In one embodiment, the compound of the invention is a compound of formula I, wherein Z is -NR 4a R 4b And R 4a As previously described, or a compound of any one of Formulas IIIa-IVp, wherein R 4b is a 4-7 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S, the heterocycloalkyl being replaced by one or more independently selected R 14b Replacement, R 14b -NR 20a R 20b , and each R 20a and R 20b As previously described. In a specific embodiment, R 20a and R 20b In another specific embodiment, R20a and R 20b One is H and the other is C 1-4 In another specific embodiment, R 20a and R 20b All C 1-4 In a more specific embodiment, R 20a and R 20b One of them is H, and the other is -CH3, -CH2CH3 or -CH(CH3)2. In another more specific embodiment, R 20a and R 20b In a most specific embodiment, R 20a and R 20b is -CH3.

[0408] In one embodiment, the compound of the invention is a compound of any one of Formulas I and IIIa-IVp, wherein Z is -NR 4a R 4b , R 4a As mentioned previously, and R 4b is a 5-6 membered monocyclic heteroaryl group containing one, two or three heteroatoms independently selected from N, O and S. In a specific embodiment, R 4b is pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl or pyrimidinyl. In a more specific embodiment, R 4b is imidazolyl, pyrazolyl, isoxazolyl or pyrimidinyl. In a most specific embodiment, R 4b Isoxazolyl.

[0409] In one embodiment, the compound of the invention is a compound of formula I, wherein Z is -NR 4a R 4b And R 4a As previously described, or a compound of any one of Formulas IIIa-IVp, wherein R 4b is a 5-6 membered monocyclic heteroaryl group containing one, two or three heteroatoms independently selected from N, O and S, the heteroaryl group being replaced by one or more independently selected C 1-4 In a specific embodiment, R 4b is pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl or pyrimidinyl, each of which is replaced by one or more independently selected C 1-4In another specific embodiment, R 4b is a 5-6 membered monocyclic heteroaryl group containing one, two or three heteroatoms independently selected from N, O and S, the heteroaryl group being separated by a C 1-4 In another specific embodiment, R 4b is a 5-6 membered monocyclic heteroaryl group containing one, two or three heteroatoms independently selected from N, O and S, which is substituted by one or more independently selected -CH3, -CH2CH3 or -CH(CH3)2. In a more specific embodiment, R 4b is imidazolyl, pyrazolyl or pyrimidinyl, each of which is replaced by one or more independently selected C 1-4 In another more specific embodiment, R 4b is a 5-6 membered monocyclic heteroaryl group containing one, two or three heteroatoms independently selected from N, O and S, which is substituted with one -CH3. In another more specific embodiment, R 4b is pyrrolyl, furyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl or pyrimidinyl, each of which is replaced by a C 1-4 In another more specific embodiment, R 4b is a 5-6 membered monocyclic heteroaryl group containing one, two or three heteroatoms independently selected from N, O and S, which is substituted with one -CH3, -CH2CH3 or -CH(CH3)2. In a more specific embodiment, R 4b is imidazolyl, pyrazolyl or pyrimidinyl, each of which is replaced by a C 1-4 In another more specific embodiment, R 4b is imidazolyl, pyrazolyl or pyrimidinyl, each of which is substituted with one or more -CH3, -CH2CH3 or -CH(CH3)2. In another more specific embodiment, R 4b is pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl or pyrimidinyl, each of which is substituted with one or more -CH3. In another more specific embodiment, R 4b is pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl or pyrimidinyl, each of which is substituted with one -CH3, -CH2CH3 or -CH(CH3)2. In another more specific embodiment, R 4bis a 5-6 membered monocyclic heteroaryl group containing one, two or three heteroatoms independently selected from N, O and S, which is substituted with one -CH3. In a most specific embodiment, R 4b is imidazolyl, pyrazolyl or pyrimidinyl, each of which is substituted by one -CH3.

[0410] In one embodiment, the compound of the invention is a compound of formula I, wherein Z is -NR 4a R 4b And R 4a As previously described, or a compound of any one of Formulas IIIa-IVp, wherein R 4b In a specific embodiment, Z is -NR 4a R 4b , R 4a is H, and R 4b is cyclopropyl or (1R,2S)-2-fluorocyclopropyl.

[0411] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IVp, wherein R 1a For H.

[0412] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IVp, wherein R 1a is halogen, -OH, -CN or -S(=O)2-C 1-4 In a specific embodiment, R 1a is F, Cl, Br, -OH, -CN, -S(=O)2-CH3, -S(=O)2-CH2CH3 or -S(=O)2-CH(CH3)2. In a more specific embodiment, R 1a is F, Cl, -OH, -CN or -S(=O)2-CH3. In a most specific embodiment, R 1a It is -CN.

[0413] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IVp, wherein R 1a C 1-6 In a specific embodiment, R 1a In a more specific embodiment, R 1aIt is -CH3, -CH2CH3 or -CH(CH3)2.

[0414] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IVp, wherein R 1a is one or more independently selected R 6 Substituted C 1-6 In a specific embodiment, R 1a is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -C(CH3)3, -CH(CH3)CH2CH3, -CH(CH3)CH(CH3)2, -CH2CH(CH3)CH2CH3 or -CH2CH2CH(CH3)2, each of which is replaced by one, two or three independently selected R 6 In a more specific embodiment, R 1a is -CH3, -CH2CH3, -CH2CH2CH3 or -CH2CH(CH3)2, each of which is replaced by one, two or three independently selected R 6 replace.

[0415] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IVp, wherein R 1a is one or more independently selected R 6 Substituted C 1-6 Alkyl, and R 6 In a specific embodiment, R 6 In a more specific embodiment, R 1a In a most specific embodiment, R 1a It is -CF3.

[0416] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IVp, wherein R 1a is one or more independently selected R 6 Substituted C 1-6 Alkyl, R 6 For-OR 16 , and R 16 As previously described. In a specific embodiment, R 16 H or -S(=O)2-C 1-4 In a more specific embodiment, R 16 is H, -S(=O)2-CH3, -S(=O)2-CH2CH3 or -S(=O)2-CH(CH3)2. In another more specific embodiment, R 16is H or -S(=O)2-CH3. In a most specific embodiment, R 1a -CH2-OH or -CH 2- OS(=O)2-CH3.

[0417] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IVp, wherein R 1a is one or more independently selected R 6 Substituted C 1-6 Alkyl, R 6 For-OR 16 , and R 16 C 1-4 In a specific embodiment, R 16 In a more specific embodiment, R 16 is -CH3.

[0418] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IVp, wherein R 1a is one or more independently selected R 6 Substituted C 1-6 Alkyl, R 6 For-OR 16 , and R 16 is replaced by one or more -C(=O)-NR 21a R 21b or a 4-6 membered monocyclic heterocycloalkyl substituted with one, two or three heteroatoms independently selected from N, O and S. 1-4 Alkyl, and R 21a and R 21b As previously described. In a specific embodiment, R 16 is -CH3, -CH2CH3 or -CH(CH3)2, each of which is substituted by one -C(=O)-NH2, -C(=O)-NH-CH3, -C(=O)-NH-CH2CH3, -C(=O)-NH-CH(CH3)2, -C(=O)-N(CH3)2, -C(=O)-N(CH2CH3)2, -C(=O)-N(CH(CH3)2)2, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl or piperazinyl. In a more specific embodiment, R 16 It is -CH3 substituted by one -C(=O)-NH-CH3, -C(=O)-N(CH3)2 or oxetanyl group.

[0419] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IVp, wherein R 1a is one or more independently selected R 6 Substituted C 1-6 Alkyl, R 6 For-OR 16 , and R 16 is a 4-6 membered monocyclic heterocycloalkyl group containing one, two or three heteroatoms independently selected from N, O and S. In a specific embodiment, R 16 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl or piperazinyl. In a more specific embodiment, R 16 It is an oxetane group.

[0420] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IVp, wherein R 1a is one or more independently selected R 6 Substituted C 1-6 Alkyl, R 6 -NR 17a R 17b , and R 17a and R 17b As previously described. In a specific embodiment, R 17a and R 17b In another specific embodiment, R 17a and R 17b One of them is H, and the other is optionally substituted by a -OH or C 1-4 Alkoxy-substituted C 1-4 In another specific embodiment, R 17a and R 17b are optionally replaced by a -OH or C 1-4 Alkoxy-substituted C 1-4 In a more specific embodiment, R 17a and R 17b One of them is H, and the other is -CH3, -CH2CH3 or -CH(CH3)2. In another more specific embodiment, R 17a and R 17b One of them is H, and the other is -CH3, -CH2CH3 or -CH(CH3)2, each of which is substituted with one -OH, -O-CH3, -O-CH2CH3 or -O-CH(CH3)2. In a most specific embodiment, R 6 It is -NH2, -NH-CH(CH3)2 or -N(CH3)-CH2CH2-OH.

[0421] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IVp, wherein R 1a is one or more independently selected R 6 Substituted C 1-6 Alkyl, and R 6 is a 5-6 membered monocyclic heteroaryl group containing one, two or three heteroatoms independently selected from N, O and S. In a specific embodiment, R 6 is pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl or pyrimidinyl. In a more specific embodiment, R 6 is imidazolyl, pyrazolyl or 1,2,4-triazolyl.

[0422] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IVp, wherein R 1a is one or more independently selected R 6 Substituted C 1-6 Alkyl, and R 6 is a 4-6 membered monocyclic heterocycloalkyl group containing one, two or three heteroatoms independently selected from N, O and S. In a specific embodiment, R 6 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl or piperazinyl. In a more specific embodiment, R 6 is pyrrolidinyl, piperidinyl or morpholinyl.

[0423] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IVp, wherein R 1a is one or more independently selected R 6 Substituted C 1-6 Alkyl, and R 6 is a 4-6 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S, which is substituted with one or more independently selected halogens. In a specific embodiment, R 6 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl or piperazinyl, each of which is substituted with one, two or three F or Cl. In a more specific embodiment, R 6 is azetidinyl substituted by one, two or three F. In a most specific embodiment, R 6 for

[0424] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IVp, wherein R 1a C 1-4 In a specific embodiment, R 1a In a more specific embodiment, R 1a It is -O-CH3 or -O-CH2CH3.

[0425] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IVp, wherein R 1a is C substituted by one or more -OH or a 5-6 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S. 1-4 In a specific embodiment, R 1a is -O-CH3, -O-CH2CH3 or -O-CH(CH3)2, each of which is substituted with one -OH, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxane or piperazinyl. In a more specific embodiment, R 1a It is -O-CH2CH3 substituted by one -OH or morpholino group.

[0426] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IVp, wherein R 1a -C(=O)-R 7 , and R 7 As previously described. In a specific embodiment, R 7 -OH, C 1-4 Alkyl or C 1-4 In a more specific embodiment, R 7 In another more specific embodiment, R 7 It is -OH, -CH3 or -O-CH3.

[0427] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IVp, wherein R 1a -C(=O)-R 7 , R 7 -NR 18a R 18b , and R 18a and R18b As previously described. In a specific embodiment, R 18a and R 18b In another specific embodiment, R 18a and R 18b One of them is H, and the other is optionally substituted by a -OH or C 1-4 Alkoxy-substituted C 1-4 In another specific embodiment, R 18a and R 18b are optionally replaced by a -OH or C 1-4 Alkoxy-substituted C 1-4 In a more specific embodiment, R 18a and R 18b One of them is H, and the other is -CH3, -CH2CH3 or -CH(CH3)2. In another more specific embodiment, R 17a and R 17b One of them is H, and the other is -CH3, -CH2CH3 or -CH(CH3)2, each of which is substituted with one -OH, -O-CH3, -O-CH2CH3 or -O-CH(CH3)2. In a most specific embodiment, R 7 It is -NH2, -NH-CH3, -NH-CH2CH3, -N(CH2CH3)2, -NH-CH2CH2-OH or -NH-CH2CH2-O-CH3.

[0428] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IVp, wherein R 1a -C(=O)-R 7 , and R 7 is a 4-6 membered monocyclic heterocycloalkyl group containing one, two or three heteroatoms independently selected from N, O and S. In a specific embodiment, R 7 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl or piperazinyl. In a more specific embodiment, R 7 It is a morpholinyl group.

[0429] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IVp, wherein R 1a -C(=O)-R 7 , and R 7 is a 4-6 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S, which is substituted with one or more -OH. In a specific embodiment, R 7is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl or piperazinyl, each of which is substituted with one, two or three -OH groups. In a more specific embodiment, R 7 In a most specific embodiment, R 7 for

[0430] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IVp, wherein R 1a -NR 8a R 8b , and each R 8a and R 8b As previously described. In a specific embodiment, R 8a and R 8b In another specific embodiment, R 8a and R 8b One is H, and the other is -C(=O)-C 1-4 Alkoxy or C optionally substituted by one or more halogen, -CN or -OH 1-4 In another specific embodiment, R 8a and R 8b All are -C(=O)-C 1-4 Alkoxy or C optionally substituted by one or more halogen, -CN or -OH 1-4 In a more specific embodiment, R 8a and R 8b One of them is H, and the other is -C(=O)-O-CH3, -C(=O)-O-CH2CH3, -C(=O)-O-CH(CH3)2, -C(=O)-O-CH2CH2CH3, -C(=O)-O-CH2CH2CH2CH3, -CH3, -CH2CH3 or -CH(CH3)2. In another more specific embodiment, R 8a and R 8b One of them is H, and the other is -CH3, -CH2CH3 or -CH(CH3)2, each of which is substituted by one, two or three F, Cl, -CN or -OH. In a most specific embodiment, R 7 It is -NH2, -NH-C(=O)-O-CH3, -NH-C(=O)-O-CH2CH2CH2CH3, -NH-CH2CHF2, -NH-CH2CN or -NH-CH2CH2-OH.

[0431] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IVp, wherein R 1a is a 5-6 membered monocyclic heteroaryl group containing one, two or three heteroatoms independently selected from N, O and S. In a specific embodiment, R 1a is pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl or pyrimidinyl. In a more specific embodiment, R 1a is pyrrolyl, furyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl or tetrazolyl.

[0432] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IVp, wherein R 1a is a 5-6 membered monocyclic heteroaryl group containing one, two or three heteroatoms independently selected from N, O and S, the heteroaryl group being replaced by one or more independently selected C 1-4 In a specific embodiment, R 1a is pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl or pyrimidinyl, each of which is substituted with one, two or three independently selected -CH3, -CH2CH3 or -CH(CH3)2. In a more specific embodiment, R 1a is pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl or tetrazolyl, each of which is substituted with one -CH3. In a most specific embodiment, R 1a for

[0433] In one embodiment, the compound of the invention is a compound of any one of Formulas I-IVp, wherein R 1a is a 4-6 membered monocyclic heterocycloalkyl group containing one, two or three heteroatoms independently selected from N, O and S. In a specific embodiment, R 1a is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxane or piperazinyl. In a more specific embodiment, R 1a is oxetanyl, tetrahydropyranyl or morpholinyl.

[0434] In one embodiment, the compound of the invention is a compound of Formula I, wherein the compound is selected from:

[0435] 2,6-dimethoxy-4-[5-(1-methyl-4-piperidinyl)benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)benzamide,

[0436] tert-Butyl 4-[1-[3,5-dimethoxy-4-(2,2,2-trifluoroethylcarbamoyl)phenyl]benzimidazol-5-yl]piperidine-1-carboxylate,

[0437] 2,6-dimethoxy-4-[5-(4-piperidinyl)benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)benzamide, 4-[5-[1-(cyanomethyl)-4-piperidinyl]benzimidazol-1-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)benzamide,

[0438] 2,6-dimethoxy-4-(5-tetrahydropyran-4-ylbenzimidazol-1-yl)-N-(2,2,2-trifluoroethyl)benzamide,

[0439] 2,6-dimethoxy-4-[5-(1-methyl-3-piperidinyl)benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)benzamide,

[0440] tert-Butyl 3-[1-[3,5-dimethoxy-4-(2,2,2-trifluoroethylcarbamoyl)phenyl]benzimidazol-5-yl]piperidine-1-carboxylate,

[0441] 2,6-dimethoxy-4-[5-(3-piperidinyl)benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)benzamide,

[0442] 4-[5-[1-(cyanomethyl)-3-piperidinyl]benzimidazol-1-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)benzamide,

[0443] 4-[5-(1-cyano-1-methyl-ethyl)benzimidazol-1-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)benzamide,

[0444] 4-[5-(1-cyano-1-methyl-ethyl)benzimidazol-1-yl]-N-cyclopropyl-2,6-dimethoxy-benzamide,

[0445] 4-[5-(1-cyano-1-methyl-ethyl)benzimidazol-1-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide,

[0446] 4-[5-(1-cyanocyclobutyl)benzimidazol-1-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)benzamide,

[0447] 4-[5-(1-cyanocyclobutyl)benzimidazol-1-yl]-N-cyclopropyl-2,6-dimethoxy-benzamide,

[0448] 4-[5-(1-cyanoethyl)benzimidazol-1-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)benzamide,

[0449] tert-Butyl 4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethylcarbamoyl)phenyl]imidazo[1,2-a]pyridin-7-yl]piperidine-1-carboxylate,

[0450] 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)benzamide,

[0451] 2-[3-[4-(3,3-difluoroazetidine-1-carbonyl)-3,5-dimethoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]-2-methyl-propionitrile,

[0452] 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide,

[0453] 2-[3-(8-methoxy-1-oxo-3,4-dihydro-2H-isoquinolin-6-yl)imidazo[1,2-a]pyridin-7-yl]-2-methyl-propionitrile,

[0454] tert-Butyl 3-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethylcarbamoyl)phenyl]imidazo[1,2-a]pyridin-7-yl]piperidine-1-carboxylate,

[0455] 2,6-dimethoxy-4-[7-(1-methyl-4-piperidinyl)imidazo[1,2-a]pyridin-3-yl]-N-(2,2,2-trifluoroethyl)benzamide,

[0456] 2,6-dimethoxy-4-[7-(3-piperidinyl)imidazo[1,2-a]pyridin-3-yl]-N-(2,2,2-trifluoroethyl)benzamide,

[0457] 2,6-dimethoxy-4-[7-(1-methyl-3-piperidinyl)imidazo[1,2-a]pyridin-3-yl]-N-(2,2,2-trifluoroethyl)benzamide,

[0458] 2-[3-[8-methoxy-1-oxo-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-6-yl]imidazo[1,2-a]pyridin-7-yl]-2-methyl-propionitrile,

[0459] 4-[7-(1-cyanoethyl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide,

[0460] 4-[7-(1-cyano-1-methyl-propyl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide,

[0461] 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2,6-dimethoxy-benzamide,

[0462] 4-[7-(2-amino-1,1-dimethyl-2-oxo-ethyl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2,6-dimethoxy-benzamide,

[0463] 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-N-ethyl-2,6-dimethoxy-benzamide,

[0464] 4-[7-(2-amino-1,1-dimethyl-2-oxo-ethyl)imidazo[1,2-a]pyridin-3-yl]-N-ethyl-2,6-dimethoxy-benzamide,

[0465] N-(cyanomethyl)-4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-2,6-dimethoxy-benzamide,

[0466] 4-[7-(1-cyanocyclopropyl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide,

[0467] 4-[7-(1-cyanocyclobutyl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide,

[0468] N-cyclopropyl-2-(difluoromethoxy)-4-[7-(1-hydroxy-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide,

[0469] 4-[7-(1-allyl-1-cyano-but-3-enyl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide,

[0470] 2,6-dimethoxy-4-(7-tetrahydropyran-4-ylimidazo[1,2-a]pyridin-3-yl)-N-(2,2,2-trifluoroethyl)benzamide,

[0471] 2-[3-[3-(difluoromethoxy)-4-(1,1-dioxo-1,4-thiazinane-4-carbonyl)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]-2-methyl-propionitrile,

[0472] 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-N-(cyclopropylmethyl)-2-(difluoromethoxy)-6-methoxy-benzamide,

[0473] 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-N-ethyl-6-methoxy-N-methyl-benzamide,

[0474] 2-[3-[3-(difluoromethoxy)-4-(4-hydroxypiperidine-1-carbonyl)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]-2-methyl-propionitrile,

[0475] 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-N-(2-morpholinoethyl)benzamide,

[0476] 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-N-(oxetane-3-yl)benzamide,

[0477] 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-N-(3-hydroxypropyl)-6-methoxy-benzamide,

[0478] 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-N-(3-methoxypropyl)benzamide,

[0479] 2-[3-[3-(difluoromethoxy)-5-methoxy-4-(4-methoxypiperidine-1-carbonyl)phenyl]imidazo[1,2-a]pyridin-7-yl]-2-methyl-propionitrile,

[0480] 2-[3-[3-(difluoromethoxy)-4-(3,3-difluoropyrrolidine-1-carbonyl)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]-2-methyl-propionitrile,

[0481] 2-[3-[3-(difluoromethoxy)-5-methoxy-4-(morpholine-4-carbonyl)phenyl]imidazo[1,2-a]pyridin-7-yl]-2-methyl-propionitrile,

[0482] 2-[3-[3-(difluoromethoxy)-5-methoxy-4-(4-methylpiperazine-1-carbonyl)phenyl]imidazo[1,2-a]pyridin-7-yl]-2-methyl-propionitrile,

[0483] 2-[3-[3-(difluoromethoxy)-4-(3-hydroxyazetidine-1-carbonyl)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]-2-methyl-propionitrile,

[0484] 2-[3-[3-(difluoromethoxy)-5-methoxy-4-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)phenyl]imidazo[1,2-a]pyridin-7-yl]-2-methyl-propionitrile,

[0485] 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-N-[(1-methylpyrazol-3-yl)methyl]benzamide,

[0486] 4-[7-(1-cyanocyclopentyl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide,

[0487] 4-[7-(1-hydroxyethyl)imidazo[1,2-a]pyridin-3-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)benzamide,

[0488] 4-[7-(1-amino-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)benzamide,

[0489] 4-[7-(1,1-dimethyl-2-oxo-propyl)imidazo[1,2-a]pyridin-3-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)benzamide,

[0490] 4-[7-(1-hydroxy-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)benzamide,

[0491] tert-Butyl 3-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethylcarbamoyl)phenyl]imidazo[1,2-a]pyridin-7-yl]azetidine-1-carboxylate,

[0492] tert-Butyl 3-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]azetidine-1-carboxylate,

[0493] tert-Butyl 4-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]piperidine-1-carboxylate,

[0494] N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[1-methyl-1-(5-methyl-1,2,4-oxadiazol-3-yl)ethyl]imidazo[1,2-a]pyridin-3-yl]benzamide,

[0495] 4-[7-(2-hydroxy-1,1-dimethyl-propyl)imidazo[1,2-a]pyridin-3-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)benzamide,

[0496] 4-[7-(1-acetylazetidin-3-yl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide,

[0497] tert-Butyl 3-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]piperidine-1-carboxylate,

[0498] N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(3-piperidinyl)imidazo[1,2-a]pyridin-3-yl]benzamide,

[0499] N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(4-piperidinyl)imidazo[1,2-a]pyridin-3-yl]benzamide,

[0500] N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(1-methyl-3-piperidinyl)imidazo[1,2-a]pyridin-3-yl]benzamide,

[0501] N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(1-methyl-4-piperidinyl)imidazo[1,2-a]pyridin-3-yl]benzamide,

[0502] 2-[3-[4-(3,3-difluoroazetidine-1-carbonyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]-2-methyl-propionitrile,

[0503] 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-N-(2,2-difluoroethyl)-2-(difluoromethoxy)-6-methoxy-benzamide,

[0504] 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-N-(2,2-difluoro-1-methyl-ethyl)-6-methoxy-benzamide,

[0505] 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-N-isobutyl-6-methoxy-benzamide,

[0506] 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-N-(1,1-dioxothietane-3-yl)-6-methoxy-benzamide,

[0507] 2-[3-[4-(3-cyclopropyl-3-hydroxy-azetidine-1-carbonyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]-2-methyl-propionitrile,

[0508] 2-[3-[3-(difluoromethoxy)-4-[3-hydroxy-3-(trifluoromethyl)azetidine-1-carbonyl]-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]-2-methyl-propionitrile,

[0509] 2-[3-[3-(difluoromethoxy)-5-methoxy-4-[3-(trifluoromethyl)azetidine-1-carbonyl]phenyl]imidazo[1,2-a]pyridin-7-yl]-2-methyl-propionitrile,

[0510] 1-[4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzoyl]azetidine-3-carbonitrile,

[0511] 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-N-isopropyl-6-methoxy-benzamide,

[0512] 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide,

[0513] 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-N-(1-isopropylcyclopropyl)-6-methoxy-benzamide,

[0514] 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-N-[1-(methoxymethyl)cyclopropyl]benzamide,

[0515] 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-N-(cyclopropylmethyl)-2-(difluoromethoxy)-6-methoxy-N-methyl-benzamide,

[0516] 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-N-(1-ethylcyclopropyl)-6-methoxy-benzamide,

[0517] 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-N-methyl-benzamide,

[0518] 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-N-(tetrahydrofuran-3-ylmethyl)benzamide,

[0519] 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-N-tetrahydrofuran-3-yl-benzamide,

[0520] 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-N-(1-cyclopropyl-2-hydroxy-ethyl)-2-(difluoromethoxy)-6-methoxy-benzamide,

[0521] 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-N-(3,3-difluorocyclobutyl)-2-(difluoromethoxy)-6-methoxy-benzamide,

[0522] 2-[3-[3-(difluoromethoxy)-4-(3-ethynyl-3-hydroxy-azetidine-1-carbonyl)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]-2-methyl-propionitrile,

[0523] 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-N-(cyclobutylmethyl)-2-(difluoromethoxy)-6-methoxy-benzamide,

[0524] N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(1-methylazetidin-3-yl)imidazo[1,2-a]pyridin-3-yl]benzamide,

[0525] N-[(1S,2S)-2-aminocyclohexyl]-4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzamide,

[0526] 4-[7-(2-amino-1,1-dimethyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide,

[0527] tert-Butyl N-[1-[4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzoyl]azetidin-3-yl]carbamate,

[0528] N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-(6-tetrahydropyran-4-ylpyrazolo[1,5-a]pyrimidin-3-yl)benzamide,

[0529] 2-[3-[3-(difluoromethoxy)-4-(3-fluoroazetidine-1-carbonyl)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]-2-methyl-propionitrile,

[0530] 2-[3-[3-(difluoromethoxy)-4-[3-(hydroxymethyl)azetidine-1-carbonyl]-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]-2-methyl-propionitrile,

[0531] 2-[3-[3-(difluoromethoxy)-5-methoxy-4-(3-methoxyazetidine-1-carbonyl)phenyl]imidazo[1,2-a]pyridin-7-yl]-2-methyl-propionitrile,

[0532] 2-[3-[3-(difluoromethoxy)-5-methoxy-4-(6-methyl-2,6-diazaspiro[3.3]heptane-2-carbonyl)phenyl]imidazo[1,2-a]pyridin-7-yl]-2-methyl-propionitrile,

[0533] 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-N-(1-cyclopropyl-2,2,2-trifluoro-ethyl)-2-(difluoromethoxy)-6-methoxy-benzamide,

[0534] 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-N-(1-cyclopropylethyl)-2-(difluoromethoxy)-6-methoxy-benzamide,

[0535] 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-N-(oxetan-3-ylmethyl)benzamide,

[0536] 2-[3-[4-(3-aminoazetidine-1-carbonyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]-2-methyl-propionitrile,

[0537] 2-[3-[3-(difluoromethoxy)-5-methoxy-4-(2-methylazetidine-1-carbonyl)phenyl]imidazo[1,2-a]pyridin-7-yl]-2-methyl-propionitrile,

[0538] 2-[3-[3-(difluoromethoxy)-4-[2-(hydroxymethyl)azetidine-1-carbonyl]-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]-2-methyl-propionitrile,

[0539] 4-[7-(1-amino-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide,

[0540] 4-[7-(4-cyanotetrahydropyran-4-yl)imidazo[1,2-a]pyridin-3-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)benzamide,

[0541] N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-(7-tetrahydropyran-4-ylimidazo[1,2-a]pyridin-3-yl)benzamide,

[0542] N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-(7-tetrahydropyran-4-ylimidazo[1,2-c]pyrimidin-3-yl)benzamide,

[0543] 4-[7-(3-cyanoazetidin-3-yl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide,

[0544] 2-[3-(7-methoxy-1-oxo-isoindolin-5-yl)imidazo[1,2-a]pyridin-7-yl]-2-methyl-propionitrile, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-(6-tetrahydropyran-4-ylpyrazolo[1,5-a]pyridin-3-yl)benzamide,

[0545] 1-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]cyclopropanecarboxylic acid methyl ester,

[0546] 1-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]cyclopropanecarboxylic acid,

[0547] N-cyclopropyl-2-(difluoromethoxy)-4-[7-[1-(hydroxymethyl)cyclopropyl]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide,

[0548] 4-[7-(4-cyanotetrahydropyran-4-yl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide,

[0549] 4-[7-(3-cyanooxetane-3-yl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide,

[0550] N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(1-methoxy-1-methyl-ethyl)imidazo[1,2-c]pyrimidin-3-yl]benzamide,

[0551] N-cyclopropyl-2-(difluoromethoxy)-4-[7-(1-hydroxy-1-methyl-ethyl)imidazo[1,2-c]pyrimidin-3-yl]-6-methoxy-benzamide,

[0552] N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(1-methoxy-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]benzamide,

[0553] 4-[7-(3-cyano-1-methyl-azetidin-3-yl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide,

[0554] 4-[7-(1-acetyl-3-cyano-azetidin-3-yl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide,

[0555] 4-[7-(3-cyanotetrahydrofuran-3-yl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide,

[0556] N-cyclopropyl-2-(difluoromethoxy)-4-[7-(1-ethyl-1-hydroxy-propyl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide,

[0557] 5-[7-(3-cyanooxetane-3-yl)imidazo[1,2-a]pyridin-3-yl]-3-methoxy-N-(2,2,2-trifluoroethyl)pyridine-2-carboxamide,

[0558] N-cyclopropyl-2-(difluoromethoxy)-4-[7-(1-ethyl-1-methoxy-propyl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide,

[0559] 5-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-3-methoxy-N-(2,2,2-trifluoroethyl)pyridine-2-carboxamide,

[0560] N-cyclopropyl-2-(difluoromethoxy)-4-[7-(1-ethoxy-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide,

[0561] N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]benzamide,

[0562] 4-[7-(3-cyanooxetane-3-yl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide,

[0563] 2-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]-2,2-difluoro-acetic acid methyl ester,

[0564] 2-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]-2,2-difluoro-acetic acid,

[0565] N-cyclopropyl-2-(difluoromethoxy)-4-[7-(1-fluoro-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide,

[0566] N-cyclopropyl-2-(difluoromethoxy)-4-[7-(1-hydroxy-1-tetrahydropyran-4-yl-ethyl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide,

[0567] N-cyclopropyl-2-(difluoromethoxy)-4-[7-(1-hydroxy-1,2-dimethyl-propyl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide,

[0568] N-cyclopropyl-4-[7-(1,1-difluoro-2-hydroxy-ethyl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzamide,

[0569] N-cyclopropyl-2-(difluoromethoxy)-4-[7-(1-hydroxy-1-methyl-propyl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide,

[0570] N-cyclopropyl-4-[7-(1-cyclopropyl-1-hydroxy-ethyl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzamide,

[0571] N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(1-morpholinoethyl)imidazo[1,2-a]pyridin-3-yl]benzamide,

[0572] N-cyclopropyl-2-(difluoromethoxy)-4-[7-(1-hydroxyethyl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide,

[0573] N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[1-(morpholine-4-carbonyl)cyclopropyl]imidazo[1,2-a]pyridin-3-yl]benzamide,

[0574] N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[1-(2-methoxyethylcarbamoyl)cyclopropyl]imidazo[1,2-a]pyridin-3-yl]benzamide,

[0575] N-cyclopropyl-4-[7-[1-(diethylcarbamoyl)cyclopropyl]imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzamide,

[0576] N-cyclopropyl-2-(difluoromethoxy)-4-[7-[1-(3-hydroxyazetidine-1-carbonyl)cyclopropyl]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide,

[0577] N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[1-(morpholinomethyl)cyclopropyl]imidazo[1,2-a]pyridin-3-yl]benzamide,

[0578] N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[1-(1-piperidinyl)ethyl]imidazo[1,2-a]pyridin-3-yl]benzamide,

[0579] N-cyclopropyl-2-(difluoromethoxy)-4-[7-[1-(2-hydroxyethylcarbamoyl)cyclopropyl]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide,

[0580] N-cyclopropyl-4-[7-[1-(diethylamino)ethyl]imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzamide,

[0581] N-cyclopropyl-2-(difluoromethoxy)-4-[7-[1-(isopropylamino)ethyl]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide,

[0582] N-cyclopropyl-2-(difluoromethoxy)-4-[7-(2-hydroxy-1,1-dimethyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide,

[0583] N-cyclopropyl-2-(difluoromethoxy)-4-[7-[1-[(isopropylamino)methyl]cyclopropyl]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide,

[0584] N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[1-(2-oxa-6-azaspiro[3.3]heptane-6-yl)ethyl]imidazo[1,2-a]pyridin-3-yl]benzamide,

[0585] N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(1-pyrrolidin-1-ylethyl)imidazo[1,2-a]pyridin-3-yl]benzamide,

[0586] N-cyclopropyl-2-(difluoromethoxy)-4-[7-[1-[2-hydroxyethyl(methyl)amino]ethyl]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide,

[0587] N-cyclopropyl-2-(difluoromethoxy)-4-[7-[1-(3-hydroxyazetidin-1-yl)ethyl]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide,

[0588] N-cyclopropyl-4-[7-[1-(3,3-difluoroazetidin-1-yl)ethyl]imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzamide,

[0589] N-cyclopropyl-2-(difluoromethoxy)-4-[7-[1-[(2S)-2-(hydroxymethyl)morpholin-4-yl]ethyl]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide,

[0590] tert-Butyl 3-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]-6-fluoro-imidazo[1,2-a]pyridin-7-yl]azetidine-1-carboxylate,

[0591] 4-(7-cyclobutylimidazo[1,2-a]pyridin-3-yl)-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide,

[0592] N-cyclopropyl-2-(difluoromethoxy)-4-[7-(1,1-dimethyl-2-morpholino-ethyl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide,

[0593] N-cyclopropyl-2-(difluoromethoxy)-4-[7-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide,

[0594] N-cyclopropyl-2-(difluoromethoxy)-4-(6-fluoro-7-tetrahydropyran-4-yl-imidazo[1,2-a]pyridin-3-yl)-6-methoxy-benzamide,

[0595] N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-(6-methoxy-7-tetrahydropyran-4-yl-imidazo[1,2-a]pyridin-3-yl)benzamide,

[0596] 4-(7-cyclobutyl-6-fluoro-imidazo[1,2-a]pyridin-3-yl)-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide,

[0597] 4-[7-(1-acetylazetidin-3-yl)-6-fluoro-imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide,

[0598] N-cyclopropyl-2-(difluoromethoxy)-4-[7-(4-hydroxytetrahydropyran-4-yl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide,

[0599] N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(1-methylpyrrolidin-2-yl)imidazo[1,2-a]pyridin-3-yl]benzamide,

[0600] N-cyclopropyl-2-(difluoromethoxy)-4-[7-(2-hydroxy-1,1-dimethyl-propyl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide,

[0601] N-cyclopropyl-2-(difluoromethoxy)-4-[7-(1-hydroxycyclobutyl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide,

[0602] N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(oxetan-3-yl)imidazo[1,2-a]pyridin-3-yl]benzamide,

[0603] 4-[7-(2-cyano-1-hydroxy-ethyl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide,

[0604] 4-[7-(1-cyano-2-hydroxy-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide,

[0605] N-cyclopropyl-2-(difluoromethoxy)-4-[7-(3-hydroxyoxetane-3-yl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide,

[0606] N-cyclopropyl-2-(difluoromethoxy)-4-[7-(1-hydroxy-1-methyl-2-morpholino-ethyl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide,

[0607] 4-[7-(2-cyano-1-hydroxy-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide,

[0608] tert-Butyl 2-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]pyrrolidine-1-carboxylate,

[0609] N-cyclopropyl-2-(difluoromethoxy)-4-[7-(1-hydroxy-2-imidazol-1-yl-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide,

[0610] N-cyclopropyl-2-(difluoromethoxy)-4-[7-(1-hydroxy-2-methoxy-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide,

[0611] N-cyclopropyl-2-(difluoromethoxy)-4-[6-(2-hydroxyethoxy)-7-tetrahydropyran-4-yl-imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide,

[0612] 2-cyano-2-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]propionic acid methyl ester,

[0613] N-cyclopropyl-2-(difluoromethoxy)-4-[7-[1-hydroxy-1-methyl-2-(1-piperidinyl)ethyl]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide,

[0614] tert-Butyl 3-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]morpholine-4-carboxylate,

[0615] N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-(7-morpholin-3-ylimidazo[1,2-a]pyridin-3-yl)benzamide,

[0616] N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-(7-pyrrolidin-2-ylimidazo[1,2-a]pyridin-3-yl)benzamide,

[0617] N-cyclopropyl-4-[7-[2-(3,3-difluoroazetidin-1-yl)-1-hydroxy-1-methyl-ethyl]imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzamide,

[0618] N-cyclopropyl-2-(difluoromethoxy)-4-[7-(1-hydroxy-1-methyl-2-pyrazol-1-yl-ethyl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide,

[0619] N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(4-methylmorpholin-3-yl)imidazo[1,2-a]pyridin-3-yl]benzamide,

[0620] N-cyclopropyl-2-(difluoromethoxy)-4-[7-[1-hydroxy-1-methyl-2-(1,2,4-triazol-1-yl)ethyl]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide,

[0621] 4-[7-(1-cyano-2-methoxy-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide,

[0622] N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[1-(2-methoxyethyl)pyrrolidin-2-yl]imidazo[1,2-a]pyridin-3-yl]benzamide,

[0623] N-cyclopropyl-2-(difluoromethoxy)-4-[7-(1-isopropylpyrrolidin-2-yl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide,

[0624] 4-[7-(1-acetylpyrrolidin-2-yl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide,

[0625] 4-[7-[cyclobutyl(hydroxy)methyl]imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide,

[0626] 4-[7-(1-cyano-1-methyl-ethyl)-6-methoxy-imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide,

[0627] N-cyclopropyl-2-(difluoromethoxy)-4-[7-(2-hydroxy-1,1-dimethyl-butyl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide,

[0628] N-cyclopropyl-2-(difluoromethoxy)-4-[7-(2-hydroxy-1,1,3-trimethyl-butyl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide,

[0629] 4-[7-(azetidin-2-yl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide,

[0630] N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(1-methylazetidin-2-yl)imidazo[1,2-a]pyridin-3-yl]benzamide,

[0631] 2-(Difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-4-[7-(1-hydroxycyclobutyl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide,

[0632] 2-(difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-4-[7-(oxetan-3-yl)imidazo[1,2-a]pyridin-3-yl]benzamide,

[0633] N-cyclopropyl-2-(difluoromethoxy)-4-[7-(3-fluorooxetane-3-yl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide,

[0634] 4-[6-(1-cyano-1-methyl-ethyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide,

[0635] N-cyclopropyl-2-(difluoromethoxy)-4-[7-[1-hydroxy-2-[2-hydroxyethyl(methyl)amino]-1-methyl-ethyl]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide,

[0636] N-cyclopropyl-2-(difluoromethoxy)-4-[7-(2,4-dimethylmorpholin-2-yl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide,

[0637] 2-(Difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-4-[7-(1-hydroxy-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide,

[0638] N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(3-methoxyoxetane-3-yl)imidazo[1,2-a]pyridin-3-yl]benzamide,

[0639] N-cyclopropyl-2-(difluoromethoxy)-4-[7-(3-hydroxytetrahydrofuran-3-yl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide,

[0640] 2-(difluoromethoxy)-4-[7-(2,4-dimethylmorpholin-2-yl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-N-(2,2,2-trifluoroethyl)benzamide,

[0641] N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[6-methoxy-7-(oxetan-3-yl)imidazo[1,2-a]pyridin-3-yl]benzamide,

[0642] N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[6-(oxetan-3-yl)pyrazolo[1,5-a]pyridin-3-yl]benzamide,

[0643] 4-[7-(3-chlorooxetane-3-yl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide,

[0644] 2-(difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-4-[6-(oxetan-3-yl)pyrazolo[1,5-a]pyridin-3-yl]benzamide,

[0645] 4-[6-(1-cyano-1-methyl-ethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-(difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide,

[0646] N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(2-methyl-1,4-dioxan-2-yl)imidazo[1,2-a]pyridin-3-yl]benzamide,

[0647] 4-[7-(1-cyano-1-methyl-ethyl)-6-(2-hydroxyethoxy)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide,

[0648] N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(3-morpholinooxetane-3-yl)imidazo[1,2-a]pyridin-3-yl]benzamide,

[0649] 2-(difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-4-[7-(3-hydroxyoxetane-3-yl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide,

[0650] 2-(difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-4-[7-(3-fluorooxetane-3-yl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide,

[0651] 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-N-(2-fluorocyclopropyl)-6-methoxy-benzamide,

[0652] N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(1-methyl-1-morpholino-ethyl)imidazo[1,2-a]pyridin-3-yl]benzamide,

[0653] 2-(Difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-4-[6-(1-hydroxy-1-methyl-ethyl)pyrazolo[1,5-a]pyridin-3-yl]-6-methoxy-benzamide,

[0654] 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-b]pyridazin-3-yl]-2-(difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide,

[0655] N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[1-methyl-1-(oxetan-2-yl)ethyl]imidazo[1,2-a]pyridin-3-yl]benzamide,

[0656] 4-[7-[1-cyano-2,2,2-trideuterio-1-(trideuteriomethyl)ethyl]imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide,

[0657] 4-[6-(1-cyano-1-methyl-ethyl)pyrazolo[1,5-a]pyrimidin-3-yl]-2-(difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide,

[0658] N-cyclopropyl-2-(difluoromethoxy)-4-[6-(1,4-dioxan-2-yl)pyrazolo[1,5-a]pyridin-3-yl]-6-methoxy-benzamide,

[0659] 4-[6-(1-cyano-1-methyl-ethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-(difluoromethoxy)-N-(2-fluorocyclopropyl)-6-methoxy-benzamide,

[0660] 4-[6-(1-cyano-1-methyl-ethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-(difluoromethoxy)-N-[(1S,2R)-2-fluorocyclopropyl]-6-methoxy-benzamide,

[0661] 4-[6-(1-cyanocyclopropyl)pyrazolo[1,5-a]pyridin-3-yl]-2-(difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide,

[0662] N-cyclopropyl-2-(difluoromethoxy)-4-[6-(2-hydroxy-1,1-dimethyl-ethyl)pyrazolo[1,5-a]pyridin-3-yl]-6-methoxy-benzamide,

[0663] 4-[6-(4-cyanotetrahydropyran-4-yl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide,

[0664] N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[6-(2-methoxy-1,1-dimethyl-ethyl)pyrazolo[1,5-a]pyridin-3-yl]benzamide,

[0665] N-cyclopropyl-2-(difluoromethoxy)-4-[6-[1-(2-hydroxyethoxy)-1-methyl-ethyl]pyrazolo[1,5-a]pyridin-3-yl]-6-methoxy-benzamide,

[0666] 2-(Difluoromethoxy)-4-[6-(1,4-dioxane-2-yl)pyrazolo[1,5-a]pyridin-3-yl]-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide,

[0667] 2-(Difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-4-[6-(2-hydroxy-1,1-dimethyl-ethyl)pyrazolo[1,5-a]pyridin-3-yl]-6-methoxy-benzamide,

[0668] 4-[6-(4-cyanotetrahydropyran-4-yl)pyrazolo[1,5-a]pyridin-3-yl]-2-(difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide,

[0669] 4-[6-(2-amino-1,1-dimethyl-2-oxo-ethyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide,

[0670] 4-[6-(1-cyano-1-methyl-ethyl)pyrazolo[1,5-a]pyridin-3-yl]-N-[(1R,2S)-2-fluorocyclopropyl]-2,6-dimethoxy-benzamide,

[0671] 2-(difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-4-[6-(1-methyl-1-methylsulfonyl-ethyl)pyrazolo[1,5-a]pyridin-3-yl]benzamide,

[0672] N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[6-[1-methyl-1-(5-methyl-1,2,4-oxadiazol-3-yl)ethyl]pyrazolo[1,5-a]pyridin-3-yl]benzamide,

[0673] N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[6-[1-methyl-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]pyrazolo[1,5-a]pyridin-3-yl]benzamide,

[0674] N-cyclopropyl-2-(difluoromethoxy)-4-[6-[2-(ethylamino)-1,1-dimethyl-2-oxo-ethyl]pyrazolo[1,5-a]pyridin-3-yl]-6-methoxy-benzamide, and

[0675] 4-[6-(1-cyanocyclobutyl)pyrazolo[1,5-a]pyridin-3-yl]-2-(difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide,

[0676] 2-(Difluoromethoxy)-4-[6-[2-[2-(dimethylamino)-2-oxo-ethoxy]-1,1-dimethyl-ethyl]pyrazolo[1,5-a]pyridin-3-yl]-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide,

[0677] 4-[6-(1-cyano-1-methyl-ethyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropyl-2-fluoro-6-methoxy-benzamide,

[0678] 2-(Difluoromethoxy)-4-[6-[1,1-dimethyl-2-[2-(methylamino)-2-oxo-ethoxy]ethyl]pyrazolo[1,5-a]pyridin-3-yl]-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide,

[0679] 4-[6-(1-Carbamoylcyclobutyl)pyrazolo[1,5-a]pyridin-3-yl]-2-(difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide,

[0680] 2-(difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-4-[6-[1-methyl-1-(2-morpholinoethoxy)ethyl]pyrazolo[1,5-a]pyridin-3-yl]benzamide,

[0681] 4-[6-(1-amino-1-methyl-ethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-(difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide,

[0682] 4-[6-(1-cyano-1-methyl-ethyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropyl-2,6-dimethoxy-benzamide,

[0683] 4-[6-(1-cyano-1-methyl-ethyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropyl-2-methoxy-6-(2-methoxyethoxy)benzamide,

[0684] 4-[6-(1-aminocyclobutyl)pyrazolo[1,5-a]pyridin-3-yl]-2-(difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide,

[0685] 2-(difluoromethoxy)-4-[6-[1,1-dimethyl-2-(oxetan-3-ylmethoxy)ethyl]pyrazolo[1,5-a]pyridin-3-yl]-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide,

[0686] 4-[6-(1-cyano-1-methyl-ethyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropyl-2-(2-hydroxyethoxy)-6-methoxy-benzamide,

[0687] Butyl N-[1-[3-[3-(difluoromethoxy)-4-[[(1R,2S)-2-fluorocyclopropyl]carbamoyl]-5-methoxy-phenyl]pyrazolo[1,5-a]pyridin-6-yl]-1-methyl-ethyl]carbamate,

[0688] 2-(difluoromethoxy)-4-[6-[1,1-dimethyl-2-(oxetan-3-yloxy)ethyl]pyrazolo[1,5-a]pyridin-3-yl]-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide,

[0689] 2-(Difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-4-[6-(1-hydroxycyclobutyl)pyrazolo[1,5-a]pyridin-3-yl]-6-methoxy-benzamide,

[0690] [2-[3-[3-(difluoromethoxy)-4-[[(1R,2S)-2-fluorocyclopropyl]carbamoyl]-5-methoxy-phenyl]pyrazolo[1,5-a]pyridin-6-yl]-2-methyl-propyl]methanesulfonate,

[0691] 2-(Difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-4-[6-[1-(2-hydroxyethylamino)-1-methyl-ethyl]pyrazolo[1,5-a]pyridin-3-yl]-6-methoxy-benzamide,

[0692] 2-(Difluoromethoxy)-4-[6-(1,1-dimethyl-2-morpholino-ethyl)pyrazolo[1,5-a]pyridin-3-yl]-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide,

[0693] 4-[6-[1-(Cyanomethylamino)cyclobutyl]pyrazolo[1,5-a]pyridin-3-yl]-2-(difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide,

[0694] 4-[6-[1-(2,2-difluoroethylamino)cyclobutyl]pyrazolo[1,5-a]pyridin-3-yl]-2-(difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide,

[0695] Methyl N-[1-[3-[3-(difluoromethoxy)-4-[[(1R,2S)-2-fluorocyclopropyl]carbamoyl]-5-methoxy-phenyl]pyrazolo[1,5-a]pyridin-6-yl]cyclobutyl]carbamate,

[0696] 2-(difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-4-[6-[1-(methylcarbamoyl)cyclobutyl]pyrazolo[1,5-a]pyridin-3-yl]benzamide, and

[0697] 2-(Difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-4-[6-[1-(morpholine-4-carbonyl)cyclobutyl]pyrazolo[1,5-a]pyridin-3-yl]benzamide.

[0698] In one embodiment, the compound of the invention is a compound of Formula I, wherein the compound is selected from:

[0699] 4-[6-[1-cyano-2,2,2-trideuterio-1-(trideuteriomethyl)ethyl]pyrazolo[1,5-a]pyridin-3-yl]-2-(difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide, and

[0700] 4-[6-[2-(Diethylamino)-1,1-dimethyl-ethyl]pyrazolo[1,5-a]pyridin-3-yl]-2-(difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide.

[0701] In one embodiment, the compound of the invention is according to Formula I, wherein the compound is 4-[6-(1-cyano-1-methyl-ethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-(difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide.

[0702] In one embodiment, the compound of the invention is a compound of Formula I, wherein the compound is not 4-[6-(1-cyano-1-methyl-ethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-(difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide.

[0703] In one embodiment, the compound of the invention is according to Formula I, wherein the compound is 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide.

[0704] In one embodiment, the compound of the invention is a compound of Formula I, wherein the compound is not 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide.

[0705] In one embodiment, the compounds of the present invention are not isotopic variants.

[0706] In one aspect, the compound of the invention according to any one of the embodiments described herein exists in free base form.

[0707] In one aspect, the compound of the invention according to any one of the embodiments described herein is a pharmaceutically acceptable salt.

[0708] In one aspect, a compound of the invention according to any one of the embodiments described herein is a solvate of the compound.

[0709] 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.

[0710] Although specific groups of embodiments have been summarized above, the compounds of the present invention include compounds in which several or each of the embodiments in the above formula and other formulas given herein are selected from one or more specific members or groups specified for each variable. Therefore, the scope of the present invention is intended to include all combinations of these embodiments.

[0711] Although specific groups of embodiments have been summarized above, the compounds of the present invention can be compounds in which one or more variables (e.g., R groups) are selected from one or more embodiments of any of the formulae listed above. Thus, the scope of the present invention is intended to include all combinations of variables from any disclosed embodiment.

[0712] Alternatively, the invention also encompasses excluding one or more specified variables from a group or embodiment or combination thereof.

[0713] In some aspects, the present invention provides prodrugs and derivatives of the compounds according to the above chemical formula. Prodrugs are derivatives of the compounds of the present invention that have metabolically cleavable groups and, upon solvolysis or under physiological conditions, become pharmaceutically active compounds of the present invention in vivo. Examples of such compounds include, but are not limited to, choline ester derivatives, N-alkylmorpholine esters, and the like.

[0714] Other derivatives of the compounds of the invention are active in both their acid and acid derivative forms, but the acid-sensitive forms generally provide advantages in solubility, tissue compatibility, or delayed release in mammalian organisms (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 compound with a substituted or unsubstituted amine, or anhydrides or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acid groups pendant from the compounds of the invention are preferred prodrugs. In some cases, it is desirable to prepare diester-type prodrugs, such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. The C1-C8 alkyl, C2-C8 alkenyl, aryl, C7-C8 12 Substituted aryl and C7-C 12 Aryl alkyl esters are particularly useful.

[0715] Pharmaceutical composition

[0716] When used as medicine, the compound of the present invention is usually used in the form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical field, comprising the active compound of the present invention of at least one Formula I. Usually, the compound of the present invention is used in a pharmaceutically effective amount. The amount of the compound of the present invention actually used will usually be determined by a physician according to relevant circumstances, including the severity of the disease to be treated, the selected route of administration, the actual compound of the present invention used, the age, body weight and response of the individual patient, and the symptoms of the patient, etc.

[0717] The pharmaceutical compositions of the present invention can be administered by various 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 into injectable or oral compositions or ointments, emulsions or patches for transdermal administration.

[0718] Compositions for oral administration can take the form of bulk liquid solutions or suspensions or bulk powders. However, compositions are more typically presented in unit dosage forms for the purpose of accurate administration. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dose for human individuals and other mammals, each unit containing a predetermined amount of active material calculated to produce an expected therapeutic effect in combination with a suitable pharmaceutical excipient, adjuvant or carrier. Typical unit dosage forms include pre-loaded, pre-measured ampoules or syringes of liquid compositions or pills, tablets, capsules, etc. for solid compositions. In such compositions, the compound of the present invention of Formula I is typically a small amount of component (about 0.1 to about 50% by weight or preferably about 1 to about 40% by weight), and the rest are various adjuvants or carriers and processing aids that contribute to the formation of the expected dosage form.

[0719] Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous excipients containing buffers, suspending and dispersing agents, colorants, flavors, etc. Solid forms may include, for example, any of the following ingredients or compounds of the invention having similar properties: a binder such as microcrystalline cellulose, 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 flavor.

[0720] Injectable compositions are usually based on injectable sterile saline or phosphate buffered saline or other injectable carriers known in the art. As mentioned above, the active compound of the present invention of formula I in the composition is usually a small amount component, usually about 0.05 to 10% by weight, and the rest is the injectable carrier, etc.

[0721] Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient, typically in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, preferably about 0.1 to about 10% by weight, and more preferably about 0.5 to about 15% by weight. When formulated as an ointment, the active ingredient is typically combined with a paraffin or water-miscible ointment base. Alternatively, the active ingredient can be formulated into a cream using, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art and typically include additional ingredients to enhance skin penetration or stability of the active ingredient or formulation. All such known transdermal formulations and ingredients are encompassed within the scope of the present invention.

[0722] The compounds of the present invention may also be administered by transdermal devices.Thus, transdermal administration may be achieved using patches of the reservoir or porous membrane type or of the solid matrix type.

[0723] The components of the compositions described above for oral administration, injection or topical administration are representative only. Other materials and processing techniques are given in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0724] The compounds of the present invention can also be administered in a sustained release form or from a sustained release drug delivery system. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences. (Remington 1985)

[0725] The following formulation examples illustrate representative pharmaceutical compositions that can be prepared according to the present invention. However, the present invention is not limited to the following pharmaceutical compositions.

[0726] Formulation 1 - Tablet

[0727] The compound of the present invention of Formula I can be mixed with a dry gelatin binder in an approximately 1:2 weight ratio to form a dry powder. A small amount of magnesium stearate can be added as a lubricant. The mixture can be formed into 240-270 mg tablets (80-90 mg of the active compound of the present invention of Formula I per tablet) in a tablet press.

[0728] Preparation 2 - Capsules

[0729] The compound of the invention of formula I can be mixed with a starch diluent in a weight ratio of about 1: 1 to form a dry powder. The mixture can be filled into 250 mg capsules (125 mg of the active compound of the invention of formula I per capsule).

[0730] Preparation 3 - Liquid

[0731] The compound of the present invention (125mg) of Formula I can be mixed with sucrose (1.75g) and xanthan gum (4mg), the resulting mixture is blended, passed through No. 10 mesh American sieves, then mixed with previously prepared microcrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50mg) solution in water. Sodium benzoate (10mg), flavorings and coloring agents can be diluted with water, added under agitation. Then enough water can be added under agitation. Then enough water can be further added to produce a cumulative volume of 5mL.

[0732] Formulation 4 - Tablets

[0733] The compound of the present invention of formula I can be mixed into dry powder with dry gelatin binder in about 1:2 weight ratio. A small amount of magnesium stearate can be added as a lubricant. The mixture can be formed into 450-900mg mg tablets (active compound of the present invention of 150-300mg formula I per tablet) in a tablet press.

[0734] Preparation 5 - Injection

[0735] The compounds of the invention of formula I can be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of about 5 mg / mL.

[0736] Preparation 6 - Topical

[0737] Stearyl alcohol (250 g) and white petrolatum (250 g) can be melted at about 75° C., and then a mixture of a compound of the present invention of 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.

[0738] Treatment

[0739] 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.

[0740] 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 preventing and / or treating 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).

[0741] In another 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 manufacture of a medicament for preventing and / or treating 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).

[0742] In additional therapeutic methods, the present invention provides a method for preventing and / or treating a mammal suffering from an inflammatory disease, the method comprising administering an effective amount of one or more of the compounds of the present invention or the pharmaceutical compositions described herein to treat or prevent the condition. 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).

[0743] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and an additional therapeutic agent. In a specific embodiment, the additional therapeutic agent is an inflammatory disease therapeutic agent. 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).

[0744] 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 preventing and / or treating an autoinflammatory disease. In particular, the term autoinflammatory disease refers to cryopyrin-associated periodic syndrome (CAPS), familial Mediterranean fever (FMF) and tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Behçet's disease, systemic onset juvenile idiopathic arthritis (SJIA) or Still's disease. More particularly, the term refers to CAPS, FMF, TRAPS and Still's disease.

[0745] 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 preventing and / or treating an autoinflammatory disease. In particular, the term autoinflammatory disease refers to cryopyrin-associated periodic syndrome (CAPS), familial Mediterranean fever (FMF) and tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Behçet's disease, systemic onset juvenile idiopathic arthritis (SJIA) or Still's disease. More particularly, the term refers to CAPS, FMF, TRAPS and Still's disease.

[0746] In additional therapeutic methods, the present invention provides a method for preventing and / or treating a mammal suffering from an autoinflammatory disease, the method comprising administering an effective amount of one or more of the compounds of the present invention or the pharmaceutical compositions described herein to treat or prevent the condition. In particular, the term autoinflammatory disease refers to cryopyrin-associated periodic syndrome (CAPS), familial Mediterranean fever (FMF), and tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Behçet's disease, systemic-onset juvenile idiopathic arthritis (SJIA), or Still's disease. More particularly, the term refers to CAPS, FMF, TRAPS, and Still's disease.

[0747] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and an additional therapeutic agent. In a specific embodiment, the additional therapeutic agent is an autoinflammatory disease therapeutic agent. In particular, the term autoinflammatory disease refers to cryopyrin-associated periodic syndrome (CAPS), familial Mediterranean fever (FMF) and tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Behçet's disease, systemic onset juvenile idiopathic arthritis (SJIA) or Still's disease. More particularly, the term refers to CAPS, FMF, TRAPS and Still's disease.

[0748] In one embodiment, the invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention, which is used to prevent and / or treat 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, type i diabetes, atopic dermatitis, thyroiditis, contact dermatitis, eczematous dermatitis, inflammatory bowel disease (such as 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.

[0749] In another embodiment, the invention provides the purposes of the compound of the present invention or the pharmaceutical composition comprising the compound of the present invention in the manufacture of the medicine for preventing and / or treating autoimmune diseases. Especially, 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, type i diabetes, atopic dermatitis, thyroiditis, contact dermatitis, eczematous dermatitis, inflammatory bowel disease (such as 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.

[0750] In terms of additional methods of treatment, the present invention provides methods for preventing and / or treating a mammal suffering from an autoimmune disease, comprising administering an effective amount of a compound of the present invention or one or more of the pharmaceutical compositions described herein to treat or prevent the condition. 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, 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.

[0751] In one embodiment, the invention provides a pharmaceutical composition comprising a compound of the present invention and another therapeutic agent. In a specific embodiment, another therapeutic agent is an autoimmune disease therapeutic agent. 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, type i diabetes, atopic dermatitis, thyroiditis, contact dermatitis, eczematous dermatitis, inflammatory bowel disease (such as 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.

[0752] 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 preventing and / or treating a proliferative disease. In particular, the term proliferative disease refers to cancer, myeloproliferative disease, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma, or fibrosis. More particularly, the term refers to cancer, leukemia, multiple myeloma, and psoriasis.

[0753] 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 preventing and / or treating a proliferative disease. In particular, the term proliferative disease refers to cancer, myeloproliferative disease, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma, or fibrosis. More particularly, the term refers to cancer, leukemia, multiple myeloma, and psoriasis.

[0754] In additional therapeutic methods, the present invention provides a method for preventing and / or treating a mammal suffering from a proliferative disease, the method comprising administering an effective amount of one or more of the compounds of the present invention or the pharmaceutical compositions described herein to treat or prevent the condition. In particular, the term proliferative disease refers to cancer, myeloproliferative disease, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma, or fibrosis. More particularly, the term refers to cancer, leukemia, multiple myeloma, and psoriasis.

[0755] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and an additional therapeutic agent. In a specific embodiment, the additional therapeutic agent is a proliferative disease therapeutic agent. In particular, the term proliferative disease refers to cancer, myeloproliferative disease, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma, or fibrosis. More particularly, the term refers to cancer, leukemia, multiple myeloma, and psoriasis.

[0756] 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 preventing and / or treating 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.

[0757] In another 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 manufacture of a medicament for preventing and / or treating 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.

[0758] In additional therapeutic methods, the present invention provides a method for preventing and / or treating a mammal suffering from a fibrotic disease, the method comprising administering an effective amount of one or more of the compounds of the present invention or the pharmaceutical compositions described herein to treat or prevent the condition. 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.

[0759] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and an additional therapeutic agent. In a specific embodiment, the additional therapeutic agent is a fibrotic disease therapeutic agent. 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.

[0760] 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 preventing and / or treating transplant rejection. In particular, the term transplant rejection refers to acute or chronic rejection of an allogeneic or xenotransplanted cell, tissue, or solid organ, such as pancreatic islets, stem cells, bone marrow, skin, muscle, corneal tissue, neuronal 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.

[0761] 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 preventing and / or treating transplant rejection. In particular, the term transplant rejection refers to acute or chronic rejection of an allogeneic or xenotransplanted cell, tissue, or solid organ, such as pancreatic islets, stem cells, bone marrow, skin, muscle, corneal tissue, neuronal 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.

[0762] In additional therapeutic methods, the present invention provides a method for preventing and / or treating a mammal suffering from transplant rejection, the method comprising administering an effective amount of a compound of the present invention or one or more of the pharmaceutical compositions described herein to treat or prevent the condition. 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, neuronal 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.

[0763] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and an additional therapeutic agent. In a specific embodiment, the additional therapeutic agent is a transplant rejection therapeutic agent. 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, neuronal 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.

[0764] 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 preventing and / or treating a disease involving abnormal cartilage turnover. In particular, the term refers to a disease involving abnormal cartilage turnover and refers to osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, pain dystrophy, Tietze syndrome or costochondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, endemic arthritis such as endemic deforming osteoarthritis, Mseleni disease and Handigodu 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.

[0765] In another 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 manufacture of a medicament for preventing and / or treating a disease involving abnormal cartilage turnover. In particular, the term refers to a disease involving abnormal cartilage turnover and refers to osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, pain dystrophy, Tietze syndrome or costochondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, endemic arthritis such as endemic deforming osteoarthritis, Mseleni disease and Handigodu 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.

[0766] In terms of additional treatment methods, the present invention provides a method for preventing and / or treating a mammal suffering from a disease involving abnormal cartilage turnover, the method comprising administering an effective amount of one or more of the compounds of the present invention or the pharmaceutical compositions described herein to treat or prevent the condition. In particular, the term disease involving abnormal cartilage turnover refers to osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, pain dystrophy, Tietze syndrome or costochondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, endemic arthritis such as endemic deforming osteoarthritis, Mseleni disease and Handigodu 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.

[0767] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and an additional therapeutic agent. In a specific embodiment, the additional therapeutic agent is a therapeutic agent for a disease involving abnormal cartilage turnover. In particular, the term refers to a disease involving abnormal cartilage turnover and refers to osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, pain dystrophy, Tietze syndrome or costochondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, endemic arthritis such as endemic deforming osteoarthritis, Mseleni disease and Handigodu 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.

[0768] 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 preventing and / or treating congenital cartilage malformations. In particular, the term congenital cartilage malformations refers to hereditary chondrolysis, chondrodysplasia and pseudochondrodysplasia, microtia, anotia, metaphyseal chondrodysplasia. More particularly, the term refers to microtia, anotia, metaphyseal chondrodysplasia.

[0769] 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 preventing and / or treating 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.

[0770] In additional therapeutic methods, the present invention provides methods for preventing and / or treating 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 the pharmaceutical compositions described herein to treat or prevent the condition. In particular, the term congenital cartilage malformation refers to hereditary chondrolysis, achondroplasias and pseudoachondroplasias, microtia, anotia, and metaphyseal chondrodysplasia. More particularly, the term refers to microtia, anotia, and metaphyseal chondrodysplasia.

[0771] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and an additional therapeutic agent. In a specific embodiment, the additional therapeutic agent is an agent for treating congenital cartilage malformations. In particular, the term congenital cartilage malformations refers to hereditary chondrolysis, achondroplasias and pseudoachondroplasias, microtia, anotia, and metaphyseal chondrodysplasia. More particularly, the term refers to microtia, anotia, and metaphyseal chondrodysplasia.

[0772] 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 preventing and / or treating a disease involving abnormal bone turnover. In particular, the term "disease involving abnormal bone turnover" refers to osteoporosis, osteopenia, hormone deficiency, hormone excess, Paget's disease, osteoarthritis, renal osteodystrophy, osteogenesis imperfecta, and hypophosphatasia. More particularly, the term refers to osteoporosis.

[0773] 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 preventing and / or treating a disease involving abnormal bone turnover. In particular, the term disease involving abnormal bone turnover refers to osteoporosis, osteopenia, hormone deficiency, hormone excess, Paget's disease, osteoarthritis, renal osteodystrophy, osteogenesis imperfecta, and hypophosphatasia. More particularly, the term refers to osteoporosis.

[0774] In additional therapeutic methods, the present invention provides methods for preventing and / or treating a mammal suffering from a disease involving abnormal bone turnover, the methods comprising administering an effective amount of one or more of the compounds of the present invention or the pharmaceutical compositions described herein to treat or prevent the condition. In particular, the term disease involving abnormal bone turnover refers to osteoporosis, osteopenia, hormone deficiency, hormone excess, Paget's disease, osteoarthritis, renal osteodystrophy, osteogenesis imperfecta, and hypophosphatasia. More particularly, the term refers to osteoporosis.

[0775] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and an additional therapeutic agent. In a specific embodiment, the additional therapeutic agent is a therapeutic agent for a disease involving abnormal bone turnover. In particular, the term "disease involving abnormal bone turnover" refers to osteoporosis, osteopenia, hormone deficiency, hormone excess, Paget's disease, osteoarthritis, renal osteodystrophy, osteogenesis imperfecta, and hypophosphatasia. More particularly, the term refers to osteoporosis.

[0776] 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 preventing and / or treating 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.

[0777] 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 preventing and / or treating 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.

[0778] In additional therapeutic methods, the present invention provides a method for preventing and / or treating a mammal suffering from a disease associated with excessive secretion of IL-6, comprising administering an effective amount of one or more of the compounds of the present invention or the pharmaceutical compositions described herein to treat or prevent the condition. 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.

[0779] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and an additional therapeutic agent. In a specific embodiment, the additional 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.

[0780] 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 preventing and / or treating 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.

[0781] In another 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 manufacture of a medicament for preventing and / or treating 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.

[0782] In terms of additional therapeutic methods, the present invention provides a method for preventing and / or treating a mammal suffering from a disease associated with excessive secretion of TNFα, interferon, IL-12 and / or IL-23, the method comprising administering an effective amount of one or more of the compounds of the present invention or the pharmaceutical compositions described herein to treat or prevent the condition. 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.

[0783] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and an additional therapeutic agent. In a specific embodiment, the additional 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.

[0784] 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 preventing and / or treating 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.

[0785] 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 preventing and / or treating 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.

[0786] In additional therapeutic methods, the present invention provides a method for preventing and / or treating a mammal suffering from a respiratory disease, the method comprising administering an effective amount of one or more of the compounds of the present invention or the pharmaceutical compositions described herein to treat or prevent the condition. 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.

[0787] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and an additional therapeutic agent. In a specific embodiment, the additional therapeutic agent is a respiratory disease therapeutic agent. 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.

[0788] In one embodiment, the invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for preventing and / or treating endocrine and / or metabolic diseases. In particular, the term endocrine and / or metabolic diseases refers to hypothyroidism, congenital adrenal hyperplasia, parathyroid disease, diabetes, adrenal disease, Cushing's syndrome and Addison's disease and ovarian dysfunction, polycystic ovary syndrome, cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout and rickets. More particularly, the term refers to obesity and / or type ii diabetes.

[0789] In another embodiment, the invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in the manufacture of a medicine for preventing and / or treating endocrine and / or metabolic diseases. In particular, term endocrine and / or metabolic diseases refers to hypothyroidism, congenital adrenal hyperplasia, parathyroid disease, diabetes, adrenal disease, Cushing's syndrome and Addison's disease and ovarian dysfunction, polycystic ovary syndrome, cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout and rickets. More particularly, the term refers to obesity and / or type ii diabetes.

[0790] In terms of additional treatment methods, the present invention provides a method for preventing and / or treating a mammal suffering from an endocrine and / or metabolic disease, the method comprising administering an effective amount of one or more of the compounds of the present invention or the pharmaceutical compositions described herein to treat or prevent the condition. In particular, the term endocrine and / or metabolic disease refers to hypothyroidism, congenital adrenal hyperplasia, parathyroid disease, diabetes, adrenal disease, Cushing's syndrome and Addison's disease and ovarian dysfunction, polycystic ovary syndrome, cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout and rickets. More particularly, the term refers to obesity and / or type II diabetes.

[0791] In one embodiment, the invention provides a pharmaceutical composition comprising a compound of the present invention and another therapeutic agent. In a specific embodiment, another therapeutic agent is an endocrine and / or metabolic disease therapeutic agent. In particular, the term endocrine and / or metabolic disease refers to hypothyroidism, congenital adrenal hyperplasia, parathyroid disease, diabetes, adrenal disease, Cushing's syndrome and Addison's disease and ovarian dysfunction, polycystic ovary syndrome, cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout and rickets. More particularly, the term refers to obesity and / or type ii diabetes.

[0792] 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 preventing and / or treating cardiovascular disease. In particular, the term cardiovascular disease refers to arrhythmias (atrial or ventricular or both); atherosclerosis and its sequelae; angina pectoris; heart rhythm disturbances; myocardial ischemia; myocardial infarction; heart or vascular aneurysms; vasculitis; stroke; peripheral occlusive arterial disease of a limb, organ or tissue; reperfusion injury after ischemia of the brain, heart, kidney or other organs or tissues; endotoxic, surgical or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; vasoconstriction (including vasoconstriction 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.

[0793] In another embodiment, the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for the manufacture of a medicament for preventing and / or treating cardiovascular disease. In particular, the term cardiovascular disease refers to arrhythmias (atrial or ventricular or both); atherosclerosis and its sequelae; angina pectoris; heart rhythm disturbances; myocardial ischemia; myocardial infarction; heart or vascular aneurysms; vasculitis; stroke; peripheral occlusive arterial disease of a limb, organ or tissue; reperfusion injury after ischemia of the brain, heart, kidney or other organs or tissues; endotoxic, surgical or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; vasoconstriction (including vasoconstriction 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.

[0794] In additional therapeutic methods, the present invention provides a method for preventing and / or treating a mammal suffering from cardiovascular disease, the method comprising administering an effective amount of a compound of the present invention or one or more of the pharmaceutical compositions described herein to treat or prevent the condition. In particular, the term cardiovascular disease refers to arrhythmias (atrial or ventricular or both); atherosclerosis and its sequelae; angina pectoris; cardiac rhythm disturbances; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysms; vasculitis; stroke; peripheral occlusive arterial disease of a limb, organ or tissue; reperfusion injury following ischemia of the brain, heart, kidney or other organs or tissues; endotoxic, surgical or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; vasoconstriction (including vasoconstriction 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.

[0795] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and an additional therapeutic agent. In a specific embodiment, the additional therapeutic agent is a cardiovascular disease therapeutic agent. In particular, the term cardiovascular disease refers to arrhythmias (atrial or ventricular or both); atherosclerosis and its sequelae; angina pectoris; heart rhythm disturbances; myocardial ischemia; myocardial infarction; heart or vascular aneurysms; vasculitis; stroke; peripheral occlusive arterial disease of a limb, organ or tissue; reperfusion injury after ischemia of the brain, heart, kidney or other organs or tissues; endotoxic, surgical or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; vasoconstriction (including vasoconstriction 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.

[0796] 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 preventing and / or treating a dermatological disease. In particular, the term dermatological disease refers to atopic dermatitis, bullous diseases, collagen diseases, psoriasis, psoriatic lesions, dermatitis, contact dermatitis, eczema, vitiligo, pruritus, scleroderma, wound healing, scarring, hypertrophic scarring, keloids, Kawasaki disease, rosacea, Sjögren-Larsen syndrome, or urticaria. More particularly, the term refers to atopic dermatitis, scleroderma, Sjögren-Larsen syndrome, vitiligo, or urticaria.

[0797] 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 preventing and / or treating a dermatological disease. In particular, the term dermatological disease refers to atopic dermatitis, bullous diseases, collagen diseases, psoriasis, psoriatic lesions, dermatitis, contact dermatitis, eczema, vitiligo, pruritus, scleroderma, wound healing, scarring, hypertrophic scarring, keloids, Kawasaki disease, rosacea, Sjögren-Larsen syndrome, or urticaria. More particularly, the term refers to atopic dermatitis, scleroderma, Sjögren-Larsen syndrome, vitiligo, or urticaria.

[0798] In additional therapeutic methods, the present invention provides a method for preventing and / or treating a mammal suffering from a dermatological disorder, the method comprising administering an effective amount of one or more of the compounds of the present invention or the pharmaceutical compositions described herein to treat or prevent the disorder. In particular, the term dermatological disorder refers to atopic dermatitis, bullous diseases, collagen diseases, psoriasis, psoriatic lesions, dermatitis, contact dermatitis, eczema, vitiligo, pruritus, scleroderma, wound healing, scarring, hypertrophic scarring, keloids, Kawasaki disease, rosacea, Sjögren-Larsen syndrome, or urticaria. More particularly, the term refers to atopic dermatitis, scleroderma, Sjögren-Larsen syndrome, vitiligo, or urticaria.

[0799] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and an additional therapeutic agent. In a specific embodiment, the additional therapeutic agent is a dermatological disease therapeutic agent. In particular, the term dermatological disease refers to atopic dermatitis, bullous diseases, collagen diseases, psoriasis, psoriatic lesions, dermatitis, contact dermatitis, eczema, vitiligo, pruritus, scleroderma, wound healing, scarring, hypertrophic scarring, keloids, Kawasaki disease, rosacea, Sjögren-Larsen syndrome, or urticaria. More particularly, the term refers to atopic dermatitis, scleroderma, Sjögren-Larsen syndrome, vitiligo, or urticaria.

[0800] 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 preventing and / or treating 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.

[0801] 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 preventing and / or treating a disease associated with abnormal angiogenesis. In particular, the term abnormal angiogenesis-related disease 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.

[0802] In terms of additional treatment methods, the present invention provides a method for preventing and / or treating a mammal suffering from a disease associated with abnormal angiogenesis, the method comprising administering an effective amount of one or more of the compounds of the present invention or the pharmaceutical compositions described herein to treat or prevent the condition. In particular, the term abnormal angiogenesis-related disease 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.

[0803] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and an additional therapeutic agent. In a specific embodiment, the additional therapeutic agent is an agent for treating a disease associated with abnormal angiogenesis. In particular, the term abnormal angiogenesis-related disease 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.

[0804] The range of injection dose levels is from about 0.1 mg / kg / h to at least 10 mg / kg / h, all for about 1 to about 120 hours and particularly for 24 to 96 hours. A pre-loading bolus of about 0.1 mg / kg to about 10 mg / kg or more may also be administered to achieve adequate steady-state levels. For a 40 to 80 kg human patient, the maximum total dose is not expected to exceed about 1 gram / day.

[0805] For the prevention and / or treatment of long-term conditions such as degenerative conditions, treatment regimens typically extend for months or years, so oral administration is preferred for patient convenience and tolerability. For oral administration, one to four (1 to 4) regular doses per day, especially one to three (1 to 3) regular doses per day, usually one to two (1 to 2) regular doses per day, and most usually one (1) regular dose per day are representative regimens. Alternatively, for long-lasting, effective drugs, for oral administration, once every other week, once a week, and once a day are representative regimens. In particular, the dosing regimen can be every 1 to 14 days, more particularly 1 to 10 days, even more particularly 1 to 7 days, and most particularly 1 to 3 days.

[0806] Using these modes of administration, each dose provides about 1 to about 1000 mg of a compound of the invention, with specific doses each providing about 10 to about 500 mg, particularly about 30 to about 250 mg.

[0807] Transdermal administration is generally chosen to provide blood levels similar to or lower than those achieved using administration by injection.

[0808] When used to prevent the onset of a disorder, the compounds of the invention are administered to a patient at risk of developing the disorder at the dosage levels described above, usually under the advice and supervision of a physician. Patients at risk of developing a particular disorder generally include those with a family history of the disorder or those who have been identified by genetic testing or screening as being particularly susceptible to developing the disorder.

[0809] The compounds of the present invention can be administered as a single active agent, or can be administered in combination with other therapeutic agents, including other compounds of the present invention that exhibit the same or similar therapeutic activity and are determined to be safe and effective for such combined administration. In a specific embodiment, the co-administration of two (or more) active agents allows for a significant reduction in the dose of the active agent used, thereby reducing the side effects seen.

[0810] In one embodiment, the compound of the invention or the pharmaceutical composition comprising the compound of the invention is administered as a medicament. In a particular embodiment, the pharmaceutical composition additionally comprises other active ingredients.

[0811] In one embodiment, the compounds of the present invention are co-administered with other therapeutic agents for the treatment and / or prevention of diseases involving inflammation, including but not limited to immunomodulators such as azathioprine, corticosteroids (e.g., prednisolone or dexamethasone), cyclophosphamide, cyclosporine A, tacrolimus, mycophenolate mofetil, mofetil, muromonab-CD3 (OKT3, e.g., ), ATG, aspirin, acetaminophen, ibuprofen, naproxen, and piroxicam.

[0812] In one embodiment, the compounds of this invention are co-administered with other therapeutic agents for the treatment and / or prevention of arthritis (e.g., rheumatoid arthritis), specific therapeutic agents include, but are not limited to, analgesics, nonsteroidal anti-inflammatory drugs (NSAIDS), steroids, synthetic DMARDS (such as, but not limited to, methotrexate, leflunomide, sulfasalazine, auranofin, aurothiobutane, penicillamine, chloroquine, hydroxychloroquine, azathioprine, tofacitinib, baricitinib, fostamatinib, and cyclosporine) and biologic DMARDS (such as, but not limited to, infliximab, etanercept, adalimumab, rituximab, and abatacept).

[0813] In one embodiment, the compounds of the present invention are co-administered with another therapeutic agent to treat and / or prevent a proliferative disease, specific therapeutic agents include but are not limited to methotrexate, folinic acid, adriamycin, prednisone, bleomycin, cyclophosphamide, 5-fluorouracil, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, doxorubicin, tamoxifen, toremifene, megestrol acetate, anastrozole, goserelin, anti-HER2 monoclonal antibodies (e.g., ), capecitabine, raloxifene hydrochloride, EGFR inhibitors (e.g. ), VEGF inhibitors (e.g. ), proteasome inhibitors (e.g. ), and hsp90 inhibitors (e.g., 17-AAG). In addition, the compounds of the present invention of Formula I can be administered in combination with other therapies, including but not limited to radiation therapy or surgery. In a specific embodiment, the proliferative disease is selected from cancer, myeloproliferative disease, or leukemia.

[0814] In one embodiment, the compounds of the present invention are co-administered with an additional therapeutic agent to treat and / or prevent autoimmune diseases, specific therapeutic agents include but are not limited to: glucocorticoids, cytostatic agents (e.g., purine analogs), alkylating agents (e.g., nitrogen mustards (cyclophosphamide), nitrosoureas, platinum compounds of the present invention, and others), antimetabolites (e.g., methotrexate, azathioprine, and mercaptopurine), cytotoxic antibiotics (e.g., dactinomycin, anthracyclines, mitomycin C, bleomycin, and mithramycin), antibodies (e.g., anti-CD20, anti-CD25, or anti-CD3 (OTK3) monoclonal antibodies), and ), cyclosporine, tacrolimus, rapamycin (sirolimus), interferons (such as IFN-β), TNF-binding proteins (such as infliximab, etanercept, or adalimumab), mycophenolate, fingolimod, and myriocin.

[0815] In one embodiment, the compounds of the invention are co-administered with an additional therapeutic agent to treat and / or prevent transplant rejection, specific therapeutic agents include but are not limited to: calcineurin inhibitors (e.g., cyclosporine or tacrolimus (FK506)), mTOR inhibitors (e.g., sirolimus, everolimus), antiproliferatives (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)).

[0816] In one embodiment, the compounds of the present invention are co-administered with another therapeutic agent to treat and / or prevent asthma and / or rhinitis and / or COPD, specific therapeutic agents include but are not limited to: beta2-adrenergic receptor agonists (e.g., albuterol, levalbuterol, terbutaline, and bitolterol), epinephrine (inhaled or tablet), anticholinergics (e.g., ipratropium bromide), glucocorticoids (oral or inhaled), long-acting beta2-agonists (e.g., salmeterol, formoterol, bambuterol, and extended-release oral albuterol), inhaled steroids and long-acting bronchodilators. Combinations of dilators (e.g., fluticasone / salmeterol, budesonide / formoterol), leukotriene antagonists and synthesis inhibitors (e.g., montelukast, zafirlukast, and zileuton), mediator release inhibitors (e.g., cromolyn and ketotifen), IgE response biomodulators (e.g., omalizumab), antihistamines (e.g., cetirizine, cinnarizine, fexofenadine), and vasoconstrictors (e.g., oxymethazoline, xylomethazoline, naphazoline, and tramazoline).

[0817] In addition, the compounds of the present invention can be administered in combination with emergency therapies for asthma and / or COPD, including oxygen or helium oxygen administration, nebulized albuterol or terbutaline (optionally in combination with anticholinergics (e.g., ipratropine), systemic steroids (oral or intravenous, such as prednisone, prednisolone, methylprednisolone, dexamethasone, or hydrocortisone), intravenous albuterol, injected or inhaled nonspecific beta agonists (e.g., epinephrine, isoetharine, isoproterenol, metaproterenol), anticholinergics (IV or nebulized, such as glycopyrronium, atropine, ipratropine), methylxanthines (theophylline, aminophylline, bamiphylline), inhaled anesthetics with bronchodilatory effects (e.g., isoflurane, halothane, enflurane), ketamine, and intravenous magnesium sulfate.

[0818] In one embodiment, the compounds of the present invention are co-administered with an additional therapeutic agent to treat and / or prevent inflammatory bowel disease (IBD), specific therapeutic agents include, but are not limited to, glucocorticoids (e.g., prednisone, budesonide), synthetic disease-altering immunomodulators (e.g., methotrexate, leflunomide, sulfasalazine, mesalamine, azathioprine, 6-mercaptopurine, and cyclosporine), and biologic disease-altering immunomodulators (infliximab, adalimumab, rituximab, and abatacept).

[0819] In one embodiment, the compounds of the present invention are co-administered with an additional therapeutic agent to treat and / or prevent SLE, specific therapeutic agents include, but are not limited to, human monoclonal antibodies (belimumab (Benlysta)), disease-modifying antirheumatic drugs (DMARDs) such as antimalarials (e.g., hydroxychloroquine sulfate (plaquenil), hydroxychloroquine), immunosuppressants (e.g., methotrexate and azathioprine), cyclophosphamide and mycophenolic acid, immunosuppressive drugs and analgesics such as nonsteroidal anti-inflammatory drugs, opiates (e.g., dextropropoxyphene and co-codamol), opioids (e.g., hydrocodone, oxycodone, MSContin or methadone), and the fentanyl Duragesic transdermal patch.

[0820] In one embodiment, the compounds of the present invention are co-administered with another therapeutic agent to treat and / or prevent psoriasis. Specific therapeutic agents include, but are not limited to, topical treatments such as those containing coal tar, dihydroxyanthraquinone (anthraquinone), corticosteroids such as desoximetasone, Fluocinonide, vitamin D3 analogs (e.g., calcipotriol), argan oil, and retinoids (etretinate, acitretin, tazarotene) in baths, moisturizers, medicated creams, and ointments; systemic therapies such as methotrexate, cyclosporine, retinoids, thioguanine, hydroxyurea, sulfasalazine, mycophenolate mofetil, azathioprine, tacrolimus, fumarate esters, or biologics such as and ustekinumab (an IL-12 and IL-23 blocker). In addition, the compounds of the present invention can be administered in combination with other therapies, including but not limited to phototherapy or photochemotherapy (e.g., psoralen and ultraviolet A phototherapy (PUVA)).

[0821] In one embodiment, the compounds of this invention are co-administered with another therapeutic agent to treat and / or prevent allergic reactions, specific therapeutic agents include, but are not limited to, antihistamines (e.g., cetirizine, diphenhydramine, fexofenadine, levocetirizine), glucocorticoids (e.g., prednisone, betamethasone, beclomethasone, dexamethasone), epinephrine, theophylline or antileukotrienes (e.g., montelukast or zafirlukast), anticholinergics, and decongestants.

[0822] As will be apparent to those skilled in the art, co-administration includes any means of delivering two or more therapeutic agents to a patient as part of the same treatment regimen. Although two or more therapeutic agents can be administered simultaneously in a single formulation (i.e., as a single pharmaceutical composition), this is not required. The therapeutic agents can be administered in different formulations and at different times.

[0823] Chemical synthesis operations

[0824] General

[0825] Compound of the present invention can use following universal method and operation, is prepared by the parent material that is easily obtained.It will be appreciated that, when providing typical or preferred method conditions (i.e. reaction temperature, time, the mol ratio of reactant, solvent, pressure etc.), other method conditions can also be used, except otherwise indicated.Optimum reaction conditions can change according to used specific reactant or solvent, but this type of condition can be determined by conventional optimization operation by those skilled in the art.

[0826] Additionally, those skilled in the art will readily appreciate that conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The selection of suitable protecting groups for particular functional groups and suitable conditions for protection and deprotection are well known in the art (Wuts and Greene 2006).

[0827] The following is a detailed description of the methods for preparing the compounds of the present invention and the comparative examples defined above. The compounds of the present invention can be prepared by those skilled in the art of organic synthesis using known or commercially available starting materials and reagents.

[0828] Unless otherwise specified, all reagents were of commercial grade and used without further purification. Reactions performed under an inert atmosphere used commercially available anhydrous solvents. All other cases used reagent grade solvents unless otherwise specified. SNAP KP-NH, SNAP Ultra or Column chromatography was performed using Si HC flash chromatography columns. Thin layer chromatography was performed using pre-coated silica gel F-254 plates (0.25 mm thick). The aqueous phase was separated using a phase separator (e.g., catalog number 120-1907-E). The data were recorded on a Bruker DPX 400 NMR spectrometer (400 MHz) or a Bruker Advance 300 NMR spectrometer (300 MHz). 1 H NMR spectra are reported in parts per million (ppm) relative to tetramethylsilane (δ 0.00) as an internal reference or the appropriate residual solvent peak, i.e., CHCl3 (δ 7.27). 1Chemical shifts (δ) for H NMR spectra. Multiplicities are given as singlets (s), doublets (d), triplet (t), quartets (q), quintets (quin), multiplets (m), and broad peaks (br). Electrospray ionization mass spectra were obtained on a Waters Acquity H-Class UPLC system coupled to a UVPDA detector and a Waters SQD or SQD2 mass spectrometer. Columns used: Waters Acquity UPLC BEH C18 1.7 μm, 2.1 mm ID × 30 / 50 mm L; Waters Acquity UPLC CSH C18 1.7 μm, 2.1 mm ID × 50 / 100 mm L; Waters Acquity UPLC PhenylHexyl 1.7 μm, 2.1 mm ID × 100 mm L; Waters Acquity UPLC HSS PFP 1.8 μm, 2.1 mm ID × 100 mm L. The method used an ACN / H2O gradient containing 0.1% formic acid in both mobile phases, 0.05% NH3 in both mobile phases, or 10 mM NH4HCO3 in H2O (adjusted to pH 10 with ammonia). Preparative HPLC was performed on a Waters AutoPurification system with UV and MS detection using a Waters XBRIDGE BEH C18 OBD 30 mm ID×100 / 150 mm L column and an ACN / H2O gradient containing 0.1% formic acid in both mobile phases, 0.1% diethylamine in both mobile phases, 0.1% formic acid in H2O, or 10 mM NH4HCO3 in H2O (adjusted to pH 10 with ammonia). Initiator for microwave heating.

[0829] Table I. List of abbreviations used in the experimental section:

[0830]

[0831]

[0832]

[0833]

[0834] Synthesis and preparation of the compounds of the present invention

[0835] Example 1. General Synthesis Method

[0836] 1.1. Overview of Synthesis Methods

[0837]

[0838]

[0839] General Method A: Functionalization of Halogenated Heteroaryl Compounds

[0840] Method A1: Alkylation

[0841] Method A2: Palladium-catalyzed decarboxylative coupling

[0842] Method A3: Negishi coupling

[0843] Method A4: Nickel coupling

[0844] Method A5: Addition of ketone derivatives

[0845] Method A6: Photochemical reaction

[0846] Method A7: Functionalization of halogenated pyridines by metallation

[0847] Method A8: Functionalization of halogenated heteroaryl compounds by Suzuki coupling / degradation

[0848] General Method B: Iodination of Heteroaryl Compounds

[0849] General Method C: Suzuki Coupling of Heteroaryl Compounds

[0850] General Method D: Synthesis of Amides from Esters

[0851] Method D1: tert-Butyl ester hydrolysis followed by peptide coupling

[0852] Method D2: Methyl ester saponification followed by peptide coupling

[0853] General Method E: C-H Activation of Heteroaryl Compounds

[0854] General Method F: S-Hydroxybenzoic Acids of Di- or Tri-Substituted Anilines or Pyridine Derivatives N Ar

[0855] Method F1: S-S of disubstituted aminobenzoates via LiHMDS to halogenated nitrophenyl derivatives N Ar

[0856] Method F2: S-Hydroxylation of Disubstituted Aminobenzamides or Benzoates with NaH N Ar

[0857] General Method G: Nitro Reduction

[0858] Method G1: Nitro reduction via SnCl2, 2H2O / SnCl2

[0859] Method G2: Nitro reduction via Zn / AcOH

[0860] General Method H: Cyclization to benzimidazole

[0861] General Method I: O-Alkylation / N-Alkylation

[0862] Method I1: O-alkylation

[0863] Method I2: N-alkylation

[0864] General Procedure J: N-acylation

[0865] General Method K: Reductive Amination

[0866] Method K1: Amine functionalization via reductive amination

[0867] Method K2: Ketone Functionalization via Reductive Amination

[0868] Method K3: Aldehyde Functionalization via Reductive Amination

[0869] General Procedure L: Olefin Reduction

[0870] General Method M: Amine Deprotection

[0871] Method M1: Amine deprotection using TFA

[0872] Method M2: Amine Deprotection Using HCl

[0873] General Method N: Alcohol Synthesis

[0874] Method N1: Ketone or ester reduction

[0875] Method N2: Addition of magnesium reagents to ketones

[0876] Method N3: Epoxidation / epoxide ring-opening sequence

[0877] General Method O: Cyclization of Aminopyridines to Imidazolopyridines

[0878] General Method P: Synthesis of Boronic Esters

[0879] Method P1: Bromide Boration

[0880] Method P2: Boration via C-H activation

[0881] General Method Q: Fluorine Displacement of Trisubstituted Benzamides or Benzoates by Alkoxides

[0882] General Procedure R: Difluoromethylation of Phenolic Intermediates

[0883] General Method S: Nitration of Benzyl Cyanide Halides

[0884] General Method T: Fluorination of Alcohols

[0885] General Procedure U: Oxidation of Alcohols to Aldehydes

[0886] General Method V: Amine Synthesis via Hofmann Rearrangement

[0887] General Procedure W: Potassium Carboxylate Synthesis

[0888] 1.2 General Methods

[0889] 1.2.1. Method A1: Functionalization of halogenated heteroaryl compounds by alkylation

[0890] To a degassed solution of 7-fluoroimidazo[1,2-a]pyridine (CAS No. 1260903-17-0; 1 equivalent) and an alkyl nitrile (1 to 1.5 equivalents) in anhydrous THF or toluene at -78°C or 0°C under an inert atmosphere, LiHMDS (1 M in THF, CAS No. 4039-32-1; 1.3 to 1.45 equivalents) or KHMDS (0.5 M in THF, CAS No. 40949-94-8; 1.3 to 1.45 equivalents) was added dropwise. The reaction mixture was stirred at 60°C for 3 to 18 hours, quenched with water, and concentrated to dryness. The residue was triturated in pentane; the solid was filtered and dried under vacuum.

[0891] Alternative workup: The reaction mixture was quenched with water and extracted with EtOAc, followed by or without n-BuOH extraction. The combined organic layers were washed with brine, dried over Na2SO4 or MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel.

[0892] Exemplary synthesis of Int 96

[0893]

[0894] To a degassed solution of 7-fluoroimidazo[1,2-a]pyridine (150 mg, 1.10 mmol, 1 eq) and 1-boc-3-cyanoazetidine (CAS No. 142253-54-1; 301 mg, 1.65 mmol, 1.5 eq) in anhydrous toluene (3 mL) was added KHMDS (0.5 M in THF, 2.9 mL, 1.43 mmol, 1.3 eq) dropwise at 0 ° C. under an inert atmosphere. The reaction mixture was stirred at room temperature for 1.5 hours, then at 60 ° C. for 3 hours, quenched with water and brine, extracted with EtOAc, and then extracted with n-BuOH. The combined organic layers were dried over MgSO 4 , filtered, and concentrated in vacuo. The residue was purified by flash chromatography (eluted with heptane / EtOAc 100 / 0 to 0 / 100) to obtain the desired intermediate.

[0895] 1.2.2 Method A2: Functionalization of halogenated heteroaryl compounds via palladium-catalyzed decarboxylative coupling

[0896] Under an inert atmosphere, to a solution of heteroaryl halide (1 equivalent) in 1,3,5-trimethylbenzene, the corresponding carboxylic acid potassium salt (2 equivalents), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (CAS No. 161265-03-8; 0.06 equivalents) and allylpalladium chloride dimer (CAS No. 12012-95-2; 0.02 equivalents) or Xantphos Pd G4 (CAS No. 1621274-19-8; 0.05 equivalents) were added. The reaction mixture was stirred at 140° C. for 30 minutes to 6 hours, then cooled to room temperature and heated in a Dicalite TM The product was filtered, rinsed with EtOAc and concentrated in vacuo. The residue was purified by flash chromatography on silica gel. Alternatively, the reaction mixture was directly concentrated in vacuo and the residue was purified by flash chromatography on silica gel.

[0897] Exemplary synthesis of Int 171

[0898]

[0899] Under N2 atmosphere, in a round-bottom flask, to a solution of 6-bromopyrazolo[1,5-a]pyridine (CAS No. 1264193-11-4; 10 g, 50 mmol, 1 eq) in 1,3,5-trimethylbenzene (74 mL) was added potassium 2-cyano-2-methyl-propionate Int170 (15 g, 99 mmol, 2 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.8 g, 3.0 mmol, 0.06 eq) and allylpalladium chloride dimer (370 mg, 0.99 mmol, 0.02 eq). The reaction mixture was stirred at 140 °C for 30 min, then cooled to room temperature and heated in a DicaliteTM Filter over Celite®, rinse with EtOAc and concentrate in vacuo. The residue is purified by flash chromatography on silica gel (eluting with heptane / EtOAc 100 / 0 to 50 / 50) to afford the desired intermediate.

[0900] 1.2.3 Method A3: Functionalization of halogenated heteroaryl compounds via Negishi coupling

[0901] Under N2 atmosphere, a halogenated heteroaryl compound (1 equivalent) and DMAC or THF were introduced into a sealed vial. The resulting solution was degassed and then Pd-PEPPSI was added. TM -IPent catalyst (CAS No. 1158652-41-5; 0.1 equivalent) or copper iodide (CAS No. 7681-65-4; 0.1 equivalent) and Pd (dppf) Cl2 DCM (CAS No. 95464-05-4; 0.05 equivalent). The resulting solution was degassed and then a solution of alkyl zinc halide (0.94 to 3 equivalents) was introduced. The reaction mixture was heated to 80 ° C for 2 to 18 hours and then The product was filtered and concentrated in vacuo. The residue was diluted with water and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered or passed through a phase separator and concentrated. The residue was purified by flash chromatography.

[0902] Alternative workup: The reaction mixture was diluted with EtOAc, stirred for 1 hour, and The mixture was filtered and quenched with saturated NH4Cl solution. The solution was stirred for 30 minutes, then 2N NaOH solution was added and extracted with EtOAc. The combined organic layers were washed with 10% Na2S2O3 aqueous solution, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel.

[0903] Exemplary synthesis of Int 127

[0904]

[0905] 7-Chloromidazo[1,2-a]pyridine (100 mg, 0.65 mmol, 1 eq) and THF (0.5 mL) were added to a sealed vial. The resulting solution was degassed and then Pd-PEPPSI was added. TM -IPent catalyst (CAS No. 1158652-41-5; 52 mg, 0.065 mmol, 0.1 equivalent). The resulting solution was degassed, and then a solution of bromocyclobutylzinc (0.5 M THF solution, CAS No. 1019205-65-2; 4 mL, 1.96 mmol, 3 equivalents) was introduced. The reaction mixture was heated to 80°C and maintained for 18 hours, and then The residue was filtered and concentrated in vacuo. The residue was diluted with water and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (eluted with DCM / MeOH 100 / 0 to 95 / 5) to obtain the desired compound.

[0906] 1.2.4 Method A4: Functionalization of halogenated heteroaryl compounds via nickel coupling

[0907] Under N2 atmosphere, degassed DMAC, halogenated heteroaryl compound (1 equivalent), alkyl bromide (1.5 to 2 equivalents), NiCl2, ethylene glycol dimethyl ether (CAS No. 29046-78-4; 0.05 to 0.1 equivalents), Int 230 (0.05 to 0.1 equivalents), sodium iodide (CAS No. 7681-82-5; 0.25 equivalents), zinc powder (CAS No. 7440-66-6; 2 equivalents) and TFA (CAS No. 76-05-1; 0.1 equivalents) were introduced into a sealed vial. The resulting solution was heated to 60°C and maintained for 1 to 18 hours, and then Filter over Celite®, wash with EtOAc and concentrate in vacuo. The residue is purified by flash chromatography on silica gel.

[0908] Alternative post-processing: The reaction mixture was filtered on Celite(R). The filtrate was quenched with water or 5% ammonia solution and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered or passed through a phase separator and concentrated to afford the desired compound.

[0909] Exemplary synthesis of Int 142

[0910]

[0911] Under N2 atmosphere, degassed DMAc, 7-bromoimidazo[1,2-a]pyridine (CAS No. 808744-34-5; 300 mg, 1.52 mmol, 1 eq), 3-bromooxetane (CAS No. 39264-79-3; 253 μL, 3.05 mmol, 2 eq), NiCl2, ethylene glycol dimethyl ether (34 mg, 0.15 mmol, 0.1 eq), ligand Int 230 (36 mg, 0.15 mmol, 0.1 eq), sodium iodide (57 mg, 0.38 mmol, 0.25 eq), zinc powder (199 mg, 3.05 mmol, 2 eq) and TFA (12 μL, 0.15 mmol, 0.1 eq) were introduced into a sealed vial. The resulting solution was heated to 60°C for 1 hour and then The mixture was filtered and washed with EtOAc. The filtrate was quenched with 5% aqueous ammonia solution and extracted with EtOAc. The combined organic layers were passed through a phase separator and concentrated in vacuo to obtain the desired compound.

[0912] 1.2.5 Method A5: Functionalization of halogenated heteroaryl compounds by addition of ketone derivatives

[0913] To a solution of 7-bromoimidazo[1,2-a]pyridine (CAS No. 808744-34-5; 1 equivalent) in anhydrous THF at 0°C under an inert atmosphere was added iPrMgCl.LiCl solution (1.3 M in THF, CAS No. 745038-86-2; 3 equivalents). The resulting solution was warmed to room temperature, stirred at room temperature for 1.5 to 2 hours, then cooled to 0°C, followed by the dropwise addition of a solution of the corresponding ketone or Weinreb amide (4 to 6 equivalents) in THF. The resulting solution was stirred at room temperature for 4 to 48 hours, then quenched with saturated NH4Cl solution and concentrated. The residue was purified by reverse phase flash chromatography.

[0914] Alternative workup: The solution was quenched with saturated NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered or passed through a phase separator and concentrated. The residue was purified by flash chromatography on silica gel.

[0915] Exemplary synthesis of Int 141

[0916]

[0917] At 0 ° C, under N2 atmosphere, iPrMgCl.LiCl solution (1.3M in THF, 11.7 mL, 15.2 mmol, 3 equivalents) was added to a solution of 7-bromoimidazo[1,2-a]pyridine (1 g, 5.07 mmol, 1 equivalent) in anhydrous THF (3 mL). The resulting solution was stirred at room temperature for 1.5 hours, then cooled to 0 ° C, and then a solution of cyclobutanone (CAS No. 1191-95-3; 1.9 mL, 25.4 mmol, 5 equivalents) in THF (10 mL) was added dropwise. The resulting solution was stirred at room temperature for 4 hours, then quenched with saturated NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with brine, passed through a phase separator and concentrated. The residue was purified by flash chromatography on silica gel (eluted with DCM / MeOH 100 / 0 to 95 / 5) to obtain the desired compound.

[0918] 1.2.6 Method A6: Functionalization of halogenated heteroaryl compounds via photochemical reactions

[0919] To a sealed vial containing 2-amino-4-bromopyridine (CAS No. 84249-14-9; 1 equiv), the corresponding carboxylic acid (2 equiv), and Cs2CO3 (CAS No. 534-17-8; 2 equiv) in anhydrous DMF were added NiCl2, ethylene glycol dimethyl ether (CAS No. 29046-78-4; 0.2 equiv), dtbpy (CAS No. 72914-19-3; 0.15 equiv), and (Ir[dF(CF3)ppy]2(dtbpy))PF6 (CAS No. 870987-63-6; 0.01 equiv). The resulting mixture was degassed for 15 minutes, then the vial was sealed and irradiated at 34 W for 48 to 72 hours. The reaction mixture was then concentrated to dryness, and the residue was diluted with 2N NaOH solution or saturated NaHCO3 solution and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel.

[0920] Exemplary synthesis of Int 150

[0921]

[0922] To a sealed vial containing 2-amino-4-bromopyridine (138 mg, 0.80 mmol, 1 eq), N-(tert-butoxycarbonyl)-L-proline (CAS No. 15761-39-4; 345 mg, 1.6 mmol, 2 eq) and Cs2CO3 (521 mg, 1.6 mmol, 2 eq) in anhydrous DMF (1 mL) was added NiCl2. Ethylene glycol dimethyl ether (35 mg, 0.16 mmol, 0.2 eq), dtbpy (32 mg, 0.12 mmol, 0.15 eq) and (Ir[dF(CF3)ppy]2(dtbpy))PF6 (9 mg, 0.008 mmol, 0.01 eq). The resulting mixture was degassed for 15 minutes, then the vial was sealed and irradiated at 34 W for 48 hours. The reaction mixture was then concentrated to dryness, and the residue was diluted with 2N NaOH solution and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated.The residue was purified by flash chromatography on silica gel (eluting with heptane / EtOAc 90 / 10 to 0 / 100) to give the desired compound.

[0923] 1.2.7 Method A7: Functionalization of halogenated pyridines by metallation

[0924] At -78 ° C, under an inert atmosphere, to a solution of a bromopyridine derivative (1 equivalent) in anhydrous THF, a methyllithium solution (1.6 M in Et2O, CAS No. 917-54-4; 1.2 equivalents) was added. The resulting solution was stirred at -78 ° C for 15 minutes, and then nBuLi solution (2.5 M in hexane, CAS No. 109-72-8; 1.2 equivalents) was added. Alternatively, only nBuLi was added. After stirring at -78 ° C for 15 minutes, a solution of the corresponding ketone (1.2 to 3 equivalents) was introduced. The resulting solution was allowed to warm to room temperature and maintained for 10 minutes, then quenched with water and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel.

[0925] Exemplary synthesis of Int 178

[0926]

[0927] To a solution of 2-(Boc-amino)-4-bromopyridine (CAS No. 207799-10-8; 400 mg, 1.46 mmol, 1 eq) in anhydrous THF (4.5 mL) was added methyllithium (1.6 M in Et2O, 1.1 mL, 1.76 mmol, 1.2 eq) at -78°C under an inert atmosphere. The resulting solution was stirred at -78°C for 15 minutes, followed by the addition of nBuLi solution (2.5 M in hexane, 0.7 mL, 1.76 mmol, 1.2 eq). After stirring at -78°C for 15 minutes, a solution of 4,5-dihydro-3(2H)-furanone (CAS No. 22929-52-8; 378 mg, 4.39 mmol, 3 eq) was introduced. The resulting solution was allowed to warm to room temperature and maintained for 10 minutes before being quenched with water and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated.The residue was purified by flash chromatography on silica gel (eluting with heptane / EtOAc 100 / 0 to 0 / 100) to afford the desired intermediate.

[0928] 1.2.8 Method A8: Functionalization of halogenated heteroaryl compounds via Suzuki coupling / degradation

[0929] To a solution of 7-bromoimidazo[1,2-a]pyridine (CAS No. 808744-34-5; 1 equiv.) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (CAS No. 928664-98-6; 1.1 equiv.) in DMSO was added water and potassium fluoride (CAS No. 7789-23-3; 3 equiv.) under a N2 atmosphere. The resulting solution was degassed and Pd(dppf)Cl2·DCM adduct (CAS No. 95464-05-4; 0.10 equiv.) was added. The mixture was stirred at 90-135°C for 3 to 18 hours. The reaction mixture was cooled at room temperature and heated over Dicalite TM The filtrate was diluted with brine and water and extracted with EtOAc. The combined organic layers were dried over MgSO4 or Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography on silica gel.

[0930] Exemplary synthesis of Int 62

[0931]

[0932] To a solution of 7-bromoimidazo[1,2-a]pyridine (1.3 g, 6.6 mmol, 1 eq) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (1.4 g, 7.3 mmol, 1.1 eq) in DMSO (47 mL) was added water (20 mL) and potassium fluoride (1.15 g, 19.8 mmol, 3 eq) under a N2 atmosphere. The resulting solution was degassed and Pd(dppf)Cl2·DCM adduct (483 mg, 0.66 mmol, 0.10 eq) was added. The mixture was stirred at 130°C for 3.5 hours and then at 90°C for 18 hours. The reaction mixture was cooled at room temperature and purified by Dicalite TM The mixture was filtered. The filtrate was diluted with brine and water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography on silica gel (eluting with DCM / MeOH 100 / 0 to 98 / 2) to obtain the desired intermediate.

[0933] Exemplary synthesis of Int 207

[0934]

[0935] To a solution of 6-bromopyrazolo[1,5-a]pyridine (600 mg, 3.0 mmol, 1 eq) in DMSO (21 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (650 mg, 3.3 mmol, 1.1 eq), water (9 mL) and potassium fluoride (530 mg, 9.1 mmol, 3 eq). The resulting solution was degassed and Pd(dppf)Cl2·DCM adduct (230 mg, 0.30 mmol, 0.10 eq) was added. The mixture was stirred at 135°C for 18 h, then cooled at room temperature and purified by Dicalite TM The filtrate was diluted with brine and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated to dryness. The residue was purified by flash chromatography on silica gel (eluting with heptane / EtOAc 100 / 0 to 50 / 50) to obtain the desired intermediate.

[0936] 1.2.9 Method A9: Functionalization of halogenated heteroaryl compounds by coupling with organolithium derivatives

[0937] Degassed THF (0.24 mL) was added to a round-bottom flask containing BINAP (CAS No. 98327-87-8; 0.15 equivalents) and Pd2dba3 (CAS No. 51364-51-3; 0.075 equivalents) that had been previously degassed with N2. The resulting suspension was stirred under N2 for 20 minutes. In another flask, bromide (1.0 equivalents) and formonitrile (2 to 3 equivalents) were diluted with cyclopentyl methyl ether. The solution was degassed by bubbling N2 through the resulting solution for 10 minutes. The aforementioned catalyst suspension was then added to the reagent solution via a syringe, and LiHMDS (1M THF solution, 2 to 3 equivalents) was added dropwise at room temperature. The reaction mixture was heated to 80°C and maintained for 3 hours, then stirred at room temperature for 18 hours. The reaction solution was quenched by adding a saturated NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified by flash chromatography on silica gel or by preparative HPLC, followed by recrystallization from hot ACN, filtration, washing with ACN and Et2O and drying to afford the desired compound.

[0938] Exemplary synthesis of Cpd 107

[0939]

[0940] To a round-bottom flask previously degassed with N2 containing BINAP (CAS No. 98327-87-8; 10 mg, 0.016 mmol, 0.15 equiv) and Pd2dba3 (CAS No. 51364-51-3; 7.4 mg, 0.008 mmol, 0.075 equiv) was added degassed THF (0.24 mL). The resulting suspension was stirred under N2 for 20 minutes. In a separate flask, bromide Int 36 (50 mg, 0.11 mmol, 1.0 equiv) and tetrahydropyran-4-carbonitrile (CAS No. 4295-99-2; 36 mg, 0.33 mmol, 3 equiv) were diluted with cyclopentyl methyl ether (0.63 mL). The solution was degassed by bubbling N2 through it for 10 minutes. The catalyst suspension was then added to the reagent solution via syringe. To the resulting mixture was added dropwise LiHMDS (1M in THF, 0.33 mL, 0.33 mmol, 3 equivalents) at room temperature. The reaction mixture was heated to 80 ° C and maintained for 3 hours, then stirred at room temperature for 18 hours. The reaction solution was quenched by adding saturated NH4Cl solution and extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC, then recrystallized in hot ACN, filtered, washed with ACN and Et2O and dried to obtain the desired compound.

[0941] 1.2.10. Method B: Iodination of Heteroaryl Compounds

[0942] To a solution of the heteroaryl compound (1 equivalent) in ACN or DMF is introduced N-iodosuccinimide (CAS No. 516-12-1; 1.1 to 1.2 equivalents) under an N2 atmosphere. The resulting solution is stirred at room temperature for 18 hours or at 60°C for 1 to 18 hours until complete. The reaction mixture is quenched with a 10% aqueous Na2S2O3 solution and extracted with EtOAc or DCM. The combined organic layers are washed with brine, dried over Na2SO4 or MgSO4, filtered or passed through a phase separator and concentrated. The residue is used directly in the next step without further purification or purified by flash chromatography on silica gel.

[0943] Alternative workup: When the reaction is carried out in DMF, the reaction mixture is quenched with water and the formed precipitate is filtered and dried in vacuo to afford the desired iodinated heteroaryl compound.

[0944] Exemplary synthesis of Int 190

[0945]

[0946] To a solution of Int 191 (80 mg, 0.45 mmol, 1 eq) in ACN (2.3 mL) was introduced N-iodosuccinimide (118 mg, 0.50 mmol, 1.1 eq) under N atmosphere. The resulting solution was stirred at room temperature for 18 h. The reaction mixture was quenched with 10% aqueous Na2S2O3 and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered or passed through a phase separator and concentrated. The residue was used directly in the next step without further purification.

[0947] Exemplary synthesis of Int 169

[0948]

[0949] To a solution of Int 171 (5.0 g, 27.0 mmol, 1 eq) in DMF (50 mL) was introduced N-iodosuccinimide (7.3 g, 32.4 mmol, 1.2 eq) under N atmosphere. The resulting solution was stirred at room temperature for 18 h. The reaction mixture was quenched with water (150 mL), and the resulting precipitate was filtered and dried under vacuum to afford the desired iodoheteroaryl compound.

[0950] 1.2.11. Method C: Suzuki coupling of heteroaryl compounds

[0951] A pressure reactor or an open round-bottom flask equipped with a condenser is charged with a heteroaryl bromide or iodine derivative (1 equivalent), boronic acid or pinacol boronic acid ester (1.2 to 1.5 equivalents), a base (CsCO, KCO, or KF, 1.3 to 3 equivalents), and a 4 / 1 or 3 / 1 dioxane / water solvent mixture or a 4 / 1 DMF / water solvent mixture. The mixture is heated to 100°C and degassed with N2 before adding a Pd catalyst (Pd(PPh3)4, CAS No. 14221-01-3; Pd(dppf)Cl2·DCM adduct, CAS No. 95464-05-4; or Xphos Pd G3, CAS No. 1445085-55-1; 0.07 to 0.2 equivalents). Alternatively, the mixture is degassed with N2 or Ar at room temperature before adding the Pd catalyst. The mixture is stirred at 90 to 100°C for 5 minutes to 18 hours. The reaction mixture was concentrated in vacuo or without vacuum and diluted in EtOAc or DCM and water or saturated NaHCO3 solution. TM Filter or not.Then extract the mixture with EtOAc or DCM.The combined organic layer is optionally washed with salt water, dried over anhydrous Na2SO4 or MgSO4, filtered, or passed through a phase separator, and then concentrated in vacuo.The residue is purified by flash chromatography on silica gel to obtain the desired compound.

[0952] Alternative workup 1: Heat the reaction mixture over diatomaceous earth or Dicalite TM The product was filtered, washed with EtOAc and concentrated in vacuo. The residue was directly purified by flash chromatography, or diluted with water and EtOAc or DCM. The combined organic layer was washed with salt water, dried over anhydrous Na2SO4 or MgSO4, filtered, or passed through a phase separator, and then concentrated in vacuo. The residue was purified by flash chromatography on silica gel to obtain the desired compound.

[0953] Alternative workup 2: Concentrate the reaction mixture in vacuo and then extract with DCM. Wash the combined organic layers with water, pass through a phase separator and then concentrate in vacuo. Dissolve the residue in hot ACN or DCM and filter the insoluble material to obtain the desired compound.

[0954] Alternative workup 3: The reaction mixture was concentrated in vacuo, then diluted in DMSO and purified by preparative HPLC.

[0955] Exemplary synthesis of Cpd 219

[0956]

[0957] Under N2 atmosphere, to a round-bottom flask containing a solution of 2-(3-iodopyrazolo[1,5-a]pyridin-6-yl)-2-methyl-propionitrile Int 169 (10 g, 32.1 mmol, 1 eq) in a 4 / 1 degassed mixture of 1,4-dioxane (178 mL) and water (52 mL) was added Int 8 (14.2 g, 35.4 mmol, 1.1 eq), Cs2CO3 (32 g, 96 mmol, 3 eq) and Pd(dppf)Cl2·DCM (2.8 g, 3.2 mmol, 0.1 eq). The reaction mixture was stirred at 90 ° C for 30 minutes, then quenched with saturated NaHCO3 solution and extracted with EtOAc (×3). The combined organic layers were dried over Na2SO4, filtered on celite and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluting with heptane / EtOAc 100 / 0 to 30 / 70) to afford Cpd 219.

[0958] Exemplary synthesis of Int 59

[0959]

[0960] To a solution of bromide Int 36 (75 mg, 0.16 mmol, 1 eq), borate (CAS No. 885693-20-9; 43 mg, 0.19 mmol, 1.2 eq), Cs2CO3 (156 mg, 0.48 mmol, 3 eq) in a 4 / 1 mixture of dioxane / water (2 mL) was added Pd(dppf)Cl2·DCM (104 mg, 0.32 mmol, 2 eq). The reaction mixture was stirred at 90 ° C for 1 hour. The reaction mixture was concentrated in vacuo and diluted in DCM and water. The combined organic layers were passed through a phase separator and then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluted with DCM / EtOAc 90 / 10 to 20 / 80) to obtain the desired compound.

[0961] Exemplary synthesis of Int 60

[0962]

[0963] To a stirred solution of bromide Int 33 (75 mg, 0.16 mmol, 1 eq) and the corresponding boronate (CAS No. 454482-11-2; 43 mg, 0.19 mmol, 1.2 eq) in degassed dioxane (2 mL) was added a solution of Cs2CO3 (104 mg, 0.32 mmol, 2 eq) in H2O (0.5 mL). The mixture was degassed with argon for 10 minutes and Pd(PPh3)4 (19 mg, 0.016 mmol, 0.1 eq) was added. The reaction mixture was stirred at 90 ° C for 1 hour. The reaction mixture was concentrated in vacuo and diluted in DCM and water. The combined organic layers were dried over anhydrous MgSO4, filtered and then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with DCM / MeOH 100 / 0 to 90 / 10) to obtain the desired compound.

[0964] 1.2.12 Method D1: Synthesis of amide compounds from tert-butyl ester intermediates (sequence: D1i, then D1ii or D1iii)

[0965] 1.2.12.1.D1i: tert-Butyl Ester Hydrolysis

[0966] A solution of the tert-butyl ester (1 equivalent) in a mixture of DCM / TFA (4 / 1 to 9 / 1) was stirred at room temperature for 4 to 18 hours. The reaction mixture was then diluted with toluene and concentrated in vacuo to afford the desired compound.

[0967] Illustrative synthesis of Int 204

[0968]

[0969] A solution of tert-butyl 4-[6-(1-cyanocyclopropyl)pyrazolo[1,5-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzoate Int 203 (115 mg, 0.25 mmol, 1 equiv) in a mixture 8 / 2 DCM / TFA (1.6 mL / 0.4 mL) was stirred at room temperature for 3.5 hours. The reaction mixture was concentrated, triturated with toluene, and concentrated under reduced pressure to provide the desired acid intermediate.

[0970] 1.2.12.2.D1ii: Peptide Coupling

[0971] Into the flask, carboxylic acid derivative (1 equivalent), anhydrous DMF or DMSO or DCM, HATU (1.2 to 2 equivalents), DIPEA (3 to 10 equivalents) are loaded. The mixture is stirred at room temperature for 5 to 15 minutes, then amine or amine hydrochloride or sulfonate (1.1 to 4.8 equivalents) is added. The mixture is stirred at room temperature for 1 to 72 hours. The reaction mixture is concentrated in vacuo, then diluted with water or saturated NaHCO or NH4Cl solution and extracted with EtOAc. The organic layer merged is washed with salt water or not, through anhydrous Na2SO4 or MgSO4 is dried and filtered, or passed through a phase separator, then concentrated in vacuo. By flash chromatography on silica gel or preparative HPLC purification of residue.

[0972] Alternative workup 1: The mixture was concentrated in vacuo and purified by chromatography on silica gel or C18 Purification by flash chromatography on a reverse phase cartridge afforded the desired amide derivative.

[0973] Alternative workup 2: When the reaction was carried out in DMSO, the reaction mixture was purified directly by preparative HPLC.

[0974] Exemplary composition of Int 5

[0975]

[0976] 6-Methoxysalicylic acid (CAS No. 3147-64-6; 10 g, 0.06 mmol, 1 eq) was dissolved in DMF (50 mL), and HATU (33.93 g, 0.09 mmol, 1.5 eq) was added. After 15 minutes, cyclopropylamine (CAS No. 765-30-0; 10.18 g, 0.18 mmol, 3 eq) and DIPEA (34.55 g, 0.26 mmol, 4.5 eq) were added. The reaction mixture was stirred at room temperature for 18 hours; then, 1 eq of HATU, 2 eq of cyclopropylamine, and 2 eq of DIPEA were added. The reaction mixture was stirred at room temperature for 68 hours. The reaction mixture was concentrated in vacuo, and the residue was purified by flash chromatography on silica gel (eluting with heptane / EtOAc 100 / 0 to 50 / 50). The collected fractions were concentrated in vacuo and triturated twice with MeOH / EtO. The filtrate was concentrated in vacuo to obtain the desired compound.

[0977] Exemplary synthesis of Int 33

[0978]

[0979] A flask was charged with Int 32 (0.3 g, 0.795 mmol, 1 eq), HATU (332 mg, 0.874 mmol, 1.1 eq), anhydrous DMF (9 mL) and DIPEA (0.4 mL, 2.39 mmol, 3 eq). The mixture was stirred at room temperature for 10 minutes, then 2,2,2-trifluoroethylamine hydrochloride (CAS No. 373-88-6; 216 mg, 1.6 mmol, 2 eq) was added. The mixture was stirred at room temperature overnight. After evaporation of DMF, the residue was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated in vacuo and purified by flash chromatography on silica gel (eluting with DCM / MeOH 100 / 0 to 95 / 5) to obtain the desired intermediate.

[0980] Exemplary synthesis of Cpd 235

[0981]

[0982] To a solution of 4-[6-(1-cyanocyclopropyl)pyrazolo[1,5-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzoic acid Int 204 (95 mg, 0.23 mmol, 1 eq) and HATU (105 mg, 0.28 mmol, 1.2 eq) in anhydrous DCM (2 mL) was added DIPEA (121 μL, 0.69 mmol, 3 eq). The reaction mixture was stirred at room temperature for 5 minutes and (1R,2S)-2-fluorocyclopropylamine 4-methylbenzenesulfonate (CAS No. 143062-84-4; 64 mg, 0.25 mmol, 1.1 eq) was added. The reaction mixture was stirred at room temperature for 45 minutes, then quenched with saturated NaHCO solution, and the aqueous phase was extracted with EtOAc (×3). The combined organic layers were dried over MgSO, filtered, and concentrated. The residue was purified by flash chromatography on a Biotage SNAP KP-NH column (eluting with heptane / EtOAc 90 / 10 to 20 / 80) to give the desired compound.

[0983] Exemplary synthesis of Cpd 141

[0984]

[0985] To a vial containing Cpd 114 (30 mg, 0.066 mmol, 1 eq) was added HATU (50 mg, 0.13 mmol, 2 eq), anhydrous DMSO (1 mL), and DIPEA (46 μL, 0.26 mmol, 4 eq). The mixture was stirred at room temperature for 10 minutes, then morpholine (CAS No. 110-91-8; 15 μL, 0.13 mmol, 2 eq) was added. The mixture was stirred at room temperature for 1 hour, then directly purified by preparative HPLC to obtain the desired compound.

[0986] 1.2.12.3.D1iii: Amide synthesis via acyl chloride

[0987] To a solution of the carboxylic acid derivative (1 equivalent) in DCM, oxalyl chloride (1.2 equivalents) and a drop of DMF are added at 0°C. The resulting solution is stirred at 0°C for 1 hour, then diluted with toluene and concentrated. The obtained residue is dissolved in DCM at 0°C, and DIPEA (6 equivalents) and the corresponding amine (1.3 equivalents) are added. The mixture is stirred at 0°C for 1 hour, diluted with saturated NaHCO solution and extracted with DCM. The combined organic layer is passed through a phase separator and then concentrated in vacuo. The residue is purified by flash chromatography on silica gel or preparative HPLC.

[0988] Exemplary synthesis of Cpd 243

[0989]

[0990] To a solution of 4-[6-(4-cyanotetrahydropyran-4-yl)pyrazolo[1,5-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzoic acid Int 231 (180 mg, 0.40 mmol, 1.0 equiv) in DCM (2 mL) was added one drop of DMF and oxalyl chloride (0.24 mL, 0.48 mmol, 1.2 equiv) at 0°C. The resulting mixture was stirred at 0°C for 1 hour, then concentrated and co-evaporated twice with toluene. The resulting beige solid was dissolved in DCM (2 mL), and DIPEA (0.420 mL, 2.41 mmol, 6 equiv) and (1R,2S)-2-fluorocyclopropylamine 4-methylbenzenesulfonate (0.523 mmol, 0.132 g, 1.3 equiv) were added dropwise. The reaction mixture was stirred at 0° C. for 1 hour, then quenched with saturated NaHCO solution and extracted with DCM. The combined organic layers were passed through a phase separator and concentrated in vacuo, and the residue was purified by flash chromatography on silica gel (eluted with DCM / MeOH 100 / 0 to 96 / 4). The resulting white solid was dissolved in ACN / H O, concentrated, and finally dried in vacuo for 18 hours to obtain the desired compound.

[0991] 1.2.13. Method D2: Synthesis of amide compounds from methyl ester intermediates (sequence: D2i, then D1ii as described above)

[0992] 1.2.13.1.D2i: Methyl ester saponification

[0993] To a solution of the methyl ester derivative (1 equivalent) in MeOH or a mixture MeOH / THF (1: 1) is added 2N NaOH solution (5 to 20 equivalents) or NaOH pellets (15 equivalents) and water. The resulting solution is stirred at room temperature or 75 ° C for 1 to 72 hours. After cooling to room temperature, the organic solvent is removed under reduced pressure. The residue is diluted with water and the pH is adjusted with HCl (2N or 6N) until the pH is acidic. The resulting suspension is filtered. The precipitate is washed with water and / or DCM and ACN and dried in vacuo to obtain the desired compound.

[0994] Alternative workup: The reaction mixture was quenched with 1N HCl solution until the pH was adjusted to 2 and extracted with EtOAc. The combined organic layers were dried over MgSO4 or passed through a phase separator and then concentrated in vacuo.

[0995] Exemplary synthesis of Int 232

[0996]

[0997] To a solution of the methyl ester derivative Int 78 (855 mg, 2.06 mmol, 1 equivalent) in a mixture of MeOH / THF (1:1, 24 mL) was added NaOH pellets (1.23 g, 30.9 mmol, 15 equivalents) and water (5 mL). The resulting solution was heated at 75 ° C for 1 hour. After cooling to ambient temperature, the organic solvent was removed under reduced pressure. The residue was diluted with water, the pH was adjusted to acidic pH with 2N HCl, and the resulting suspension was stirred at room temperature for 10 minutes. The suspension was filtered, the precipitate was washed with water and DCM and ACN and dried in vacuo to obtain the desired compound.

[0998] Exemplary synthesis of Int 32

[0999]

[1000] A mixture of methyl 4-(5-bromobenzimidazol-1-yl)-2,6-dimethoxybenzoate Int 31 (82 g, 210 mmol, 1 eq), MeOH (450 mL), THF (550 mL) and 2N NaOH (550 mL, 1100 mmol, 5.2 eq) was stirred at 75 ° C for 18 hours. After cooling to room temperature, the organic solvent was removed under reduced pressure. The residue was diluted with water (800 mL). The pH was adjusted from 12.4 to 1.6 with 6N HCl solution. The resulting suspension was stirred at 2 ° C for 30 minutes and then filtered. The filter cake was washed with water (800 mL) and left on the funnel for 20 minutes to obtain a dark red solid. The solid was dried in a vacuum oven at 45 ° C for 2 hours to obtain the desired intermediate.

[1001] 1.2.14. Method E: CH Activation at Position 3 of Imidazopyridine

[1002] The imidazopyridine derivative (1 equivalent), the bromo derivative (0.6 to 1.5 equivalents), and KOAc (2 to 3 equivalents) are suspended in anhydrous DMAC or DMSO. The mixture is degassed with N2, followed by the addition of Pd(dppf)Cl2·DCM adduct (CAS No. 95464-05-4, 0.03 to 0.1 equivalents). Alternatively, all reagents are suspended in an anhydrous, degassed solvent, or all reagents are suspended in an anhydrous solvent. The mixture is stirred at 90-120°C for 1 to 18 hours. The reaction mixture is cooled to room temperature and directly purified by preparative HPLC to obtain the desired compound.

[1003] Alternative workup 1: The reaction mixture was concentrated in vacuo and purified by silica gel flash chromatography to afford the desired compound.

[1004] Alternative workup 2: The reaction mixture was diluted with or without EtOAc or DCM, and water could also be added. The resulting suspension was purified by The crude residue is then purified by flash chromatography on silica gel or preparative HPLC to afford the desired compound.

[1005] Alternative workup 3: The reaction mixture was quenched with saturated NaHCO3 solution or water, extracted with EtOAc, and the combined organic layers were washed with water, then with brine, dried (over anhydrous Na2SO4 or MgSO4), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel to afford the desired compound.

[1006] Exemplary synthesis of Cpd 213

[1007]

[1008] The imidazopyridine derivative Int 176 (40 mg, 0.20 mmol, 1 eq), the bromo derivative Int 4 (99 mg, 0.30 mmol, 1.5 eq), KOAc (38 mg, 0.39 mmol, 2 eq), and Pd(dppf)Cl2·DCM adduct (CAS No. 95464-05-4, 16 mg, 0.019 mmol, 0.1 eq) were suspended in anhydrous DMAC and the mixture was degassed with N2. The mixture was stirred at 110°C for 1 hour. The reaction mixture was cooled to room temperature, concentrated in vacuo, and purified by flash chromatography (eluting with DCM / MeOH 100 / 0 to 90 / 10) to obtain Cpd 213.

[1009] 1.2.15. Method F1: S-Hydroxylation of Disubstituted Aminobenzoates by LiHMDS N Ar

[1010] A THF solution of 4-amino-2,6-dimethoxy-benzoic acid methyl ester (CAS No. 3956-34-1; 1 equivalent) and 4-bromo-1-fluoro-2-nitro-benzene (CAS No. 364-73-8; 1 equivalent) was cooled at 0 ° C under N2. LiHMDS (1M THF solution, CAS No. 4039-32-1; 2.3 equivalents) was then added dropwise over 2 hours. The reactants were quenched with water. THF was evaporated and the remaining reaction mixture was stirred at 3 ° C for 18 hours. 2N HCl was slowly added to the reaction mixture while stirring rapidly, and the mixture was stirred at 3 ° C for 1 hour. The precipitate was filtered off and then dried in a vacuum oven at 45 ° C and 20 mbar for 5 hours to obtain the desired intermediate.

[1011] Exemplary synthesis of Int 29

[1012]

[1013] A solution of 4-amino-2,6-dimethoxy-benzoic acid methyl ester (40 g, 189.4 mmol, 1 equivalent) and 4-bromo-1-fluoro-2-nitro-benzene (23.3 mL, 189.4 mmol, 1 equivalent) in THF (1 L) was cooled at 0 ° C under N2. LiHMDS (1M in THF, 435.6 mL, 435.6 mmol, 2.3 equivalents) was then added dropwise over 2 hours. The reactants were quenched with water (800 mL). THF was evaporated and the remaining reaction mixture was stirred at 3 ° C for 18 hours. 2M HCl (600 mL) was slowly added to the reaction mixture while stirring rapidly, and the mixture was stirred at 3 ° C for 1 hour. The precipitate was filtered off and then dried in a vacuum oven at 45 ° C and 20 mbar for 5 hours to obtain the desired compound.

[1014] 1.2.16. Method F2: S-Hydroxylation of Disubstituted Aminobenzamides or Benzoates with NaH N Ar

[1015]

[1016] To a solution of disubstituted aminobenzamide or 4-amino-2,6-disubstituted-benzoic acid methyl ester (1 to 1.1 equivalents) in anhydrous THF under an argon atmosphere is added a fluoronitro derivative (1 to 1.7 equivalents). The mixture is cooled at 0 ° C and NaH (CAS No. 7646-69-7; 3 equivalents) is added portionwise. The mixture is stirred at 0 ° C for 10 minutes and then stirred at room temperature for 18 hours. The mixture is cooled to 0 ° C, quenched with water or saturated NH4Cl solution, diluted with EtOAc or DCM and water, saturated NH4Cl solution or brine, and extracted with EtOAc or DCM. The combined organic layer is dried or washed with brine, then dried (Na2SO4 or MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel gives the desired compound.

[1017] Exemplary synthesis of Int 41

[1018]

[1019] To a solution of Int 28 (82 mg, 0.30 mmol, 1 eq) in anhydrous THF (2 mL) degassed with N2 and then placed under an argon atmosphere was added Int 38 (69 mg, 0.33 mmol, 1.1 eq). The mixture was cooled at 0 ° C and NaH (36 mg, 0.90 mmol, 3 eq) was added. The mixture was warmed to room temperature and stirred at room temperature for 18 hours. The mixture was cooled to 0 ° C, quenched with saturated NH4Cl solution and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluted with a gradient of DCM / MeOH 100 / 0 to 99 / 1) to obtain the desired compound.

[1020] 1.2.17. Method G1: Nitro reduction by SnCl2, 2H2O / SnCl2

[1021] A mixture of a nitroaniline derivative (1 equivalent), tin(II) chloride dihydrate (CAS No. 10025-69-1; 2.3 equivalents) and tin(II) chloride (CAS No. 7772-99-8; 1.7 equivalents) in EtOH was stirred under reflux for 2 hours. After UPLC monitoring showed complete reduction to amine, trimethyl orthoformate (CAS No. 149-73-5; 4 equivalents) was slowly added to the mixture and continued stirring under reflux for 2 hours. The mixture was cooled to room temperature and concentrated to dryness. The residue was dissolved in EtOAc and washed with 2NNaOH solution. The formed suspension (tin tetrachloride) was filtered. The layers were separated. Saturated NaHCO3 solution was added to the organic layer. A suspension was formed again. 20% NaOH (exothermic) was added to the suspension. The layers were separated for 18 hours. The organic layer was dried over K2CO3 and filtered. All filter residues were washed with EtOAc, combined with the aqueous layer and the layers were separated. The organic layers were combined and concentrated to dryness under reduced pressure. The residue was suspended in Et2O, stirred for 30 minutes and filtered. The filter cake was left on the funnel and suction was applied for 20 minutes to obtain the desired compound.

[1022] Exemplary synthesis of Int 30

[1023]

[1024] A mixture of Int 29 (148.2 g, 360.4 mmol, 1 equivalent), tin (II) chloride dihydrate (188 g, 833.1 mmol, 2.3 equivalents) and tin (II) chloride (116.2 g, 612.8 mmol, 1.7 equivalents) in EtOH (1800 mL) was stirred under reflux for 2 hours. After UPLC monitoring showed complete reduction to amine, trimethyl orthoformate (157.7 mL, 1441.5 mmol, 4 equivalents) was slowly added to the mixture and continued stirring under reflux for 2 hours. The mixture was cooled to room temperature and concentrated to dryness. Residue was dissolved in EtOAc (1400 mL) and washed with 2N NaOH solution (600 mL). A suspension (tin tetrachloride) was formed and filtered (keeping filtration for 18 hours). Each layer was separated. Saturated NaHCO3 aqueous solution (1000 mL) was added to the organic layer. A suspension was formed again. 20% NaOH (2000 mL) was added to the suspension. The layers were allowed to separate for 18 hours. The organic layer was dried over KCO and filtered. All filter residues were washed with EtOAc, combined with the aqueous layer and the layers were separated. The organic layers were combined and concentrated to dryness under reduced pressure. The residue was suspended in EtO (500 mL), stirred for 30 minutes and filtered. The filter cake was left on the funnel and suctioned for 20 minutes to obtain Int 30.

[1025] 1.2.18. Method G2: Nitro Reduction by Zn / AcOH

[1026] To a solution of a nitroamino derivative (1 equivalent) in glacial AcOH stirred at room temperature or under reflux, zinc powder (CAS No. 7440-66-6; 5 to 11.1 equivalents) was added portionwise. The resulting mixture was stirred (75°C or under reflux) for 10 minutes to 1 hour. (Reaction completion was monitored by TLC and / or UPLC-MS). The reaction mixture was cooled to room temperature and either undiluted or diluted in EtOAc or toluene. Filter, rinse with EtOAc or toluene or AcOH or EtOAc and toluene.Evaporate the filtrate to dryness and use the diamino derivative directly in the next step or purify the residue by flash chromatography and use in the next step.

[1027] Exemplary synthesis of Int 42

[1028]

[1029] To a solution of Int 41 (75 mg, 0.16 mmol, 1 eq) in glacial AcOH (1 mL) stirred at 75° C. was introduced zinc powder (105 mg, 1.6 mmol, 10 eq). The resulting mixture was stirred at 75° C. for 1 hour. The reaction mixture was cooled to room temperature and precipitated with Dicalite TMFilter through a pad of Celite®, rinsing with EtOAc. Concentrate the filtrate in vacuo to obtain the desired compound.

[1030] 1.2.19. Method H: Cyclization to benzimidazole

[1031] To a solution of the diamino derivative (1 equivalent) in MeOH, p-toluenesulfonic acid or p-toluenesulfonic acid monohydrate (CAS No. 6192-52-5; 0.2 to 0.6 equivalents) or AcOH (0.2 to 1 equivalent) and trimethyl orthoformate (CAS No. 149-73-5; 3 to 5 equivalents) are introduced. The resulting mixture is stirred to 75°C and refluxed (30 minutes to 18 hours) and cooled to room temperature. The reaction mixture is concentrated in vacuo and purified by flash chromatography on silica gel, or extracted with water / EtOAc and purified by flash chromatography on silica gel.

[1032] Exemplary synthesis of Cpd 12

[1033]

[1034] To a solution of intermediate Int 42 (69 mg, 0.16 mmol, 1 eq) in MeOH (2 mL) was introduced AcOH (10 μL, 0.133 mmol, 0.2 eq) and trimethyl orthoformate (88 μL, 0.80 mmol, 5 eq). The resulting mixture was stirred to 75 ° C and maintained for 18 hours. The reaction mixture was concentrated in vacuo and purified by flash chromatography on silica gel (eluted with DCM / MeOH 100 / 0 to 98 / 2) to obtain the desired compound.

[1035] 1.2.20. Method I1: O-alkylation

[1036] To a solution of an alcohol (1 equivalent) in THF, DMF, or DMAc, NaH (60% dispersion in mineral oil, CAS No. 7646-69-7; 1.2 to 1.3 equivalents) was added at 0°C with or without an inert atmosphere, and the mixture was stirred for 15 minutes. Iodomethane (CAS No. 74-88-4; 1.2 to 2 equivalents) or iodoethane (CAS No. 75-03-6; 2 equivalents) was then added, and the reaction mixture was warmed to room temperature and stirred for 1 to 72 hours. The reaction mixture was then concentrated to dryness and diluted with water and DCM. The aqueous phase was extracted with DCM, and the combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel.

[1037] Alternative workup 1: The reaction mixture was quenched with saturated NH4Cl solution and extracted with EtOAc. The combined organic layers were dried over a desiccant, filtered, and concentrated. The residue was purified by flash chromatography on silica gel.

[1038] Alternative workup 2: The reaction mixture was quenched with saturated aqueous NH4Cl and extracted sequentially with chloroform and EtOAc. The combined organic layers were dried over a desiccant, filtered, and concentrated to obtain the desired compound. The aqueous layer was then basified with 2N NaOH solution and re-extracted with chloroform. The combined organic layers were dried over a desiccant, filtered, and concentrated to obtain the desired compound.

[1039] Alternative workup 3: The reaction mixture was quenched with water and concentrated in vacuo. The residue was purified by flash chromatography on silica gel.

[1040] Exemplary synthesis of Int 214

[1041]

[1042] To a solution of alcohol Int 208 (100 mg, 0.32 mmol, 1 eq) in DMF (1.6 mL) was added NaH (60% dispersion in mineral oil, 16 mg, 0.40 mmol, 1.3 eq) at 0 ° C, and the mixture was stirred for 15 minutes. Iodomethane (29 μL, 0.48 mmol, 1.5 eq) was then added, and the reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was quenched with saturated NH4Cl aqueous solution and extracted with EtOAc. The combined organic layer was dried over a drying agent, filtered and concentrated. The residue was purified by flash chromatography on silica gel (eluted with heptane / EtOAc 100 / 0 to 60 / 40) to obtain the desired intermediate.

[1043] 1.2.21. Method I2: Amine Alkylation

[1044] To a stirred solution of the amine derivative (1 equivalent) in ACN, EtOH, or DCM, potassium carbonate (CAS No. 584-08-7; 2 to 3 equivalents) and the corresponding halogenated derivative (1.1 to 3 equivalents) are added. The reaction mixture is stirred at room temperature or 90°C for 18 to 72 hours. The reaction mixture is concentrated in vacuo, diluted with DCM and water, and the organic layer is separated and concentrated in vacuo; or saturated NaHCO3 solution is added and the mixture is extracted with EtOAc, and the combined organic layers are dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue is purified by flash chromatography on silica gel to obtain the desired compound.

[1045] Exem...

Claims

1. A compound of formula I, in, W 1 CR 3 And W 2 N or CH; X 1 , X 2 and X 3 One of them is N and the other two are C; Y is CR 2b ; Z is --NR 4a R 4b , --NR 4c -, wherein the N atom and R 2a together with the atoms to which it is attached, form a fused 5-6 membered heterocycloalkenyl containing one double bond, or -N-linked 4-7 membered monocyclic or spirocyclic heterocycloalkyl further comprising zero, one or two additional heteroatoms independently selected from N, O and S, optionally replaced by one, two or three independently selected R 5 Group substitution; R 1a Selected from -H， -halogen, --OH, --CN, -C 1-6 Alkyl, which is optionally substituted by one, two or three independently selected R 6 replace, -C 1-4 alkoxy, which is optionally substituted by one, two or three -OH or a 5-6 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S, --C(=O)-R 7 , --NO 8a R 8b , --S(=O) 2 -C 1-4 alkyl, -5-6 membered monocyclic heteroaryl, which contains one, two or three heteroatoms independently selected from N, O and S, the heteroaryl being optionally substituted by one, two or three independently selected C 1-4 Alkyl substitution, and -4-6 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S; R 1b and R 1c Independently selected from -halogen, --OH, --CN, -C 1-4 Alkyl, which is optionally substituted by one, two or three independently selected -OH, -CN or C 2-4 Alkenyl substitution, -C 3-7 Cycloalkyl, -4-8 membered monocyclic or spirocyclic heterocycloalkyl, which contains one, two or three heteroatoms independently selected from N, O and S, the heterocycloalkyl being optionally substituted by one, two or three independently selected R 9 group substitution, and --NO 10a R 10b , or R 1b and R 1c Together with the atoms to which it is attached, it forms C 3-6 Cycloalkyl, or R 1b and R 1c Together with the atoms to which they are attached, they form a 4-6 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S, the heterocycloalkyl being optionally substituted by one, two or three independently selected R 11 Group substitution; R 2a Selected from -C 1-4 Alkoxy, which is optionally substituted by one, two or three independently selected halogens, -OH or C 1-4 Alkoxy substitution; R 2b C 1-4 Alkoxy; R 3 is H; R 4a is H; R 4b Selected from -C 1-6 Alkyl, which is optionally substituted by one, two or three independently selected R 13 replace, -C 3-7 Cycloalkyl, optionally substituted by one, two or three independently selected R 14a Replace, and -4-7 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S, the heterocycloalkyl optionally being replaced by one, two or three independently selected R 14b replace; R 4c H, C 3-7 Cycloalkyl or C optionally substituted with one, two or three independently selected halogen or -CN 1-6 alkyl; Each R 5 Independently selected from: -Oxo, -halogen, --CN, --OH, --NO 15a R 15b , -phenyl, -C 3-7 Cycloalkyl, -C 2-4 Alkynyl, --C(=O)-C 1-4 Alkoxy, -C 1-4 alkoxy, which is optionally substituted with one, two or three independently selected halogens or phenyl, -C 1-4 Alkyl, which is optionally substituted by one, two or three independently selected halogens, -OH or C 1-4 Alkoxy substituted, and -4-7 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S; Each R 6 Independently selected from -halogen, --O-R 16 , --NO 17a R 17b , - a 5-6 membered monocyclic heteroaryl group containing one, two or three heteroatoms independently selected from N, O and S, and -4-6 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S, which heterocycloalkyl is optionally substituted by one, two or three independently selected halogens; R 7 -OH, C 1-4 Alkyl, C 1-4 Alkoxy, -NR 18a R 18b or a 4-6 membered monocyclic heterocycloalkyl group containing one, two or three heteroatoms independently selected from N, O and S, the heterocycloalkyl group being optionally substituted with one, two or three -OH groups; R 8a and R 8b are independently H, -C(=O)-C 1-4 Alkoxy or C optionally substituted with one, two or three independently selected halogens, -CN or -OH 1-4 alkyl; Each R 9 is independently halogen, -OH or C optionally substituted with one, two or three -OH 1-4 alkyl; Each R 10a and R 10b is independently H or C optionally substituted with one, two or three -OH 1-4 alkyl; Each R 11 Independently selected from -C 1-4 Alkyl, which is optionally substituted with one, two or three independently selected -CN or C 1-4 Alkoxy substitution, --C(=O)-C 1-6 Alkyl, and --C(=O)-C 1-6 Alkoxy; Each R 13 Independently selected from -halogen, --CN, --NO 19a R 19b , --OH, -C 1-4 Alkoxy, -C 3-7 Cycloalkyl, --S(=O) 2 -C 1-4 alkyl, - a 4-7 membered monocyclic heterocycloalkyl group containing one, two or three heteroatoms independently selected from N, O and S, and -5-6 membered monocyclic heteroaryl, which contains one, two or three heteroatoms independently selected from N, O and S, the heteroaryl being optionally substituted by one, two or three independently selected C 1-4 Alkyl substitution; Each R 14a and R 14b Independently selected from -halogen, -Oxo, -C 1-4 Alkyl, which is optionally substituted by one, two or three independently selected halogens, -OH or C 1-4 Alkoxy substitution, --OH, -C 1-4 Alkoxy, and --NO 20a R 20b ; Each R 15a and R 15b Independently H, C 1-4 Alkyl or -C(=O)-C 1-4 Alkoxy; Each R 16 Independently selected from -H， --S(=O) 2 -C 1-4 alkyl, -C 1-4 Alkyl, which is optionally substituted by one, two or three -C(=O)-NR 21a R 21b or substituted by a 4-6 membered monocyclic heterocycloalkyl group containing one, two or three heteroatoms independently selected from N, O and S, and -4-6 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S; Each R 17a and R 17b is independently H or optionally one, two or three independently selected -OH or C 1-4 Alkoxy substituted C 1-4 alkyl; R 18a and R 18b is independently H or optionally one, two or three independently selected -OH or C 1-4 Alkoxy substituted C 1-4 alkyl; Each R 19a , R 19b , R 20a , R 20b , R 21a and R 21b are independently H or C 1-4 alkyl; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2a is -O-CH substituted by one, two or three independently selected halogens 3 .

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula IIIa, IIIb, IIIc or IIId:

4. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R 1b and R 1c Together with the atoms to which it is attached it forms a cyclobutyl group.

5. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R 1b and R 1c Together with the atoms to which it is attached it forms an oxetanyl or tetrahydropyranyl group.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula IVe, IVf, IVg or IVh:

7. A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 6, wherein R 4b It is cyclopropyl or 2-fluorocyclopropyl.

8. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R 1a It is H, -OH or -CN.

9. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R 1a C is substituted by a -OH 1-6 alkyl.

10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof.

11. Use of the compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9 or the pharmaceutical composition according to claim 10 in the preparation of a medicament for preventing and / or treating arthritis, psoriasis or pulmonary fibrosis.

12. Use of the compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9 or the pharmaceutical composition according to claim 10 in the preparation of a medicament for preventing and / or treating osteoarthritis or psoriatic arthritis.

13. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is: 2,6-dimethoxy-4-[5-(1-methyl-4-piperidinyl)benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)benzamide, tert-Butyl 4-[1-[3,5-dimethoxy-4-(2,2,2-trifluoroethylcarbamoyl)phenyl]benzimidazol-5-yl]piperidine-1-carboxylate, 2,6-dimethoxy-4-[5-(4-piperidinyl)benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)benzamide, 4-[5-[1-(cyanomethyl)-4-piperidinyl]benzimidazol-1-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)benzamide, 2,6-dimethoxy-4-(5-tetrahydropyran-4-ylbenzimidazol-1-yl)-N-(2,2,2-trifluoroethyl)benzamide, 2,6-dimethoxy-4-[5-(1-methyl-3-piperidinyl)benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)benzamide, tert-Butyl 3-[1-[3,5-dimethoxy-4-(2,2,2-trifluoroethylcarbamoyl)phenyl]benzimidazol-5-yl]piperidine-1-carboxylate, 2,6-dimethoxy-4-[5-(3-piperidinyl)benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)benzamide, 4-[5-[1-(cyanomethyl)-3-piperidinyl]benzimidazol-1-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)benzamide, 4-[5-(1-cyano-1-methyl-ethyl)benzimidazol-1-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)benzamide, 4-[5-(1-cyano-1-methyl-ethyl)benzimidazol-1-yl]-N-cyclopropyl-2,6-dimethoxy-benzamide, 4-[5-(1-cyano-1-methyl-ethyl)benzimidazol-1-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 4-[5-(1-cyanocyclobutyl)benzimidazol-1-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)benzamide, 4-[5-(1-cyanocyclobutyl)benzimidazol-1-yl]-N-cyclopropyl-2,6-dimethoxy-benzamide, 4-[5-(1-cyanoethyl)benzimidazol-1-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)benzamide, tert-butyl 4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethylcarbamoyl)phenyl]imidazo[1,2-a]pyridin-7-yl]piperidine-1-carboxylate, 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)benzamide, 2-[3-[4-(3,3-difluoroazetidine-1-carbonyl)-3,5-dimethoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]-2-methyl-propionitrile, 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 2-[3-(8-methoxy-1-oxo-3,4-dihydro-2H-isoquinolin-6-yl)imidazo[1,2-a]pyridin-7-yl]-2-methyl-propionitrile, tert-Butyl 3-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethylcarbamoyl)phenyl]imidazo[1,2-a]pyridin-7-yl]piperidine-1-carboxylate, 2,6-dimethoxy-4-[7-(1-methyl-4-piperidinyl)imidazo[1,2-a]pyridin-3-yl]-N-(2,2,2-trifluoroethyl)benzamide, 2,6-dimethoxy-4-[7-(3-piperidinyl)imidazo[1,2-a]pyridin-3-yl]-N-(2,2,2-trifluoroethyl)benzamide, 2,6-dimethoxy-4-[7-(1-methyl-3-piperidinyl)imidazo[1,2-a]pyridin-3-yl]-N-(2,2,2-trifluoroethyl)benzamide, 2-[3-[8-methoxy-1-oxo-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-6-yl]imidazo[1,2-a]pyridin-7-yl]-2-methyl-propionitrile, 4-[7-(1-cyanoethyl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 4-[7-(1-cyano-1-methyl-propyl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2,6-dimethoxy-benzamide, 4-[7-(2-amino-1,1-dimethyl-2-oxo-ethyl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2,6-dimethoxy-benzamide, 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-N-ethyl-2,6-dimethoxy-benzamide, 4-[7-(2-amino-1,1-dimethyl-2-oxo-ethyl)imidazo[1,2-a]pyridin-3-yl]-N-ethyl-2,6-dimethoxy-benzamide, N-(Cyanomethyl)-4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-2,6-dimethoxy-benzamide, 4-[7-(1-cyanocyclopropyl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 4-[7-(1-cyanocyclobutyl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-(1-hydroxy-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, 4-[7-(1-allyl-1-cyano-but-3-enyl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 2,6-dimethoxy-4-(7-tetrahydropyran-4-ylimidazo[1,2-a]pyridin-3-yl)-N-(2,2,2-trifluoroethyl)benzamide, 2-[3-[3-(difluoromethoxy)-4-(1,1-dioxo-1,4-thiazinane-4-carbonyl)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]-2-methyl-propionitrile, 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-N-(cyclopropylmethyl)-2-(difluoromethoxy)-6-methoxy-benzamide, 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-N-ethyl-6-methoxy-N-methyl-benzamide, 2-[3-[3-(difluoromethoxy)-4-(4-hydroxypiperidine-1-carbonyl)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]-2-methyl-propionitrile, 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-N-(2-morpholinoethyl)benzamide, 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-N-(oxetane-3-yl)benzamide, 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-N-(3-hydroxypropyl)-6-methoxy-benzamide, 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-N-(3-methoxypropyl)benzamide, 2-[3-[3-(difluoromethoxy)-5-methoxy-4-(4-methoxypiperidine-1-carbonyl)phenyl]imidazo[1,2-a]pyridin-7-yl]-2-methyl-propionitrile, 2-[3-[3-(difluoromethoxy)-4-(3,3-difluoropyrrolidine-1-carbonyl)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]-2-methyl-propionitrile, 2-[3-[3-(difluoromethoxy)-5-methoxy-4-(morpholine-4-carbonyl)phenyl]imidazo[1,2-a]pyridin-7-yl]-2-methyl-propionitrile, 2-[3-[3-(difluoromethoxy)-5-methoxy-4-(4-methylpiperazine-1-carbonyl)phenyl]imidazo[1,2-a]pyridin-7-yl]-2-methyl-propionitrile, 2-[3-[3-(difluoromethoxy)-4-(3-hydroxyazetidine-1-carbonyl)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]-2-methyl-propionitrile, 2-[3-[3-(difluoromethoxy)-5-methoxy-4-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)phenyl]imidazo[1,2-a]pyridin-7-yl]-2-methyl-propionitrile, 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-N-[(1-methylpyrazol-3-yl)methyl]benzamide, 4-[7-(1-cyanocyclopentyl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 4-[7-(1-hydroxyethyl)imidazo[1,2-a]pyridin-3-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)benzamide, 4-[7-(1-amino-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)benzamide, 4-[7-(1,1-dimethyl-2-oxo-propyl)imidazo[1,2-a]pyridin-3-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)benzamide, 4-[7-(1-hydroxy-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)benzamide, tert-Butyl 3-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethylcarbamoyl)phenyl]imidazo[1,2-a]pyridin-7-yl]azetidine-1-carboxylate, tert-butyl 3-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]azetidine-1-carboxylate, 4-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]piperidine-1-carboxylic acid tert-butyl ester, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[1-methyl-1-(5-methyl-1,2,4-oxadiazol-3-yl)ethyl]imidazo[1,2-a]pyridin-3-yl]benzamide, 4-[7-(2-hydroxy-1,1-dimethyl-propyl)imidazo[1,2-a]pyridin-3-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)benzamide, 4-[7-(1-acetylazetidin-3-yl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 3-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]piperidine-1-carboxylic acid tert-butyl ester, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(3-piperidinyl)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(4-piperidinyl)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(1-methyl-3-piperidinyl)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(1-methyl-4-piperidinyl)imidazo[1,2-a]pyridin-3-yl]benzamide, 2-[3-[4-(3,3-difluoroazetidine-1-carbonyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]-2-methyl-propionitrile, 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-N-(2,2-difluoroethyl)-2-(difluoromethoxy)-6-methoxy-benzamide, 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-N-(2,2-difluoro-1-methyl-ethyl)-6-methoxy-benzamide, 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-N-isobutyl-6-methoxy-benzamide, 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-N-(1,1-dioxothietane-3-yl)-6-methoxy-benzamide, 2-[3-[4-(3-cyclopropyl-3-hydroxy-azetidine-1-carbonyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]-2-methyl-propionitrile, 2-[3-[3-(difluoromethoxy)-4-[3-hydroxy-3-(trifluoromethyl)azetidine-1-carbonyl]-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]-2-methyl-propionitrile, 2-[3-[3-(difluoromethoxy)-5-methoxy-4-[3-(trifluoromethyl)azetidine-1-carbonyl]phenyl]imidazo[1,2-a]pyridin-7-yl]-2-methyl-propionitrile, 1-[4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzoyl]azetidine-3-carbonitrile, 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-N-isopropyl-6-methoxy-benzamide, 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide, 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-N-(1-isopropylcyclopropyl)-6-methoxy-benzamide, 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-N-[1-(methoxymethyl)cyclopropyl]benzamide, 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-N-(cyclopropylmethyl)-2-(difluoromethoxy)-6-methoxy-N-methyl-benzamide, 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-N-(1-ethylcyclopropyl)-6-methoxy-benzamide, 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-N-methyl-benzamide, 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-N-(tetrahydrofuran-3-ylmethyl)benzamide, 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-N-tetrahydrofuran-3-yl-benzamide, 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-N-(1-cyclopropyl-2-hydroxy-ethyl)-2-(difluoromethoxy)-6-methoxy-benzamide, 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-N-(3,3-difluorocyclobutyl)-2-(difluoromethoxy)-6-methoxy-benzamide, 2-[3-[3-(difluoromethoxy)-4-(3-ethynyl-3-hydroxy-azetidine-1-carbonyl)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]-2-methyl-propionitrile, 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-N-(cyclobutylmethyl)-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(1-methylazetidin-3-yl)imidazo[1,2-a]pyridin-3-yl]benzamide, N-[(1S,2S)-2-aminocyclohexyl]-4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzamide, 4-[7-(2-amino-1,1-dimethyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, N-[1-[4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzoyl]azetidin-3-yl]carbamic acid tert-butyl ester, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-(6-tetrahydropyran-4-ylpyrazolo[1,5-a]pyrimidin-3-yl)benzamide, 2-[3-[3-(difluoromethoxy)-4-(3-fluoroazetidine-1-carbonyl)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]-2-methyl-propionitrile, 2-[3-[3-(difluoromethoxy)-4-[3-(hydroxymethyl)azetidine-1-carbonyl]-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]-2-methyl-propionitrile, 2-[3-[3-(difluoromethoxy)-5-methoxy-4-(3-methoxyazetidine-1-carbonyl)phenyl]imidazo[1,2-a]pyridin-7-yl]-2-methyl-propionitrile, 2-[3-[3-(difluoromethoxy)-5-methoxy-4-(6-methyl-2,6-diazaspiro[3.3]heptane-2-carbonyl)phenyl]imidazo[1,2-a]pyridin-7-yl]-2-methyl-propionitrile, 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-N-(1-cyclopropyl-2,2,2-trifluoro-ethyl)-2-(difluoromethoxy)-6-methoxy-benzamide, 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-N-(1-cyclopropylethyl)-2-(difluoromethoxy)-6-methoxy-benzamide, 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-N-(oxetan-3-ylmethyl)benzamide, 2-[3-[4-(3-aminoazetidine-1-carbonyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]-2-methyl-propionitrile, 2-[3-[3-(difluoromethoxy)-5-methoxy-4-(2-methylazetidine-1-carbonyl)phenyl]imidazo[1,2-a]pyridin-7-yl]-2-methyl-propionitrile, 2-[3-[3-(difluoromethoxy)-4-[2-(hydroxymethyl)azetidine-1-carbonyl]-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]-2-methyl-propionitrile, 4-[7-(1-amino-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 4-[7-(4-cyanotetrahydropyran-4-yl)imidazo[1,2-a]pyridin-3-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-(7-tetrahydropyran-4-ylimidazo[1,2-a]pyridin-3-yl)benzamide, 4-[7-(3-cyanoazetidin-3-yl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 2-[3-(7-methoxy-1-oxo-isoindolin-5-yl)imidazo[1,2-a]pyridin-7-yl]-2-methyl-propionitrile, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-(6-tetrahydropyran-4-ylpyrazolo[1,5-a]pyridin-3-yl)benzamide, 1-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]cyclopropanecarboxylic acid methyl ester, 1-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]cyclopropanecarboxylic acid, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[1-(hydroxymethyl)cyclopropyl]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, 4-[7-(4-cyanotetrahydropyran-4-yl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 4-[7-(3-cyanooxetane-3-yl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(1-methoxy-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]benzamide, 4-[7-(3-cyano-1-methyl-azetidin-3-yl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 4-[7-(1-acetyl-3-cyano-azetidin-3-yl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 4-[7-(3-cyanotetrahydrofuran-3-yl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-(1-ethyl-1-hydroxy-propyl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-(1-ethyl-1-methoxy-propyl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-(1-ethoxy-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]benzamide, 4-[7-(3-cyanooxetane-3-yl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide, 2-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]-2,2-difluoro-acetic acid methyl ester, 2-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]-2,2-difluoro-acetic acid, N-cyclopropyl-2-(difluoromethoxy)-4-[7-(1-fluoro-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-(1-hydroxy-1-tetrahydropyran-4-yl-ethyl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-(1-hydroxy-1,2-dimethyl-propyl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-4-[7-(1,1-difluoro-2-hydroxy-ethyl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-(1-hydroxy-1-methyl-propyl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-4-[7-(1-cyclopropyl-1-hydroxy-ethyl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(1-morpholinoethyl)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-(1-hydroxyethyl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[1-(morpholine-4-carbonyl)cyclopropyl]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[1-(2-methoxyethylcarbamoyl)cyclopropyl]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-4-[7-[1-(diethylcarbamoyl)cyclopropyl]imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[1-(3-hydroxyazetidine-1-carbonyl)cyclopropyl]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[1-(morpholinomethyl)cyclopropyl]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[1-(1-piperidinyl)ethyl]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[1-(2-hydroxyethylcarbamoyl)cyclopropyl]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-4-[7-[1-(diethylamino)ethyl]imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[1-(isopropylamino)ethyl]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-(2-hydroxy-1,1-dimethyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[1-[(isopropylamino)methyl]cyclopropyl]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[1-(2-oxa-6-azaspiro[3.3]heptane-6-yl)ethyl]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(1-pyrrolidin-1-ylethyl)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[1-[2-hydroxyethyl(methyl)amino]ethyl]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[1-(3-hydroxyazetidin-1-yl)ethyl]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-4-[7-[1-(3,3-difluoroazetidin-1-yl)ethyl]imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[1-[(2S)-2-(hydroxymethyl)morpholin-4-yl]ethyl]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, 4-(7-cyclobutylimidazo[1,2-a]pyridin-3-yl)-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-(1,1-dimethyl-2-morpholino-ethyl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-(4-hydroxytetrahydropyran-4-yl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(1-methylpyrrolidin-2-yl)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-(2-hydroxy-1,1-dimethyl-propyl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-(1-hydroxycyclobutyl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(oxetan-3-yl)imidazo[1,2-a]pyridin-3-yl]benzamide, 4-[7-(2-cyano-1-hydroxy-ethyl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 4-[7-(1-cyano-2-hydroxy-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-(3-hydroxyoxetane-3-yl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-(1-hydroxy-1-methyl-2-morpholino-ethyl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, 4-[7-(2-cyano-1-hydroxy-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 2-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]pyrrolidine-1-carboxylic acid tert-butyl ester, N-cyclopropyl-2-(difluoromethoxy)-4-[7-(1-hydroxy-2-imidazol-1-yl-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-(1-hydroxy-2-methoxy-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, 2-cyano-2-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]propionic acid methyl ester, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[1-hydroxy-1-methyl-2-(1-piperidinyl)ethyl]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, 3-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]morpholine-4-carboxylic acid tert-butyl ester, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-(7-morpholin-3-ylimidazo[1,2-a]pyridin-3-yl)benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-(7-pyrrolidin-2-ylimidazo[1,2-a]pyridin-3-yl)benzamide, N-cyclopropyl-4-[7-[2-(3,3-difluoroazetidin-1-yl)-1-hydroxy-1-methyl-ethyl]imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-(1-hydroxy-1-methyl-2-pyrazol-1-yl-ethyl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(4-methylmorpholin-3-yl)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[1-hydroxy-1-methyl-2-(1,2,4-triazol-1-yl)ethyl]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, 4-[7-(1-cyano-2-methoxy-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[1-(2-methoxyethyl)pyrrolidin-2-yl]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-(1-isopropylpyrrolidin-2-yl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, 4-[7-(1-acetylpyrrolidin-2-yl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 4-[7-[Cyclobutyl(hydroxy)methyl]imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-(2-hydroxy-1,1-dimethyl-butyl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-(2-hydroxy-1,1,3-trimethyl-butyl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, 4-[7-(azetidin-2-yl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(1-methylazetidin-2-yl)imidazo[1,2-a]pyridin-3-yl]benzamide, 2-(Difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-4-[7-(1-hydroxycyclobutyl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, 2-(difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-4-[7-(oxetane-3-yl)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-(3-fluorooxetane-3-yl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, 4-[6-(1-cyano-1-methyl-ethyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[1-hydroxy-2-[2-hydroxyethyl(methyl)amino]-1-methyl-ethyl]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-(2,4-dimethylmorpholin-2-yl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, 2-(Difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-4-[7-(1-hydroxy-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(3-methoxyoxetane-3-yl)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-(3-hydroxytetrahydrofuran-3-yl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, 2-(difluoromethoxy)-4-[7-(2,4-dimethylmorpholin-2-yl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-N-(2,2,2-trifluoroethyl)benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[6-(oxetan-3-yl)pyrazolo[1,5-a]pyridin-3-yl]benzamide, 4-[7-(3-chlorooxetane-3-yl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 2-(difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-4-[6-(oxetan-3-yl)pyrazolo[1,5-a]pyridin-3-yl]benzamide, 4-[6-(1-cyano-1-methyl-ethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-(difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(2-methyl-1,4-dioxane-2-yl)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(3-morpholinooxetane-3-yl)imidazo[1,2-a]pyridin-3-yl]benzamide, 2-(Difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-4-[7-(3-hydroxyoxetane-3-yl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, 2-(Difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-4-[7-(3-fluorooxetane-3-yl)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-N-(2-fluorocyclopropyl)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(1-methyl-1-morpholino-ethyl)imidazo[1,2-a]pyridin-3-yl]benzamide, 2-(Difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-4-[6-(1-hydroxy-1-methyl-ethyl)pyrazolo[1,5-a]pyridin-3-yl]-6-methoxy-benzamide, 4-[7-(1-cyano-1-methyl-ethyl)imidazo[1,2-b]pyridazin-3-yl]-2-(difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[1-methyl-1-(oxetan-2-yl)ethyl]imidazo[1,2-a]pyridin-3-yl]benzamide, 4-[7-[1-cyano-2,2,2-trideuterio-1-(trideuteriomethyl)ethyl]imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 4-[6-(1-cyano-1-methyl-ethyl)pyrazolo[1,5-a]pyrimidin-3-yl]-2-(difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[6-(1,4-dioxane-2-yl)pyrazolo[1,5-a]pyridin-3-yl]-6-methoxy-benzamide, 4-[6-(1-cyano-1-methyl-ethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-(difluoromethoxy)-N-(2-fluorocyclopropyl)-6-methoxy-benzamide, 4-[6-(1-cyano-1-methyl-ethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-(difluoromethoxy)-N-[(1S,2R)-2-fluorocyclopropyl]-6-methoxy-benzamide, 4-[6-(1-cyanocyclopropyl)pyrazolo[1,5-a]pyridin-3-yl]-2-(difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[6-(2-hydroxy-1,1-dimethyl-ethyl)pyrazolo[1,5-a]pyridin-3-yl]-6-methoxy-benzamide, 4-[6-(4-cyanotetrahydropyran-4-yl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[6-(2-methoxy-1,1-dimethyl-ethyl)pyrazolo[1,5-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[6-[1-(2-hydroxyethoxy)-1-methyl-ethyl]pyrazolo[1,5-a]pyridin-3-yl]-6-methoxy-benzamide, 2-(Difluoromethoxy)-4-[6-(1,4-dioxane-2-yl)pyrazolo[1,5-a]pyridin-3-yl]-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide, 2-(Difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-4-[6-(2-hydroxy-1,1-dimethyl-ethyl)pyrazolo[1,5-a]pyridin-3-yl]-6-methoxy-benzamide, 4-[6-(4-cyanotetrahydropyran-4-yl)pyrazolo[1,5-a]pyridin-3-yl]-2-(difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide, 4-[6-(2-amino-1,1-dimethyl-2-oxo-ethyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 4-[6-(1-cyano-1-methyl-ethyl)pyrazolo[1,5-a]pyridin-3-yl]-N-[(1R,2S)-2-fluorocyclopropyl]-2,6-dimethoxy-benzamide, 2-(Difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-4-[6-(1-methyl-1-methylsulfonyl-ethyl)pyrazolo[1,5-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[6-[1-methyl-1-(5-methyl-1,2,4-oxadiazol-3-yl)ethyl]pyrazolo[1,5-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[6-[1-methyl-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]pyrazolo[1,5-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[6-[2-(ethylamino)-1,1-dimethyl-2-oxo-ethyl]pyrazolo[1,5-a]pyridin-3-yl]-6-methoxy-benzamide, and 4-[6-(1-cyanocyclobutyl)pyrazolo[1,5-a]pyridin-3-yl]-2-(difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide, 2-(Difluoromethoxy)-4-[6-[2-[2-(dimethylamino)-2-oxo-ethoxy]-1,1-dimethyl-ethyl]pyrazolo[1,5-a]pyridin-3-yl]-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide, 4-[6-(1-cyano-1-methyl-ethyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropyl-2-fluoro-6-methoxy-benzamide, 2-(Difluoromethoxy)-4-[6-[1,1-dimethyl-2-[2-(methylamino)-2-oxo-ethoxy]ethyl]pyrazolo[1,5-a]pyridin-3-yl]-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide, 4-[6-(1-Carbamoylcyclobutyl)pyrazolo[1,5-a]pyridin-3-yl]-2-(difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide, 2-(difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-4-[6-[1-methyl-1-(2-morpholinoethoxy)ethyl]pyrazolo[1,5-a]pyridin-3-yl]benzamide, 4-[6-(1-amino-1-methyl-ethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-(difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide, 4-[6-(1-cyano-1-methyl-ethyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropyl-2,6-dimethoxy-benzamide, 4-[6-(1-cyano-1-methyl-ethyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropyl-2-methoxy-6-(2-methoxyethoxy)benzamide, 4-[6-(1-aminocyclobutyl)pyrazolo[1,5-a]pyridin-3-yl]-2-(difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide, 2-(Difluoromethoxy)-4-[6-[1,1-dimethyl-2-(oxetan-3-ylmethoxy)ethyl]pyrazolo[1,5-a]pyridin-3-yl]-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide, 4-[6-(1-cyano-1-methyl-ethyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropyl-2-(2-hydroxyethoxy)-6-methoxy-benzamide, Butyl N-[1-[3-[3-(difluoromethoxy)-4-[[(1R,2S)-2-fluorocyclopropyl]carbamoyl]-5-methoxy-phenyl]pyrazolo[1,5-a]pyridin-6-yl]-1-methyl-ethyl]carbamate, 2-(Difluoromethoxy)-4-[6-[1,1-dimethyl-2-(oxetan-3-yloxy)ethyl]pyrazolo[1,5-a]pyridin-3-yl]-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide, 2-(Difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-4-[6-(1-hydroxycyclobutyl)pyrazolo[1,5-a]pyridin-3-yl]-6-methoxy-benzamide, [2-[3-[3-(difluoromethoxy)-4-[[(1R,2S)-2-fluorocyclopropyl]carbamoyl]-5-methoxy-phenyl]pyrazolo[1,5-a]pyridin-6-yl]-2-methyl-propyl]methanesulfonate, 2-(Difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-4-[6-[1-(2-hydroxyethylamino)-1-methyl-ethyl]pyrazolo[1,5-a]pyridin-3-yl]-6-methoxy-benzamide, 2-(Difluoromethoxy)-4-[6-(1,1-dimethyl-2-morpholino-ethyl)pyrazolo[1,5-a]pyridin-3-yl]-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide, 4-[6-[1-(Cyanomethylamino)cyclobutyl]pyrazolo[1,5-a]pyridin-3-yl]-2-(difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide, 4-[6-[1-(2,2-difluoroethylamino)cyclobutyl]pyrazolo[1,5-a]pyridin-3-yl]-2-(difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide, Methyl N-[1-[3-[3-(difluoromethoxy)-4-[[(1R,2S)-2-fluorocyclopropyl]carbamoyl]-5-methoxy-phenyl]pyrazolo[1,5-a]pyridin-6-yl]cyclobutyl]carbamate, 2-(Difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-4-[6-[1-(methylcarbamoyl)cyclobutyl]pyrazolo[1,5-a]pyridin-3-yl]benzamide, 2-(difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-4-[6-[1-(morpholine-4-carbonyl)cyclobutyl]pyrazolo[1,5-a]pyridin-3-yl]benzamide, 4-[6-[1-cyano-2,2,2-trideutero-1-(trideuteromethyl)ethyl]pyrazolo[1,5-a]pyridin-3-yl]-2-(difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide, or 4-[6-[2-(Diethylamino)-1,1-dimethyl-ethyl]pyrazolo[1,5-a]pyridin-3-yl]-2-(difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide.

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