RU2782375C2 - New compounds and their pharmaceutical compositions for treatment of diseases - Google Patents

Abstract

FIELD: biotechnology.

SUBSTANCE: invention relates to compounds corresponding to the formula I, which have the capability of inhibiting salt-inducible kinases (SIK kinases). In the formula I, X is N or CR⁴; one of Y¹, Y², and Y³ is N, and the other two are C; Z is -NR^5aR^5b, -NR^5c-, where atom N and R^3b, together with atoms, to which they are attached, form condensed 5-6-element heterocycloalkenyl including one double bond and including, in addition, zero, one, or two additional heteroatoms independently selected from N, O, and S, or N-bound 4-7-element heterocycloalkyl, in addition including zero, one, or two additional heteroatoms independently selected from N, O, and S, optionally substituted with one, two, or three groups R⁶; R¹ is H, halogen, C_1-4 alkyl, or C_1-4 alkoxy optionally substituted with C_1-4 alkoxy, phenyl, -CN, -C(=O)OH, or -C(=O)-C_1-4 alkoxy; R² is imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, each of which is optionally substituted with one or more independently selected groups R⁷; R^3a and R^3b are independently selected from halogen, C_1-4 alkyl, C_1-4 alkoxy optionally substituted with one or more selected halogen, -OH, or C_1-4 alkoxy, -NR^8aR^8b, and -OH; R⁴ is H; R^5a is H or C_1-4 alkyl; R^5b is selected from C_1-6 alkyl optionally substituted with one or more selected R⁹, C_3-7 cycloalkyl optionally substituted with one or more selected R¹⁰, etc.; R^5c is selected from C_3-7 cycloalkyl and C_1-6 alkyl optionally substituted with one or more independently selected halogen; each R⁶ is independently selected from oxo, halogen, -CN, -OH, -NR^11aR^11b, phenyl, etc.; each R⁷ is selected from halogen, -CN, C_1-6 alkyl, etc.; each R^8a and R^8b are independently selected from H and C_1-4 alkyl; each R⁹ is independently selected from halogen, -CN, -NR^11eR^11f, -OH, C_1-4 alkoxy, etc.; each R¹⁰ is independently selected from halogen, C_1-4 alkyl, -OH, etc.; each R^11a, R^11b, R^11c, R^11d, R^11e, R^11f, R^11g, and R^11h is independently selected from H and C_1-4 alkyl; each R¹² is -NR^14aR^14b, where each R^14a and R^14b are independently selected from H, C_1-4 alkyl, -OH, C_1-4 alkoxy, etc.; each R^13a, R^13b, R^13c, and R^13d are independently selected from H and C_1-4 alkyl; each R^15a and R^15b are independently selected from H and C_1-4 alkyl. The invention also relates to a pharmaceutical composition including the specified compounds.

EFFECT: obtaining new compounds and a pharmaceutical composition based on them for the treatment of diseases.

I

15 cl, 1 dwg, 11 tbl, 4 ex

Description

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

[0001] The present invention relates to compounds, to methods for preparing compounds of the invention, to pharmaceutical compositions comprising compounds of the invention, to uses and methods for the prevention and/or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, rejection in transplantation, diseases related to impaired cartilage renewal, congenital cartilage defects, diseases related to impaired bone remodeling, diseases associated with hypersecretion of TNFα, interferons, IL-6, IL-12 and/or IL-23, respiratory diseases, endocrine and/or metabolic diseases, cardiovascular diseases, dermatological diseases and/or diseases associated with abnormal angiogenesis by administering the compounds of the invention. In particular, the compounds of the invention can inhibit salt-inducible kinases ("SIK" kinases).

BACKGROUND OF THE INVENTION

[0002] Protein kinases belong to a large family of structurally related enzymes that are responsible for controlling a wide range of cellular signaling processes. In particular, they have been shown to be key regulators of cellular functions including, for example, proliferation, metabolism and apoptosis. And therefore, impaired control of protein phosphorylation, which leads to uncontrolled signaling, is associated with a number of diseases, including, for example, inflammation, allergies, cancer, autoimmune diseases, disorders of the central nervous system (CNS), angiogenesis.

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

[0004] Indeed, in the normal process of inflammation in the body, an initial pro-inflammatory response is followed by a pro-resolution response that turns off inflammation after removal of the damaging factor, resulting in a decrease in pro-inflammatory cytokines such as TNFα and IL-12, combined with an increase in anti-inflammatory levels. cytokines such as IL-10 and TGF-β, which leads to the formation of the so-called tolerogenic environment.

[0005] Adenosine monophosphate-activated protein kinases (AMPKs) belong to the protein kinase family, which includes salt-inducible kinases (SIKs), a family of serine/threonine kinases widely expressed in the body and involved in particular in energy homeostasis in cells. Three isoforms of SIK have been identified, termed SIK1 (also referred to as SNFI-like kinase (SNF1LK) or myocardial Snfl-like kinase (MSK)), SIK2 (SNF1LK2 or KIAA0781), and SIK3 (KIAA0999) (Katoh et al. 2004).

[0006] SIKs have been found to perform a number of specific functions in different cell types associated with the phosphorylation of a number of substrates, including CREB-sensitive transcription coactivator (CRTC) proteins, as well as histone deacetylase (HDAC) proteins, thereby regulating the transcription of a number of different genes. One function of CRTC signaling relates to the control of macrophage phenotype, specifically macrophage polarization resulting from CRTC3 phosphorylation, as measured by decreased secretion of the pro-inflammatory cytokine IL-12 and concomitant increase in secretion of the pro-permissive cytokine IL-10 (Clark et al. 2012; Ozanne et al. 2015).

[0007] SIK1 has recently been shown to affect skeletal muscle sensitivity in obese mice and may be a promising target for the prevention of type II diabetes (Nixon et al. 2016) and diabetic nephropathy (Yu et al. 2013).

[0008] SIK2 and SIK3 have recently been shown to play a role in inflammation through the secretion of high levels of anti-inflammatory cytokines, particularly interleukin-10 (IL-10), and very low levels of pro-inflammatory cytokines, such as TNF-α (Darling et al. 2017).

[0009] Recently, the involvement of SIK2 in T helper 1 (Th1) differentiation through the regulation of IFNγ and IL-12 signaling has been described, suggesting that SIK2 may be a promising target in inflammatory diseases (Yao et al. 2013).

[0010] It has also recently been shown that, like parathyroid hormone (PTH), small molecule inhibitors of SIK cause a decrease in phosphorylation and an increase in HDAC4/5 and CRTC2 nuclear translocation. Treatment with the small molecule SIK inhibitor YKL-05-099 resulted in increased bone formation and bone mass in mice (Web et al. 2016), suggesting that SIK inhibition could be useful in the treatment of bone remodeling diseases.

[0011] In addition, inhibition of SIK2 after oxygen-glucose deprivation has been shown to increase neuronal survival (Sasaki et al. 2011) or promote melanogenesis in melanoma cells (Kumagai et al. 2011). In this case, since appropriate therapeutic strategies are needed to modulate the cellular response to stress, for example, during ischemia and after tissue reperfusion, in the chronic phase of myocardial remodeling, in diabetes and neurodegenerative conditions, the rapid activation or degradation of SIK proteins after many different species stress makes them promising targets for inflammatory, cardiac or metabolic diseases and neurodegenerative disorders. SIK inhibition can also be used in cosmetic or pigmentation-related diseases to induce melanogenesis.

[0012] The regulation of ALK5 by SIK1 (Yu et al. 2013) and the identification of the SIK2 gene as a risk locus for the occurrence of primary sclerosing cholangitis (Liu et al. 2013) suggest the involvement of SIK proteins in fibrotic diseases.

[0013] In addition to the central function in energy homeostasis in cells, SIK proteins are also involved in the regulation of the cell cycle. Higher SIK2 expression significantly correlated with poor survival in patients with high-grade serous ovarian cancer (Ashour Ahmed et al. 2010), moreover, SIK3 expression was increased in ovarian cancer types, especially in the serous subtype and at later stages (Charoenfuprasert et al. . 2011)). Therefore, SIK inhibition can be used in the treatment of cancer.

[0014] Despite significant advances over the past two decades in the treatment of patients suffering from autoimmune disorders through the use of antibodies that target pro-inflammatory cytokines such as anti-TNFα, nevertheless, a significant proportion of patients do not respond to these treatments or exposed to serious side effects such as opportunistic infections. Therefore, there is still a large unmet need in medicine for new approaches in the treatment of these diseases and new drugs are required for the prevention and/or treatment of the diseases mentioned above.

DESCRIPTION OF THE DRAWINGS

Figure 1, which refers to example 4.2, graphically presents data on the change in clinical score in an experimental model of collagen-induced arthritis (CIA) in mice in the case of placebo (solid diamonds), Enbrel (solid squares), Cpd 53 at a dose of 2 mg/kg (solid triangles), Cpd 53 at a dose of 5 mg/kg (crosses) and Cpd 53 at a dose of 30 mg/kg (asterisks) [x-axis: protocol day, y-axis: clinical score].

SUMMARY OF THE INVENTION

[0015] The present invention is based on the discovery of new compounds and their use for the prevention and/or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases related to impaired cartilage renewal, cartilage congenital defect, diseases related to impaired bone remodeling, diseases associated with hypersecretion of TNFα, interferons, IL-6, IL-12 and/or IL-23, respiratory diseases, endocrine and/or metabolic diseases, cardiovascular diseases, dermatological diseases, and /or diseases associated with abnormal angiogenesis. In particular, the compounds of the invention may be SIK inhibitors, and more particularly SIK1, SIK2 and/or SIK3 inhibitors. The present invention also provides methods for the preparation of these compounds, pharmaceutical compositions comprising these compounds, and methods for the prevention and/or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases related to impaired cartilage renewal. , congenital cartilage defect, diseases related to impaired bone remodeling, diseases associated with hypersecretion of TNFα, interferons, IL-6, IL-12 and/or IL-23, respiratory diseases, endocrine and/or metabolic diseases, cardiovascular diseases , dermatological diseases, and/or diseases associated with abnormal angiogenesis by administering the compounds of the invention.

[0016] Accordingly, in a first aspect of the invention, there are provided compounds of the invention having formula (I):

I

where

X is N or CR ⁴ ;

one of Y ₁ , Y ₂ and Y ₃ is N and the other two are C;

Z represents

- -NR ^5a R ^5b ,

- -NR ^5c -, where the atom N and R ^3b together with the atoms to which they are attached, form a fused 5-6-membered heterocycloalkenyl, including one double bond and including, in addition, zero, one or two additional heteroatoms, independently selected from N, O and S, or

N-linked 4-7 membered heterocycloalkyl further comprising zero, one or two additional heteroatoms independently selected from N, O and S, optionally substituted with one, two or three R ⁶ groups;

R ¹ is H, halogen, C _1-4 alkyl or C _1-4 alkoxy optionally substituted with C _1-4 alkoxy, phenyl, -CN, -C(=O)OH or -C(=O)- C _1-4 alkoxy;

R ² is a 5-6 membered monocyclic heteroaryl containing one, two or three heteroatoms independently selected from N, O and S, where the heteroaryl is optionally substituted with one or more independently selected R ⁷ groups;

R ^3a and R ^3b are independently selected from

- halogen,

- C _1-4 alkyl,

- C _1-4 alkoxy optionally substituted with one or more selected halo, -OH or C _1-4 alkoxy,

- -NR ^8a R ^8b , and

- -OH;

R ⁴ is H or C _1-4 alkyl;

R ^5a is H or C _1-4 alkyl;

R ^5b choose from

- C _1-6 alkyl, optionally substituted with one or more selected R ⁹ ,

- C _3-7 cycloalkyl, optionally substituted with one or more selected R ¹⁰ ,

- 4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O and S, where the heterocycloalkyl is optionally substituted with one or more oxo, and

- 5-6-membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O and S, where the heteroaryl is optionally substituted with one or more independently selected C _1-4 alkyl;

R ^5c is selected from C _3-7 cycloalkyl and C _1-6 alkyl optionally substituted with one or more independently selected halo;

each R ⁶ is independently selected from

- oxo,

- halogen,

- -CN,

- -OH,

- -NR ^11a R ^11b ,

- phenyl,

- C _3-7 cycloalkyl,

- C _2-4 alkynyl,

- -C(=O)-C _1-4 alkoxy,

- C _1-4 alkoxy, optionally substituted with one or more halo or phenyl,

- C _1-4 alkyl optionally substituted with one or more halo, -OH or C _1-4 alkoxy, and

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

each R ⁷ choose from

- halogen,

- -CN,

- C _1-6 alkyl optionally substituted with one or more independently selected

halogen,

-CN,

-OH,

C _1-4 alkoxy optionally substituted with one or more selected halo,

-NR ^11c R ^11d ,

-C(=O)R ¹² , or

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

- C _1-4 alkoxy,

- C _3-7 cycloalkyl,

- 4-6-membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O and S, where heterocycloalkyl is optionally substituted with -C(=O)C _1-4 alkoxy or C _1-4 alkyl, optionally substituted with -CN,

- -NR ^13a R ^13b , and

- -C(=O)NR ^13c R ^13d ;

each R ^8a and R ^8b is independently selected from H and C _1-4 alkyl optionally substituted with one -OH or C _1-4 alkoxy;

each R ⁹ is independently selected from

- halogen,

- -CN,

- -NR ^11e R ^11f ,

- -OH,

- C _1-4 alkoxy,

- -S(=O) ₂ -C _1-4 alkyl,

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

- 5-6-membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O and S, where the heteroaryl is optionally substituted with one or more independently selected C _1-4 alkyl;

each R ¹⁰ is independently selected from

- halogen,

- C _1-4 alkyl optionally substituted with one or more independently selected halo, -OH or C _1-4 alkoxy,

- -OH,

- C _1-4 alkoxy, and

- -NR ^11g R ^11h ;

each R ^11a , R ^11b , R ^11c , R ^11d , R ^11e , R ^11f , R ^11g , and R ^{11h is} independently selected from H and C _1-4 alkyl;

each R ¹² represents

- -NR ^14a R ^14b , where each R ^14a and R ^14b are independently selected from H and C _1-4 alkyl,

- -OH,

- C _1-4 alkoxy optionally substituted with one or more selected C _3-7 cycloalkyl, halogen, -NR ^15a R ^15b or 4-6 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S

- -O- (4-6-membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S), or

- -O-(C _3-7 monocyclic cycloalkyl);

every R^13a, R^13b, R^13c, and R^13d independently choose from H and C_1-4 alkyl;

each R ^15a and R ^15b is independently selected from H and C _1-4 alkyl.

[0017] In a specific aspect, the compounds of the invention are provided for use in the prevention and/or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases related to impaired cartilage renewal, cartilage congenital defect, diseases related to impaired bone remodeling, diseases associated with hypersecretion of TNFα, interferons, IL-6, IL-12 and/or IL-23, respiratory diseases, endocrine and/or metabolic diseases, cardiovascular diseases, dermatological diseases, and /or diseases associated with abnormal angiogenesis.

[0018] In addition, the compounds of the invention were unexpectedly found to exhibit activity against the SIK family of kinases, resulting in a tolerogenic therapy (i.e., achieving a reduction in pro-inflammatory cytokines such as TNFα and IL-12, in combination with increased levels of anti-inflammatory cytokines such as IL-10 and TGF-β).

[0019] In a further aspect, the present invention provides pharmaceutical compositions comprising a compound of the invention and a pharmaceutical carrier, excipient or diluent. In a particular aspect, the pharmaceutical composition may further comprise therapeutically active ingredients suitable for use in combination with the compounds of the invention. In a more specific aspect, the additional therapeutically active ingredient is an agent for the treatment of inflammatory diseases, auto-inflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases related to impaired cartilage renewal, congenital defect of cartilage, diseases related to disorders bone remodeling, diseases associated with hypersecretion of TNFα, interferons, IL-6, IL-12 and/or IL-23, respiratory diseases, endocrine and/or metabolic diseases, cardiovascular diseases, dermatological diseases, and/or diseases associated with abnormal angiogenesis.

[0020] Moreover, the compounds of the invention used in the pharmaceutical compositions and methods of treatment described herein are pharmaceutically acceptable in terms of their preparation and use.

[0021] In a further aspect of the invention, this invention provides a method of treating a mammal, in particular humans, suffering from a disease selected from the diseases listed in the invention, and in particular inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases related to impaired cartilage renewal, congenital cartilage defect, diseases related to impaired bone remodeling, diseases associated with hypersecretion of TNFα, interferons, IL-6, IL-12 and/or IL-23, respiratory diseases, endocrine and/or metabolic diseases, cardiovascular diseases, dermatological diseases, and/or diseases associated with abnormal angiogenesis, where the method includes administering an effective amount of the pharmaceutical composition or compounds of the invention described in the invention.

[0022] The present invention also provides pharmaceutical compositions comprising a compound of the invention and a suitable pharmaceutical carrier, excipient or diluent for use in medicine. In a specific aspect, the pharmaceutical composition is used for the prevention and/or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases related to impaired cartilage renewal, congenital cartilage defect, diseases related to impaired remodeling. bone, diseases associated with hypersecretion of TNFα, interferons, IL-6, IL-12 and/or IL-23, respiratory diseases, endocrine and/or metabolic diseases, cardiovascular diseases, dermatological diseases, and/or diseases associated with abnormal angiogenesis.

[0023] In additional aspects, this invention provides methods for the synthesis of compounds according to the invention with typical schemes and directions of synthesis described in the invention below.

[0024] Other objects and advantages of the invention will become apparent to those skilled in the art upon reading the following detailed description of the invention.

[0025] It should be borne in mind that the compounds of the invention can be metabolized to form biologically active metabolites.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

[0026] The following terms are intended to have the meanings given below and are used to facilitate understanding of the description and intended scope of the present invention.

[0027] When describing the invention, which may include compounds, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions, the following terms, if present, have the following meanings, unless otherwise indicated. It should also be understood that where any moieties defined below are described herein, they may be substituted with various substituents, and the respective definitions are intended to include such substituted moieties as described below. Unless otherwise specified, the term "substituted" shall be defined as described below. In addition, it should be borne in mind that when used in the invention, the terms "groups" and "radicals", these terms can be considered interchangeable.

[0028] The singular form may be used in the invention to refer to one or more than one (i.e., at least one) grammatical subject. For example, "analogue" means one analogue or more than one analogue.

[0029] "Alkyl" means a linear or branched aliphatic hydrocarbon having the indicated number of carbon atoms. Particular alkyl groups have 1 to 6 carbon atoms or 1 to 4 carbon atoms. "Branched" means that one or more alkyl groups such as methyl, ethyl or propyl are attached to a straight alkyl chain. Specific alkyl groups are methyl (-CH ₃ ), ethyl (-CH ₂ -CH ₃ ), n-propyl (-CH ₂ -CH ₂ -CH ₃ ), isopropyl (-CH(CH ₃ ) ₂ ), n- butyl (-CH ₂ -CH ₂ -CH ₂ -CH ₃ ), tert-butyl (-CH ₂ -C(CH ₃ ) ₃ ), sec-butyl (-CH ₂ -CH(CH ₃ ) ₂ ), n-pentyl (-CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₃ ), n-hexyl (-CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₃ ) and 1,2-dimethylbutyl (-CHCH ₃ )- C(CH ₃ )H ₂ -CH ₂ -CH ₃ ). Specific alkyl groups have 1 to 4 carbon atoms.

[0030] "Alkenyl" refers to monovalent olefinic (unsaturated) hydrocarbon groups with the specified number of carbon atoms. Particular alkenyls have from 2 to 8 carbon atoms, and more specifically from 2 to 6 carbon atoms, which may form a straight or branched chain and have at least 1 and, in particular, from 1 to 2 sites of olefinic unsaturation. Specific alkenyl groups include ethenyl (-CH=CH ₂ ), n-propenyl (-CH ₂ CH=CH ₂ ), isopropenyl (-C(CH ₃ )=CH ₂ ) and other such alkenyls.

[0031] "Alkylene" refers to divalent alkene radical groups having the indicated number of carbon atoms, in particular having from 1 to 6 carbon atoms, and more specifically from 1 to 4 carbon atoms, which may form a straight or branched chain. Examples of this term are groups such as methylene (-CH ₂ -), ethylene (-CH ₂ -CH ₂ -) or -CH(CH ₃ )- and other similar groups.

[0032] "Alkynylene" refers to divalent alkyne radical groups having the specified number of carbon atoms and the specified number of triple bonds, in particular from 2 to 6 carbon atoms, and more specifically from 2 to 4 carbon atoms, which can form a linear or branched chain. Examples of this term are groups such as -C≡C-, -CH ₂ -C≡C- and -C(CH ₃ )HC≡CH-.

[0033] "Alkoxy" refers to an O-alkyl group, where the alkyl group has the indicated number of carbon atoms. In particular, the term refers to the group -OC _1-6 alkyl. Specific alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentoxy, n-hexoxy and 1,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy, ie containing from 1 to 6 carbon atoms. In addition, specific alkoxy groups have from 1 to 4 carbon atoms.

[0034] "Amino" refers to the radical-NH ₂ .

[0035] "Aryl" refers to a monovalent aromatic hydrocarbon group formed by the removal of one hydrogen atom from one carbon atom of the original aromatic ring system. In particular, aryl refers to an aromatic ring structure, monocyclic or fused polycyclic, with the specified number of ring atoms. In particular, the term includes groups that contain from 6 to 10 ring atoms. Specific aryl groups include phenyl and naphthyl.

[0036] "Cycloalkyl" refers to a non-aromatic hydrocarbyl ring structure, monocyclic, fused polycyclic, bridged polycyclic, or spirocyclic, with the specified number of ring atoms. Cycloalkyl may have 3 to 12 carbon atoms, in particular 3 to 10, and more specifically 3 to 7 carbon atoms. Such cycloalkyl groups include, for example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[0037] "Cyano" refers to the -CN radical.

[0038] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). Specific halogen groups are either fluorine or chlorine.

[0039] "Hetero", when used to describe a compound or a group present in a compound, means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. The term "hetero" can be applied to any of the hydrocarbyl groups described above, such as alkyl, eg heteroalkyl, cycloalkyl, eg heterocycloalkyl, aryl, eg heteroaryl, and other similar groups having 1 to 4, and in particular , from 1 to 3 heteroatoms, more often 1 or 2 heteroatoms, for example, only one heteroatom.

[0040] "Heteroaryl" means an aromatic ring structure, monocyclic or fused polycyclic, which includes one or more heteroatoms independently selected from O, N, and S, and the number of ring atoms indicated. In particular, an aromatic ring structure may have 5 to 9 ring atoms. The heteroaryl group may be, for example, a five-membered or six-membered monocyclic ring or a fused bicyclic structure formed from fused five-membered and six-membered rings or two fused six-membered rings, or, as another example, two fused five-membered rings. Each ring may contain up to four heteroatoms, usually selected from nitrogen, sulfur and oxygen. Typically, a heteroaryl ring may contain up to 4 heteroatoms, more typically up to 3 heteroatoms, most commonly up to 2 heteroatoms, eg only one heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in heteroaryl rings may be basic, as in the case of imidazole or pyridine, or substantially non-basic, as in the case of indole or pyrrole. Typically, the number of nitrogen atoms having basic properties that are present in a heteroaryl group including any substituents from the amino group in the ring will be less than five.

[0041] Examples of five-membered monocyclic heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl groups.

[0042] Examples of six-membered monocyclic heteroaryl groups include, but are not limited to, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl.

[0043] 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.

[0044] 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, isobenzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, pudolisinyl (eg adenine, guanine), indazolyl, pyrazolopyrimidinyl, triazolopyrimidinyl and pyrazolopyridinyl groups.

[0045] Specific examples of bicyclic heteroaryl groups containing two fused six-membered rings include, but are not limited to, quinolinyl, isoquinolinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl groups. Particular heteroaryl groups are those derived from thiophenyl, pyrrolyl, benzothiophenyl, benzofuranyl, indolyl, pyridinyl, quinolinyl, imidazolyl, oxazolyl and pyrazinyl.

[0046] Exemplary heteroaryls include the following compounds:

[0047] where each Y is selected from >C=O, NH, O and S.

[0048] "Heterocycloalkyl" means a non-aromatic fully saturated ring structure, monocyclic, fused polycyclic, spirocyclic, or bridged polycyclic, which includes 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 atoms, in particular 4 to 10 ring atoms, and more specifically 4 to 7 ring atoms. Each ring may contain up to four heteroatoms, usually selected from nitrogen, sulfur and oxygen. Typically, a heterocycloalkyl ring may contain up to 4 heteroatoms, more typically up to 3 heteroatoms, most commonly up to 2 heteroatoms, eg only one heteroatom. Examples of heterocyclic rings include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl (for example 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), tetrahydrofuranyl (for example 1-tetrahydro-furanyl, 2-tetrahydrofuranyl and 3-tetrahydrofuranyl), tetrahydrothiophenyl (eg 1-tetrahydrothiophenyl, 2-tetrahydro-thiophenyl and 3-tetrahydrothiophenyl), piperidinyl (eg 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), tetrahydropyranyl (eg 4-tetrahydropyranyl), tetrahydrothiopyranyl (eg 4 -tetrahydrothiopyranil), morpholinyl, thiomorpholinyl, dioxanil or piperazinil.

[0049] As used herein, the term "heterocycloalkenyl" means "heterocycloalkyl" which includes at least one double bond. Specific examples of heterocycloalkenyl groups are shown in the following illustrative examples:

[0050] where each W is selected from CH ₂ , NH, O and S; each Y is selected from NH, O, C(=O), SO ₂ and S; and each Z is selected from N or CH.

[0051] Specific examples of monocyclic rings are shown in the following illustrative examples:

[0052] where each W and Y is independently selected from -CH ₂ -, -NH-, -O- and -S-.

[0053] Specific examples of fused bicyclic rings are shown in the following illustrative examples:

[0054] where each W and Y are independently selected from -CH ₂ -, -NH-, -O- and -S-.

[0055] Specific examples of bridged bicyclic rings are shown in the following illustrative examples:

[0056] where each W and Y is independently selected from -CH ₂ -, -NH-, -O- and -S-.

[0057] Specific examples of spirocyclic rings are shown in the following illustrative examples:

[0058] where each Y is selected from -CH ₂ -, -NH-, -O- and -S-.

[0059] "Hydroxy" refers to the -OH radical.

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

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

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

[0063] "thiol" refers to the -SH group.

[0064] As used herein, the term "substituted with one or more" refers to one to four substituents. In one embodiment, the term refers to one to three substituents. In additional embodiments, the term refers to one or two substituents. In yet another embodiment, the term refers to one substituent.

[0065] "Thioalkoxy" refers to a -S-alkyl group, where the alkyl group has the indicated number of carbon atoms. In particular, this term refers to the group -SC _1-6 alkyl. Specific thioalkoxy groups are thiomethoxy, thioethoxy, n-thiopropoxy, isothiopropoxy, n-thiobutoxy, tertthiobutoxy, sec-thiobutoxy, n-thiopentoxy, n-thiohexoxy, and 1,2-dimethylthiobutoxy. Particular thioalkoxy groups are lower thioalkoxy, ie containing from 1 to 6 carbon atoms. In addition, specific alkoxy groups have from 1 to 4 carbon atoms.

[0066] It is apparent to any one of ordinary skill in the art of organic synthesis that the maximum number of heteroatoms in a stable, chemically feasible heterocyclic ring, whether aromatic or non-aromatic, is determined by ring size, degree of unsaturation, and valence of the heteroatoms. Typically, a heterocyclic ring may have from one to four heteroatoms, provided that the heteroaromatic ring can be synthesized and is stable.

[0067] A "pharmaceutically acceptable" substance is a substance that is authorized or approved by a federal or state regulatory agency in the United States or by an appropriate agency in other countries, or that is listed in the United States Pharmacopeia or other generally recognized pharmacopoeias, for clinical use in animals. and more specifically, in humans.

[0068] A "pharmaceutically acceptable salt" refers to a salt of a compound of the invention that is pharmaceutically acceptable and that has the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and may be inorganic 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, and other such inorganic acids; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentane propionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2,2.2]-oct-2-en-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, laurylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and other similar organic acids; or (2) salts formed when an acidic proton present in the parent compound is either replaced by a metal ion, such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and other similar organic bases. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium salts, and the like; and in the case where the compound contains a basic functionality, non-toxic organic or inorganic acid salts such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. The term "pharmaceutically acceptable cation" refers to an acceptable cationic counterion of an acid functional group. Examples of such cations are sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium and the like.

[0069] A "pharmaceutically acceptable medium" refers to a diluent, excipient, excipient, or carrier with which a compound of the invention is administered.

[0070] "Prodrugs" refers to compounds comprising derivatives of compounds of the invention that have cleavable groups and are converted by solvolysis or exposure to physiological conditions into compounds of the invention that are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters, and the like.

[0071] "Solvate" refers to forms of a compound that are associated with a solvent, usually as a result of a solvolysis reaction. This physical association includes a hydrogen bond. Conventional solvents include water, EtOH, acetic acid, and other such solvents. The compounds of the invention may be obtained, for example, in crystalline form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates such as hydrates and further include both stoichiometric solvates and non-stoichiometric solvates. In specific cases, the solvate may be isolated, for example, when one or more solvent molecules are included in the crystal lattice of a crystalline solid. The term "solvate" includes both the solvate in the liquid phase and the isolated solvates. Representative solvates include hydrates, ethanolates and methanolates.

[0072] The term "subject" includes people. The terms "person", "patient" and "subject" are used interchangeably in the invention.

[0073] "Effective amount" means the amount of a compound of the invention which, when administered to a subject for the purpose of treating a disease, is sufficient to effect such treatment of the disease. An "effective amount" may vary depending on the compound, the disease and its severity, and the age, body weight, and the like of the subject being treated.

[0074] "Prevention" refers to reducing the risk of occurrence or development of a disease or disorder (i.e., reducing the risk of at least one of the clinical symptoms of a disease in a subject who may be exposed to a pathogen or predisposed to the disease before the onset of the disease .

[0075] The term "prevention" refers to "prevention" and refers to a system of measures or procedure, the purpose of which is the prevention, and not the treatment or cure of the disease. Non-limiting examples of preventive measures may include administering vaccines, administering low molecular weight heparin to hospitalized patients at increased risk of thrombosis due to, for example, immobility, and administering an antimalarial such as chloroquine before visiting a geographic region in which malaria is endemic or in which there is a high risk of contracting malaria.

[0076] "Treatment" of any disease or disorder refers, in one embodiment, to amelioration of the disease or disorder (i.e., cessation of the disease or reduction in the manifestation, extent, or severity of at least one of its clinical symptoms). In another embodiment, "treatment" refers to an improvement in at least one medical parameter that the subject cannot perceive. In yet another embodiment, "treatment" refers to modulating a disease or disorder, either physically (eg, by stabilizing an overt symptom), physiologically (eg, by stabilizing a medical condition), or both. In a further embodiment, "treatment" refers to slowing the progression of a disease.

[0077] As used herein, the term "inflammatory disease(s)" refers to a group of pathological conditions including rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, allergic respiratory disease (e.g., asthma, rhinitis), chronic obstructive pulmonary disease (COPD), inflammatory bowel disease (eg Crohn's disease, ulcerative colitis), endotoxin-mediated disease states (eg complications after coronary artery bypass grafting or chronic endotoxin conditions contributing to the development of, for example, chronic heart failure), and related diseases, affecting cartilage, such as articular cartilage. In particular, the term refers to rheumatoid arthritis, osteoarthritis, allergic airway disease (eg, asthma), chronic obstructive pulmonary disease (COPD), and inflammatory bowel disease. More specifically, the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD) and inflammatory bowel disease.

[0078] As used herein, the term "autoinflammatory disease(s)" refers to a group of diseases including cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), and tumor necrosis factor receptor-associated periodic syndrome (TRAPS), syndrome Behcet, systemic-onset juvenile idiopathic arthritis (SJIA), or Still's disease.

[0079] As used herein, the term "autoimmune disease(s)" refers to a group of diseases including obstructive airway disease, including conditions such as chronic obstructive pulmonary disease (COPD), asthma (e.g., endogenous bronchial asthma, exogenous bronchial asthma, dust asthma, bronchial asthma of the newborn), in particular, chronic or inveterate asthma (eg, late asthma and airway hyperreactivity), bronchitis, including bronchial asthma, systemic lupus erythematosus (SLE), cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, autoimmune liver disease (eg, autoimmune hepatitis, primary sclerosing cholangitis, and primary biliary cirrhosis), Sjögren's syndrome, multiple sclerosis, psoriasis, dry eye, type 1 diabetes mellitus and related complications, atopic eczema (atopic dermatitis), thyroiditis (Hashimoto's thyroiditis and autoimmune thyroiditis), contact dermatitis and subsequent eczematous dermatitis, inflammatory bowel disease (eg Crohn's disease and ulcerative colitis), atherosclerosis and amyotrophic lateral sclerosis. In particular, the term refers to chronic obstructive pulmonary disease (COPD), asthma, systemic lupus erythematosus, type I diabetes mellitus, and inflammatory bowel disease.

[0080] As used herein, the term "proliferative disease(s)" refers to conditions such as cancer (eg, uterine leiomyosarcoma or prostate cancer), myeloproliferative disorders (eg, polycythemia vera, essential thrombocythemia, and myelofibrosis), leukemia (eg, 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.

[0081] As used herein, the term "cancer" refers to a malignant or benign growth of cells on the skin or in organs of the body, such as, but not limited to, the breast, prostate, lung, kidney, pancreas, stomach, or intestines. Cancer tends to infiltrate adjacent tissue and spread (metastasize) to distant organs such as the bones, liver, lung, or brain. As used herein, the term "cancer" includes both tumor cells of the metastatic type (such as, but not limited to, melanoma, lymphoma, leukemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma) and tissue carcinoma 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, renal cell carcinoma, gastrointestinal cancer, glioblastoma, primary liver cancer, ovarian cancer, prostate 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 tumors, tumors of the brain and spinal cord, breast cancer, bronchial tumors, Burkitt's lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, fetal tumors, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, Ewing's sarcoma family tumors, eye cancer, retinoblastoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gastrointestinal stromal- cell tumor, embryonic cell tumor, glioma, hairy cell leukemia, head and neck cancer, hepatocellular carcinoma, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, tumors of the pancreatic islets (endocrine part of the pancreas), Kaposi's sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, liver cancer, non-small cell lung cancer, small cell lung cancer, Burkitt's lymphoma, cutaneous T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphoma, Waldenström macroglobulinemia, medulloblastoma, medulloepithelioma, melanoma, mesothelioma, oral cancer, chronic myelogenous leukemia, myelogenous leukemia, multiple myeloma, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, oral cavity cancer, oropharyngeal cancer, OS theosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer, epithelial ovarian cancer, embryonic cell ovarian tumor, borderline ovarian tumor, pancreatic cancer, papillomatosis, parathyroid cancer, penile cancer, pharyngeal cancer, parenchymal pineal tumors of intermediate differentiation, pineoblastoma and supratentorial primitive neuroectodermal tumors, pituitary tumors, plasma cell neoplasia/multiple myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, tumors of the sarcoma family Ewing, Kaposi's sarcoma, Cesari's syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, gastric cancer, supratentorial primitive neuroectodermal tumors, T-cell lymphoma, testicular cancer ka, throat cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vaginal cancer, Waldenström's macroglobulinemia and Wilms' tumor.

[0082] 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, making the host highly susceptible to infection and bleeding. In particular, the term "leukemia" refers to acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukemia (CLL).

[0083] As used herein, the term "fibrotic disease(s)" refers to diseases characterized by excessive scarring due to excessive production, deposition, and contraction of extracellular matrix, and which is associated with abnormal accumulation of cells and/or fibronectin and/or collagen, and/or increased accumulation of fibroblasts, and which include, but are not limited to, fibrosis of individual organs or tissues such as the heart, kidney, liver, joints, lung, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal tissue and digestive tract. In particular, the term "fibrotic diseases" refers to idiopathic pulmonary fibrosis (IPF); cystic fibrosis, other diffuse parenchymal lung diseases of various etiologies, including iatrogenic drug-induced fibrosis, occupational and/or environmental fibrosis, granulomatosis (sarcoidosis, allergic alveolitis), vascular collagenosis, alveolar proteinosis, Langerhans cell granulomatosis, lymphangioleiomyomatosis, hereditary diseases (Hermansky-Pudlak syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage diseases, hereditary interstitial lung disease); to ionizing radiation-induced fibrosis; chronic obstructive pulmonary disease; scleroderma; bleomycin-induced pulmonary fibrosis; chronic asthma; silicosis; asbestos-induced pulmonary fibrosis; acute respiratory distress syndrome (ARDS); fibrosis of the kidney; tubulointerstitial fibrosis; glomerular nephritis; diabetic nephropathy, focal segmental glomerulosclerosis; IgA nephropathy; hypertension; Alport syndrome; intestinal fibrosis; fibrosis of the liver; cirrhosis; alcoholic fibrosis of the liver; toxic/drug-induced fibrosis of the liver; hemochromatosis; non-alcoholic steatohepatitis (NASH); damage to the bile duct; primary biliary cirrhosis; infectious fibrosis of the liver; viral fibrosis of the liver; autoimmune hepatitis; scarring of the cornea; hypertrophic scarring; Dupuytren's disease, skin fibrosis with keloid scars; skin scleroderma; systemic sclerosis, spinal injury/fibrosis; myelofibrosis; Duchenne muscular dystrophy (DMD) associated with musculoskeletal fibrosis, vascular restenosis; atherosclerosis; arteriosclerosis; Wegener's granulomatosis; Peyronie's disease or chronic lymphocytosis. More specifically, the term "fibrotic diseases" refers to idiopathic pulmonary fibrosis (IPF), Dupuytren's disease, non-alcoholic steatohepatitis (NASH), systemic sclerosis, renal fibrosis, and skin fibrosis.

[0084] As used herein, the term "transplant rejection" refers to acute or chronic rejection of allo- or xenografts of cells, tissue, or a solid organ, such as pancreatic islets, stem cells, bone marrow, skin, muscle, corneal tissue, neuronal tissue, heart, lung, heart-lung combination, kidney, liver, intestine, pancreas, trachea or esophagus, or graft versus host disease.

[0085] As used herein, the term "diseases related to impaired cartilage renewal" includes conditions such as osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, sympathetic reflex dystrophy, algodystrophy, Tietze's syndrome, or costal chondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, endemic forms of arthritis such as osteoarthritis deformans endemic, Mseleni's disease and Handigodu's disease; degeneration due to fibromyalgia, systemic lupus erythematosus, scleroderma, and ankylosing spondylitis.

[0086] As used herein, the term "congenital cartilage defect(s)" includes conditions such as hereditary chondrolysis, chondrodysplasia, and pseudochondrodysplasia, in particular, but not limited to, microtia, anotia, metaphyseal chondrodysplasia, and related disorders.

[0087] As used herein, the term "diseases related to impaired bone remodeling" includes conditions such as osteoporosis (including postmenopausal osteoporosis, male osteoporosis, glycocorticosteroid-induced osteoporosis, and juvenile osteoporosis), osteoporosis due to neoplastic diseases of the bone marrow, osteopenia , hormonal deficiency (vitamin D deficiency, male and female hypogonadism), excess hormones (hyperprolactinemia, excess glucocorticoids, hyperthyroidism, hyperparathyroidism), Paget's disease, osteoarthritis, renal osteodystrophy, osteogenesis incomplete, hypophosphatasia.

[0088] As used herein, the term "disease(s) associated with IL-6 hypersecretion" includes conditions such as Castleman's disease, multiple myeloma, psoriasis, Kaposi's sarcoma, and/or mesangial proliferative glomerulonephritis.

[0089] As used herein, the term "disease(s) associated with hypersecretion of TNFα, interferons, 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.

[0090] As used herein, the term "respiratory disease" refers to diseases that affect organs that are involved in the breathing process, such as the nose, larynx, windpipe, Eustachian tubes, trachea, bronchi, lungs, associated muscles (e.g., diaphragm and intercostal muscles) and nerves. In particular, examples of respiratory diseases include asthma, adult acute respiratory distress syndrome and allergic (exogenous) asthma, non-allergic (endogenous) asthma, acute severe asthma, chronic asthma, symptomatic asthma, nocturnal asthma, allergen-induced asthma, aspirin-induced asthma. exercise-induced asthma, isocapnic hyperventilation, childhood onset of asthma, adult onset of asthma, cough asthma, occupational asthma, steroid-resistant asthma, seasonal asthma, seasonal allergic rhinitis, prolonged allergic rhinitis, chronic obstructive pulmonary disease, including chronic bronchitis or emphysema, pulmonary hypertension, interstitial pulmonary fibrosis and/or airway inflammation, cystic fibrosis, and hypoxia.

[0091] As used herein, the term "endocrine and/or metabolic disease(s)" refers to a group of conditions involving the body's production of an excess or deficiency of specific hormones in which metabolic disturbances adversely affect the body's ability to process certain nutrients and vitamins. Endocrine disorders include, among others, hypothyroidism, congenital adrenal hyperplasia, parathyroid disease, diabetes mellitus, adrenal disease (including Cushing's syndrome and Addison's disease), and ovarian dysfunction (including polycystic ovary syndrome). Some examples of metabolic disorders include cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets. A specific example of metabolic disorders is obesity and/or type II diabetes.

[0092] Used in the invention, the term "cardiovascular disease" refers to diseases that affect the heart or blood vessels, or both. In particular, cardiovascular disease includes arrhythmia (atrial or ventricular, or both); atherosclerosis and its complications; angina; heart rhythm disturbances; myocardial ischemia; myocardial infarction; aneurysm of the heart or blood vessels; vasculitis, stroke; peripheral obstructive arteriopathy of a limb, organ or tissue; reperfusion injury after ischemia of the brain, heart, kidney or other organ or tissue; endotoxic, operational or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; shock; vasoconstriction (including vasoconstriction associated with migraines); vascular disorders, inflammation, insufficiency related to only one organ or tissue. More specifically, cardiovascular disease refers to atherosclerosis.

[0093] As used herein, the term "dermatological disease(s)" refers to a skin disorder. In particular, dermatological disorders include proliferative or inflammatory skin disorders such as atopic dermatitis, bullous disorders, collagenosis, psoriasis, psoriatic lesions, dermatitis, contact dermatitis, eczema, vitiligo, pruritus, urticaria, rosacea, scleroderma, wound healing, formation scarring, hypertrophic scarring, keloid scarring, Kawasaki disease, rosacea, Sjögren-Larsson syndrome, or urticaria.

[0094] As used herein, the term "disease associated with abnormal angiogenesis" refers to diseases caused by dysregulation of angiogenesis mediating processes. In particular, the disease associated with abnormal angiogenesis refers to atherosclerosis, hypertension, tumor growth, inflammation, rheumatoid arthritis, wet macular degeneration, choroidal neovascularization, retinal neovascularization, and diabetic retinopathy.

[0095] "Compound(s) of the invention" and equivalent expressions are intended to encompass compounds of the formula(s) described herein, where the expression includes pharmaceutically acceptable salts and solvates, e.g., hydrates and solvates of pharmaceutically acceptable salts where the context so permits. . Likewise, with respect to intermediates, whether or not they are claimed per se, they are intended to encompass their salts and solvates where the context so permits.

[0096] When the invention uses ranges of values, for example, but without limitation, as in the case of C ₁ - ₈ alkyl, the indication of the range should be considered as a representation of each member of the specified range.

[0097] Other derivatives of the compounds of this invention have activity in both their acid form and the acid form of their derivatives, but the presence of compounds in the low-stable acid form often provides advantages related to solubility, tissue compatibility or delayed release in the mammalian body ( Bundgaard 1985). Prodrugs include acid derivatives well known to those skilled in the art, such as, for example, esters obtained by reacting a parent acid with a suitable alcohol, or amides obtained by reacting a parent acid compound with a substituted or unsubstituted amine, or acid anhydrides or mixed anhydrides. . The aliphatic or aromatic esters, amides and anhydrides derived from the acid groups that the compounds of this invention contain are particularly suitable prodrugs. In some cases, it is desirable to prepare diester type prodrugs such as (acyloxy)alkyl ethers or ((alkoxycarbonyl)oxy)alkyl esters. Such specific prodrugs are C _1-8 alkyl, C _2-8 alkenyl, C _6-10 optionally substituted aryl and (C _6-10 aryl)-(C _1-4 alkyl) esters of the compounds of the invention.

[0098] The present invention includes all isotopic forms of the inventive compounds of the invention, either in form (i) in which all atoms with a given atomic number have a mass number (or mixture of mass numbers) that predominates in nature (referred to in the invention as " natural isotopic form"), or in the form (ii), in which one or more atoms are replaced by atoms having the same atomic number, but their mass number differs from the mass number of atoms that prevails in nature (referred to in the invention as "a variant of the non-natural isotopic form "). It should be borne in mind that an atom can exist in nature in the form of a mixture of mass numbers. The term "variant non-natural isotope form" also includes embodiments in which the proportion of an atom with a given atomic number having a mass number normally found in nature in negligible amounts (referred to in the invention as a "rare isotope") has been increased relative to the proportion that is normally found in nature, for example, to levels of >20%, >50%, >75%, >90%, >95%, or >99% of the number of atoms of that atomic number (the latter embodiment referred to is referred to as the "isotopically enriched form variant" ). The term "variant non-natural isotopic form" of the rare isotope has also been reduced relative to the proportion that normally occurs in nature. Isotopic forms may include radioactive forms (ie, they include radioactive isotopes) and non-radioactive forms. The radioactive forms can typically be variants of the isotopically enriched forms.

[0099] A variant of the non-natural isotopic form of the compound may, therefore, contain one or more artificial or rare 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), in one or more atoms, or may contain an increased proportion of these isotopes in comparison with the proportion that prevails in nature in one or more atoms.

[0100] A variant of non-natural isotopic forms, including radioactive isotopes, can, for example, be used for tissue distribution studies of the drug and/or substrate. The radioactive isotopes tritium, i.e. ³ H, and carbon-14, i.e. ¹⁴ C, are particularly suitable for this purpose because of their ease of administration and available means of detection. The non-natural isotopic form variant that includes deuterium, i.e. ² H or D, allows for particular therapeutic benefits resulting from higher metabolic stability, such as increased in vivo half-life, or reduced dosage levels required, and therefore may be preferred when some circumstances. In addition, a variant of non-natural isotopic forms can be prepared that includes positron active isotopes such as ¹¹ C, ¹⁸ F, ¹⁵ O and ¹³ N, and this variant can be used in positron emission tomography (PET) studies of the degree of receptor occupancy substrate.

[0101] It should also be borne in mind that compounds that have the same molecular formula but differ in the nature or sequence of binding of their atoms or the arrangement of their atoms in space, are called "isomers". Isomers that differ in the arrangement of their atoms in space are called "stereoisomers".

[0102] Stereoisomers that are not mirror images of each other are called "diastereomers", and those stereoisomers whose mirror images are not superimposed on each other are called "enantiomers". In cases where a compound has an asymmetric center, such as one associated with four different groups, a pair of enantiomers may be present. An enantiomer can be characterized by the absolute configuration of its center of asymmetry and described using the R- and S- precedence sequence rules of Kahn and Prelog, or by the method in which the molecule rotates the plane of polarized light and is designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers, respectively). A chiral compound may exist either as an individual enantiomer or as a mixture of enantiomers. A mixture containing equal proportions of enantiomers is referred to as a "racemic mixture".

[0103] "Tautomers" refers to compounds that are interchangeable forms of the structure of a particular compound, and that change with the movement of hydrogen atoms and electrons. For example, two structures can be in equilibrium as a result of the movement of π electrons and an atom (usually H). For example, enols and ketones are tautomers, as they quickly interconvert into each other when treated with either an acid or a base. Another example of tautomerism is the acyl and nitro forms of phenylnitromethane, which also form upon treatment with acid or base.

[0104] Tautomeric forms can be used to impart optimal chemical reactivity and biological activity to the compound of interest.

[0105] the Compounds of the invention may have one or more centers of asymmetry, and therefore, such compounds can be synthesized in the form of individual (R) - or (S) - stereoisomers or in the form of mixtures thereof.

[0106] Unless otherwise indicated, the definition or name of a particular compound in the specification and patent claims is intended to include both individual enantiomers and racemic or other mixtures thereof. Methods for determining stereochemistry and methods for separating stereoisomers are well known in the art.

[0107] It should be borne in mind that the compounds of the invention can be metabolized to form biologically active metabolites.

INVENTION

[0108] The present invention is based on the discovery of new compounds and their use for the prevention and/or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases related to impaired cartilage renewal, cartilage congenital defect, diseases related to impaired bone remodeling, diseases associated with hypersecretion of TNFα, interferons, IL-6, IL-12 and/or IL-23, respiratory diseases, endocrine and/or metabolic diseases, cardiovascular diseases, dermatological diseases, and /or diseases associated with abnormal angiogenesis. In particular, the compounds of the invention may be SIK inhibitors, and more particularly SIK1, SIK2 and/or SIK3 inhibitors.

[0109] The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods for the prevention and/or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases related to disorders of cartilage renewal, congenital cartilage defect, diseases related to impaired bone remodeling, diseases associated with hypersecretion of TNFα, interferons, IL-6, IL-12 and/or IL-23, respiratory diseases, endocrine and/or metabolic diseases, cardiovascular vascular diseases, dermatological diseases, and/or diseases associated with abnormal angiogenesis by administering the compounds of the invention.

[0110] Accordingly, in a first aspect of the invention, compounds of the invention are provided having formula I:

where,

X is N or CR ⁴ ;

one of Y ₁ , Y ₂ and Y ₃ is N and the other two are C;

Z represents

- -NR ^5a R ^5b ,

- -NR ^5c -, where the atom N and R ^3b together with the atoms to which they are attached, form a fused 5-6-membered heterocycloalkenyl, including one double bond and including, in addition, zero, one or two additional heteroatoms, independently selected from N, O and S, or

N-linked 4-7 membered heterocycloalkyl further comprising zero, one or two additional heteroatoms independently selected from N, O and S, optionally substituted with one, two or three R ⁶ groups;

R ¹ is H, halogen, C _1-4 alkyl or C _1-4 alkoxy optionally substituted with C _1-4 alkoxy, phenyl, -CN, -C(=O)OH or -C(=O)- C _1-4 alkoxy;

R ² is a 5-6 membered monocyclic heteroaryl containing one, two or three heteroatoms independently selected from N, O and S, where the heteroaryl is optionally substituted with one or more independently selected R ⁷ groups;

R ^3a and R ^3b are independently selected from

- halogen,

- C _1-4 alkyl,

- C _1-4 alkoxy optionally substituted with one or more selected halo, -OH or C _1-4 alkoxy,

- -NR ^8a R ^8b , and

- -OH;

R ⁴ is H or C _1-4 alkyl;

R ^5a is H or C _1-4 alkyl;

R ^5b choose from

- C _1-6 alkyl, optionally substituted with one or more selected R ⁹ ,

- C _3-7 cycloalkyl, optionally substituted with one or more selected R ¹⁰ ,

- 4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O and S, where the heterocycloalkyl is optionally substituted with one or more oxo, and

- 5-6-membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O and S, where the heteroaryl is optionally substituted with one or more independently selected C _1-4 alkyl;

R ^5c is selected from C _3-7 cycloalkyl and C _1-6 alkyl optionally substituted with one or more independently selected halo;

each R ⁶ is independently selected from

- oxo,

- halogen,

- -CN,

- -OH,

- -NR ^11a R ^11b ,

- phenyl,

- C _3-7 cycloalkyl,

- C _2-4 alkynyl,

- -C(=O)-C _1-4 alkoxy,

- C _1-4 alkoxy, optionally substituted with one or more halo or phenyl,

- C _1-4 alkyl optionally substituted with one or more halo, -OH or C _1-4 alkoxy, and

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

each R ⁷ choose from

- halogen,

- -CN,

- C _1-6 alkyl optionally substituted with one or more independently selected

halogen,

-CN,

-OH,

C _1-4 alkoxy optionally substituted with one or more selected halo,

-NR ^11c R ^11d ,

-C(=O)R ¹² , or

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

- C _1-4 alkoxy,

- C _3-7 cycloalkyl,

- 4-6-membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O and S, where heterocycloalkyl is optionally substituted with -C(=O)C _1-4 alkoxy or C _1-4 alkyl, optionally substituted with -CN,

- -NR ^13a R ^13b , and

- -C(=O)NR ^13c R ^13d ;

each R ^8a and R ^8b is independently selected from H and C _1-4 alkyl optionally substituted with one -OH or C _1-4 alkoxy;

each R ⁹ is independently selected from

- halogen,

- -CN,

- -NR ^11e R ^11f ,

- -OH,

- C _1-4 alkoxy,

- -S(=O) ₂ -C _1-4 alkyl,

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

- 5-6-membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O and S, where the heteroaryl is optionally substituted with one or more independently selected C _1-4 alkyl;

each R ¹⁰ is independently selected from

- halogen,

- C _1-4 alkyl optionally substituted with one or more independently selected halo, -OH or C _1-4 alkoxy,

- -OH,

- C _1-4 alkoxy, and

- -NR ^11g R ^11h ;

each R ^11a , R ^11b , R ^11c , R ^11d , R ^11e , R ^11f , R ^11g , and R ^{11h is} independently selected from H and C _1-4 alkyl;

each R ¹² represents

- -NR ^14a R ^14b , where each R ^14a and R ^14b are independently selected from H and C _1-4 alkyl,

- -OH,

- C _1-4 alkoxy optionally substituted with one or more selected C _3-7 cycloalkyl, halogen, -NR ^15a R ^15b or 4-6 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S

- -O- (4-6-membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S), or

- -O-(C _3-7 monocyclic cycloalkyl);

every R^13a, R^13b, R^13c, and R^13d independently choose from H and C_1-4 alkyl;

each R ^15a and R ^15b is independently selected from H and C _1-4 alkyl.

[0111] In one embodiment, a compound of the invention is of formula I, wherein X is CR ⁴ and R ⁴ is H.

[0112] In one embodiment, the compound of the invention corresponds to formula I, where X is CR ⁴ and R ⁴ is C _1-4 alkyl. In a particular embodiment, R ⁴ is -CH ₃ , -CH ₂ CH ₃ , or -CH(CH ₃ ) ₂ . In yet another specific embodiment, R ⁴ is -CH ₃ .

[0113] In one embodiment, the compound of the invention is of formula IIa, IIb, IIc, IId, IIe, or IIf:

where R ¹ , R ² , R ^3a , R ^3b and Z are defined above.

[0114] In one embodiment, a compound of the invention is any one of formulas I-IIf, where R ¹ is H.

[0115] In one embodiment, the compound of the invention corresponds to any one of formulas I-IIf, where R ¹ is halogen. In a particular embodiment, R ¹ is F, Cl, or Br.

[0116] In one embodiment, the compound of the invention corresponds to any one of formulas I-IIf, where R ¹ is C _1-4 alkyl. In a particular embodiment, R ¹ is -CH ₃ , -CH ₂ CH ₃ , or -CH(CH ₃ ) ₂ . In yet another specific embodiment, R ¹ is -CH ₃ .

[0117] In one embodiment, the compound of the invention corresponds to any one of formulas I-IIf, where R ¹ is C _1-4 alkoxy. In a particular embodiment, R ¹ is -O-CH ₃ , -O-CH ₂ CH ₃ , or -O-CH(CH ₃ ) ₂ . In yet another specific embodiment, R ¹ is -O-CH ₃ .

[0118] In one embodiment, the compound of the invention corresponds to any one of formulas I-IIf, where R ¹ is C _1-4 alkoxy substituted with C _1-4 alkoxy, phenyl, -CN, -C(=O )OH or -C(=O)-C _1-4 alkoxy. In a specific embodiment, R ¹ is -O-CH ₂ CH ₃ or -O-CH(CH ₃ ) ₂ substituted with C _1-4 alkoxy, phenyl, -CN, -C(=O)OH, or - C(=O)-C _1-4 alkoxy. In another specific embodiment, R ¹ is C _1-4 alkoxy substituted with -O-CH ₃ or -O-CH ₂ CH ₃ , phenyl, -CN, -C(=O)OH or -C(= O)-O-CH ₂ CH ₃ . In yet another specific embodiment, R ¹ is -O-CH ₂ CH ₂ -O-CH ₃ , benzyloxy, -O-CH(CN)CH ₃ , -O-CH ₂ -C(=O)OH, - O-CH(CH ₃ )-C(=O)OH, -O-CH ₂ -C(=O)-O-CH ₂ CH ₃ or -O-CH(CH ₃ )-C(=O)-O -CH ₂ CH ₃ .

[0119] In one embodiment, the compound of the invention corresponds to any one of formulas I-IIf, where R ¹ is C _1-4 alkoxy substituted with C _1-4 alkoxy. In a particular embodiment, R ¹ is -O-CH ₂ CH ₃ or -O-CH(CH ₃ ) ₂ substituted with C _1-4 alkoxy. In another specific embodiment, R ¹ is C _1-4 alkoxy substituted with -O-CH ₃ or -O-CH ₂ CH ₃ . In yet another specific embodiment, R ¹ is -O-CH ₂ CH ₂ -O-CH ₃ .

[0120] In one embodiment, the compound of the invention is of formula IIIa, IIIb, IIIc, IIId, IIIe, or IIIf:

where R ² , R ^3a , R ^3b and Z are defined above.

[0121] In one embodiment, the compound of the invention corresponds to any one of formulas I-IIIf, where Z is -NR ^5c -, where the N atom and R ^3b together with the atoms to which they are attached form a fused 5-6- a membered heterocycloalkenyl containing one double bond and further including zero, one or two additional heteroatoms independently selected from N, O and S, and R ^5c is defined above. In a particular embodiment, Z is -NR ^5c - where N and R ^3b together with the atoms to which they are attached form a fused 3,4-dihydro-2H-1,3-oxazine, 1,2,3, 4-tetrahydropyrimidine, 3-pyrroline, 1,2,3,6-tetrahydropyridine or 3,4-dihydro-2H-1,3-thiazine. In yet another particular embodiment, Z is -NR ^5c - where N and R ^3b together with the atoms to which they are attached form a fused 3,4-dihydro-2H-1,3-oxazine, 3-pyrroline, or 1,2,3,6-tetrahydropyridine.

[0122] In one embodiment, the compound of the invention is of formula IVa, IVb, IVc, or IVd:

where R ² , R ^3a and R ^5c are defined above.

[0123] In one embodiment, the compound of the invention corresponds to any one of formulas I-IVd, where R ^5c is C _3-7 cycloalkyl. In a particular embodiment, R ^5c is cyclopropyl, cyclobutyl, or cyclopentyl. In yet another specific embodiment, R ^5c is cyclopropyl.

[0124] In one embodiment, the compound of the invention corresponds to any one of formulas I-IVd, where R ^5c is C _1-6 alkyl. In a particular embodiment, R ^5c is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , or -C(CH ₃ ) ₃ . In yet another specific embodiment, R ^5c is -CH ₂ CH ₃ .

[0125] In one embodiment, the compound of the invention corresponds to any one of formulas I-IVd, where R ^5c is C _1-6 alkyl substituted with one or more independently selected halo. In a specific embodiment, R ^5c is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , or -C(CH ₃ ) ₃ , each of which is substituted with one or more independently selected halogen. In another specific embodiment, R ^5c is C _1-6 alkyl substituted with one, two or three independently selected halogens. In yet another specific embodiment, R ^5c is C _1-6 alkyl substituted with one or more independently selected F or Cl. In another specific embodiment, R ^5c is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , or -C(CH ₃ ) ₃ , each of which is substituted with using one, two or three independently selected halogens. In another more specific embodiment, R ^5c is C _1-6 alkyl substituted with one, two or three independently selected F or Cl. In yet another more specific embodiment, R ^5c is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , or -C(CH ₃ ) ₃ , each of which is substituted with one or more independently selected F or Cl. In yet another more specific embodiment, R ^5c is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , or -C(CH ₃ ) ₃ , each of which is substituted with one, two or three independently selected F or Cl. In yet another more specific embodiment, R ^5c is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , or -C(CH ₃ ) ₃ , each of which is substituted with one or more Fs. In yet another more specific embodiment, R ^5c is C _1-6 alkyl substituted with one, two or three independently selected Fs. In a most specific embodiment, R ^5c is -CH ₂ CH ₃ substituted with one, two or three F.

[0126] In one embodiment, the compound of the invention corresponds to any one of formulas I-IVd, where R ² is a 5-6 membered monocyclic heteroaryl containing one, two or three heteroatoms independently selected from N, O and S. In a particular embodiment, R ² is imidazolyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl. In yet another specific embodiment, R ² is pyrazolyl.

[0127] In one embodiment, the compound of the invention corresponds to any one of formulas I-IVd, where R ² is a 5-6 membered monocyclic heteroaryl containing one, two or three heteroatoms independently selected from N, O and S, where heteroaryl is substituted with one or more independently selected R ⁷ groups. In a specific embodiment, R ² is a 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O and S, wherein the heteroaryl is substituted with one, two or three independently selected R ⁷ groups. In another specific embodiment, R ² is imidazolyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, each substituted with one or more independently selected R ⁷ groups. In another specific embodiment, R ² is imidazolyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, each substituted with one R ⁷ group. In the most specific embodiment, R ² is pyrazolyl substituted with one R ⁷ group.

[0128] In one embodiment, the compound of the invention corresponds to any one of formulas I-IVd, where R ² is a 5-6 membered monocyclic heteroaryl containing one, two or three heteroatoms independently selected from N, O and S, where heteroaryl is substituted with one or more independently selected R ⁷ groups, and R ⁷ is halo or —CN. In a particular embodiment, R ⁷ is F, Cl, Br, or -CN. In yet another specific embodiment, R ⁷ is F or -CN.

[0129] In one embodiment, the compound of the invention corresponds to any one of formulas I-IVd, where R ² is a 5-6 membered monocyclic heteroaryl containing one, two or three heteroatoms independently selected from N, O and S, where heteroaryl is substituted with one or more independently selected R ⁷ groups, and R ⁷ is C _1-4 alkoxy. In a particular embodiment, R ⁷ is -O-CH ₃ , -O-CH ₂ CH ₃ , or -O-CH(CH ₃ ) ₂ . In yet another specific embodiment, R ⁷ is -O-CH ₃ or -O-CH ₂ CH ₃ .

[0130] In one embodiment, the compound of the invention corresponds to any one of formulas I-IVd, where R ² is a 5-6 membered monocyclic heteroaryl containing one, two or three heteroatoms independently selected from N, O and S, where heteroaryl is substituted with one or more independently selected R ⁷ groups, R ⁷ is -NR ^13a R ^13b , and R ^13a and R ^13b are each as defined above. In a specific embodiment, R ^13a and R ^13b are both H. In another specific embodiment, one of R ^13a and R ^13b is H and the other is C _1-4 alkyl. In yet another specific embodiment, R ^13a and R ^13b are both C _1-4 alkyl. In another more specific embodiment, each R ^13a and R ^13b is independently selected H, -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . In yet another specific embodiment, one of R ^13a and R ^13b is H and the other is -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . In the most specific embodiment, R ⁷ is -NH ₂ or -N(CH ₃ ) ₂ .

[0131] In one embodiment, the compound of the invention corresponds to any one of formulas I-IVd, where R ² is a 5-6 membered monocyclic heteroaryl containing one, two or three heteroatoms independently selected from N, O and S, where heteroaryl is substituted with one or more independently selected R ⁷ groups, R ⁷ is -C(=O)NR ^13c R ^13d , and R ^13c and R ^13d are each as defined above. In a specific embodiment, R ^13c and R ^13d are both H. In another specific embodiment, one of R ^13c and R ^13d is H and the other is C _1-4 alkyl. In yet another specific embodiment, R ^13c and R ^13d are both C _1-4 alkyl. In yet another specific embodiment, one of R ^13c and R ^13d is H and the other is -CH ₃ , -CH ₂ CH ₃ , or -CH(CH ₃ ) ₂ . In another specific embodiment, each R ^13c and R ^13d is independently selected H, -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . In another more specific embodiment, R ^13c and R ^13d are -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ .

[0132] In one embodiment, the compound of the invention has the formula Va, Vb, Vc, Vd, Ve, or Vf:

where R ^3a , R ^3b , R ⁷ and Z are defined above.

[0133] In one embodiment, the compound of the invention corresponds to any one of formulas I-Vf, where R ⁷ is C _1-6 alkyl. In a particular embodiment, R ⁷ is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -C(CH ₃ ) ₃ , -CH(CH ₃ )CH ₂ CH ₃ , -CH(CH ₃ )CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ )CH ₂ CH ₃ or -CH ₂ CH ₂ CH(CH ₃ ) ₂ . In yet another specific embodiment, R ⁷ is -CH ₃ or -CH ₂ CH ₃ . In the most specific embodiment, R ⁷ is -CH ₃ .

[0134] In one embodiment, the compound of the invention corresponds to any one of formulas I-Vf, where R ⁷ is C _1-4 alkyl. In a particular embodiment, R ⁷ is -CH ₃ , -CH ₂ CH ₃ , or -CH(CH ₃ ) ₂ . In yet another specific embodiment, R ⁷ is -CH ₃ or -CH ₂ CH ₃ . In the most specific embodiment, R ⁷ is -CH ₃ .

[0135] In one embodiment, the compound of the invention corresponds to any one of formulas I-Vf, where R ⁷ is C _1-6 alkyl substituted with one or more independently selected halo, -CN, -OH, C _{1- 4} alkoxy optionally substituted with one or more selected halogens, -NR ^11c R ^11d , -C(=O)R ¹² or 4-6 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S. In a particular embodiment, R ⁷ is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -C (CH ₃ ) ₃ , -CH(CH ₃ )CH ₂ CH ₃ , -CH(CH ₃ )CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ )CH ₂ CH ₃ or -CH ₂ CH ₂ CH( CH ₃ ) ₂ each substituted with one or more independently selected halogens, -CN, -OH, C _1-4 alkoxy optionally substituted with one or more selected halogens, -NR ^11c R ^11d , -C(= O)R ¹² or 4-6-membered monocyclic heterocycloalkyl, including one, two or three heteroatoms independently selected from N, O and S. In another specific embodiment, R ⁷ is C _1-6 alkyl substituted with one, two or three independently selected halogens, -CN, -OH, C _{1 -4} alkoxy optionally substituted with one or more selected halogens, -NR ^11c R ^11d , -C(=O)R ¹² or 4-6 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S. In yet another specific embodiment, R ⁷ is C _1-6 alkyl substituted with one or more independently selected F, Cl, -CN, -OH, -O-CH ₃ , -O-CH ₂ CH ₃ , -O-CH(CH ₃ ) ₂ , -O-CHF ₂ , -O-CF ₃ , -O-CH ₂ CHF ₂ , -NR ^11c R ^11d , -C(=O)R ¹² , azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl or piperazinyl. In yet another specific embodiment, R ⁷ is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH( CH ₃ )CH ₂ CH ₃ , -CH(CH ₃ )CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ )CH ₂ CH ₃ , or -CH ₂ CH ₂ CH(CH ₃ ) ₂ , each of which is substituted with one, two or three independently selected halogens, -CN, -OH, C _1-4 alkoxy optionally substituted with one or more selected halogens, -NR ^11c R ^11d , -C(=O)R ¹² or 4- 6-membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S. In yet another more specific embodiment, R ⁷ is C _1-6 alkyl substituted with one, two or three independently selected F, Cl, -CN, -OH, -O-CH ₃ , -O-CH ₂ CH ₃ , -O-CH(CH ₃ ) ₂ , -O-CHF ₂ , -O-CF ₃ , -O- CH ₂ CHF ₂ , -NR ^11c R ^11d or -C(=O)R ¹² . In another more specific embodiment, R ⁷ is C _1-6 alkyl substituted with one azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl. In another more specific embodiment, R ⁷ is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , or -CH ₂ CH ₂ CH(CH ₃ ) ₂ each substituted with one, two or three independently selected F, Cl, -CN, -OH, -O-CH ₃ , -O-CH ₂ CH ₃ , -O- CH(CH ₃ ) ₂ , -O-CHF ₂ , -O-CF ₃ , -O-CH ₂ CHF ₂ , -NR ^11c R ^11d or -C(=O)R ¹² . In another more specific embodiment, R ⁷ is -CH ₃ or -CH ₂ CH ₃ each substituted with one azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl . In the most specific embodiment, R ⁷ is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , or -CH ₂ CH ₂ CH(CH ₃ ) ₂ each substituted with one, two or three independently selected F, -CN, -OH, -O-CH ₃ or -C(=O)R ¹² . In another most specific embodiment, R ⁷ is -CH ₃ or -CH ₂ CH ₃ , each of which is substituted with one tetrahydrofuranyl or morpholinyl.

[0136] In one embodiment, the compound of the invention corresponds to any one of formulas I-Vf, where R ⁷ is C _1-4 alkyl substituted with one or more independently selected halo, -CN, -OH, C _{1- 4} alkoxy optionally substituted with one or more selected halogens, -NR ^11c R ^11d , -C(=O)R ¹² or 4-6 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S. In a specific embodiment, R ⁷ is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , or -CH(CH ₃ ) ₂ , each of which is substituted with one or more independently selected halo , -CN, -OH, C _1-4 alkoxy, optionally substituted with one or more selected halogens, -NR ^11c R ^11d , -C(=O)R ¹² or 4-6-membered monocyclic heterocycloalkyl, including one, two or three heteroatoms independently selected from N, O, and S. In another specific embodiment, R ⁷ is C _1-4 alkyl substituted with one, two or three independently selected halogens, -CN, -OH, C _1-4 alkoxy optionally substituted with one or more selected halogens, -NR ^11c R ^11d , -C(=O)R ¹² or a 4-6 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S. In yet another specific embodiment, R ⁷ is C _1-4 alkyl substituted with one or more independently selected F, Cl, -CN, -OH, -O-CH ₃ , -O-CH ₂ CH ₃ , -O-CH(CH ₃ ) ₂ , -O-CHF ₂ , -O-CF ₃ , -O- CH ₂ CHF ₂ , -NR ^11c R ^11d , -C(=O)R ¹² , azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl or piperazinyl. In yet another specific embodiment, R ⁷ is -CH ₃ , -CH ₂ CH ₃ , or -CH ₂ CH ₂ CH ₃ , each of which is substituted with one, two or three independently selected halo, -CN, -OH, C _1-4 alkoxy optionally substituted with one or more selected halogens, -NR ^11c R ^11d , -C(=O)R ¹² or 4-6 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S. In another more specific embodiment, R ⁷ is C _1-4 alkyl substituted with one, two or three independently selected F, Cl, -CN, -OH, -O-CH ₃ , -O-CH ₂ CH ₃ , -O-CH(CH ₃ ) ₂ , -O-CHF ₂ , -O-CF ₃ , -O-CH ₂ CHF ₂ , -NR ^11c R ^11d or -C(=O) ^R12 . In another more specific embodiment, R ⁷ is C _1-4 alkyl substituted with one azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl. In yet another more specific embodiment, R ⁷ is -CH ₃ , -CH ₂ CH ₃ , or -CH ₂ CH ₂ CH ₃ , each of which is substituted with one, two or three independently selected F, Cl, -CN, -OH, -O-CH ₃ , -O-CH ₂ CH ₃ , -O-CH(CH ₃ ) ₂ , -O-CHF ₂ , -O-CF ₃ , -O-CH ₂ CHF ₂ , -NR ^11c R ^11d or -C(=O)R ¹² . In another more specific embodiment, R ⁷ is -CH ₃ or -CH ₂ CH ₃ each substituted with one azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl . In the most specific embodiment, R ⁷ is -CH ₃ , -CH ₂ CH ₃ , or -CH ₂ CH ₂ CH ₃ , each of which is substituted with one, two or three independently selected F, -CN, -OH, - O-CH ₃ or -C(=O)R ¹² . In another most specific embodiment, R ⁷ is -CH ₃ or -CH ₂ CH ₃ , each of which is substituted with one tetrahydrofuranyl or morpholinyl.

[0137] In one embodiment, a compound of the invention corresponds to any one of formulas I-Vf, where R ⁷ is C _1-6 alkyl substituted with one or more independently selected -NR ^11c R ^11d , and R ^11c and R ^11d are both H. In another embodiment, one of R ^11c and R ^11d is H and the other is C _1-4 alkyl. In yet another embodiment, R ^11c and R ^11d are both C _1-4 alkyl. In a particular embodiment, one of R ^11c and R ^11d is H and the other is -CH ₃ , -CH ₂ CH ₃ , or -CH(CH ₃ ) ₂ . In another more specific embodiment, R ^11c and R ^11d are -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ .

[0138] In one embodiment, the compound of the invention corresponds to any one of formulas I-Vf, where R ⁷ is C _1-4 alkyl substituted with one or more independently selected -NR ^11c R ^11d , and R ^11c and R ^11d are both H. In another embodiment, one of R ^11c and R ^11d is H and the other is C _1-4 alkyl. In another embodiment, R ^11c and R ^11d are both C _1-4 alkyl. In a particular embodiment, one of R ^11c and R ^11d is H and the other is -CH ₃ , -CH ₂ CH ₃ , or -CH(CH ₃ ) ₂ . In another more specific embodiment, R ^11c and R ^11d are -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ .

[0139] In one embodiment, the compound of the invention corresponds to any one of formulas I-Vf, where R ⁷ is C _1-6 alkyl substituted with one or more independently selected -C(=O)R ¹² , R ¹² is -NR ^14a R ^14b , and R ^14a and R ^14b are each as defined above. In a specific embodiment, R ^14a and R ^14b are both H. In another specific embodiment, one of R ^14a and R ^14b is H and the other is C _1-4 alkyl. In yet another specific embodiment, R ^14a and R ^14b are both C _1-4 alkyl. In another specific embodiment, one of R ^14a and R ^14b is H and the other is -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . In another more specific embodiment, R ^14a and R ^14b are -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ .

[0140] In one embodiment, the compound of the invention corresponds to any one of formulas I-Vf, where R ⁷ is C _1-4 alkyl substituted with one or more independently selected -C(=O)R ¹² , R ¹² is -NR ^14a R ^14b , and R ^14a and R ^14b are each as defined above. In a specific embodiment, R ^14a and R ^14b are both H. In another specific embodiment, one of R ^14a and R ^14b is H and the other is C _1-4 alkyl. In yet another specific embodiment, R ^14a and R ^14b are both C _1-4 alkyl. In yet another specific embodiment, one of R ^14a and R ^14b is H and the other is -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . In another more specific embodiment, R ^14a and R ^14b are -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ .

[0141] In one embodiment, the compound of the invention corresponds to any one of formulas I-Vf, where R ⁷ is C _1-6 alkyl substituted with one or more independently selected -C(=O)R ¹² , and R ¹² is -OH.

[0142] In one embodiment, the compound of the invention corresponds to any one of formulas I-Vf, where R ⁷ is C _1-4 alkyl substituted with one or more independently selected -C(=O)R ¹² , and R ¹² is -OH.

[0143] In one embodiment, the compound of the invention corresponds to any one of formulas I-Vf, where R ⁷ is C _1-6 alkyl substituted with one or more independently selected -C(=O)R ¹² , and R ¹² is C _1-4 alkoxy. In a particular embodiment, R ¹² is -O-CH ₃ , -O-CH ₂ CH ₃ , -O-CH(CH ₃ ) ₂ , or -OC(CH ₃ ) ₃ .

[0144] In one embodiment, the compound of the invention corresponds to any one of formulas I-Vf, where R ⁷ is C _1-4 alkyl substituted with one or more independently selected -C(=O)R ¹² , and R ¹² is C _1-4 alkoxy. In a particular embodiment, R ¹² is -O-CH ₃ , -O-CH ₂ CH ₃ , -O-CH(CH ₃ ) ₂ , or -OC(CH ₃ ) ₃ .

[0145] In one embodiment, the compound of the invention corresponds to any one of formulas I-Vf, where R ⁷ is C _1-6 alkyl substituted with one or more independently selected -C(=O)R ¹² , and R ¹² is C _1-4 alkoxy substituted with one or more independently selected C _3-7 cycloalkyl, halogen, -NR ^15a R ^15b or 4-6 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S. In a particular embodiment, R ¹² is -O-CH ₃ , -O-CH ₂ CH ₃ , or -O-CH(CH ₃ ) ₂ , each of which is substituted with one or more independently selected C _3-7 cycloalkyl, halogen, -NR ^15a R ^15b or 4-6 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S. In another specific embodiment, R ¹² is C _1-4 alkoxy substituted with one, two or three independently selected C _3-7 cyc loalkyl, halogen, -NR ^15a R ^15b or 4-6 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S. In yet another specific embodiment, R ¹² is C _1-4 alkoxy substituted with one or more independently selected cyclopropyl, cyclobutyl, cyclopentyl, F, Cl, -NR ^15a R ^15b , azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl. In yet another specific embodiment, R ¹² is -O-CH ₃ or -O-CH ₂ CH ₃ , each of which is substituted with one, two or three C _3-7 cycloalkyl, halogen, -NR ^15a R ^15b or 4-6 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S. In another more specific embodiment, R ¹² is C _1-4 alkoxy substituted with one, two or three cyclopropyl, cyclobutyl or cyclopentyl, F, -NR ^15a R ^15b or tetrahydrofuranyl. In a most specific embodiment, R ¹² is -O-CH ₃ or -O-CH ₂ CH ₃ , each of which is substituted with one, two or three Fs. In another most specific embodiment, R ¹² is -O -CH ₃ or -O-CH ₂ CH ₃ each substituted with one cyclopropyl, cyclobutyl, cyclopentyl, -NR ^15a R ^15b or tetrahydrofuranyl.

[0146] In one embodiment, the compound of the invention corresponds to any one of formulas I-Vf, where R ⁷ is C _1-6 alkyl substituted with one or more independently selected -C(=O)R ¹² , R ¹² is C _1-4 alkoxy substituted with one or more independently selected -NR ^15a R ^15b , and R ^15a and R ^15b are each as defined above. In a specific embodiment, R ^15a and R ^15b are both H. In another specific embodiment, one of R ^15a and R ^15b is H and the other is C _1-4 alkyl. In yet another specific embodiment, both R ^15a and R ^15b are C _1-4 alkyl. In yet another specific embodiment, one of R ^15a and R ^15b is H and the other is -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . In another more specific embodiment, both R ^15a and R ^15b are -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . In the most specific embodiment, both R ^15a and R ^15b are -CH ₂ CH ₃ .

[0147] In one embodiment, the compound of the invention corresponds to any one of formulas I-Vf, where R ⁷ is C _1-4 alkyl substituted with one or more independently selected -C(=O)R ¹² , and R ¹² is C _1-4 alkoxy substituted with one or more independently selected C _3-7 cycloalkyl or halo. In a particular embodiment, R ¹² is -O-CH ₃ , -O-CH ₂ CH ₃ , or -O-CH(CH ₃ ) ₂ , each of which is substituted with one or more independently selected C _3-7 cycloalkyl or halogen. In another specific embodiment, R ¹² is C _1-4 alkoxy substituted with one, two or three independently selected C _3-7 cycloalkyl or halo. In yet another specific embodiment, R ¹² is C _1-4 alkoxy substituted with one or more independently selected cyclopropyl, cyclobutyl, cyclopentyl, F, or Cl. In yet another specific embodiment, R ¹² is -O-CH ₃ or -O-CH ₂ CH ₃ , each of which is substituted with one, two or three C _3-7 cycloalkyl or halo. In another more specific embodiment, R ¹² is C _1-4 alkoxy substituted with one, two or three cyclopropyl, cyclobutyl or cyclopentyl or F. In a most specific embodiment, R ¹² is -O-CH ₃ or -O-CH ₂ CH ₃ , each of which is substituted with one, two or three F. In another most specific embodiment, R ¹² is -O-CH ₃ or -O-CH ₂ CH ₃ , each of which is substituted using one cyclopropyl, cyclobutyl or cyclopentyl.

[0148] In one embodiment, the compound of the invention corresponds to any one of formulas I-Vf, where R ⁷ is C _1-6 alkyl substituted with one or more independently selected -C(=O)R ¹² , and R ¹² is -O-(4-6 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S). In a specific embodiment, R ¹² is -O-azetidinyl, -O-oxetanyl, -O-pyrrolidinyl, -O-tetrahydrofuranyl, -O-piperidinyl, -O-tetrahydropyranyl, -O-tetrahydrothiopyranyl, -O-morpholinyl, - O-thiomorpholinyl, -O-dioxanyl or -O-piperazinyl. In yet another specific embodiment, R ¹² is -O-tetrahydrofuranyl.

[0149] In one embodiment, the compound of the invention corresponds to any one of formulas I-Vf, where R ⁷ is C _1-6 alkyl substituted with one or more independently selected -C(=O)R ¹² , and R ¹² is -O-(C _3-7 monocyclic cycloalkyl). In a particular embodiment, R ¹² is -O-cyclopropyl, -O-cyclobutyl, or -O-cyclopentyl. In yet another specific embodiment, R ¹² is -O-cyclopropyl.

[0150] In one embodiment, the compound of the invention corresponds to any one of formulas I-Vf, where R ⁷ is C _3-7 cycloalkyl. In a particular embodiment, R ⁷ is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In yet another specific embodiment, R ⁷ is cyclopropyl.

[0151] In one embodiment, the compound of the invention corresponds to any one of formulas I-Vf, where R ⁷ is a 4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O and S. In a particular embodiment, R ⁷ is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl. In yet another specific embodiment, R ⁷ is azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl, or piperazinyl.

[0152] In one embodiment, the compound of the invention corresponds to any one of formulas I-Vf, where R ⁷ is a 4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O and S, substituted with -C(=O)C _1-4 alkoxy or C _1-4 alkyl optionally substituted with -CN. In a particular embodiment, R ⁷ is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl, each substituted with -C(=O)C _1-4 alkoxy or C _1-4 alkyl optionally substituted with -CN. In another specific embodiment, R ⁷ is a 4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O and S, substituted with -C(=O)-O-CH ₃ , -C(=O)-O-CH ₂ CH ₃ , -C(=O)-O-CH(CH ₃ ) ₂ , -C(=O)-OC(CH ₃ ) ₃ , -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ -CN, -CH ₂ CH ₂ -CN, -CH ₂ CH(CH ₃ )-CN or -CH(CH ₃ )CH ₂ -CN. In yet another specific embodiment, R ⁷ is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl, each of which is substituted with -C(=O)-O-CH ₃ , -C(=O)-O-CH ₂ CH ₃ , -C(=O)-O-CH(CH ₃ ) ₂ , -C(=O)-OC(CH ₃ ) ₃ , -CH ₃ , - CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ -CN, -CH ₂ CH ₂ -CN, -CH ₂ CH(CH ₃ )-CN or -CH(CH ₃ )CH ₂ -CN. In another more specific embodiment, R ⁷ is azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is substituted with -C(=O)-O-CH ₃ , -C(=O)-O-CH ₂ CH ₃ , -C(=O)-O-CH(CH ₃ ) ₂ , -C(=O)-OC(CH ₃ ) ₃ , -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ -CN, -CH ₂ CH ₂ -CN, -CH ₂ CH(CH ₃ )-CN or -CH(CH ₃ )CH ₂ -CN. In yet another more specific embodiment, R ⁷ is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl, each of which is substituted with -C(=O)-OC(CH ₃ ) ₃ , -CH ₃ , -CH ₂ -CN or -CH ₂ CH ₂ -CN. In the most specific embodiment, R ⁷ is azetidinyl, pyrrolidinyl, piperidinyl or piperazinyl, each of which is substituted with -C(=O)-OC(CH ₃ ) ₃ , -CH ₃ , -CH ₂ -CN or -CH ₂ CH ₂ -CN.

[0153] In one embodiment, the compound of the invention corresponds to any one of Formulas I-IIIf and Va-Vf, where R ^3b is halo or -OH. In a particular embodiment, R ^3b is F, Cl, or -OH.

[0154] In one embodiment, the compound of the invention corresponds to any one of formulas I-IIIf and Va-f, where R ^3b is C _1-4 alkyl. In a particular embodiment, R ^3b is -CH ₃ , -CH ₂ CH ₃ , or -CH(CH ₃ ) ₂ . In yet another specific embodiment, R ^3b is -CH ₃ or -CH ₂ CH ₃ . In the most specific embodiment, R ^3b is -CH ₃ .

[0155] In one embodiment, the compound of the invention corresponds to any one of formulas I-IIIf and Va-f, where R ^3b is C _1-4 alkoxy. In a particular embodiment, R ^3b is -O-CH ₃ , -O-CH ₂ CH ₃ , or -O-CH(CH ₃ ) ₂ . In yet another specific embodiment, R ^3b is -O-CH ₃ or -O-CH(CH ₃ ) ₂ . In the most specific embodiment, R ^3b is -O-CH ₃ .

[0156] In one embodiment, the compound of the invention corresponds to any one of formulas I-IIIf and Va-f, where R^3b represents C_1-4 alkoxy substituted with one or more independently selected halo, -OH or C_1-4 alkoxy. In a specific embodiment, R^3b is -O-CH₃,-O-CH₂CH₃ or -O-CH(CH₃)₂, each substituted with one or more independently selected halo, -OH or C_1-4 alkoxy. In another specific embodiment, R^3b represents C_1-4 alkoxy substituted with one, two or three independently selected halo, -OH or C_1-4 alkoxy. In yet another specific embodiment, R^3b represents C_1-4 alkoxy substituted with one or more independently selected F, Cl, -OH, -O-CH₃,-O-CH₂CH₃ or -O-CH(CH₃)₂. In yet another specific embodiment, R^3b is -O-CH₃ or -O-CH₂CH₃, each substituted with one or more independently selected halo, -OH or C_1-4 alkoxy. In another more specific embodiment, R^3b represents C_1-4 alkoxy substituted with one, two or three F or Cl. In another more specific embodiment, R^3b represents C_1-4 alkoxy substituted with one -OH, -O-CH₃,-O-CH₂CH₃ or -O-CH(CH₃)₂. In another more specific embodiment, R^3b represents C_1-4 alkoxy substituted with one or more independently selected F, -OH, or -O-CH₃. And in yet another more specific embodiment, R^3b is -O-CH₃ or -O-CH₂CH₃, each of which is substituted with one, two or three F. And in yet another more specific embodiment, R^3b is -O-CH₃ or -O-CH₂CH₃, each substituted with one -OH or -O-CH₃. In the most specific embodiment, R^3b is -O-CHF₂.

[0157] In one embodiment, the compound of the invention corresponds to any one of Formulas I-IIIf and Va-f, wherein R ^3b is -NR ^8a R ^8b and R ^8a and R ^8b are each as defined above. In a specific embodiment, R ^8a and R ^8b are both H. In another specific embodiment, one of R ^8a and R ^8b is H and the other is C _1-4 alkyl optionally substituted with one -OH or C _1-4 alkoxy. In yet another specific embodiment, R ^8a and R ^8b are both C _1-4 alkyl optionally substituted with one -OH or C _1-4 alkoxy. In yet another specific embodiment, one of R ^8a and R ^8b is H and the other is -CH ₃ , -CH ₂ CH ₃ , or -CH(CH ₃ ) ₂ . In another more specific embodiment, one of R ^8a and R ^8b is H and the other is -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ each substituted with one -OH , -O-CH ₃ , -O-CH ₂ CH ₃ or -O-CH(CH ₃ ) ₂ . In the most specific embodiment, R ^3b is -NH-CH ₃ , -NH-CH(CH ₃ ) ₂ or -NH-CH ₂ CH ₂ -OH.

[0158] In one embodiment, the compound of the invention is of formula VIa, VIb, VIc, VId, VIe, or VIf:

where R ^3a , R ⁷ and Z are defined above.

[0159] In one embodiment, the compound of the invention corresponds to any one of formulas VIa-f, where R ⁷ is C _1-4 alkyl. In a particular embodiment, R ⁷ is -CH ₃ , -CH ₂ CH ₃ , or -CH(CH ₃ ) ₂ . In yet another specific embodiment, R ⁷ is -CH ₃ or -CH ₂ CH ₃ . In the most specific embodiment, R ⁷ is -CH ₃ .

[0160] In one embodiment, the compound of the invention corresponds to the formula VIIa, VIIb, VIIc, VIId, VIIe or VIIf:

where R ^3a and Z are defined above.

[0161] In one embodiment, the compound of the invention corresponds to any one of formulas I-VIIf, where R ^3a is halogen or -OH. In a particular embodiment, R ^3a is F, Cl, or -OH.

[0162] In one embodiment, the compound of the invention corresponds to any one of formulas I-VIIf, where R ^3a is C _1-4 alkyl. In a particular embodiment, R ^3a is -CH ₃ , -CH ₂ CH ₃ , or -CH(CH ₃ ) ₂ . In yet another specific embodiment, R ^3a is -CH ₃ or -CH ₂ CH ₃ . In the most specific embodiment, R ^3a is -CH ₃ .

[0163] In one embodiment, the compound of the invention corresponds to any one of formulas I-VIIf, where R ^3a is C _1-4 alkoxy. In a particular embodiment, R ^3a is -O-CH ₃ , -O-CH ₂ CH ₃ , or -O-CH(CH ₃ ) ₂ . In yet another specific embodiment, R ^3a is -O-CH ₃ or -O-CH(CH ₃ ) ₂ . In the most specific embodiment, R ^3a is -O-CH ₃ .

[0164] In one embodiment, the compound of the invention corresponds to any one of formulas I-VIIf, where R^3a represents C_1-4 alkoxy substituted with one or more independently selected halo, -OH or C_1-4 alkoxy. In a specific embodiment, R^3a is -O-CH₃,-O-CH₂CH₃ or -O-CH(CH₃)₂, each substituted with one or more independently selected halo, -OH or C_1-4 alkoxy. In another specific embodiment, R^3a represents C_1-4 alkoxy substituted with one, two or three independently selected halo, -OH or C_1-4 alkoxy. In yet another specific embodiment, R^3a represents C_1-4 alkoxy substituted with one or more independently selected F, Cl, -OH, -O-CH₃,-O-CH₂CH₃ or -O-CH(CH₃)₂. In yet another specific embodiment, R^3a is -O-CH₃ or -O-CH₂CH₃, each substituted with one or more independently selected halo, -OH or C_1-4 alkoxy. In another more specific embodiment, R^3a represents C_1-4 alkoxy substituted with one, two or three F or Cl. In another more specific embodiment, R^3a represents C_1-4 alkoxy substituted with one -OH, -O-CH₃,-O-CH₂CH₃ or -O-CH(CH₃)₂. In another more specific embodiment, R^3a represents C_1-4 alkoxy substituted with one or more independently selected F, -OH, or -O-CH₃. In another more specific embodiment, R^3a is -O-CH₃ or -O-CH₂CH₃, each of which is substituted with one, two or three F. In yet another more specific embodiment, R^3a is -O-CH₃ or -O-CH₂CH₃, each substituted with one -OH or -O-CH₃. In the most specific embodiment, R^3a is -O-CHF₂.

[0165] In one embodiment, the compound of the invention corresponds to any one of Formulas I-VIIf, wherein R ^3a is -NR ^8a R ^8b and R ^8a and R ^8b are each as defined above. In a specific embodiment, R ^8a and R ^8b are both H. In another specific embodiment, one of R ^8a and R ^8b is H and the other is C _1-4 alkyl optionally substituted with one -OH or C _1-4 alkoxy. In yet another specific embodiment, R ^8a and R ^8b are both C _1-4 alkyl optionally substituted with one -OH or C _1-4 alkoxy. In yet another specific embodiment, one of R ^8a and R ^8b is H and the other is -CH ₃ , -CH ₂ CH ₃ , or -CH(CH ₃ ) ₂ . In another more specific embodiment, one of R ^8a and R ^8b is H and the other is -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ each substituted with one -OH , -O-CH ₃ , -O-CH ₂ CH ₃ or -O-CH(CH ₃ ) ₂ . In the most specific embodiment, R ^3a is -NH-CH ₃ , -NH-CH(CH ₃ ) ₂ or -NH-CH ₂ CH ₂ -OH.

[0166] In one embodiment, the compound of the invention is of formula VIIIa, VIIIb, VIIIc, or VIIId:

where Z is defined above.

[0167] In one embodiment, the compound of the invention corresponds to any one of Formulas I-IIIf and Va-VIIId, wherein Z is -NR ^5a R ^5b and R ^5a and R ^5b are as defined above. In a specific embodiment, R ^5a is H. In another specific embodiment, R ^5a is C _1-4 alkyl. In yet another specific embodiment, R ^5a is -CH ₃ , -CH ₂ CH ₃ , or -CH(CH ₃ ) ₂ . In the most specific embodiment, R ^5a is -CH ₃ .

[0168] In one embodiment, the compound of the invention corresponds to any one of formulas I-IIIf and Va-VIIId, where Z is -NR ^5a R ^5b , R ^5a is as defined above, and R ^5b is C _1-6 alkyl. In a particular embodiment, R ^5b is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -C(CH ₃ ) ₃ , -CH(CH ₃ )CH ₂ CH ₃ or -CH(CH ₃ )CH(CH ₃ ) ₂ . In yet another specific embodiment, R ^5b is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , or -CH ₂ CH(CH ₃ ) ₂ . In the most specific embodiment, R ^5b is -CH ₂ CH ₃ .

[0169] In one embodiment, the compound of the invention corresponds to any one of formulas I-IIIf and Va-VIIId, where Z is -NR ^5a R ^5b , R ^5a is as defined above, and R ^5b is C _1-6 alkyl, substituted with one or more independently selected R ⁹ . In a particular embodiment, R ^5b is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -C(CH ₃ ) ₃ , -CH(CH ₃ )CH ₂ CH ₃ , or -CH(CH ₃ )CH(CH ₃ ) ₂ , each substituted with one or more independently selected R ⁹ . In another specific embodiment, R ^5b is C _1-6 alkyl substituted with one, two or three independently selected R ⁹ . In another specific embodiment, R ^5b is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -C(CH ₃ ) ₃ , or -CH(CH ₃ )CH(CH ₃ ) ₂ , each of which is substituted with one or more independently selected R ⁹ . In another more specific embodiment, R ^5b is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -C (CH ₃ ) ₃ , -CH(CH ₃ )CH ₂ CH ₃ , or -CH(CH ₃ )CH(CH ₃ ) ₂ , each substituted with one, two or three independently selected R ⁹ . In another more specific embodiment, R ^5b is C _1-6 alkyl substituted with one R ⁹ . In another more specific embodiment, R ^5b is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -C(CH ₃ ) ₃ , or -CH(CH ₃ )CH(CH ₃ ) ₂ each substituted with one, two or three independently selected R ⁹ . In another more specific embodiment, R ^5b is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -C (CH ₃ ) ₃ , -CH(CH ₃ )CH ₂ CH ₃ , or -CH(CH ₃ )CH(CH ₃ ) ₂ each substituted with one R ⁹ . In the most specific embodiment, R ^5b is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -C(CH ₃ ) ₃ , or -CH(CH ₃ ) CH(CH ₃ ) ₂ each substituted with one R ⁹ .

[0170] In one embodiment, a compound of the invention is any one of formulas I-IIIf and Va-VIIId, where Z is -NR ^5a R ^5b , R ^5a is as defined above, R ^5b is C _1-6 alkyl substituted with one or more independently selected R ⁹ , and R ⁹ is halogen, -CN, -OH, C _1-4 alkoxy or -S(=O) ₂ -C _1-4 alkyl. In a particular embodiment, each R ⁹ is independently F, Cl, -CN, -OH, -O-CH ₃ , -O-CH ₂ CH ₃ , -O-CH(CH ₃ ) ₂ , -S(=O ) ₂ -CH ₃ , -S(=O) ₂ -CH ₂ CH ₃ or -S(=O) ₂ -CH(CH ₃ ) ₂ . In yet another specific embodiment, each R ⁹ is independently F, -CN, -OH, -O-CH ₃ or -S(=O) ₂ -CH ₃ .

[0171] In one embodiment, a compound of the invention is any one of formulas I-IIIf and Va-VIIId, where Z is -NR ^5a R ^5b , R ^5a is as defined above, R ^5b is C _1-6 alkyl substituted with one or more independently selected R ⁹ , and R ⁹ is -NR ^11e R ^11f , and each R ^11e and R ^11f are defined above. In a specific embodiment, R ^11e and R ^11f are both H. In another specific embodiment, one of R ^11e and R ^11f is H and the other is C _1-4 alkyl. In yet another specific embodiment, R ^11e and R ^11f are both C _1-4 alkyl. In yet another specific embodiment, one of R ^11e and R ^11f is H and the other is -CH ₃ , -CH ₂ CH ₃ , or -CH(CH ₃ ) ₂ . In another more specific embodiment, R ^11e and R ^11f represent -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . In the most specific embodiment, R ^11e and R ^11f are -CH ₃ .

[0172] In one embodiment, a compound of the invention is any one of formulas I-IIIf and Va-VIIId, where Z is -NR ^5a R ^5b , R ^5a is as defined above, R ^5b is C _1-6 alkyl substituted with one or more independently selected R ⁹ , and R ⁹ is a 4-7 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S. In a specific embodiment, R ⁹ is azetidinyl , oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl or piperazinyl. In yet another specific embodiment, R ⁹ is dioxanyl.

[0173] In one embodiment, a compound of the invention is any one of formulas I-IIIf and Va-VIIId, where Z is -NR ^5a R ^5b , R ^5a is as defined above, R ^5b is C _1-6 alkyl substituted with one or more independently selected R ⁹ , and R ⁹ is a 5-6 membered monocyclic heteroaryl containing one, two or three heteroatoms independently selected from N, O and S. In a particular embodiment, R ⁹ is pyrrolyl , furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl or pyrimidinyl. In yet another specific embodiment, R ⁹ is imidazolyl, pyrazolyl, or pyridinyl. In the most specific embodiment, R ⁹ is pyridinyl.

[0174] In one embodiment, a compound of the invention is any one of formulas I-IIIf and Va-VIIId, where Z is -NR ^5a R ^5b , R ^5a is as defined above, R ^5b is C _1-6 alkyl substituted with one or more independently selected R ⁹ , and R ⁹ is a 5-6 membered monocyclic heteroaryl containing one, two or three heteroatoms independently selected from N, O and S, where the heteroaryl is substituted with one or more independently selected C _1-4 alkyl. In a particular embodiment, R ⁹ is pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, or pyrimidinyl, each substituted with one or more independently selected C _1-4 alkyl. In another specific embodiment, R ⁹ is a 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O and S, wherein the heteroaryl is substituted with one C _1-4 alkyl. In another specific embodiment, R ⁹ is a 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O and S, where the heteroaryl is substituted with one or more independently selected -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . In yet another specific embodiment, R ⁹ is imidazolyl or pyrazolyl, each substituted with one or more independently selected C _1-4 alkyl. In another more specific embodiment, R ⁹ is pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, or pyrimidinyl, each of which is substituted with one C _1-4 alkyl. In another more specific embodiment, R ⁹ is pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, or pyrimidinyl, each of which is substituted using one or more independently selected -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . In yet another more specific embodiment, R ⁹ is a 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O and S, where the heteroaryl is substituted with one -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . In yet another more specific embodiment, R ⁹ is a 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O and S, wherein the heteroaryl is substituted with one or more -CH ₃ . In another more specific embodiment, R ⁹ is imidazolyl or pyrazolyl, each of which is substituted with one C _1-4 alkyl. In another more specific embodiment, R ⁹ is pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, or pyrimidinyl, each of which is substituted with one -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . In another more specific embodiment, R ⁹ is a 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O and S, wherein the heteroaryl is substituted with one -CH ₃ . In the most specific embodiment, R ⁹ is imidazolyl or pyrazolyl, each of which is substituted with one -CH ₃ .

[0175] In one embodiment, the compound of the invention corresponds to any one of formulas I-IIIf and Va-VIIId, where Z is -NR ^5a R ^5b , R ^5a is as defined above, and R ^5b is C _3-7 cycloalkyl. In a particular embodiment, R ^5b is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In yet another specific embodiment, R ^5b is cyclopropyl, cyclobutyl, cyclopentyl. In the most specific embodiment, R ^5b is cyclopropyl.

[0176] In one embodiment, the compound of the invention corresponds to any one of formulas I-IIIf and Va-VIIId, where Z is -NR ^5a R ^5b , R ^5a is as defined above, and R ^5b is C _3-7 cycloalkyl, substituted with one or more independently selected R ¹⁰ . In a specific embodiment, R ^5b is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one or more independently selected R ¹⁰ . In another specific embodiment, R ^5b is C _3-7 cycloalkyl substituted with one, two or three independently selected R ¹⁰ . In yet another specific embodiment, R ^5b is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one, two or three independently selected R ¹⁰ . In another more specific embodiment, R ^5b is C _3-7 cycloalkyl substituted with one R ¹⁰ . In the most specific embodiment, R ^5b is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one R ¹⁰ .

[0177] In one embodiment, a compound of the invention is any one of formulas I-IIIf and Va-VIIId, wherein Z is -NR ^5a R ^5b , R ^5a is as defined above, R ^5b is C _3-7 cycloalkyl substituted with one or more independently selected R ¹⁰ , and R ¹⁰ is halogen, -OH, or C _1-4 alkoxy. In a particular embodiment, R ¹⁰ is F, Cl, -OH, -O-CH ₃ , -O-CH ₂ CH ₃ , or -O-CH(CH ₃ ) ₂ . In yet another specific embodiment, R ¹⁰ is F, -OH, or -O-CH ₃ .

[0178] In one embodiment, a compound of the invention is any one of formulas I-IIIf and Va-VIIId, where Z is -NR ^5a R ^5b , R ^5a is as defined above, R ^5b is C _3-7 cycloalkyl substituted with one or more independently selected R ¹⁰ , and R ¹⁰ is C _1-4 alkyl. In a particular embodiment, R ¹⁰ is -CH ₃ , -CH ₂ CH ₃ , or -CH(CH ₃ ) ₂ . In yet another specific embodiment, R ¹⁰ is -CH ₃ .

[0179] In one embodiment, a compound of the invention is any one of formulas I-IIIf and Va-VIIId, wherein Z is -NR ^5a R ^5b , R ^5a is as defined above, R ^5b is C _3-7 cycloalkyl substituted with one or more independently selected R ¹⁰ , and R ¹⁰ is C _1-4 alkyl substituted with one or more independently selected halogen, -OH, or C _1-4 alkoxy. In a particular embodiment, R ¹⁰ is -CH ₃ , -CH ₂ CH ₃ , or -CH(CH ₃ ) ₂ , each of which is substituted with one or more independently selected halo, -OH, or C _1-4 alkoxy. In another specific embodiment, R ¹⁰ is C _1-4 alkyl substituted with one, two or three independently selected halo, -OH, or C _1-4 alkoxy. In yet another specific embodiment, R ¹⁰ is C _1-4 alkyl substituted with one or more F, Cl, -OH, -O-CH ₃ , -O-CH ₂ CH ₃ , or -O-CH(CH ₃ ) ₂ . In yet another specific embodiment, R ¹⁰ is -CH ₃ substituted with one or more independently selected halo, -OH, or C _1-4 alkoxy. In another more specific embodiment, R ¹⁰ is C _1-4 alkyl substituted with one halogen, -OH, or C _1-4 alkoxy. In yet another more specific embodiment, R ¹⁰ is C _1-4 alkyl substituted with one or more independently selected F or -OH. In another more specific embodiment, R ¹⁰ is -CH ₃ , -CH ₂ CH ₃ , or -CH(CH ₃ ) ₂ , each of which is substituted with one, two or three independently selected halo, -OH or C _{1 -4} alkoxy. In another more specific embodiment, R ¹⁰ is C _1-4 alkyl substituted with one, two or three independently selected F, Cl, -OH, -O-CH ₃ , -O-CH ₂ CH ₃ , or - O-CH(CH ₃ ) ₂ . In the most specific embodiment, R ¹⁰ is -CH ₂ F, -CHF ₂ , -CF ₃ or -CH ₂ -OH.

[0180] In one embodiment, the compound of the invention corresponds to any one of formulas I-IIIf and Va-VIIId, where Z is -NR ^5a R ^5b , R ^5a is as defined above, R ^5b is C _3-7 cycloalkyl substituted with one or more independently selected R ¹⁰ , and R ¹⁰ is -NR ^11g R ^11h and R ^11g and R ^11h are each as defined above. In a specific embodiment, R ^11g and R ^11h are both H. In another specific embodiment, one of R ^11g and R ^11h is H and the other is C _1-4 alkyl. In yet another specific embodiment, R ^11g and R ^11h are both C _1-4 alkyl. In yet another specific embodiment, one of R ^11g and R ^11h is H and the other is -CH ₃ , -CH ₂ CH ₃ , or -CH(CH ₃ ) ₂ . In another more specific embodiment, R ^11g and R ^11h represent -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . In the most specific embodiment, R ^11g and R ^11h are -CH ₃ .

[0181] In one embodiment, the compound of the invention corresponds to any one of formulas I-IIIf and Va-VIIId, where Z is -NR ^5a R ^5b , R ^5a is as defined above, and R ^5b is a 4-7 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S. In a specific embodiment, R ^5b is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, or tetrahydrothiopyranyl. In yet another specific embodiment, R ^5b is oxetanyl, thietanyl, or tetrahydrothiopyranil. In the most specific embodiment, R ^5b is oxetanyl.

[0182] In one embodiment, the compound of the invention corresponds to any one of formulas I-IIIf and Va-VIIId, where Z is -NR ^5a R ^5b , R ^5a is as defined above, and R ^5b is a 4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O and S, wherein the heterocycloalkyl is substituted with one or more oxo. In a specific embodiment, R ^5b is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, or tetrahydrothiopyranyl, each of which is substituted with one or more oxo. In another specific embodiment, R ^5b is a 4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O and S, wherein the heterocycloalkyl is substituted with one oxo. In yet another specific embodiment, R ^5b is thietanyl or tetrahydrothiophenyl, each of which is substituted with one or more oxo. In another more specific embodiment, R ^5b is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, or tetrahydrothiopyranyl, each of which is substituted with one oxo. In the most specific embodiment, R ^5b is thietanyl or tetrahydrothiophenyl, each of which is substituted with two oxo.

[0183] In one embodiment, the compound of the invention corresponds to any one of formulas I-IIIf and Va-VIIId, where Z is -NR ^5a R ^5b , R ^5a is as defined above, and R ^5b is a 5-6 membered monocyclic heteroaryl containing one, two or three heteroatoms independently selected from N, O and S. In a particular embodiment, R ^5b is imidazolyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl. In yet another specific embodiment, R ^5b is imidazolyl, pyrazolyl, isoxazolyl, or pyrimidinyl. In the most specific embodiment, R ^5b is isoxazolyl.

[0184] In one embodiment, the compound of the invention corresponds to any one of formulas I-IIIf and Va-VIIId, where Z is -NR ^5a R ^5b , R ^5a is as defined above, and R ^5b is a 5-6 membered monocyclic heteroaryl containing one, two or three heteroatoms independently selected from N, O and S, where heteroaryl is substituted with one or more independently selected C _1-4 alkyl. In a particular embodiment, R ^5b is imidazolyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, each substituted with one or more independently selected C _1-4 alkyls. In another specific embodiment, R ^5b is a 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O and S, wherein the heteroaryl is substituted with one C _1-4 alkyl. In yet another specific embodiment, R ^5b is a 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O and S, where the heteroaryl is substituted with one or more independently selected -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . In yet another specific embodiment, R ^5b is imidazolyl, pyrazolyl, or pyrimidinyl, each of which is substituted with one or more independently selected C _1-4 alkyl. In another more specific embodiment, R ^5b is a 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O and S, wherein the heteroaryl is substituted with one -CH ₃ . In another more specific embodiment, R ^5b is imidazolyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, each substituted with one C _1-4 alkyl. In yet another more specific embodiment, R ^5b is a 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O and S, wherein the heteroaryl is substituted with one -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . In another more specific embodiment, R ^5b is imidazolyl, pyrazolyl, or pyrimidinyl, each substituted with one C _1-4 alkyl. In another more specific embodiment, R ^5b is imidazolyl, pyrazolyl or pyrimidinyl, each of which is substituted with one or more -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . In another more specific embodiment, R ^5b is imidazolyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, each substituted with one or more -CH ₃ . In another more specific embodiment, R ^5b is imidazolyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, each substituted with one -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . In another more specific embodiment, R ^5b is a 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O and S, wherein the heteroaryl is substituted with one -CH ₃ . In the most specific embodiment, R ^5b is imidazolyl, pyrazolyl or pyrimidinyl, each of which is substituted with one -CH ₃ .

[0185] In one embodiment, the compound of the invention corresponds to any one of formulas I-IIIf and Va-VIIId, where Z is -NR ^5a R ^5b , R ^5a is H, and R ^5b is -CH ₂ CH ₃ , -CH ₂ CF ₃ , -CH(CH ₃ )CF ₃ or cyclopropyl.

[0186] In one embodiment, the compound of the invention corresponds to any one of formulas I-IIIf and Va-VIIId, where Z is an N-linked 4-7 membered heterocycloalkyl, further comprising zero, one or two additional heteroatoms, independently selected from N, O and S. In a particular embodiment, Z is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 2-azaspiro[3,3]heptanyl, 1,6-diazaspiro[3,3]heptanyl, 2,6-diazaspiro[3,3]heptanil, 1-oxa-6-azaspiro[3,3]heptanil, 2-oxa-6-azaspiro[3,3]heptanil, 1-thia-6-azaspiro[3, 3]heptanyl or 2-thia-6-azaspiro[3,3]heptanyl. In yet another specific embodiment, Z is azetidinyl, pyrrolidinyl, piperidinyl, 2-oxa-6-azaspiro-[3,3]heptanyl, or 2-thia-6-azaspiro[3,3]heptanyl.

[0187] In one embodiment, the compound of the invention corresponds to any one of formulas I-IIIf and Va-VIIId, where Z is an N-linked 4-7 membered heterocycloalkyl, further comprising zero, one or two additional heteroatoms, independently selected from N, O and S, substituted with one, two or three independently selected R ⁶ groups. In a particular embodiment, Z is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 2-azaspiro[3,3]heptanyl, 1,6-diazaspiro[3,3]heptanyl, 2,6-diazaspiro[3, 3]heptanyl, 1-oxa-6-azaspiro[3,3]heptanyl, 2-oxa-6-azaspiro[3,3]heptanyl, 1-thia-6-azaspiro[3,3]heptanyl, or 2-thia- 6-azaspiro[3,3]heptanyl, each substituted with one, two or three independently selected R ⁶ groups. In yet another specific embodiment, Z is azetidinyl, pyrrolidinyl, piperidinyl, or 2-thia-6-azaspiro[3,3]heptanyl, each substituted with one, two, or three independently selected R ⁶ groups.

[0188] In one embodiment, the compound of the invention corresponds to any one of formulas I-IIIf and Va-VIIId, where Z is an N-linked 4-7 membered heterocycloalkyl, further comprising zero, one or two additional heteroatoms, independently selected from N, O and S, substituted with one, two or three independently selected R ⁶ groups, and R ⁶ is oxo, halogen, -CN, -OH, phenyl, C _3-7 cycloalkyl, C _2-4 alkynyl or -C(=O)-C _1-4 alkoxy. In a specific embodiment, R ⁶ is oxo, F, Cl, -CN, -OH, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, -C≡CH, -C(=O)-O-CH ₃ , -C(= O)-O-CH ₂ CH ₃ or -C(=O)-O-CH(CH ₃ ) ₂ . In yet another specific embodiment, R ⁶ is oxo, F, -CN, -OH, phenyl, cyclopropyl, -C≡CH, or -C(=O)-O-CH ₃ .

[0189] In one embodiment, the compound of the invention corresponds to any one of formulas I-IIIf and Va-VIIId, where Z is an N-linked 4-7 membered heterocycloalkyl, further comprising zero, one or two additional heteroatoms, independently selected from N, O and S, substituted with one, two or three independently selected R ⁶ groups, and R ⁶ is -NR ^11a R ^11b and each R ^11a and R ^11b is defined above. In a specific embodiment, R ^11a and R ^11b are both H. In another specific embodiment, one of R ^11a and R ^11b is H and the other is C _1-4 alkyl. In yet another specific embodiment, R ^11a and R ^11b are both C _1-4 alkyl. In yet another specific embodiment, one of R ^11a and R ^11b is H and the other is -CH ₃ , -CH ₂ CH ₃ , or -CH(CH ₃ ) ₂ . In another more specific embodiment, R ^11a and R ^11b represent -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . In the most specific embodiment, R ^11a and R ^11b are -CH ₃ .

[0190] In one embodiment, the compound of the invention corresponds to any one of formulas I-IIIf and Va-VIIId, where Z is an N-linked 4-7 membered heterocycloalkyl, further comprising zero, one or two additional heteroatoms, independently selected from N, O and S, substituted with one, two or three independently selected R ⁶ groups, and R ⁶ is C _1-4 alkoxy. In a particular embodiment, R ⁶ is -O-CH ₃ , -O-CH ₂ CH ₃ , or -O-CH(CH ₃ ) ₂ . In yet another specific embodiment, R ⁶ is -O-CH ₃ .

[0191] In one embodiment, the compound of the invention corresponds to any one of formulas I-IIIf and Va-VIIId, where Z is an N-linked 4-7 membered heterocycloalkyl, further comprising zero, one or two additional heteroatoms, independently selected from N, O and S, substituted with one, two or three independently selected R ⁶ groups, and R ⁶ is C _1-4 alkoxy substituted with one or more halogen or phenyl. In a particular embodiment, R ⁶ is -O-CH ₃ , -O-CH ₂ CH ₃ , or -O-CH(CH ₃ ) ₂ , each of which is substituted with one or more halo or phenyl. In another specific embodiment, R ⁶ is C _1-4 alkoxy substituted with one, two or three halo or phenyl. In yet another specific embodiment, R ⁶ is C _1-4 alkoxy substituted with one or more F, Cl, or phenyl. In yet another specific embodiment, R ⁶ is -O-CH ₃ , -O-CH ₂ CH ₃ , or -O-CH(CH ₃ ) ₂ , each of which is substituted with one or more F, Cl or phenyl. In another more specific embodiment, R ⁶ is C _1-4 alkoxy substituted with one, two or three F, Cl, or phenyl. In another more specific embodiment, R ⁶ is -O-CH ₃ substituted with one, two or three halo or phenyl. In a most specific embodiment, R ⁶ is -O-CH ₃ substituted with one, two or three F. In another most specific embodiment, R ⁶ is -O-CH ₃ substituted with one phenyl.

[0192] In one embodiment, the compound of the invention corresponds to any one of formulas I-IIIf and Va-VIIId, where Z is an N-linked 4-7 membered heterocycloalkyl, further comprising zero, one or two additional heteroatoms, independently selected from N, O and S, substituted with one, two or three independently selected R ⁶ groups, and R ⁶ is C _1-4 alkyl. In a particular embodiment, R ⁶ is -CH ₃ , -CH ₂ CH ₃ , or -CH(CH ₃ ) ₂ . In yet another specific embodiment, R ⁶ is -CH ₃ or -CH ₂ CH ₃ .

[0193] In one embodiment, the compound of the invention corresponds to any one of formulas I-IIIf and Va-VIIId, where Z is an N-linked 4-7 membered heterocycloalkyl, further comprising zero, one or two additional heteroatoms, independently selected from N, O and S substituted with one, two or three independently selected R ⁶ groups, and R ⁶ is C _1-4 alkyl substituted with one or more halo, -OH or C _1-4 alkoxy. In a particular embodiment, R ⁶ is -CH ₃ , -CH ₂ CH ₃ , or -CH(CH ₃ ) ₂ substituted with one or more halo, -OH, or C _1-4 alkoxy. In another specific embodiment, R ⁶ is C _1-4 alkyl substituted with one, two or three halo, -OH, or C _1-4 alkoxy. In another specific embodiment, R ⁶ is C _1-4 alkyl substituted with one or more F, Cl, -OH, -O-CH ₃ , -O-CH ₂ CH ₃ , or -O-CH(CH ₃ ) ₂ . In yet another specific embodiment, R ⁶ is -CH ₃ substituted with one, two or three halo, -OH, or C _1-4 alkoxy. In another more specific embodiment, R ⁶ is C _1-4 alkyl substituted with one, two or three F, Cl, -OH, -O-CH ₃ , -O-CH ₂ CH ₃ , or -O- CH(CH ₃ ) ₂ . In yet another more specific embodiment, R ⁶ is -CH ₃ , -CH ₂ CH ₃ , or -CH(CH ₃ ) ₂ , each of which is substituted with one, two or three F, Cl, -OH, -O -CH ₃ , -O-CH ₂ CH ₃ or -O-CH(CH ₃ ) ₂ . In the most specific embodiment, R ⁶ is -CH ₃ substituted with one, two or three F or -OH.

[0194] In one embodiment, the compound of the invention corresponds to any one of formulas I-IIIf and Va-VIIId, where Z is an N-linked 4-7 membered heterocycloalkyl, further comprising zero, one or two additional heteroatoms, independently selected from N, O and S substituted with one, two or three independently selected R ⁶ groups, and R ⁶ is a 4-7 membered monocyclic heterocycloalkyl 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 yet another specific embodiment, R ⁶ is tetrahydropyranyl or morpholinyl.

.[0195] In one embodiment, a compound of the invention is any one of formulas I-IIIf and Va-VIIId, where Z is

.

[0196] In one embodiment, the compound of the invention corresponds to formula I, where the compound is selected from the following compounds:

N-ethyl-4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-2,6-dimethoxybenzamide,

N-ethyl-2,6-dimethoxy-4-[5-(3-pyridyl)benzimidazol-1-yl]-benzamide,

N-ethyl-2,6-dimethoxy-4-[5-(6-morpholino-3-pyridyl)-benzimidazol-1-yl]benzamide,

N-ethyl-2,6-dimethoxy-4-[5-[1-(2-morpholinoethyl)pyrazol-4-yl]benzimidazol-1-yl]benzamide,

4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-N-(2-hydroxy-ethyl)-2,6-dimethoxybenzamide,

4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-2,6-dimethoxy-N-methylbenzamide,

N-ethyl-2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)-benzimidazol-1-yl]benzamide,

4-[5-(1,3-dimethylpyrazol-4-yl)benzimidazol-1-yl]-N-ethyl-2,6-dimethoxybenzamide,

N-ethyl-4-[6-(1-ethylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl]-2,6-dimethoxybenzamide,

4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-N-(2-fluoroethyl)-2,6-dimethoxybenzamide,

N-(2,2-difluoroethyl)-4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-2,6-dimethoxybenzamide,

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

N-ethyl-2,6-dimethoxy-4-[5-[1-(2-methoxyethyl)pyrazol-4-yl]-benzimidazol-1-yl]benzamide,

N-ethyl-2,6-dimethoxy-4-[5-(1-tetrahydropyran-4-ylpyrazol-4-yl)benzimidazol-1-yl]benzamide,

4-[5-[1-(cyanomethyl)pyrazol-4-yl]benzimidazol-1-yl]-N-ethyl-2,6-dimethoxybenzamide,

N-ethyl-4-[5-[1-(2-hydroxyethyl)pyrazol-4-yl]benzimidazol-1-yl]-2,6-dimethoxybenzamide,

2-(difluoromethoxy)-N-ethyl-4-[5-(1-ethylpyrazol-4-yl)-benzimidazol-1-yl]-6-methoxybenzamide,

4-[5-[1-(2-amino-2-oxo-ethyl)pyrazol-4-yl]benzimidazol-1-yl]-N-ethyl-2,6-dimethoxybenzamide,

N-cyclopropyl-4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-2,6-dimethoxybenzamide,

4-[6-(1-ethylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)benzamide,

N-(2,2-difluoroethyl)-4-[6-(1-ethylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl]-2,6-dimethoxybenzamide,

4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-2,6-dimethoxy-N-propylbenzamide,

N-ethyl-4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-2-hydroxy-6-methoxybenzamide,

N-(2,2-difluoroethyl)-2,6-dimethoxy-4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl]benzamide,

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

N-cyclobutyl-4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-2,6-dimethoxybenzamide,

4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-2,6-dimethoxy-N-(2-methoxyethyl)-N-methylbenzamide,

4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-N-isobutyl-2,6-dimethoxy-N-methylbenzamide,

4-[6-(1-ethylpyrazol-4-yl)imidazo[4,5-b]pyridin-3-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)benzamide,

N-cyclopropyl-4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-2,6-dimethoxy-N-methylbenzamide,

N-(cyanomethyl)-4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-2,6-dimethoxy-N-methylbenzamide,

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

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

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

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

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

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

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

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

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

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

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

N-tert-butyl-4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-2,6-dimethoxybenzamide,

4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-2,6-dimethoxy-N-(3,3,3-trifluoropropyl)benzamide,

N-cyclopentyl-4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-2,6-dimethoxybenzamide,

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

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

2-(difluoromethoxy)-N-ethyl-6-methoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzamide,

4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-2,6-dimethoxy-N-[(2R)-2-methylcyclopropyl]benzamide,

N-(cyanomethyl)-4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-2,6-dimethoxybenzamide,

4-(5-isoxazol-4-ylbenzimidazol-1-yl)-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)benzamide,

2,6-dimethoxy-4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]-pyrimidin-3-yl]-N-(2,2,2-trifluoroethyl)benzamide,

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

N-cyclopropyl-2-(difluoromethoxy)-4-[5-(1-ethylpyrazol-4-yl)-benzimidazol-1-yl]-6-methoxybenzamide,

4-[5-[1-(cyanomethyl)pyrazol-4-yl]benzimidazol-1-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxybenzamide,

N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[5-[1-(2-morpholinoethyl)pyrazol-4-yl]benzimidazol-1-yl]benzamide,

2-(difluoromethoxy)-N-ethyl-6-methoxy-4-[5-[1-(2-morpholino-ethyl)pyrazol-4-yl]benzimidazol-1-yl]benzamide,

2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-N-[(1R)-2,2,2-trifluoro-1-methyl-ethyl]benzamide,

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

2,6-dimethoxy-N-(3-methoxypropyl)-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzamide,

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

2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-N-(2-pyridylmethyl)benzamide,

N-(3-hydroxypropyl)-2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzamide,

N-(1,1-dioxothietan-3-yl)-2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)benzimidazol-1-yl]benzamide,

2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-N-(2-methylsulfonylethyl)benzamide,

N-(1,1-dioxothiolan-3-yl)-2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)benzimidazol-1-yl]benzamide,

N-[[(2R)-1,4-dioxan-2-yl]methyl]-2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzamide,

2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-N-(2,2,2-trifluoro-1,1-dimethylethyl)benzamide,

N-[[(2S)-1,4-dioxan-2-yl]methyl]-2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzamide,

2,6-dimethoxy-N-(5-methylpyrazin-2-yl)-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzamide,

2,6-dimethoxy-N-[(1-methylimidazol-2-yl)methyl]-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzamide,

N-isoxazol-3-yl-2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)-benzimidazol-1-yl]benzamide,

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

N-(cyanomethyl)-2,6-dimethoxy-N-methyl-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzamide,

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

N-tert-butyl-2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)-benzimidazol-1-yl]benzamide,

N-cyclobutyl-2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)-benzimidazol-1-yl]benzamide,

N-(2,2-difluoroethyl)-2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzamide,

N-(2-fluoroethyl)-2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)-benzimidazol-1-yl]benzamide,

2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-N-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]benzamide,

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

2,6-dimethoxy-N-(1-methylimidazol-4-yl)-4-[5-(1-methyl-pyrazol-4-yl)benzimidazol-1-yl]benzamide,

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

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

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

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

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

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

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

N-(2,2-difluorocyclopentyl)-2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)benzimidazol-1-yl]benzamide,

N-(2,2-difluoro-1-methyl-ethyl)-2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)benzimidazol-1-yl]benzamide,

2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-N-(oxetan-3-yl)benzamide,

2,6-dimethoxy-4-(5-pyridazin-4-ylbenzimidazol-1-yl)-N-(2,2,2-trifluoroethyl)benzamide,

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

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

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

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

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

2,6-dimethoxy-4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]-pyridin-3-yl]-N-(2,2,2-trifluoroethyl)benzamide,

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

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

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

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

2,6-dimethoxy-4-(5-pyrimidin-5-ylbenzimidazol-1-yl)-N-(2,2,2-trifluoroethyl)benzamide,

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

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

2,6-dimethoxy-4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-b]-pyridazin-3-yl]-N-(2,2,2-trifluoroethyl)benzamide,

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

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

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

2,6-dimethoxy-4-[5-[1-(tetrahydrofuran-2-ylmethyl)pyrazol-4-yl]benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)benzamide,

N-cyclopropyl-2,6-dimethoxy-4-[7-(1-methylpyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-yl]benzamide,

N-isobutyl-2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)-benzimidazol-1-yl]benzamide,

2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-N-sec-butyl-benzamide,

N-isopropyl-2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)-benzimidazol-1-yl]benzamide,

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

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

2-(difluoromethoxy)-N-ethyl-6-methoxy-4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl]benzamide,

N-cyclopropyl-2-isopropoxy-6-methoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzamide,

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

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

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

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

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

N-(3,3-difluorocyclobutyl)-2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)benzimidazol-1-yl]benzamide,

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

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

2,6-dimethoxy-4-(5-pyrazin-2-ylbenzimidazol-1-yl)-N-(2,2,2-trifluoroethyl)benzamide,

N-isobutyl-2,6-dimethoxy-4-[7-(1-methylpyrazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]benzamide,

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

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

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

N-(2,2-difluoroethyl)-2,6-dimethoxy-4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl]benzamide,

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

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

2-(difluoromethoxy)-N-ethyl-6-methoxy-4-[5-(5-methyl-1,2,4-oxadiazol-3-yl)benzimidazol-1-yl]benzamide,

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

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

N-[(1R,2R)-2-aminocyclohexyl]-2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)benzimidazol-1-yl]benzamide,

N-[(1R,2R)-2-hydroxycyclopentyl]-2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzamide,

N-[(1R,2S)-2-hydroxycyclopentyl]-2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzamide,

(3,3-difluoroazetidin-1-yl)-[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]phenyl]methanone,

N-[(1R,2R)-2-hydroxycyclopentyl]-2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzamide,

N-[(1R,2S)-2-fluorocyclopropyl]-2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)benzimidazol-1-yl]benzamide,

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

4-[7-(6-cyano-3-pyridyl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-N-ethyl-6-methoxybenzamide,

tert-butyl 4-[4-[3-[3-(difluoromethoxy)-4-(ethylcarbamoyl)-5-methoxyphenyl]imidazo[1,2-a]pyridin-7-yl]pyrazol-1-yl]piperidin-1- carboxylate,

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

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

2-(difluoromethoxy)-N-ethyl-6-methoxy-4-[5-(5-methyl-4H-1,2,4-triazol-3-yl)benzimidazol-1-yl]benzamide,

2-(difluoromethoxy)-4-[7-[1-(difluoromethyl)pyrazol-4-yl]imidazo[1,2-a]pyridin-3-yl]-N-ethyl-6-methoxybenzamide,

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

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

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

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

N-[(1R,2R)-2-(hydroxymethyl)cyclopropyl]-2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzamide,

N-[(1R,2R)-2-(difluoromethyl)cyclopropyl]-2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzamide,

N-[(1R,2S)-2-(difluoromethyl)cyclopropyl]-2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzamide,

N-[(1R,2R)-2-hydroxycyclobutyl]-2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzamide,

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

2,6-dimethoxy-N-(2-methoxycyclohexyl)-4-[5-(1-methyl-pyrazol-4-yl)benzimidazol-1-yl]benzamide,

azetidin-1-yl-[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)-benzimidazol-1-yl]phenyl]methanone,

N-(2-aminoethyl)-2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)-benzimidazol-1-yl]benzamide,

N-[(1S,2S)-2-hydroxycyclohexyl]-2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzamide,

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

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

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

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

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

N-[(1S,2S)-2-hydroxycyclobutyl]-2,6-dimethoxy-4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl]benzamide,

N-isopropyl-2,6-dimethoxy-4-[7-(1-methylpyrazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]benzamide,

N-[(1S,2S)-2-(difluoromethyl)cyclopropyl]-2,6-dimethoxy-4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl ]benzamide,

(3,3-difluoroazetidin-1-yl)-[2,6-dimethoxy-4-[7-(1-methyl-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl]phenyl ]Methanone,

2,6-dimethoxy-4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-a]-pyridin-3-yl]-N-[(1R)-2,2,2-trifluoro -1-methylethyl]benzamide,

2-ethyl-7-fluoro-5-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-isoindolin-1-one,

2-ethyl-7-methoxy-5-[7-(1-methylpyrazol-4-yl)imidazo[1,2-a]-pyridin-3-yl]isoindolin-1-one,

2-(difluoromethoxy)-N-ethyl-6-methoxy-4-[6-(1-methylpyrazol-4-yl)imidazo[4,5-b]pyridin-3-yl]benzamide,

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

[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]phenyl]-(3,3-dimethylazetidin-1-yl)methanone,

[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]phenyl]-(3-phenylazetidin-1-yl)methanone,

[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]phenyl]-(2,4-dimethylazetidin-1-yl)methanone,

[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]phenyl]-(2-methylazetidin-1-yl)methanone,

[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]phenyl]-[3-(hydroxymethyl)azetidin-1-yl]methanone,

[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]phenyl]-(3-hydroxyazetidin-1-yl)methanone,

[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]phenyl]-[3-(dimethylamino)azetidin-1-yl]methanone,

(3-benzyloxyazetidin-1-yl)-[2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)benzimidazol-1-yl]phenyl]methanone,

[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]phenyl]-(2-phenylazetidin-1-yl)methanone,

[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]phenyl]-(3-morpholinoazetidin-1-yl)methanone,

[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]phenyl]-(2,2,4-trimethylazetidin-1-yl)methanone,

[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]phenyl]-(3-methoxyazetidin-1-yl)methanone,

[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]phenyl]-(3-tetrahydropyran-4-ylazetidin-1-yl)methanone,

1-[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzoyl]azetidine-3-carbonitrile,

[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]phenyl]-[2-(hydroxymethyl)azetidin-1-yl]methanone,

[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]phenyl]-(2-oxa-6-azaspiro[3,3]heptan-6-yl)methanone ,

[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]phenyl]-(2,2-dioxo-2λ ⁶ -thia-6-azaspiro[3,3] heptan-6-yl) methanone,

[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]phenyl]-(3-phenylpyrrolidin-1-yl)methanone,

[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]phenyl]-(4-fluoro-1-piperidyl)methanone,

[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]phenyl]-[4-(trifluoromethoxy)-1-piperidyl]methanone,

N-tert-butyl-2-(difluoromethoxy)-6-methoxy-4-[5-(1-methyl-pyrazol-4-yl)benzimidazol-1-yl]benzamide,

2,6-dimethoxy-4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-a]-pyridin-3-yl]-N-[2-methyl-1-(trifluoromethyl)propyl] benzamide,

2-ethyl-7-(2-hydroxyethylamino)-5-[7-(1-methylpyrazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]isoindolin-1-one,

2-ethyl-7-(2-hydroxyethylamino)-5-[5-(1-methylpyrazol-4-yl)-benzimidazol-1-yl]isoindolin-1-one,

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

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

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

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

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

[2,6-dimethoxy-4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-a]-pyridin-3-yl]phenyl]-(3,3-dimethylazetidin-1-yl) methanone,

1-[2,6-dimethoxy-4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-a]-pyridin-3-yl]benzoyl]azetidine-3-carbonitrile,

1-[2,6-dimethoxy-4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-a]-pyridin-3-yl]benzoyl]pyrrolidine-3-carbonitrile,

(3,3-difluoropyrrolidin-1-yl)-[2,6-dimethoxy-4-[7-(1-methyl-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl]phenyl ]Methanone,

(4,4-difluoro-1-piperidyl)-[2,6-dimethoxy-4-[7-(1-methyl-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl]phenyl ]Methanone,

[2,6-dimethoxy-4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-a]-pyridin-3-yl]phenyl]-[3-(trifluoromethyl)azetidin-1-yl ]Methanone,

8-methoxy-6-[7-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one,

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

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

[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]phenyl]-(3-hydroxy-3-methyl-azetidin-1-yl)methanone,

[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]phenyl]-(3-ethyl-3-hydroxy-azetidin-1-yl)methanone,

[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]phenyl]-[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]methanone,

(3-cyclopropyl-3-hydroxy-azetidin-1-yl)-[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]phenyl]methanone,

[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]phenyl]-(3-ethynyl-3-hydroxy-azetidin-1-yl)methanone,

2,6-dimethoxy-4-[7-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl]-N-[(1R)-2,2,2-trifluoro- 1-methylethyl]benzamide,

2,6-dimethoxy-4-[7-(3-methylisoxazol-5-yl)imidazo[1,2-a]-pyridin-3-yl]-N-[(1R)-2,2,2-trifluoro -1-methyl-ethyl]benzamide,

2,6-dimethoxy-4-[7-(3-methylisoxazol-5-yl)imidazo[1,2-a]-pyridin-3-yl]-N-[(1S)-2,2,2-trifluoro -1-methyl-ethyl]benzamide,

8-methoxy-6-[7-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinoline -1-he,

methyl 1-[2,6-dimethoxy-4-[7-(1-methylpyrazol-4-yl)imidazo-[1,2-a]pyridin-3-yl]benzoyl]azetidine-3-carboxylate,

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

2-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethylcarbamoyl)-phenyl]imidazo[1,2-a]pyridin-7-yl]pyrazol-1-yl]acetic acid,

tert-butyl 2-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethyl-carbamoyl)phenyl]imidazo[1,2-a]pyridin-7-yl]pyrazol-1-yl ]acetate,

ethyl 2-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethylcarbamoyl)-phenyl]imidazo[1,2-a]pyridin-7-yl]pyrazol-1-yl] acetate,

isopropyl 2-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethyl-carbamoyl)phenyl]imidazo[1,2-a]pyridin-7-yl]pyrazol-1-yl ]acetate,

2,6-dimethoxy-4-[7-(3-methylisoxazol-5-yl)imidazo[1,2-a]-pyridin-3-yl]-N-(2,2,2-trifluoroethyl)benzamide,

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

cyclopropyl 2-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethyl-carbamoyl)phenyl]imidazo[1,2-a]pyridin-7-yl]pyrazol-1-yl ]acetate,

2-fluoroethyl 2-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethyl-carbamoyl)phenyl]imidazo[1,2-a]pyridin-7-yl]pyrazole-1 -yl]acetate,

methyl 2-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethyl-carbamoyl)phenyl]imidazo[1,2-a]pyridin-7-yl]pyrazol-1-yl ]acetate,

tetrahydrofuran-3-yl 2-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethylcarbamoyl)phenyl]imidazo[1,2-a]pyridin-7-yl]pyrazol-1 -yl]acetate,

cyclobutylmethyl 2-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoro-ethylcarbamoyl)phenyl]imidazo[1,2-a]pyridin-7-yl]pyrazol-1-yl ]-acetate,

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

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

2,6-dimethoxy-4-[7-(2-methoxypyrimidin-5-yl)imidazo[1,2-a]-pyridin-3-yl]-N-(2,2,2-trifluoroethyl)benzamide,

2,6-dimethoxy-4-(7-pyrimidin-5-ylimidazo[1,2-a]pyridin-3-yl)-N-(2,2,2-trifluoroethyl)benzamide,

tert-butyl 2-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethyl-carbamoyl)phenyl]imidazo[1,2-a]pyridin-7-yl]pyrazol-1-yl ]-propanoate,

methyl 2-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethyl-carbamoyl)phenyl]imidazo[1,2-a]pyridin-7-yl]pyrazol-1-yl ]-propanoate,

2,6-dimethoxy-4-[7-(5-methoxy-3-pyridyl)imidazo[1,2-a]-pyridin-3-yl]-N-(2,2,2-trifluoroethyl)benzamide,

4-[7-(2-Aminopyrimidin-5-yl)imidazo[1,2-a]pyridin-3-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)benzamide,

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

4-[7-(5-ethoxy-3-pyridyl)imidazo[1,2-a]pyridin-3-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)benzamide,

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

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

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

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

4-[7-(4-isopropylpyrimidin-5-yl)imidazo[1,2-a]pyridin-3-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)benzamide,

2-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethylcarbamoyl)-phenyl]imidazo[1,2-a]pyridin-7-yl]pyrazol-1-yl]propanoic acid,

4-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethylcarbamoyl)-phenyl]imidazo[1,2-a]pyridin-7-yl]pyrazol-1-yl]butanoic acid,

methyl 4-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethyl-carbamoyl)phenyl]imidazo[1,2-a]pyridin-7-yl]pyrazol-1-yl ]-butanoate,

ethyl 4-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethylcarbamoyl)-phenyl]imidazo[1,2-a]pyridin-7-yl]pyrazol-1-yl] butanoate,

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

3-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethylcarbamoyl)phenyl]imidazo[1,2-a]pyridin-7-yl]pyridine-4-carboxamide,

tert-butyl 3-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethyl-carbamoyl)phenyl]imidazo[1,2-a]pyridin-7-yl]pyrazol-1-yl ]-azetidine-1-carboxylate,

7-methoxy-5-[7-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)isoindolin-1-one,

2-cyclopropyl-8-methoxy-6-[7-(1-methylpyrazol-4-yl)imidazo-[1,2-a]pyridin-3-yl]-3,4-dihydroisoquinolin-1-one,

ethyl 2-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethylcarbamoyl)-phenyl]imidazo[1,2-a]pyridin-7-yl]pyrazol-1-yl] propanoate,

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

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

4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl]-2,6-bis(trideuteriomethoxy)-N-(2,2,2-trifluoroethyl)benzamide ,

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

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

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

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

2,6-difluoro-4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl]-N-(2,2,2-trifluoroethyl)benzamide,

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

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

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

8-methoxy-6-[7-(6-methylpyridazin-3-yl)imidazo[1,2-a]-pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4- dihydroisoquinoline-1-one,

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

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

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

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

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

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

4-[7-(6-cyanopyridazin-3-yl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxybenzamide,

N-cyclopropyl-2-(difluoromethoxy)-4-[7-[6-(dimethylamino)-pyridazin-3-yl]imidazo[1,2-a]pyridin-3-yl]-6-methoxybenzamide,

ethyl 2-[4-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxyphenyl]imidazo[1,2-a]pyridin-7-yl]pyrazol-1-yl]acetate,

N-cyclopropyl-4-[7-(6-cyclopropylpyridazin-3-yl)imidazo-[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxybenzamide,

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

7-[5-(5-fluoro-3-pyridyl)benzimidazol-1-yl]-5-methoxy-2,3-dihydro-1,3-benzoxazin-4-one,

5-methoxy-7-[5-(5-methoxy-3-pyridyl)benzimidazol-1-yl]-2,3-dihydro-1,3-benzoxazin-4-one,

7-[5-(3-fluoro-2-pyridyl)benzimidazol-1-yl]-5-methoxy-2,3-dihydro-1,3-benzoxazin-4-one,

7-[5-(2-isopropylthiazol-4-yl)benzimidazol-1-yl]-5-methoxy-2,3-dihydro-1,3-benzoxazin-4-one,

ethyl 3-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethylcarbamoyl)-phenyl]imidazo[1,2-a]pyridin-7-yl]pyrazol-1-yl] -2-methyl-propanoate,

ethyl 2-[[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethyl-carbamoyl)phenyl]imidazo[1,2-a]pyridin-7-yl]pyrazole-1- yl]methyl]-3-methyl-butanoate,

ethyl 2-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethylcarbamoyl)-phenyl]imidazo[1,2-a]pyridin-7-yl]pyrazol-1-yl] -2-methyl-propanoate,

ethyl 2-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethylcarbamoyl)-phenyl]imidazo[1,2-a]pyridin-7-yl]pyrazol-1-yl] -3-methylbutanoate,

tetrahydrofuran-2-ylmethyl 2-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethylcarbamoyl)phenyl]imidazo[1,2-a]pyridin-7-yl]pyrazol-1 -yl]acetate,

ethyl 2-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]-7-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridin-6-yl ]hydroxyacetate,

2-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]-7-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridin-6-yl] hydroxyacetic acid,

4-[6-benzyloxy-7-(1-methylpyrazol-4-yl)imidazo[1,2-a]-pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxybenzamide,

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

ethyl 2-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxyphenyl]-7-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridin-6-yl]oxypropanoate ,

2-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]-7-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridin-6-yl] -hydroxypropanoic acid,

2-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethylcarbamoyl)-phenyl]-imidazo[1,2-a]pyridin-7-yl]pyrazol-1-yl] -2-methyl-propanoic acid,

2-(diethylamino)ethyl 2-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethylcarbamoyl)phenyl]imidazo[1,2-a]pyridin-7-yl]pyrazol- 1-yl]-2-methylpropanoate,

N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[5-(1H-pyrazol-4-yl)benzimidazol-1-yl]benzamide and

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

[0197] In one embodiment, the compound of the invention corresponds to formula I, where the compound is selected from the following compounds:

N-ethyl-4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-2,6-dimethoxybenzamide,

N-ethyl-2,6-dimethoxy-4-[5-(3-pyridyl)benzimidazol-1-yl]-benzamide,

N-ethyl-2,6-dimethoxy-4-[5-(6-morpholino-3-pyridyl)-benzimidazol-1-yl]benzamide,

N-ethyl-2,6-dimethoxy-4-[5-[1-(2-morpholinoethyl)pyrazol-4-yl]benzimidazol-1-yl]benzamide,

4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-N-(2-hydroxyethyl)-2,6-dimethoxybenzamide,

4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-2,6-dimethoxy-N-methylbenzamide,

N-ethyl-2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)-benzimidazol-1-yl]benzamide,

4-[5-(1,3-dimethylpyrazol-4-yl)benzimidazol-1-yl]-N-ethyl-2,6-dimethoxybenzamide,

N-ethyl-4-[6-(1-ethylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl]-2,6-dimethoxybenzamide,

4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-N-(2-fluoroethyl)-2,6-dimethoxybenzamide,

N-(2,2-difluoroethyl)-4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-2,6-dimethoxybenzamide,

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

N-ethyl-2,6-dimethoxy-4-[5-[1-(2-methoxyethyl)pyrazol-4-yl]-benzimidazol-1-yl]benzamide,

N-ethyl-2,6-dimethoxy-4-[5-(1-tetrahydropyran-4-ylpyrazol-4-yl)benzimidazol-1-yl]benzamide,

4-[5-[1-(cyanomethyl)pyrazol-4-yl]benzimidazol-1-yl]-N-ethyl-2,6-dimethoxybenzamide,

N-ethyl-4-[5-[1-(2-hydroxyethyl)pyrazol-4-yl]benzimidazol-1-yl]-2,6-dimethoxybenzamide,

2-(difluoromethoxy)-N-ethyl-4-[5-(1-ethylpyrazol-4-yl)-benzimidazol-1-yl]-6-methoxybenzamide,

4-[5-[1-(2-amino-2-oxo-ethyl)pyrazol-4-yl]benzimidazol-1-yl]-N-ethyl-2,6-dimethoxybenzamide,

N-cyclopropyl-4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-2,6-dimethoxybenzamide,

4-[6-(1-ethylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)benzamide,

N-(2,2-difluoroethyl)-4-[6-(1-ethylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl]-2,6-dimethoxybenzamide,

4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-2,6-dimethoxy-N-propylbenzamide,

N-ethyl-4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-2-hydroxy-6-methoxybenzamide,

N-(2,2-difluoroethyl)-2,6-dimethoxy-4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl]benzamide,

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

N-cyclobutyl-4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-2,6-dimethoxybenzamide,

4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-2,6-dimethoxy-N-(2-methoxyethyl)-N-methylbenzamide,

4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-N-isobutyl-2,6-dimethoxy-N-methylbenzamide,

4-[6-(1-ethylpyrazol-4-yl)imidazo[4,5-b]pyridin-3-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)benzamide,

N-cyclopropyl-4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-2,6-dimethoxy-N-methylbenzamide,

N-(cyanomethyl)-4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-2,6-dimethoxy-N-methylbenzamide,

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

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

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

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

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

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

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

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

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

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

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

N-tert-butyl-4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-2,6-dimethoxybenzamide,

4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-2,6-dimethoxy-N-(3,3,3-trifluoropropyl)benzamide,

N-cyclopentyl-4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-2,6-dimethoxybenzamide,

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

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

2-(difluoromethoxy)-N-ethyl-6-methoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzamide,

4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-2,6-dimethoxy-N-[(2R)-2-methylcyclopropyl]benzamide,

N-(cyanomethyl)-4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-2,6-dimethoxybenzamide,

4-(5-isoxazol-4-ylbenzimidazol-1-yl)-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)benzamide,

2,6-dimethoxy-4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]-pyrimidin-3-yl]-N-(2,2,2-trifluoroethyl)benzamide,

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

N-cyclopropyl-2-(difluoromethoxy)-4-[5-(1-ethylpyrazol-4-yl)-benzimidazol-1-yl]-6-methoxybenzamide,

4-[5-[1-(cyanomethyl)pyrazol-4-yl]benzimidazol-1-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxybenzamide,

N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[5-[1-(2-morpholinoethyl)pyrazol-4-yl]benzimidazol-1-yl]benzamide,

2-(difluoromethoxy)-N-ethyl-6-methoxy-4-[5-[1-(2-morpholino-ethyl)pyrazol-4-yl]benzimidazol-1-yl]benzamide,

2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-N-[(1R)-2,2,2-trifluoro-1-methyl-ethyl]benzamide,

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

2,6-dimethoxy-N-(3-methoxypropyl)-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzamide,

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

2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-N-(2-pyridylmethyl)benzamide,

N-(3-hydroxypropyl)-2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzamide,

N-(1,1-dioxothietan-3-yl)-2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)benzimidazol-1-yl]benzamide,

2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-N-(2-methylsulfonylethyl)benzamide,

N-(1,1-dioxothiolan-3-yl)-2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)benzimidazol-1-yl]benzamide,

N-[[(2R)-1,4-dioxan-2-yl]methyl]-2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzamide,

2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-N-(2,2,2-trifluoro-1,1-dimethyl-ethyl)benzamide,

N-[[(2S)-1,4-dioxan-2-yl]methyl]-2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzamide,

2,6-dimethoxy-N-(5-methylpyrazin-2-yl)-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzamide,

2,6-dimethoxy-N-[(1-methylimidazol-2-yl)methyl]-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzamide,

N-isoxazol-3-yl-2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)-benzimidazol-1-yl]benzamide,

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

N-(cyanomethyl)-2,6-dimethoxy-N-methyl-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzamide,

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

N-tert-butyl-2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)-benzimidazol-1-yl]benzamide,

N-cyclobutyl-2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)-benzimidazol-1-yl]benzamide,

N-(2,2-difluoroethyl)-2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzamide,

N-(2-fluoroethyl)-2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)-benzimidazol-1-yl]benzamide,

2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-N-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]benzamide,

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

2,6-dimethoxy-N-(1-methylimidazol-4-yl)-4-[5-(1-methyl-pyrazol-4-yl)benzimidazol-1-yl]benzamide,

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

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

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

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

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

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

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

N-(2,2-difluorocyclopentyl)-2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)benzimidazol-1-yl]benzamide,

N-(2,2-difluoro-1-methyl-ethyl)-2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)benzimidazol-1-yl]benzamide,

2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-N-(oxetan-3-yl)benzamide,

2,6-dimethoxy-4-(5-pyridazin-4-ylbenzimidazol-1-yl)-N-(2,2,2-trifluoroethyl)benzamide,

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

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

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

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

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

2,6-dimethoxy-4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]-pyridin-3-yl]-N-(2,2,2-trifluoroethyl)benzamide,

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

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

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

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

2,6-dimethoxy-4-(5-pyrimidin-5-ylbenzimidazol-1-yl)-N-(2,2,2-trifluoroethyl)benzamide,

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

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

2,6-dimethoxy-4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-b]-pyridazin-3-yl]-N-(2,2,2-trifluoroethyl)benzamide,

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

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

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

2,6-dimethoxy-4-[5-[1-(tetrahydrofuran-2-ylmethyl)pyrazol-4-yl]benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)benzamide,

N-cyclopropyl-2,6-dimethoxy-4-[7-(1-methylpyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-yl]benzamide,

N-isobutyl-2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)-benzimidazol-1-yl]benzamide,

2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]-N-sec-butyl-benzamide,

N-isopropyl-2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)-benzimidazol-1-yl]benzamide,

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

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

2-(difluoromethoxy)-N-ethyl-6-methoxy-4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl]benzamide,

N-cyclopropyl-2-isopropoxy-6-methoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzamide,

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

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

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

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

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

N-(3,3-difluorocyclobutyl)-2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)benzimidazol-1-yl]benzamide,

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

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

2,6-dimethoxy-4-(5-pyrazin-2-ylbenzimidazol-1-yl)-N-(2,2,2-trifluoroethyl)benzamide,

N-isobutyl-2,6-dimethoxy-4-[7-(1-methylpyrazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]benzamide,

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

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

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

N-(2,2-difluoroethyl)-2,6-dimethoxy-4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl]benzamide,

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

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

2-(difluoromethoxy)-N-ethyl-6-methoxy-4-[5-(5-methyl-1,2,4-oxadiazol-3-yl)benzimidazol-1-yl]benzamide,

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

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

N-[(1R,2R)-2-aminocyclohexyl]-2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)benzimidazol-1-yl]benzamide,

N-[(1R,2R)-2-hydroxycyclopentyl]-2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzamide,

N-[(1R,2S)-2-hydroxycyclopentyl]-2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzamide,

(3,3-difluoroazetidin-1-yl)-[2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)benzimidazol-1-yl]phenyl]methanone,

N-[(1R,2R)-2-hydroxycyclopentyl]-2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzamide,

N-[(1R,2S)-2-fluorocyclopropyl]-2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)benzimidazol-1-yl]benzamide,

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

4-[7-(6-cyano-3-pyridyl)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-N-ethyl-6-methoxybenzamide,

tert-butyl 4-[4-[3-[3-(difluoromethoxy)-4-(ethylcarbamoyl)-5-methoxyphenyl]imidazo[1,2-a]pyridin-7-yl]pyrazol-1-yl]piperidin-1- carboxylate,

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

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

2-(difluoromethoxy)-N-ethyl-6-methoxy-4-[5-(5-methyl-4H-1,2,4-triazol-3-yl)benzimidazol-1-yl]benzamide,

2-(difluoromethoxy)-4-[7-[1-(difluoromethyl)pyrazol-4-yl]imidazo[1,2-a]pyridin-3-yl]-N-ethyl-6-methoxybenzamide,

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

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

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

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

N-[(1R,2R)-2-(hydroxymethyl)cyclopropyl]-2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzamide,

N-[(1R,2R)-2-(difluoromethyl)cyclopropyl]-2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzamide,

N-[(1R,2S)-2-(difluoromethyl)cyclopropyl]-2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzamide,

N-[(1R,2R)-2-hydroxycyclobutyl]-2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzamide,

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

2,6-dimethoxy-N-(2-methoxycyclohexyl)-4-[5-(1-methyl-pyrazol-4-yl)benzimidazol-1-yl]benzamide,

azetidin-1-yl-[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)-benzimidazol-1-yl]phenyl]methanone,

N-(2-aminoethyl)-2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)-benzimidazol-1-yl]benzamide,

N-[(1S,2S)-2-hydroxycyclohexyl]-2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzamide,

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

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

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

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

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

N-[(1S,2S)-2-hydroxycyclobutyl]-2,6-dimethoxy-4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl]benzamide,

N-isopropyl-2,6-dimethoxy-4-[7-(1-methylpyrazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]benzamide,

N-[(1S,2S)-2-(difluoromethyl)cyclopropyl]-2,6-dimethoxy-4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl ]benzamide,

(3,3-difluoroazetidin-1-yl)-[2,6-dimethoxy-4-[7-(1-methyl-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl]phenyl ]Methanone,

2,6-dimethoxy-4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-a]-pyridin-3-yl]-N-[(1R)-2,2,2-trifluoro -1-methylethyl]benzamide,

2-ethyl-7-fluoro-5-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]isoindolin-1-one,

2-ethyl-7-methoxy-5-[7-(1-methylpyrazol-4-yl)imidazo[1,2-a]-pyridin-3-yl]isoindolin-1-one,

2-(difluoromethoxy)-N-ethyl-6-methoxy-4-[6-(1-methylpyrazol-4-yl)imidazo[4,5-b]pyridin-3-yl]benzamide,

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

[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]phenyl]-(3,3-dimethylazetidin-1-yl)methanone,

[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]phenyl]-(3-phenylazetidin-1-yl)methanone,

[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]phenyl]-(2,4-dimethylazetidin-1-yl)methanone,

[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]phenyl]-(2-methylazetidin-1-yl)methanone,

[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]phenyl]-[3-(hydroxymethyl)azetidin-1-yl]methanone,

[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]phenyl]-(3-hydroxyazetidin-1-yl)methanone,

[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]phenyl]-[3-(dimethylamino)azetidin-1-yl]methanone,

(3-benzyloxyazetidin-1-yl)-[2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)benzimidazol-1-yl]phenyl]methanone,

[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]phenyl]-(2-phenylazetidin-1-yl)methanone,

[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]phenyl]-(3-morpholinoazetidin-1-yl)methanone,

[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]phenyl]-(2,2,4-trimethylazetidin-1-yl)methanone,

[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]phenyl]-(3-methoxyazetidin-1-yl)methanone,

[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]phenyl]-(3-tetrahydropyran-4-ylazetidin-1-yl)methanone,

1-[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzoyl]azetidine-3-carbonitrile,

[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]phenyl]-[2-(hydroxymethyl)azetidin-1-yl]methanone,

[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]phenyl]-(2-oxa-6-azaspiro[3,3]heptan-6-yl)methanone ,

[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]phenyl]-(2,2-dioxo-2λ ⁶ -thia-6-azaspiro[3,3] heptan-6-yl) methanone,

[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]phenyl]-(3-phenylpyrrolidin-1-yl)methanone,

[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]phenyl]-(4-fluoro-1-piperidyl)methanone,

[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]phenyl]-[4-(trifluoromethoxy)-1-piperidyl]methanone,

N-tert-butyl-2-(difluoromethoxy)-6-methoxy-4-[5-(1-methyl-pyrazol-4-yl)benzimidazol-1-yl]benzamide,

2,6-dimethoxy-4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-a]-pyridin-3-yl]-N-[2-methyl-1-(trifluoromethyl)propyl] benzamide,

2-ethyl-7-(2-hydroxyethylamino)-5-[7-(1-methylpyrazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]isoindolin-1-one,

2-ethyl-7-(2-hydroxyethylamino)-5-[5-(1-methylpyrazol-4-yl)-benzimidazol-1-yl]isoindolin-1-one,

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

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

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

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

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

[2,6-dimethoxy-4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-a]-pyridin-3-yl]phenyl]-(3,3-dimethylazetidin-1-yl) methanone,

1-[2,6-dimethoxy-4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-a]-pyridin-3-yl]benzoyl]azetidine-3-carbonitrile,

1-[2,6-dimethoxy-4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-a]-pyridin-3-yl]benzoyl]pyrrolidine-3-carbonitrile,

(3,3-difluoropyrrolidin-1-yl)-[2,6-dimethoxy-4-[7-(1-methyl-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl]phenyl ]Methanone,

(4,4-difluoro-1-piperidyl)-[2,6-dimethoxy-4-[7-(1-methyl-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl]phenyl ]Methanone,

[2,6-dimethoxy-4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-a]-pyridin-3-yl]phenyl]-[3-(trifluoromethyl)azetidin-1-yl ]Methanone,

8-methoxy-6-[7-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one,

2,6-dimethoxy-4-[7-(1-methylimidazol-4-yl)imidazo[1,2-a]-pyridin-3-yl]-N-[(1R)-2,2,2-trifluoro -1-methylethyl]benzamide,

2,6-dimethoxy-4-[7-(1-methylimidazol-4-yl)imidazo[1,2-a]-pyridin-3-yl]-N-[(1S)-2,2,2-trifluoro -1-methylethyl]benzamide,

[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]phenyl]-(3-hydroxy-3-methylazetidin-1-yl)methanone,

[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]phenyl]-(3-ethyl-3-hydroxyazetidin-1-yl)methanone,

[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]phenyl]-[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]methanone,

(3-cyclopropyl-3-hydroxyazetidin-1-yl)-[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]phenyl]methanone,

[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]phenyl]-(3-ethynyl-3-hydroxy-azetidin-1-yl)methanone,

2,6-dimethoxy-4-[7-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl]-N-[(1R)-2,2,2-trifluoro- 1-methyl-ethyl]benzamide,

2,6-dimethoxy-4-[7-(3-methylisoxazol-5-yl)imidazo[1,2-a]-pyridin-3-yl]-N-[(1R)-2,2,2-trifluoro -1-methyl-ethyl]benzamide,

2,6-dimethoxy-4-[7-(3-methylisoxazol-5-yl)imidazo[1,2-a]-pyridin-3-yl]-N-[(1S)-2,2,2-trifluoro -1-methyl-ethyl]benzamide,

8-methoxy-6-[7-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinoline -1-he,

methyl 1-[2,6-dimethoxy-4-[7-(1-methylpyrazol-4-yl)imidazo-[1,2-a]pyridin-3-yl]benzoyl]azetidine-3-carboxylate,

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

2-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethylcarbamoyl)-phenyl]imidazo[1,2-a]pyridin-7-yl]pyrazol-1-yl]acetic acid,

tert-butyl 2-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethyl-carbamoyl)phenyl]imidazo[1,2-a]pyridin-7-yl]pyrazol-1-yl ]acetate,

ethyl 2-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethyl-carbamoyl)phenyl]imidazo[1,2-a]pyridin-7-yl]pyrazol-1-yl ]acetate,

isopropyl 2-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethyl-carbamoyl)phenyl]imidazo[1,2-a]pyridin-7-yl]pyrazol-1-yl ]acetate,

2,6-dimethoxy-4-[7-(3-methylisoxazol-5-yl)imidazo[1,2-a]-pyridin-3-yl]-N-(2,2,2-trifluoroethyl)benzamide,

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

cyclopropyl 2-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethyl-carbamoyl)phenyl]imidazo[1,2-a]pyridin-7-yl]pyrazol-1-yl ]acetate,

2-fluoroethyl 2-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethyl-carbamoyl)phenyl]imidazo[1,2-a]pyridin-7-yl]pyrazole-1 -yl]acetate,

methyl 2-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethyl-carbamoyl)phenyl]imidazo[1,2-a]pyridin-7-yl]pyrazol-1-yl ]acetate,

tetrahydrofuran-3-yl 2-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethylcarbamoyl)phenyl]imidazo[1,2-a]pyridin-7-yl]pyrazol-1 -yl]acetate,

cyclobutylmethyl 2-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoro-ethylcarbamoyl)phenyl]imidazo[1,2-a]pyridin-7-yl]pyrazol-1-yl ]-acetate,

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

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

2,6-dimethoxy-4-[7-(2-methoxypyrimidin-5-yl)imidazo[1,2-a]-pyridin-3-yl]-N-(2,2,2-trifluoroethyl)benzamide,

2,6-dimethoxy-4-(7-pyrimidin-5-ylimidazo[1,2-a]pyridin-3-yl)-N-(2,2,2-trifluoroethyl)benzamide,

tert-butyl 2-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethyl-carbamoyl)phenyl]imidazo[1,2-a]pyridin-7-yl]pyrazol-1-yl ]-propanoate,

methyl 2-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethyl-carbamoyl)phenyl]imidazo[1,2-a]pyridin-7-yl]pyrazol-1-yl ]-propanoate,

2,6-dimethoxy-4-[7-(5-methoxy-3-pyridyl)imidazo[1,2-a]-pyridin-3-yl]-N-(2,2,2-trifluoroethyl)benzamide,

4-[7-(2-Aminopyrimidin-5-yl)imidazo[1,2-a]pyridin-3-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)benzamide,

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

4-[7-(5-ethoxy-3-pyridyl)imidazo[1,2-a]pyridin-3-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)benzamide,

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

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

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

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

4-[7-(4-isopropylpyrimidin-5-yl)imidazo[1,2-a]pyridin-3-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)benzamide,

2-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethylcarbamoyl)-phenyl]imidazo[1,2-a]pyridin-7-yl]pyrazol-1-yl]propanoic acid,

4-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethylcarbamoyl)-phenyl]imidazo[1,2-a]pyridin-7-yl]pyrazol-1-yl]butanoic acid,

methyl 4-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethyl-carbamoyl)phenyl]imidazo[1,2-a]pyridin-7-yl]pyrazol-1-yl ]-butanoate,

ethyl 4-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethyl-carbamoyl)phenyl]imidazo[1,2-a]pyridin-7-yl]pyrazol-1-yl ]-butanoate,

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

3-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethylcarbamoyl)phenyl]imidazo[1,2-a]pyridin-7-yl]pyridine-4-carboxamide,

tert-butyl 3-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethyl-carbamoyl)phenyl]imidazo[1,2-a]pyridin-7-yl]pyrazol-1-yl ]-azetidine-1-carboxylate,

7-methoxy-5-[7-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)isoindolin-1-one,

2-cyclopropyl-8-methoxy-6-[7-(1-methylpyrazol-4-yl)imidazo-[1,2-a]pyridin-3-yl]-3,4-dihydroisoquinolin-1-one,

ethyl 2-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethylcarbamoyl)-phenyl]imidazo[1,2-a]pyridin-7-yl]pyrazol-1-yl] propanoate,

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

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

4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl]-2,6-bis(trideuteriomethoxy)-N-(2,2,2-trifluoroethyl)benzamide ,

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

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

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

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

2,6-difluoro-4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl]-N-(2,2,2-trifluoroethyl)benzamide,

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

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

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

8-methoxy-6-[7-(6-methylpyridazin-3-yl)imidazo[1,2-a]-pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4- dihydroisoquinoline-1-one,

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

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

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

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

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

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

4-[7-(6-cyanopyridazin-3-yl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxybenzamide,

N-cyclopropyl-2-(difluoromethoxy)-4-[7-[6-(dimethylamino)-pyridazin-3-yl]imidazo[1,2-a]pyridin-3-yl]-6-methoxybenzamide,

ethyl 2-[4-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxyphenyl]imidazo[1,2-a]pyridin-7-yl]pyrazol-1-yl]acetate,

N-cyclopropyl-4-[7-(6-cyclopropylpyridazin-3-yl)imidazo-[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxybenzamide,

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

7-[5-(5-fluoro-3-pyridyl)benzimidazol-1-yl]-5-methoxy-2,3-dihydro-1,3-benzoxazin-4-one,

5-methoxy-7-[5-(5-methoxy-3-pyridyl)benzimidazol-1-yl]-2,3-dihydro-1,3-benzoxazin-4-one,

7-[5-(3-fluoro-2-pyridyl)benzimidazol-1-yl]-5-methoxy-2,3-dihydro-1,3-benzoxazin-4-one and

7-[5-(2-isopropylthiazol-4-yl)benzimidazol-1-yl]-5-methoxy-2,3-dihydro-1,3-benzoxazin-4-one.

[0198] In one embodiment, the compound of the invention corresponds to Formula I, wherein the compound is N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[5-(1-methyl-pyrazol-4-yl)benzimidazole -1-yl]benzamide.

[0199] In one embodiment, the compound of the invention corresponds to Formula I, wherein the compound is not N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1 -yl]benzamide.

[0200] In one embodiment, to obtain a compound of the invention, the present invention provides a compound of formula A:

where

W is Cl, Br, I, -NH ₂ , -B(OH) ₂ or 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl;

Z represents

- -NR ^5a R ^5b or

N-linked 4-7 membered heterocycloalkyl further comprising zero, one or two additional heteroatoms independently selected from N, O and S, optionally substituted with one, two or three R ⁶ groups;

R ^3a and R ^3b are independently selected C _1-4 alkoxy, optionally substituted with one or more selected halo, -OH, or C _1-4 alkoxy;

R ^5a is H or C _1-4 alkyl;

R ^5b choose from

- C _1-6 alkyl, optionally substituted with one or more selected R ⁹ ,

- C _3-7 cycloalkyl optionally substituted with heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O and S, where heterocycloalkyl is optionally substituted with one or more oxo, and

- 5-6-membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O and S, where the heteroaryl is optionally substituted with one or more independently selected C _1-4 alkyl;

each R ⁶ is independently selected from

- oxo,

- halogen,

- -CN,

- -OH,

- -NR ^11a R ^11b ,

- phenyl,

- C _3-7 cycloalkyl,

- C _2-4 alkynyl,

- -C(=O)-C _1-4 alkoxy,

- C _1-4 alkoxy, optionally substituted with one or more halo or phenyl,

- C _1-4 alkyl optionally substituted with one or more halo, -OH or C _1-4 alkoxy, and

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

each R ⁹ is independently selected from

- halogen,

- -CN,

- -NR ^11e R ^11f ,

- -OH,

- C _1-4 alkoxy,

- -S(=O) ₂ -C _1-4 alkyl,

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

- 5-6-membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O and S, where the heteroaryl is optionally substituted with one or more independently selected C _1-4 alkyl;

each R ¹⁰ is independently selected from

- halogen,

- C _1-4 alkyl optionally substituted with one or more independently selected halo, -OH or C _1-4 alkoxy,

- -OH,

- C _1-4 alkoxy, and

- -NR ^11g R ^11h ;

each R ^11a , R ^11b , R ^11e , R ^11f , R ^11g , and R ^{11h is} independently selected from H and C _1-4 alkyl.

[0201] In a further embodiment, the present invention provides a compound of formula A for preparing a compound of the invention, wherein

[0202] In an additional embodiment, to obtain a compound of the invention, the present invention provides a compound of formula A, where R ^3a represents halogen or -OH. In a particular embodiment, R ^3a is F, Cl, or -OH.

[0203] In an additional embodiment, to obtain a compound of the invention, the present invention provides a compound of formula A, where R ^3a is C _1-4 alkyl. In a particular embodiment, R ^3a is -CH ₃ , -CH ₂ CH ₃ , or -CH(CH ₃ ) ₂ . In yet another specific embodiment, R ^3a is -CH ₃ or -CH ₂ CH ₃ . In the most specific embodiment, R ^3a is -CH ₃ .

[0204] In an additional embodiment, to obtain a compound of the invention, the present invention provides a compound of formula A, where R ^3a represents C _1-4 alkoxy. In a particular embodiment, R ^3a is -O-CH ₃ , -O-CH ₂ CH ₃ , or -O-CH(CH ₃ ) ₂ . In yet another specific embodiment, R ^3a is -O-CH ₃ or -O-CH(CH ₃ ) ₂ . In the most specific embodiment, R ^3a is -O-CH ₃ .

[0205] In an additional embodiment, to obtain a compound of the invention, the present invention provides a compound of formula A, where R^3a represents C_1-4 alkoxy substituted with one or more independently selected halo, -OH or C_1-4 alkoxy. In a specific embodiment, R^3a is -O-CH₃,-O-CH₂CH₃ or -O-CH(CH₃)₂, each substituted with one or more independently selected halo, -OH or C_1-4 alkoxy. In another specific embodiment, R^3a represents C_1-4 alkoxy substituted with one, two or three independently selected halo, -OH or C_1-4 alkoxy. In yet another specific embodiment, R^3a represents C_1-4 alkoxy substituted with one or more independently selected F, Cl, -OH, -O-CH₃,-O-CH₂CH₃ or -O-CH(CH₃)₂. In yet another specific embodiment, R^3a is -O-CH₃ or -O-CH₂CH₃, each substituted with one or more independently selected halo, -OH or C_1-4 alkoxy. In another more specific embodiment, R^3a represents C_1-4 alkoxy substituted with one, two or three F or Cl. In another more specific embodiment, R^3a represents C_1-4 alkoxy substituted with one -OH, -O-CH₃,-O-CH₂CH₃ or -O-CH(CH₃)₂. In another more specific embodiment, R^3a represents C_1-4 alkoxy substituted with one or more independently selected F, -OH, or -O-CH₃. In another more specific embodiment, R^3a is -O-CH₃ or -O-CH₂CH₃, each of which is substituted with one, two or three F. In another more specific embodiment, R^3a is -O-CH₃ or -O-CH₂CH₃, each substituted with one -OH or -O-CH₃. In the most specific embodiment, R^3a is -O-CHF₂.

[0206] In a further embodiment, for the preparation of a compound of the invention, the present invention provides a compound of formula A, wherein R ^3a is -NR ^8a R ^8b and R ^8a and R ^8b are each as defined above. In a specific embodiment, R ^8a and R ^8b are both H. In another specific embodiment, one of R ^8a and R ^8b is H and the other is C _1-4 alkyl optionally substituted with one -OH or C _1-4 alkoxy. In yet another specific embodiment, R ^8a and R ^8b are both C _1-4 alkyl optionally substituted with one -OH or C _1-4 alkoxy. In yet another specific embodiment, one of R ^8a and R ^8b is H and the other is -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . In another more specific embodiment, one of R ^8a and R ^8b is H and the other is -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ each substituted with one -OH , -O-CH ₃ , -O-CH ₂ CH ₃ or -O-CH(CH ₃ ) ₂ . In the most specific embodiment, R ^3a is -NH-CH ₃ , -NH-CH(CH ₃ ) ₂ or -NH-CH ₂ CH ₂ -OH.

[0207] In an additional embodiment, to obtain a compound of the invention, the present invention provides a compound of formula A, where R ^3b represents halogen or -OH. In a particular embodiment, R ^3b is F, Cl, or -OH.

[0208] In an additional embodiment, to obtain a compound of the invention, the present invention provides a compound of formula A, where R ^3b represents C _1-4 alkyl. In a particular embodiment, R ^3b is -CH ₃ , -CH ₂ CH ₃ , or -CH(CH ₃ ) ₂ . In yet another specific embodiment, R ^3b is -CH ₃ or -CH ₂ CH ₃ . In the most specific embodiment, R ^3b is -CH ₃ .

[0209] In an additional embodiment, to obtain a compound of the invention, the present invention provides a compound of formula A, where R ^3b represents C _1-4 alkoxy. In a particular embodiment, R ^3b is -O-CH ₃ , -O-CH ₂ CH ₃ , or -O-CH(CH ₃ ) ₂ . In yet another specific embodiment, R ^3b is -O-CH ₃ or -O-CH(CH ₃ ) ₂ . In the most specific embodiment, R ^3b is -O-CH ₃ .

[0210] In an additional embodiment, to obtain a compound of the invention, the present invention provides a compound of formula A, where R^3b represents C_1-4 alkoxy substituted with one or more independently selected halo, -OH or C_1-4 alkoxy. In a particular embodiment, R^3bis -O-CH₃,-O-CH₂CH₃ or -O-CH(CH₃)₂, each substituted with one or more independently selected halo, -OH or C_1-4 alkoxy. In another specific embodiment, R^3b represents C_1-4 alkoxy substituted with one, two or three independently selected halo, -OH or C_1-4 alkoxy. In yet another specific embodiment, R^3b represents C_1-4 alkoxy substituted with one or more independently selected F, Cl, -OH, -O-CH₃,-O-CH₂CH₃ or -O-CH(CH₃)₂. In yet another specific embodiment, R^3b is -O-CH₃ or -O-CH₂CH₃, each substituted with one or more independently selected halo, -OH or C_1-4 alkoxy. In another more specific embodiment, R^3b represents C_1-4 alkoxy substituted with one, two or three F or Cl. In another more specific embodiment, R^3b represents C_1-4 alkoxy substituted with one -OH, -O-CH₃,-O-CH₂CH₃ or -O-CH(CH₃)₂. In another more specific embodiment, R^3b represents C_1-4 alkoxy substituted with one or more independently selected F, -OH, or -O-CH₃. In another more specific embodiment, R^3b is -O-CH₃ or -O-CH₂CH₃, each of which is substituted with one, two or three F. In yet another more specific embodiment, R^3b is -O-CH₃ or -O-CH₂CH₃, each substituted with one -OH or -O-CH₃. In the most specific embodiment, R^3b is -O-CHF₂.

[0211] In a further embodiment, to prepare a compound of the invention, the present invention provides a compound of formula A, wherein R ^3b is -NR ^8a R ^8b and R ^8a and R ^8b are each as defined above. In a specific embodiment, R ^8a and R ^8b are both H. In another specific embodiment, one of R ^8a and R ^8b is H and the other is C _1-4 alkyl optionally substituted with one -OH or C _1-4 alkoxy. In yet another specific embodiment, R ^8a and R ^8b are both C _1-4 alkyl optionally substituted with one -OH or C _1-4 alkoxy. In yet another specific embodiment, one of R ^8a and R ^8b is H and the other is -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . In another more specific embodiment, one of R ^8a and R ^8b is H and the other is -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ each substituted with one -OH , -O-CH ₃ , -O-CH ₂ CH ₃ or -O-CH(CH ₃ ) ₂ . In the most specific embodiment, R ^3b is -NH-CH ₃ , -NH-CH(CH ₃ ) ₂ or -NH-CH ₂ CH ₂ -OH.

[0212] In a further embodiment, for the preparation of a compound of the invention, the present invention provides a compound of formula A wherein Z is -NR ^5a R ^5b and R ^5a and R ^5b are described above. In a specific embodiment, R ^5a is H. In another specific embodiment, R ^5a is C _1-4 alkyl. In yet another specific embodiment, R ^5a is -CH ₃ , -CH ₂ CH ₃ , or -CH(CH ₃ ) ₂ . In the most specific embodiment, R ^5a is -CH ₃ .

[0213] In a further embodiment, to prepare a compound of the invention, the present invention provides a compound of formula A, wherein Z is -NR ^5a R ^5b , R ^5a is as defined above, and R ^5b is C _1-6 alkyl. In a particular embodiment, R ^5b is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -C(CH ₃ ) ₃ , -CH(CH ₃ )CH ₂ CH ₃ or -CH(CH ₃ )CH(CH ₃ ) ₂ . In yet another specific embodiment, R ^5b is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , or -CH ₂ CH(CH ₃ ) ₂ . In the most specific embodiment, R ^5b is -CH ₂ CH ₃ .

[0214] In a further embodiment, to prepare a compound of the invention, the present invention provides a compound of formula A wherein Z is -NR ^5a R ^5b , R ^5a is as defined above, and R ^5b is C _1-6 alkyl substituted with one or more independently selected R ⁹ . In a particular embodiment, R ^5b is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -C(CH ₃ ) ₃ , -CH(CH ₃ )CH ₂ CH ₃ , or -CH(CH ₃ )CH(CH ₃ ) ₂ , each substituted with one or more independently selected R ⁹ . In another specific embodiment, R ^5b is C _1-6 alkyl substituted with one, two or three independently selected R ⁹ . In another specific embodiment, R ^5b is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -C(CH ₃ ) ₃ , or -CH(CH ₃ )CH(CH ₃ ) ₂ , each of which is substituted with one or more independently selected R ⁹ . In another more specific embodiment, R ^5b is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -C (CH ₃ ) ₃ , -CH(CH ₃ )CH ₂ CH ₃ , or -CH(CH ₃ )CH(CH ₃ ) ₂ , each substituted with one, two or three independently selected R ⁹ . In another more specific embodiment, R ^5b is C _1-6 alkyl substituted with one R ⁹ . In another more specific embodiment, R ^5b is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -C(CH ₃ ) ₃ , or -CH(CH ₃ )CH(CH ₃ ) ₂ each substituted with one, two or three independently selected R ⁹ . In another more specific embodiment, R ^5b is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -C (CH ₃ ) ₃ , -CH(CH ₃ )CH ₂ CH ₃ , or -CH(CH ₃ )CH(CH ₃ ) ₂ each substituted with one R ⁹ . In the most specific embodiment, R ^5b is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -C(CH ₃ ) ₃ , or -CH(CH ₃ ) CH(CH ₃ ) ₂ each substituted with one R ⁹ .

[0215] In a further embodiment, to prepare a compound of the invention, the present invention provides a compound of formula A wherein Z is -NR ^5a R ^5b , R ^5a is as defined above, R ^5b is C _1-6 alkyl substituted with one or more independently selected R ⁹ , and R ⁹ is halogen, -CN, -OH, C _1-4 alkoxy or -S(=O) ₂ -C _1-4 alkyl. In a particular embodiment, each R ⁹ is independently F, Cl, -CN, -OH, -O-CH ₃ , -O-CH ₂ CH ₃ , -O-CH(CH ₃ ) ₂ , -S(=O ) ₂ -CH ₃ , -S(=O) ₂ -CH ₂ CH ₃ or -S(=O) ₂ -CH(CH ₃ ) ₂ . In yet another specific embodiment, each R ⁹ is independently F, -CN, -OH, -O-CH ₃ or -S(=O) ₂ -CH ₃ .

[0216] In a further embodiment, to prepare a compound of the invention, the present invention provides a compound of formula A wherein Z is -NR ^5a R ^5b , R ^5a is as defined above, R ^5b is C _1-6 alkyl substituted with one or more independently selected R ⁹ , and R ⁹ is -NR ^11e R ^11f , and each R ^11e and R ^11f are defined above. In a specific embodiment, R ^11e and R ^11f are both H. In another specific embodiment, one of R ^11e and R ^11f is H and the other is C _1-4 alkyl. In yet another specific embodiment, R ^11e and R ^11f are both C _1-4 alkyl. In yet another specific embodiment, one of R ^11e and R ^11f is H and the other is -CH ₃ , -CH ₂ CH ₃ , or -CH(CH ₃ ) ₂ . In another more specific embodiment, R ^11e and R ^11f represent -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . In the most specific embodiment, R ^11e and R ^11f are -CH ₃ .

[0217] In a further embodiment, to prepare a compound of the invention, the present invention provides a compound of formula A wherein Z is -NR ^5a R ^5b , R ^5a is as defined above, R ^5b is C _1-6 alkyl substituted with one or more independently selected R ⁹ , and R ⁹ is a 4-7 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S. In a particular embodiment, R ⁹ is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl or piperazinyl. In yet another specific embodiment, R ⁹ is dioxanyl.

[0218] In a further embodiment, to prepare a compound of the invention, the present invention provides a compound of formula A wherein Z is -NR ^5a R ^5b , R ^5a is as defined above, R ^5b is C _1-6 alkyl substituted with one or more independently selected R ⁹ , and R ⁹ is a 5-6 membered monocyclic heteroaryl containing one, two or three heteroatoms independently selected from N, O and S. In a particular embodiment, R ⁹ is pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl or pyrimidinyl. In yet another specific embodiment, R ⁹ is imidazolyl, pyrazolyl, or pyridinyl. In the most specific embodiment, R ⁹ is pyridinyl.

[0219] In a further embodiment, to prepare a compound of the invention, the present invention provides a compound of formula A wherein Z is -NR ^5a R ^5b , R ^5a is as defined above, R ^5b is C _1-6 alkyl substituted with one or more independently selected R ⁹ , and R ⁹ is a 5-6 membered monocyclic heteroaryl containing one, two or three heteroatoms independently selected from N, O and S, where the heteroaryl is substituted with one or more independently selected C _{1- 4} alkyl. In a particular embodiment, R ⁹ is pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, or pyrimidinyl, each substituted with one or more independently selected C _1-4 alkyl. In another specific embodiment, R ⁹ is a 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O and S, wherein the heteroaryl is substituted with one C _1-4 alkyl. In another specific embodiment, R ⁹ is a 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O and S, where the heteroaryl is substituted with one or more independently selected -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . In yet another specific embodiment, R ⁹ is imidazolyl or pyrazolyl, each of which is substituted with one or more independently selected C _1-4 alkyl. In another more specific embodiment, R ⁹ is pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, or pyrimidinyl, each of which is substituted with one C _1-4 alkyl. In another more specific embodiment, R ⁹ is pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, or pyrimidinyl, each of which is substituted using one or more independently selected -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . In yet another more specific embodiment, R ⁹ is a 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O and S, where the heteroaryl is substituted with one -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . In yet another more specific embodiment, R ⁹ is a 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O and S, wherein the heteroaryl is substituted with one or more -CH ₃ . In another more specific embodiment, R ⁹ is imidazolyl or pyrazolyl, each of which is substituted with one C _1-4 alkyl. In another more specific embodiment, R ⁹ is pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, or pyrimidinyl, each of which is substituted with one -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . In another more specific embodiment, R ⁹ is a 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O and S, wherein the heteroaryl is substituted with one -CH ₃ . In the most specific embodiment, R ⁹ is imidazolyl or pyrazolyl, each of which is substituted with one -CH ₃ .

[0220] In a further embodiment, to prepare a compound of the invention, the present invention provides a compound of formula A wherein Z is -NR ^5a R ^5b , R ^5a is as defined above, and R ^5b is C _3-7 cycloalkyl. In a particular embodiment, R ^5b is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In yet another specific embodiment, R ^5b is cyclopropyl, cyclobutyl, cyclopentyl. In the most specific embodiment, R ^5b is cyclopropyl.

[0221] In a further embodiment, to prepare a compound of the invention, the present invention provides a compound of formula A wherein Z is -NR ^5a R ^5b , R ^5a is as defined above, and R ^5b is C _3-7 cycloalkyl substituted with one or more independently selected R ¹⁰ . In a specific embodiment, R ^5b is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one or more independently selected R ¹⁰ . In another specific embodiment, R ^5b is C _3-7 cycloalkyl substituted with one, two or three independently selected R ¹⁰ . In yet another specific embodiment, R ^5b is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one, two or three independently selected R ¹⁰ . In another more specific embodiment, R ^5b is C _3-7 cycloalkyl substituted with one R ¹⁰ . In the most specific embodiment, R ^5b is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one R ¹⁰ .

[0222] In a further embodiment, to prepare a compound of the invention, the present invention provides a compound of formula A wherein Z is -NR ^5a R ^5b , R ^5a is as defined above, R ^5b is C _3-7 cycloalkyl substituted with one or more independently selected R ¹⁰ , and R ¹⁰ is halogen, -OH, or C _1-4 alkoxy. In a particular embodiment, R ¹⁰ is F, Cl, -OH, -O-CH ₃ , -O-CH ₂ CH ₃ , or -O-CH(CH ₃ ) ₂ . In yet another specific embodiment, R ¹⁰ is F, -OH, or -O-CH ₃ .

[0223] In a further embodiment, to prepare a compound of the invention, the present invention provides a compound of formula A wherein Z is -NR ^5a R ^5b , R ^5a is as defined above, R ^5b is C _3-7 cycloalkyl substituted with one or more independently selected R ¹⁰ , and R ¹⁰ is C _1-4 alkyl. In a particular embodiment, R ¹⁰ is -CH ₃ , -CH ₂ CH ₃ , or -CH(CH ₃ ) ₂ . In yet another specific embodiment, R ¹⁰ is -CH ₃ .

[0224] In a further embodiment, to prepare a compound of the invention, the present invention provides a compound of formula A wherein Z is -NR ^5a R ^5b , R ^5a is as defined above, R ^5b is C _3-7 cycloalkyl substituted with one or more independently selected R ¹⁰ , and R ¹⁰ is C _1-4 alkyl substituted with one or more independently selected halogen, -OH, or C _1-4 alkoxy. In a particular embodiment, R ¹⁰ is -CH ₃ , -CH ₂ CH ₃ , or -CH(CH ₃ ) ₂ , each of which is substituted with one or more independently selected halo, -OH, or C _1-4 alkoxy. In another specific embodiment, R ¹⁰ is C _1-4 alkyl substituted with one, two or three independently selected halogens, -OH, or C _1-4 alkoxy. In yet another specific embodiment, R ¹⁰ is C _1-4 alkyl substituted with one or more F, Cl, -OH, -O-CH ₃ , -O-CH ₂ CH ₃ , or -O-CH(CH ₃ ) ₂ . In yet another specific embodiment, R ¹⁰ is -CH ₃ substituted with one or more independently selected halo, -OH, or C _1-4 alkoxy. In another more specific embodiment, R ¹⁰ is C _1-4 alkyl substituted with one halogen, -OH, or C _1-4 alkoxy. In yet another more specific embodiment, R ¹⁰ is C _1-4 alkyl substituted with one or more independently selected F or -OH. In another more specific embodiment, R ¹⁰ is -CH ₃ , -CH ₂ CH ₃ , or -CH(CH ₃ ) ₂ , each of which is substituted with one, two or three independently selected halo, -OH or C _{1 -4} alkoxy. In another more specific embodiment, R ¹⁰ is C _1-4 alkyl substituted with one, two or three independently selected F, Cl, -OH, -O-CH ₃ , -O-CH ₂ CH ₃ , or - O-CH(CH ₃ ) ₂ . In the most specific embodiment, R ¹⁰ is -CH ₂ F, -CHF ₂ , -CF ₃ or -CH ₂ -OH.

[0225] In a further embodiment, to prepare a compound of the invention, the present invention provides a compound of formula A wherein Z is -NR ^5a R ^5b , R ^5a is as defined above, R ^5b is C _3-7 cycloalkyl substituted with one or more independently selected R ¹⁰ , and R ¹⁰ is -NR ^11g R ^11h , and each R ^11g and R ^11h are defined above. In a specific embodiment, R ^11g and R ^11h are both H. In another specific embodiment, one of R ^11g and R ^11h is H and the other is C _1-4 alkyl. In yet another specific embodiment, R ^11g and R ^11h are both C _1-4 alkyl. In yet another specific embodiment, one of R ^11g and R ^11h is H and the other is -CH ₃ , -CH ₂ CH ₃ , or -CH(CH ₃ ) ₂ . In another more specific embodiment, R ^11g and R ^11h represent -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . In the most specific embodiment, R ^11g and R ^11h are -CH ₃ .

[0226] In a further embodiment, to prepare a compound of the invention, the present invention provides a compound of formula A wherein Z is -NR ^5a R ^5b , R ^5a is as defined above, and R ^5b is a 4-7 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S. In a specific embodiment, R ^5b is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, or tetrahydrothiopyranyl. In yet another specific embodiment, R ^5b is oxetanyl, thietanyl, or tetrahydrothiopyranil. In the most specific embodiment, R ^5b is oxetanyl.

[0227] In a further embodiment, to prepare a compound of the invention, the present invention provides a compound of formula A wherein Z is -NR ^5a R ^5b , R ^5a is as defined above, and R ^5b is a 4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O and S, wherein the heterocycloalkyl is substituted with one or more oxo. In a specific embodiment, R ^5b is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, or tetrahydrothiopyranyl, each of which is substituted with one or more oxo. In another specific embodiment, R ^5b is a 4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O and S, wherein the heterocycloalkyl is substituted with one oxo. In yet another specific embodiment, R ^5b is thietanyl or tetrahydrothiophenyl, each of which is substituted with one or more oxo. In another more specific embodiment, R ^5b is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, or tetrahydrothiopyranyl, each of which is substituted with one oxo. In the most specific embodiment, R ^5b is thietanyl or tetrahydrothiophenyl, each of which is substituted with two oxo.

[0228] In a further embodiment, to prepare a compound of the invention, the present invention provides a compound of formula A wherein Z is -NR ^5a R ^5b , R ^5a is as defined above, and R ^5b is a 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S. In a specific embodiment, R ^5b is imidazolyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl. In yet another specific embodiment, R ^5b is imidazolyl, pyrazolyl, isoxazolyl, or pyrimidinyl. In the most specific embodiment, R ^5b is isoxazolyl.

[0229] In a further embodiment, to prepare a compound of the invention, the present invention provides a compound of formula A wherein Z is -NR ^5a R ^5b , R ^5a is as defined above, and R ^5b is a 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O and S, wherein the heteroaryl is substituted with one or more independently selected C _1-4 alkyls. In a particular embodiment, R ^5b is imidazolyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, each substituted with one or more independently selected C _1-4 alkyls. In another specific embodiment, R ^5b is a 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O and S, wherein the heteroaryl is substituted with one C _1-4 alkyl. In yet another specific embodiment, R ^5b is a 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O and S, where the heteroaryl is substituted with one or more independently selected -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . In yet another specific embodiment, R ^5b is imidazolyl, pyrazolyl, or pyrimidinyl, each of which is substituted with one or more independently selected C _1-4 alkyl. In another more specific embodiment, R ^5b is a 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O and S, wherein the heteroaryl is substituted with one -CH ₃ . In another more specific embodiment, R ^5b is imidazolyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, each substituted with one C _1-4 alkyl. In yet another more specific embodiment, R ^5b is a 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O and S, wherein the heteroaryl is substituted with one -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . In another more specific embodiment, R ^5b is imidazolyl, pyrazolyl, or pyrimidinyl, each substituted with one C _1-4 alkyl. In another more specific embodiment, R ^5b is imidazolyl, pyrazolyl or pyrimidinyl, each of which is substituted with one or more -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . In another more specific embodiment, R ^5b is imidazolyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, each substituted with one or more -CH ₃ . In another more specific embodiment, R ^5b is imidazolyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, each substituted with one -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . In another more specific embodiment, R ^5b is a 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O and S, wherein the heteroaryl is substituted with one -CH ₃ . In the most specific embodiment, R ^5b is imidazolyl, pyrazolyl or pyrimidinyl, each of which is substituted with one -CH ₃ .

[0230] In a further embodiment, to prepare a compound of the invention, the present invention provides a compound of formula A wherein Z is -NR ^5a R ^5b , R ^5a is H, and R ^5b is -CH ₂ CH ₃ , -CH ₂ CF ₃ , -CH(CH ₃ )CF ₃ or cyclopropyl.

[0231] In an additional embodiment, to obtain a compound of the invention, the present invention provides a compound of formula A, where Z is an N-linked 4-7 membered heterocycloalkyl, further comprising zero, one or two additional heteroatoms independently selected from N , O, and S. In a particular embodiment, Z is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 2-azaspiro[3,3]heptanyl, 1,6-diazaspiro[3,3]heptanyl, 2,6 -diazaspiro[3,3]heptanil, 1-oxa-6-azaspiro[3,3]heptanil, 2-oxa-6-azaspiro[3,3]heptanil, 1-thia-6-azaspiro[3,3]heptanil or 2-thia-6-azaspiro[3,3]heptanyl. In yet another specific embodiment, Z is azetidinyl, pyrrolidinyl, piperidinyl, 2-oxa-6-azaspiro[3,3]heptanyl, or 2-thia-6-azaspiro[3,3]heptanyl.

[0232] In an additional embodiment, to obtain a compound of the invention, the present invention provides a compound of formula A, where Z is an N-linked 4-7 membered heterocycloalkyl, further comprising zero, one or two additional heteroatoms independently selected from N , O and S substituted with one, two or three independently selected R ⁶ groups. In a particular embodiment, Z is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 2-azaspiro[3,3]heptanyl, 1,6-diazaspiro[3,3]heptanyl, 2,6-diazaspiro[3, 3]heptanyl, 1-oxa-6-azaspiro[3,3]heptanyl, 2-oxa-6-azaspiro[3,3]heptanyl, 1-thia-6-azaspiro[3,3]heptanyl, or 2-thia- 6-azaspiro[3,3]heptanyl, each substituted with one, two or three independently selected R ⁶ groups. In yet another specific embodiment, Z is azetidinyl, pyrrolidinyl, piperidinyl, or 2-thia-6-azaspiro[3,3]heptanyl, each substituted with one, two, or three independently selected R ⁶ groups.

[0233] In an additional embodiment, to obtain a compound of the invention, the present invention provides a compound of formula A, where Z is an N-linked 4-7 membered heterocycloalkyl, further comprising zero, one or two additional heteroatoms independently selected from N , O and S substituted with one, two or three independently selected R ⁶ groups, and R ⁶ is oxo, halogen, -CN, -OH, phenyl, C _3-7 cycloalkyl, C _2-4 alkynyl, or -C (=O)-C _1-4 alkoxy. In a specific embodiment, R ⁶ is oxo, F, Cl, -CN, -OH, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, -C≡CH, -C(=O)-O-CH ₃ , -C(= O)-O-CH ₂ CH ₃ or -C(=O)-O-CH(CH ₃ ) ₂ . In yet another specific embodiment, R ⁶ is oxo, F, -CN, -OH, phenyl, cyclopropyl, -C≡CH, or -C(=O)-O-CH ₃ .

[0234] In an additional embodiment, to obtain a compound of the invention, the present invention provides a compound of formula A, where Z is an N-linked 4-7 membered heterocycloalkyl, further comprising zero, one or two additional heteroatoms independently selected from N , O and S substituted with one, two or three independently selected R ⁶ groups, and R ⁶ is -NR ^11a R ^11b and R ^11a and R ^11b are each as defined above. In a specific embodiment, R ^11a and R ^11b are both H. In another specific embodiment, one of R ^11a and R ^11b is H and the other is C _1-4 alkyl. In yet another specific embodiment, R ^11a and R ^11b are both C _1-4 alkyl. In yet another specific embodiment, one of R ^11a and R ^11b is H and the other is -CH ₃ , -CH ₂ CH ₃ , or -CH(CH ₃ ) ₂ . In another more specific embodiment, R ^11a and R ^11b represent -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . In the most specific embodiment, R ^11a and R ^11b are -CH ₃ .

[0235] In an additional embodiment, to obtain a compound of the invention, the present invention provides a compound of formula A, where Z is an N-linked 4-7 membered heterocycloalkyl, further comprising zero, one or two additional heteroatoms independently selected from N , O and S substituted with one, two or three independently selected R ⁶ groups, and R ⁶ is C _1-4 alkoxy. In a particular embodiment, R ⁶ is -O-CH ₃ , -O-CH ₂ CH ₃ , or -O-CH(CH ₃ ) ₂ . In yet another specific embodiment, R ⁶ is -O-CH ₃ .

[0236] In an additional embodiment, to obtain a compound of the invention, the present invention provides a compound of formula A, where Z is an N-linked 4-7 membered heterocycloalkyl, further comprising zero, one or two additional heteroatoms independently selected from N , O and S substituted with one, two or three independently selected R ⁶ groups, and R ⁶ is C _1-4 alkoxy substituted with one or more halogen or phenyl. In a particular embodiment, R ⁶ is -O-CH ₃ , -O-CH ₂ CH ₃ , or -O-CH(CH ₃ ) ₂ , each of which is substituted with one or more halo or phenyl. In another specific embodiment, R ⁶ is C _1-4 alkoxy substituted with one, two or three halo or phenyl. In yet another specific embodiment, R ⁶ is C _1-4 alkoxy substituted with one or more F, Cl, or phenyl. In yet another specific embodiment, R ⁶ is -O-CH ₃ , -O-CH ₂ CH ₃ , or -O-CH(CH ₃ ) ₂ , each of which is substituted with one or more F, Cl or phenyl. In another more specific embodiment, R ⁶ is C _1-4 alkoxy substituted with one, two or three F, Cl, or phenyl. In another more specific embodiment, R ⁶ is -O-CH ₃ substituted with one, two or three halo or phenyl. In a most specific embodiment, R ⁶ is -O-CH ₃ substituted with one, two or three F. In another most specific embodiment, R ⁶ is -O-CH ₃ substituted with one phenyl.

[0237] In an additional embodiment, to obtain a compound of the invention, the present invention provides a compound of formula A, where Z is an N-linked 4-7 membered heterocycloalkyl, further comprising zero, one or two additional heteroatoms independently selected from N , O and S substituted with one, two or three independently selected R ⁶ groups, and R ⁶ is C _1-4 alkyl. In a particular embodiment, R ⁶ is -CH ₃ , -CH ₂ CH ₃ , or -CH(CH ₃ ) ₂ . In yet another specific embodiment, R ⁶ is -CH ₃ or -CH ₂ CH ₃ .

[0238] In an additional embodiment, to obtain a compound of the invention, the present invention provides a compound of formula A, where Z is an N-linked 4-7 membered heterocycloalkyl, further comprising zero, one or two additional heteroatoms independently selected from N , O and S substituted with one, two or three independently selected R ⁶ groups, and R ⁶ is C _1-4 alkyl substituted with one or more halo, -OH or C _1-4 alkoxy. In a particular embodiment, R ⁶ is -CH ₃ , -CH ₂ CH ₃ , or -CH(CH ₃ ) ₂ substituted with one or more halo, -OH, or C _1-4 alkoxy. In another specific embodiment, R ⁶ is C _1-4 alkyl substituted with one, two or three halo, -OH, or C _1-4 alkoxy. In another specific embodiment, R ⁶ is C _1-4 alkyl substituted with one or more F, Cl, -OH, -O-CH ₃ , -O-CH ₂ CH ₃ , or -O-CH(CH ₃ ) ₂ . In yet another specific embodiment, R ⁶ is -CH ₃ substituted with one, two or three halo, -OH, or C _1-4 alkoxy. In another more specific embodiment, R ⁶ is C _1-4 alkyl substituted with one, two or three F, Cl, -OH, -O-CH ₃ , -O-CH ₂ CH ₃ , or -O- CH(CH ₃ ) ₂ . In yet another more specific embodiment, R ⁶ is -CH ₃ , -CH ₂ CH ₃ , or -CH(CH ₃ ) ₂ , each of which is substituted with one, two or three F, Cl, -OH, -O -CH ₃ , -O-CH ₂ CH ₃ or -O-CH(CH ₃ ) ₂ . In the most specific embodiment, R ⁶ is -CH ₃ substituted with one, two or three F or -OH.

[0239] In an additional embodiment, to obtain a compound of the invention, the present invention provides a compound of formula A, where Z is an N-linked 4-7 membered heterocycloalkyl, further comprising zero, one or two additional heteroatoms independently selected from N , O and S substituted with one, two or three independently selected R ⁶ groups, and R ⁶ is a 4-7 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S. in a particular embodiment, R ⁶ is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl. In yet another specific embodiment, R ⁶ is tetrahydropyranyl or morpholinyl.

.[0240] In an additional embodiment, to obtain a compound of the invention, the present invention provides a compound of formula A, where Z is

.

[0241] In one embodiment, to obtain a compound of the invention, the present invention provides a compound of formula A, where R ^3a is -O-CH ₃ , R ^3b is -O-CHF ₂ , W is Br, Z is -NR ^5a R ^5b , R ^5a is H, and R ^5b is cyclopropyl.

[0242] In one embodiment, to prepare a compound of the invention, the present invention provides a compound of formula A, wherein R ^3a and R ^3b are -O-CH ₃ , W is Br, Z is -NR ^5a R ^5b , R ^5a is H and R ^5b is -CH ₂ CF ₃ .

[0243] In one embodiment, the compound of the invention is not an isotopic variant.

[0244] In one aspect, the compound of the invention, in accordance with any one of the embodiments described herein, is present in free base form.

[0245] In one aspect, a compound of the invention according to any one of the embodiments described herein is a pharmaceutically acceptable salt.

[0246] In one aspect, a compound of the invention, in accordance with any one of the embodiments described herein, is a solvate of the compound.

[0247] In one aspect, a compound of the invention, in accordance with any one of the embodiments described herein, is a solvate of a pharmaceutically acceptable salt of the compound.

[0248] Although these groups for each embodiment have been listed above separately, nevertheless, the compound of the invention includes a compound in which several or each embodiment in the above formula, as well as in other formulas presented in the invention, choose from one or more specific members or groups, designated as appropriate for each variable. Therefore, this invention is intended to include within its scope all combinations of such embodiments.

[0249] Although these groups for each embodiment have been listed above separately, however, the compound of the invention may be a compound for which one or more variables (for example, R groups) are selected from one or more embodiments according to any of the above formulas. Therefore, this invention is intended to include within its scope all combinations of variables from any of the disclosed embodiments.

[0250] Alternatively, the present invention also contemplates the exclusion of one or more of these variables from a group or embodiment, or combinations thereof.

[0251] In specific aspects, the present invention provides prodrugs and derivatives of the compounds in accordance with the above formulas. Prodrugs and derivatives of the compounds of the invention which have metabolically cleavable groups are converted by solvolysis or exposure to physiological conditions into compounds of the invention which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters, and the like.

[0252] Other derivatives of the compounds of this invention are active in both their acidic form and the acidic form of their derivatives, but finding the compounds in a low stable acid form often offers advantages related to solubility, tissue compatibility, or delayed release in the mammalian body ( Bundgaard 1985). Prodrugs include acid derivatives well known to those skilled in the art, such as, for example, esters obtained by reacting a parent acid with a suitable alcohol, or amides obtained by reacting a parent acid compound with a substituted or unsubstituted amine, or acid anhydrides or mixed anhydrides. . The aliphatic or aromatic esters, amides and anhydrides derived from the acid groups that the compounds of this invention contain are particularly suitable prodrugs. In some cases, it is desirable to prepare diester type prodrugs such as (acyloxy)alkyl ethers or ((alkoxycarbonyl)oxy)alkyl esters. Such specific prodrugs are C _1-8 alkyl, C _2-8 alkenyl, C _6-10 optionally substituted aryl and (C _6-10 aryl)-(C _1-4 alkyl) esters of the compounds of the invention.

DIFFERENT FEATURES OF THE INVENTION

1. Compound according to formula I:

where,

X is N or CR ⁴ ;

one of Y ₁ , Y ₂ and Y ₃ is N and the other two are C;

Z represents

- -NR ^5a R ^5b ,

- -NR ^5c -, where the atom N and R ^3b together with the atoms to which they are attached, form a fused 5-6-membered heterocycloalkenyl, including one double bond and including, in addition, zero, one or two additional heteroatoms, independently selected from N, O and S or

N-linked 4-7 membered heterocycloalkyl further comprising zero, one or two additional heteroatoms independently selected from N, O and S, optionally substituted with one, two or three R ⁶ groups;

R ¹ is H, halogen, C _1-4 alkyl or C _1-4 alkoxy optionally substituted with C _1-4 alkoxy, phenyl, -CN, -C(=O)OH or -C(=O)- C _1-4 alkoxy;

R ² is a 5-6 membered monocyclic heteroaryl containing one, two or three heteroatoms independently selected from N, O and S, where the heteroaryl is optionally substituted with one or more independently selected R ⁷ groups;

R ^3a and R ^3b are independently selected from

- halogen,

- C _1-4 alkyl,

- C _1-4 alkoxy, optionally substituted with one or more selected halogens, -OH or C _1-4 alkoxy,

- -NR ^8a R ^8b , and

- -OH;

R ⁴ is H or C _1-4 alkyl;

R ^5a is H or C _1-4 alkyl;

R ^5b choose from

- C _1-6 alkyl, optionally substituted with one or more selected R ⁹ ,

- C _3-7 cycloalkyl, optionally substituted with one or more selected R ¹⁰ ,

- 4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O and S, where the heterocycloalkyl is optionally substituted with one or more oxo, and

- 5-6-membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O and S, where the heteroaryl is optionally substituted with one or more independently selected C _1-4 alkyl;

R ^5c is selected from C _3-7 cycloalkyl and C _1-6 alkyl optionally substituted with one or more independently selected halo;

each R ⁶ is independently selected from

- oxo,

- halogen,

- -CN,

- -OH,

- -NR ^11a R ^11b ,

- phenyl,

- C _3-7 cycloalkyl,

- C _2-4 alkynyl,

- -C(=O)-C _1-4 alkoxy,

- C _1-4 alkoxy, optionally substituted with one or more halo or phenyl,

- C _1-4 alkyl optionally substituted with one or more halo, -OH or C _1-4 alkoxy, and

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

each R ⁷ choose from

- halogen,

- -CN,

- C _1-6 alkyl optionally substituted with one or more independently selected

halogen,

-CN,

-OH,

C _1-4 alkoxy optionally substituted with one or more selected halogens,

-NR ^11c R ^11d ,

-C(=O)R ¹² or

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

- C _1-4 alkoxy,

- C _3-7 cycloalkyl,

- 4-6-membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O and S, where heterocycloalkyl is optionally substituted with -C(=O)C _1-4 alkoxy or C _1-4 alkyl, optionally substituted with -CN,

- -NR ^13a R ^13b , and

- -C(=O)NR ^13c R ^13d ;

each R ^8a and R ^8b is independently selected from H and C _1-4 alkyl optionally substituted with one -OH or C _1-4 alkoxy;

each R ⁹ is independently selected from

- halogen,

- -CN,

- -NR ^11e R ^11f ,

- -OH,

- C _1-4 alkoxy,

- -S(=O) ₂ -C _1-4 alkyl,

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

- 5-6-membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O and S, where the heteroaryl is optionally substituted with one or more independently selected C _1-4 alkyl;

each R ¹⁰ is independently selected from

- halogen,

- C _1-4 alkyl optionally substituted with one or more independently selected halo, -OH or C _1-4 alkoxy,

- -OH,

- C _1-4 alkoxy, and

- -NR ^11g R ^11h ;

each R ^11a , R ^11b , R ^11c , R ^11d , R ^11e , R ^11f , R ^11g , and R ^{11h is} independently selected from H and C _1-4 alkyl;

each R ¹² represents

- -NR ^14a R ^14b , where each R ^14a and R ^14b are independently selected from H and C _1-4 alkyl,

- -OH,

- C _1-4 alkoxy optionally substituted with one or more selected C _3-7 cycloalkyl, halogen, -NR ^15a R ^15b or 4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O and S

- -O-(4-6 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S) or

- -O-(C _3-7 monocyclic cycloalkyl);

every R^13a, R^13b, R^13c, and R^13d independently choose from H and C_1-4 alkyl;

each R ^15a and R ^15b is independently selected from H and C _1-4 alkyl;

or a pharmaceutically acceptable salt, MES or MES of a salt thereof.

2. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein X is CR ⁴ and R ⁴ is H.

3. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein X is CR ⁴ and R ⁴ is -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ .

4. The compound or pharmaceutically acceptable salt thereof according to claim 1, where the compound corresponds to any one of formulas IIa-IIf:

5. The compound or pharmaceutically acceptable salt thereof according to any one of 1-4, wherein R ¹ is H.

6. The compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 1-4, where R ¹ represents F, Cl or Br.

7. The compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 1-4, where R ¹ represents -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ .

8. The compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 1-4, where R ¹ represents -CH ₃ .

9. The compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 1-4, where R ¹ represents -O-CH ₃ , -O-CH ₂ CH ₃ or -O-CH(CH ₃ ) ₂ .

10. The compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 1-4, where R ¹ represents -O-CH ₃ .

11. A compound or pharmaceutically acceptable salt thereof according to any one of items 1-4, wherein R ¹ is -O-CH ₂ CH ₃ or -O-CH(CH ₃ ) ₂ substituted with C _1-4 alkoxy.

12. The compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 1-4, where R ¹ represents -O-CH ₂ CH ₂ -O-CH ₃ .

13. A compound or a pharmaceutically acceptable salt thereof according to item 1, where the compound corresponds to any one of formulas IIIa-IIIf:

14. A compound or pharmaceutically acceptable salt thereof according to any one of 1-13, wherein Z is -NR ^5c -, where N and R ^3b together with the atoms to which they are attached form a fused 3,4-dihydro-2H -1,3-oxazine, 1,2,3,4-tetrahydropyrimidine, 3-pyrroline, 1,2,3,6-tetrahydropyridine or 3,4-dihydro-2H-1,3-thiazine.

15. A compound or pharmaceutically acceptable salt thereof according to any one of items 1-13, wherein Z is -NR ^5c -, where N and R ^3b together with the atoms to which they are attached form a fused 3,4-dihydro-2H -1,3-oxazine, 3-pyrroline or 1,2,3,6-tetrahydropyridine.

16. The compound or pharmaceutically acceptable salt thereof according to item 1, where the compound corresponds to any one of the formulas Va-f:

17. A compound or pharmaceutically acceptable salt thereof according to claim 1 or 16, wherein R ^5c is C _3-7 cycloalkyl.

18. A compound or pharmaceutically acceptable salt thereof according to claim 1 or 16, wherein R ^5c is cyclopropyl, cyclobutyl, or cyclopentyl.

19. The compound or pharmaceutically acceptable salt thereof according to claim 1 or 16, wherein R ^5c is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ or -C(CH ₃ ) ₃ .

20. A compound or pharmaceutically acceptable salt thereof according to claim 1 or 16, wherein R ^5c is -CH ₂ CH ₃ .

21. The compound or pharmaceutically acceptable salt thereof according to claim 1 or 16, wherein R ^5c is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ or -C(CH ₃ ) ₃ , each of which is substituted with one, two or three independently selected halogens.

22. A compound or pharmaceutically acceptable salt thereof according to claim 1 or 16, wherein R ^5c is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ or -C(CH ₃ ) ₃ each substituted with one, two or three independently selected F or Cl.

23. A compound or pharmaceutically acceptable salt thereof according to item 1 or 16, where R ^5c is -CH ₂ CH ₃ substituted with one, two or three F.

24. A compound or pharmaceutically acceptable salt thereof according to any one of 1-23, wherein R ² is imidazolyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl.

25. A compound or pharmaceutically acceptable salt thereof according to any one of 1-23, wherein R ² is pyrazolyl.

26. The compound or pharmaceutically acceptable salt thereof according to any one of items 1-23, where R ² represents imidazolyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, each of which is substituted with one or more independently selected R ⁷ groups.

27. The compound or pharmaceutically acceptable salt thereof according to any one of items 1-23, where R ² represents imidazolyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, each of which is substituted with one group R ⁷ .

28. A compound or pharmaceutically acceptable salt thereof according to any one of items 1-23, wherein R ² is pyrazolyl substituted with one R ⁷ group.

29. The compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 1, 26-28, where R ⁷ represents F, Cl, Br or -CN.

30. A compound or pharmaceutically acceptable salt thereof according to any one of 1, 26-28, wherein R ⁷ is F or -CN.

31. A compound or pharmaceutically acceptable salt thereof according to any one of 1, 26-28, wherein R ⁷ is -O-CH ₃ , -O-CH ₂ CH ₃ , or -O-CH(CH ₃ ) ₂ .

32. The compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 1, 26-28, where R ⁷ represents -O-CH ₃ or -O-CH ₂ CH ₃ .

33. The compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 1, 26-28, where R ⁷ represents

34. The compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 1, 26-28, where R ⁷ represents -NR ^13a R ^13b and each R ^13a and R ^13b represents independently selected H, -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ .

35. The compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 1, 26-28, where R ⁷ represents -NH ₂ or -N(CH ₃ ) ₂ .

36. The compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 1, 26-28, where R ⁷ represents -C(=O)NR ^13c R ^13d and each R ^13c and R ^13d represents independently selected H, -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ .

37. The compound or pharmaceutically acceptable salt thereof according to any one of 1, 26-28, wherein R ⁷ is -C(=O)NR ^13c R ^13d and one of R ^13c and R ^13d is H and the other is is -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ .

38. The compound or pharmaceutically acceptable salt thereof according to paragraph 1, where the compound corresponds to any one of the formulas Va-Vf:

39. A compound or pharmaceutically acceptable salt thereof according to any one of 1-13, 24-28, and 38, wherein R ⁷ is -CH ₃ , -CH ₂ CH ₃ , or -CH(CH ₃ ) ₂ .

40. A compound or pharmaceutically acceptable salt thereof according to any one of 1-13, 24-28, and 38, wherein R ⁷ is -CH ₂ CH ₃ .

41. A compound or pharmaceutically acceptable salt thereof according to any one of 1-13, 24-28, and 38, wherein R ⁷ is -CH ₃ .

42. A compound or pharmaceutically acceptable salt thereof according to any one of 1-13, 24-28, and 38, wherein R ⁷ is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , or -CH( CH ₃ ) ₂ each substituted with one or more independently selected halogens, -CN, -OH, C _1-4 alkoxy optionally substituted with one or more selected halogens, -NR ^11c R ^11d , -C(= O)R ¹² or 4-6 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S.

43. A compound or pharmaceutically acceptable salt thereof according to any one of 1-13, 24-28, and 38, wherein R ⁷ is C _1-4 alkyl substituted with one or more independently selected F, Cl, -CN, -OH, -O-CH ₃ , -O-CH ₂ CH ₃ , -O-CH(CH ₃ ) ₂ , -O-CHF ₂ , -O-CF ₃ , -O-CH ₂ CHF ₂ , -NR ^11c R ^11d , -C(=O)R ¹² , azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl or piperazinyl.

44. A compound or pharmaceutically acceptable salt thereof according to any one of 1-13, 24-28, and 38, wherein R ⁷ is -CH ₃ or -CH ₂ CH ₃ , each of which is substituted with one tetrahydrofuranyl or morpholinyl.

45. The compound or pharmaceutically acceptable salt thereof according to items 42 and 43, wherein one of R ^11c and R ^11d is H and the other is C _1-4 alkyl.

46. The compound or pharmaceutically acceptable salt thereof according to paragraphs 42 and 43, where R ^11c and R ^11d represent -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ .

47. The compound or pharmaceutically acceptable salt thereof according to items 42 and 43, wherein R ¹² is -NR ^14a R ^14b and one of R ^14a and R ^14b is H and the other is C _1-4 alkyl.

48. The compound or pharmaceutically acceptable salt thereof according to paragraphs 42 and 43, where R ¹² is -NR ^14a R ^14b and R ^14a and R ^14b are -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ .

49. The compound or pharmaceutically acceptable salt thereof according to paragraphs 42 and 43, where R ¹² represents -OH.

50. The compound or pharmaceutically acceptable salt thereof according to paragraphs 42 and 43, where R ¹² represents -O-CH ₃ , -O-CH ₂ CH ₃ , -O-CH(CH ₃ ) ₂ or -OC(CH ₃ ) ₃ .

51. The compound or pharmaceutically acceptable salt thereof according to paragraphs 42 and 43, where R ¹² represents -O-CH ₃ or -O-CH ₂ CH ₃ each of which is substituted with one, two or three C _3-7 cycloalkyl or halogen.

52. The compound or pharmaceutically acceptable salt thereof according to paragraphs 42 and 43, where R ¹² represents -O-CH ₃ or -O-CH ₂ CH ₃ , each of which is substituted with one, two or three F.

53. The compound or pharmaceutically acceptable salt thereof according to paragraphs 42 and 43, where R ¹² represents -O-CH ₃ or -O-CH ₂ CH ₃ , each of which is substituted with one cyclopropyl, cyclobutyl or cyclopentyl.

54. A compound or pharmaceutically acceptable salt thereof according to any one of 1-13, 24-28, and 38, wherein R ⁷ is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

55. A compound or pharmaceutically acceptable salt thereof according to any one of 1-13, 24-28, and 38, wherein R ⁷ is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl .

56. A compound or pharmaceutically acceptable salt thereof according to any one of 1-13, 24-28, and 38, wherein R ⁷ is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl , each of which is substituted with -C(=O)C _1-4 alkoxy or C _1-4 alkyl optionally substituted with -CN.

57. A compound or pharmaceutically acceptable salt thereof according to any one of 1-13, 24-28, and 38, wherein R ⁷ is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl , each of which is substituted with -C(=O)-OC(CH ₃ ) ₃ , -CH ₃ , -CH ₂ -CN or -CH ₂ CH ₂ -CN.

58. The compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 1-13, 24-28, and 38, where R ⁷ represents azetidinyl, pyrrolidinyl, piperidinyl or piperazinyl, each of which is substituted with -C(=O)- OC(CH ₃ ) ₃ , -CH ₃ , -CH ₂ -CN or -CH ₂ CH ₂ -CN.

59. A compound or pharmaceutically acceptable salt thereof according to any one of 1-13, and 24-59, wherein R ^3b is -O-CH ₃ , -O-CH ₂ CH ₃ , or -O-CH(CH ₃ ) ₂ .

60. A compound or pharmaceutically acceptable salt thereof according to any one of 1-13, and 24-59, wherein R ^3b is -O-CH ₃ .

61. A compound or pharmaceutically acceptable salt thereof according to any one of 1-13, and 24-59, wherein R ^3b is -O-CH ₃ , -O-CH ₂ CH ₃ , or -O-CH(CH ₃ ) ₂ , each of which is substituted with one or more independently selected halo, -OH, or C _1-4 alkoxy.

62. A compound or pharmaceutically acceptable salt thereof according to any one of 1-13 and 24-59, wherein R ^3b is C _1-4 alkoxy substituted with one or more independently selected F, Cl, -OH, -O- CH ₃ , -O-CH ₂ CH ₃ or -O-CH(CH ₃ ) ₂ .

63. A compound or pharmaceutically acceptable salt thereof according to any one of 1-13 and 24-59, wherein R ^3b is -O-CHF ₂ .

64. The compound or pharmaceutically acceptable salt thereof according to any one of 1-13 and 24-59, wherein R ^3b is -NR ^8a R ^8b and R ^8a and R ^8b are both H.

65. The compound or pharmaceutically acceptable salt thereof according to any one of 1-13 and 24-59, wherein R ^3b is -NR ^8a R ^8b and R ^8a and R ^8b are H and the other is C _1-4 alkyl optionally substituted with one -OH or C _1-4 alkoxy.

66. The compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 1-13 and 24-59, where R ^3b represents -NH-CH ₃ , -NH-CH(CH ₃ ) ₂ or -NH-CH ₂ CH ₂ - Oh.

67. A compound or a pharmaceutically acceptable salt thereof according to paragraph 1, where the compound corresponds to any one of formulas VIa-VIf:

68. A compound or pharmaceutically acceptable salt thereof according to any one of 1-13 and 24-67, wherein R ⁷ is -CH ₃ , -CH ₂ CH ₃ , or -CH(CH ₃ ) ₂ .

69. The compound or pharmaceutically acceptable salt thereof according to paragraph 1, where the compound corresponds to any one of the formulas VIIa-f:

70. A compound or pharmaceutically acceptable salt thereof according to any one of items 1-69, wherein R ^3a is F, Cl, or -OH.

71. A compound or pharmaceutically acceptable salt thereof according to any one of items 1-69, wherein R ^3a is -CH ₃ , -CH ₂ CH ₃ , or -CH(CH ₃ ) ₂ .

72. A compound or pharmaceutically acceptable salt thereof according to any one of 1-69, wherein R ^3a is -O-CH ₃ , -O-CH ₂ CH ₃ , or -O-CH(CH ₃ ) ₂ .

73. A compound or pharmaceutically acceptable salt thereof according to any one of items 1-69, wherein R ^3a is -O-CH ₃ .

74. The compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 1-69, where R ^3a represents -O-CH ₃ , -O-CH ₂ CH ₃ or -O-CH(CH ₃ ) ₂ , each of which is substituted with one or more independently selected halo, -OH, or C _1-4 alkoxy.

75. A compound or pharmaceutically acceptable salt thereof according to any one of items 1-69, wherein R ^3a is C _1-4 alkoxy substituted with one, two or three F or Cl.

76. The compound or pharmaceutically acceptable salt thereof according to any one of items 1-69, where R ^3a represents -O-CH ₃ or -O-CH ₂ CH ₃ , each of which is substituted with one -OH or -O-CH ₃ .

77. A compound or pharmaceutically acceptable salt thereof according to any one of items 1-69, wherein R ^3a is -O-CHF ₂ .

78. The compound or pharmaceutically acceptable salt thereof according to any one of 1-69, wherein R ^3a is -NR ^8a R ^8b and R ^8a and R ^8b are both H.

79. The compound or pharmaceutically acceptable salt thereof according to any one of 1-69, wherein R ^3a is -NR ^8a R ^8b and one of R ^8a and R ^8b is H and the other is C _1-4 alkyl, optionally substituted with one -OH or C _1-4 alkoxy.

80. A compound or pharmaceutically acceptable salt thereof according to any one of 1-69, wherein R ^3a is -NH-CH ₃ , -NH-CH(CH ₃ ) ₂ , or -NH-CH ₂ CH ₂ -OH.

81. A compound or a pharmaceutically acceptable salt thereof according to paragraph 1, where the compound corresponds to any one of formulas VIIIa-VIIId:

82. The compound or pharmaceutically acceptable salt thereof according to any one of 1-13 and 24-81, wherein Z is -NR ^5a R ^5b .

83. The compound or pharmaceutically acceptable salt thereof according to item 82, where R ^5a is H.

84. The compound or pharmaceutically acceptable salt thereof according to item 82, where R ^5a represents -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ .

85. The compound or pharmaceutically acceptable salt thereof according to item 82, where R ^5a represents -CH ₃ .

86. The compound or pharmaceutically acceptable salt thereof according to item 82, where R ^5a represents -CH ₂ CH ₃ .

87. The compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 82-86 wherein R ^5b is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -C(CH ₃ ) ₃ , -CH(CH ₃ )CH ₂ CH ₃ , or -CH(CH ₃ )CH(CH ₃ ) ₂ .

88. The compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 82-86, where R ^5b represents -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -C(CH ₃ ) ₃ , -CH(CH ₃ )CH ₂ CH ₃ , or -CH(CH ₃ )CH(CH ₃ ) ₂ , each of which is substituted with one or more independently selected R ⁹ .

89. The compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 82-86, where R ^5b represents -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -C(CH ₃ ) ₃ , -CH(CH ₃ )CH ₂ CH ₃ , or -CH(CH ₃ )CH(CH ₃ ) ₂ , each of which is substituted with one, two or three independently chosen R ⁹ .

90. The compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 82-86, where R ^5b represents -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -C(CH ₃ ) ₃ , -CH(CH ₃ )CH ₂ CH ₃ , or -CH(CH ₃ )CH(CH ₃ ) ₂ , each of which is substituted with one R ⁹ .

91. The compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 88-90, where each R ⁹ is independently F, Cl, -CN, -OH, -O-CH ₃ , -O-CH ₂ CH ₃ , -O -CH(CH ₃ ) ₂ , -S(=O) ₂ -CH ₃ , -S(=O) ₂ -CH ₂ CH ₃ or -S(=O) ₂ -CH(CH ₃ ) ₂ .

92. The compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 88-90, where R ⁹ represents F, -CN, -OH, -O-CH ₃ or -S(=O) ₂ -CH ₃ .

93. A compound or pharmaceutically acceptable salt thereof according to any one of items 88-90, wherein R ⁹ is -NR ^11e R ^11f and R ^11e and R ^11f are both H.

94. The compound or pharmaceutically acceptable salt thereof according to any one of items 88-90, wherein R ⁹ is -NR ^11e R ^11f and R ^11e and R ^11f are H and the other is -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ .

95. The compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 88-90, where R ⁹ represents -N(CH ₃ ) ₂ .

96. A compound or pharmaceutically acceptable salt thereof according to any one of items 88-90, wherein R ⁹ is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl.

97. A compound or pharmaceutically acceptable salt thereof according to any one of items 88-90, wherein R ⁹ is dioxanyl.

98. The compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 88-90, where R ⁹ is pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl or pyrimidinyl

99. A compound or pharmaceutically acceptable salt thereof according to any one of items 88-90, wherein R ⁹ is imidazolyl, pyrazolyl, or pyridinyl.

100. The compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 88-90, where R ⁹ is pyrrolyl, furanyl, thiophenyl, 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 C _1-4 alkyl.

101. The compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 88-90, where R ⁹ is pyrrolyl, furanyl, thiophenyl, 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 -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ .

102. A compound or pharmaceutically acceptable salt thereof according to any one of items 82-86, wherein R ^5b is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

103. The compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 82-86, where R ^5b represents cyclopropyl.

104. A compound or pharmaceutically acceptable salt thereof according to any one of items 82-86, wherein R ^5b is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each substituted with one, two or three independently selected R ¹⁰ .

105. A compound or pharmaceutically acceptable salt thereof according to any one of items 82-86, wherein R ^5b is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one R ¹⁰ .

106. The compound or pharmaceutically acceptable salt thereof according to item 104 or 105, where R ¹⁰ is halogen, -OH, or C _1-4 alkoxy.

107. The compound or pharmaceutically acceptable salt thereof according to item 104 or 105, where R ¹⁰ is F, Cl, -OH, -O-CH ₃ , -O-CH ₂ CH ₃ or -O-CH(CH ₃ ) ₂ .

108. The compound or pharmaceutically acceptable salt thereof according to item 104 or 105, where R ¹⁰ represents -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ .

109. The compound or pharmaceutically acceptable salt thereof according to paragraph 104 or 105, where R ¹⁰ represents -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ , each of which is substituted with one, two or three independently selected halogen, -OH or C _1-4 alkoxy.

110. The compound or pharmaceutically acceptable salt thereof according to item 104 or 105, where R ¹⁰ represents -CH ₂ F, -CHF ₂ , -CF ₃ or -CH ₂ -OH.

111. The compound or pharmaceutically acceptable salt thereof according to item 104 or 105, where R ¹⁰ is -NR ^11g R ^11h .

112. The compound or pharmaceutically acceptable salt thereof according to item 111, where R ^11g and R ^11h independently represent, H, -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ .

113. The compound or pharmaceutically acceptable salt thereof according to item 104 or 105, where R ¹⁰ is -N(CH ₃ ) ₂ .

114. A compound or pharmaceutically acceptable salt thereof according to any one of items 82-86, wherein R ^5b is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, or tetrahydrothiopyranyl. In yet another specific embodiment, R ^5b is oxetanyl, thietanyl, or tetrahydrothiopyranil.

115. The compound or pharmaceutically acceptable salt thereof according to any one of items 82-86, wherein R ^5b is oxetanyl.

116. The compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 82-86, where R ^5b represents azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl or tetrahydrothiopyranyl, each of which is substituted with one or more oxo .

117. The compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 82-86, where R ^5b represents thietanyl or tetrahydrothiophenyl, each of which is substituted with two oxo.

118. A compound or pharmaceutically acceptable salt thereof according to any one of 82-86, wherein R ^5b is imidazolyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl.

119. A compound or pharmaceutically acceptable salt thereof according to any one of items 82-86, wherein R ^5b is imidazolyl, pyrazolyl, isoxazolyl, or pyrimidinyl.

120. The compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 82-86, where R ^5b represents imidazolyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, each of which is substituted with one or more independently selected C _1-4 alkyl.

121. The compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 82-86, where R ^5b represents imidazolyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, each of which is substituted with one -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ .

122. A compound or pharmaceutically acceptable salt thereof according to any one of items 82-86, wherein R ^5b is imidazolyl, pyrazolyl, or pyrimidinyl, each of which is substituted with one -CH ₃ .

123. The compound or pharmaceutically acceptable salt thereof according to item 82 wherein R ^5a is H and R ^5b is -CH ₂ CH ₃ , -CH ₂ CF ₃ , -CH(CH ₃ )CF ₃ , or cyclopropyl.

124. The compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 1-13 and 24-81, where Z is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 2-azaspiro[3,3]heptanil, 1.6 -diazaspiro[3,3]heptanil, 2,6-diazaspiro[3,3]heptanil, 1-oxa-6-azaspiro[3,3]heptanil, 2-oxa-6-azaspiro[3,3]heptanil, 1 -thia-6-azaspiro[3,3]heptanyl or 2-thia-6-azaspiro[3,3]heptanyl. In yet another specific embodiment, Z is azetidinyl, pyrrolidinyl, piperidinyl, 2-oxa-6-azaspiro[3,3]heptanyl, or 2-thia-6-azaspiro[3,3]heptanyl.

125. The compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 1-13 and 24-81, where Z is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 2-azaspiro[3,3]heptanil, 1.6 -diazaspiro[3,3]heptanil, 2,6-diazaspiro[3,3]heptanil, 1-oxa-6-azaspiro[3,3]heptanil, 2-oxa-6-azaspiro[3,3]heptanil, 1 -thia-6-azaspiro[3,3]heptanyl or 2-thia-6-azaspiro[3,3]heptanyl, each substituted with one, two or three independently selected R ⁶ groups.

126. A compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 1-13 and 24-81 wherein Z is azetidinyl, pyrrolidinyl, piperidinyl, or 2-thia-6-azaspiro[3,3]heptanil, each of which is substituted with one, two or three independently selected R ⁶ groups.

127. The compound or pharmaceutically acceptable salt thereof according to paragraphs 125 or 126, where R ⁶ represents oxo, F, Cl, -CN, -OH, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, -C≡CH, -C(=O) -O-CH ₃ , -C(=O)-O-CH ₂ CH ₃ or -C(=O)-O-CH(CH ₃ ) ₂ .

128. The compound or pharmaceutically acceptable salt thereof according to paragraphs 125 or 126, where R ⁶ represents -NR ^11a R ^11b and each R ^11a and R ^11b are independently selected from H, -CH ₃ , -CH ₂ CH ₃ and -CH(CH ₃ ) ₂ .

129. The compound or pharmaceutically acceptable salt thereof according to paragraphs 125 or 126, where R ⁶ represents -N(CH ₃ ) ₂ .

130. The compound or pharmaceutically acceptable salt thereof according to paragraphs 125 or 126, where R ⁶ represents -O-CH ₃ , -O-CH ₂ CH ₃ or -O-CH(CH ₃ ) ₂ .

131. The compound or pharmaceutically acceptable salt thereof according to paragraphs 125 or 126, where R ⁶ represents -O-CH ₃ , -O-CH ₂ CH ₃ or -O-CH(CH ₃ ) ₂ , each of which is substituted with one or more F, Cl or phenyl.

132. The compound or pharmaceutically acceptable salt thereof according to paragraphs 125 or 126, where R ⁶ represents -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ .

133. The compound or pharmaceutically acceptable salt thereof according to paragraphs 125 or 126, where R ⁶ represents -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ , each of which is substituted with one, two or three F, Cl, -OH, -O-CH ₃ , -O-CH ₂ CH ₃ or -O-CH(CH ₃ ) ₂ .

134. The compound or pharmaceutically acceptable salt thereof according to paragraphs 125 or 126, where R ⁶ represents -CH ₃ substituted with one, two or three F or -OH.

135. The compound or pharmaceutically acceptable salt thereof according to paragraphs 125 or 126, where R ⁶ is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl.

136. The compound or pharmaceutically acceptable salt thereof according to paragraphs 125 or 126, where R ⁶ is tetrahydropyranyl or morpholinyl

.137. The compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 1-13 and 24-81, where Z is

.

138. The compound or pharmaceutically acceptable salt thereof according to paragraph 1, where the compound is selected from table III.

139. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound according to any one of paragraphs 1-138.

140. The pharmaceutical composition according to item 138, including an additional therapeutic agent.

141. A compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 1-138 or a pharmaceutical composition according to paragraph 139 or 140 for use in medicine.

142. A compound or a pharmaceutically acceptable salt thereof according to any one of paragraphs 1-138 or a pharmaceutical composition according to paragraph 139 or 140 for use in the prevention and/or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection , diseases related to impaired cartilage renewal, congenital cartilage defect, diseases related to impaired bone remodeling, diseases associated with hypersecretion of TNFα, interferons, IL-6, IL-12 and/or IL-23, respiratory diseases, endocrine and/ or metabolic diseases, cardiovascular diseases, dermatological diseases, and/or diseases associated with abnormal angiogenesis.

143. The compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 1-138 or the pharmaceutical composition according to paragraph 139 or 140, where the specified compound or pharmaceutical composition is administered in combination with an additional therapeutic agent.

144. The pharmaceutical composition according to item 140 or the use according to item 143, where the additional therapeutic agent is an agent for the prevention and / or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases related to the violation cartilage renewal, congenital cartilage defect, diseases related to impaired bone remodeling, diseases associated with hypersecretion of TNFα, interferons, IL-6, IL-12 and/or IL-23, respiratory diseases, endocrine and/or metabolic diseases, cardiovascular vascular diseases, dermatological diseases, and/or diseases associated with abnormal angiogenesis.

PHARMACEUTICAL COMPOSITIONS

[0253] When used as a drug, the compound of the invention is usually administered in the form of a pharmaceutical composition. Such compositions may be prepared by methods well known in the art of pharmacy and may include at least one active compound of the invention according to formula I. Typically, the compound of the invention is administered in a pharmaceutically effective amount. The actual amount of a compound of the invention administered will generally be determined by the attending physician, taking into account relevant circumstances including the condition being treated, the mode of administration chosen, the compound of the invention specifically administered, the age, body weight and objective response to treatment of the particular patient, the severity of the patient's symptoms, and others. similar factors.

[0254] The pharmaceutical compositions of this invention can be administered by various routes, including orally, rectally, transdermally, subcutaneously, intra-articularly, intravenously, intramuscularly, and intranasally. Depending on the intended route of administration, the compound of the invention is suitably formulated either in the form of injectable or oral compositions, or in the form of ointments, lotions, patches for transdermal administration.

[0255] Compositions for oral administration may take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are formulated in single dose dosage forms to facilitate accurate dosing. The term "single dose dosage forms" refers to physically discrete units used as unit doses in humans and other mammals, each unit containing a predetermined amount of active material, calculated to achieve the desired therapeutic effect, in combination with a suitable pharmaceutical excipient. , medium or carrier. Typical single dose dosage forms include ampoules or syringes filled with a pre-measured amount of liquid compositions, or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the compound of the invention corresponding to formula I is usually a minor component (from about 0.1 to about 50% by weight, or preferably from about 1 to about 40% by weight), with the rest being various media or carriers, and excipients used in the manufacturing process necessary to prepare the required dosage form.

[0256] Liquid forms used for oral administration may include a suitable aqueous or non-aqueous medium, along with buffers, suspending and distributing agents, coloring agents, taste and odor correcting agents, and other similar substances. Solid forms may include, for example, any of the following ingredients or a compound of the invention with similar properties: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a tablet disintegrating agent 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 mint or orange flavor.

[0257] Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, or other known injectable carriers. As previously mentioned, the active compound of the invention according to formula I in such compositions is usually a minor component, comprising from about 0.05 to 10% by weight, with the balance being the injectable carrier and other similar substances.

[0258] Transdermal compositions are usually prepared in the form of a topical ointment or cream containing the active ingredient(s), usually in an amount of from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight. , preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight. When formulated as an ointment, the active ingredients are usually combined with either a paraffinic or water-miscible oil base. Alternatively, the active ingredients may be formulated into a cream, for example with an oil-in-water cream base. Such transdermal formulations are well known and typically include additional ingredients to enhance skin penetration or to enhance the stability of the active ingredients or dosage form. All of these known transdermal dosage forms and ingredients are within the scope of this invention.

[0259] The compound of the invention may also be administered via a transdermal device. Accordingly, transdermal administration can be accomplished by using a patch with either a reservoir or a porous membrane or various solid-based matrices.

[0260] The above-described components for orally administered, injectable and topically applied compositions are only typical examples. Other materials, as well as processing methods and other similar methods, are given in section 8 of the monograph Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, the entire content of which is incorporated into the present invention by reference.

[0261] The compound of the invention may also be administered in sustained release dosage forms or using sustained release drug delivery systems. A description of typical sustained release materials can be found in Remington's Pharmaceutical Sciences.

[0262] The following formulation examples illustrate typical pharmaceutical compositions that can be prepared in accordance with this invention. However, the present invention is not limited to the following pharmaceutical compositions.

Composition 1 - tablets

[0263] The compound according to the invention corresponding to formula I can be mixed in the form of a dry powder with a dry gelatin binder in an approximate mass ratio of 1:2. A small amount of magnesium stearate may be added as a lubricant. The mixture can be formed into tablets weighing 240-270 mg (80-90 mg of the active compound of the invention according to formula I in one tablet) in a tablet press.

Composition 2 - capsules

[0264] The compound according to the invention corresponding to formula I can be mixed in the form of a dry powder with a starch diluent at an approximate mass ratio of 1:1. The mixture may be filled into capsules weighing 250 mg (125 mg of the active compound of the invention according to formula I in one capsule).

Composition 3 - liquid

[0265] The compound of the invention corresponding to formula I (125 mg) may be mixed with sucrose (1.75 g) and xanthan gum (4 mg) and the resulting mixture may be stirred, passed through a No. 10 U.S., and then mixed with a pre-mixed solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50 mg) in water. Sodium benzoate (10 mg) diluted with water, a taste and odor corrector, and color may be added with stirring. Sufficient water may then be added with stirring. An appropriate amount of water may then be added until a total volume of 5 ml is reached.

Composition 4 - tablets

[0266] The compound according to the invention corresponding to formula I can be mixed in the form of a dry powder with a dry gelatin binder in an approximate mass ratio of 1:2. A small amount of magnesium stearate may be added as a lubricant. The mixture can be formed into tablets weighing 450-900 mg (150-300 mg of the active compound of the invention according to Formula I per tablet) in a tablet press.

Composition 5 - injectable preparation

[0267] A compound of the invention according to formula I may be dissolved or suspended in a buffered sterile aqueous medium of saline for injection to a concentration of approximately 5 mg/ml.

Composition 6 - preparation for topical application

[0268] Stearyl alcohol (250 g) and petroleum jelly (250 g) can be melted at a temperature of approximately 75ºC, and then a mixture of the compound of the invention corresponding to formula I (50 g), methyl paraben (0.25 g), propylparaben (0.15 g), sodium lauryl sulfate (10 g) and propylene glycol (120 g) dissolved in water (approximately 370 g), and the resulting mixture can be subjected to stirring until it thickens.

TREATMENT METHODS

[0269] In one embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention for use in medicine.

[0270] In one embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in the prevention and/or treatment of inflammatory diseases. In particular, the term "inflammatory diseases" refers to rheumatoid arthritis, osteoarthritis, allergic airway disease (eg, asthma), chronic obstructive pulmonary disease (COPD), and inflammatory bowel diseases (eg, Crohn's disease, ulcerative colitis). More specifically, the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (eg Crohn's disease, ulcerative colitis).

[0271] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prevention and/or treatment of inflammatory diseases. In particular, the term "inflammatory diseases" refers to rheumatoid arthritis, osteoarthritis, allergic airway disease (eg, asthma), chronic obstructive pulmonary disease (COPD), and inflammatory bowel diseases (eg, Crohn's disease, ulcerative colitis). More specifically, the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (eg Crohn's disease, ulcerative colitis).

[0272] In additional aspects of the method of treatment, this invention provides methods for the prevention and/or treatment of a mammal suffering from inflammatory diseases, where the methods include the introduction of an effective amount of the compounds according to the invention or one or more of the pharmaceutical compositions described in the invention for the treatment or prevention of the specified pathological states. In particular, the term "inflammatory diseases" refers to rheumatoid arthritis, osteoarthritis, allergic airway disease (eg, asthma), chronic obstructive pulmonary disease (COPD), and inflammatory bowel diseases (eg, Crohn's disease, ulcerative colitis). More specifically, the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (eg Crohn's disease, ulcerative colitis).

[0273] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent. In a specific embodiment, the other therapeutic agent is an agent for the treatment of inflammatory diseases. In particular, the term "inflammatory diseases" refers to rheumatoid arthritis, osteoarthritis, allergic airway disease (eg, asthma), chronic obstructive pulmonary disease (COPD), and inflammatory bowel diseases (eg, Crohn's disease, ulcerative colitis). More specifically, the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (eg Crohn's disease, ulcerative colitis).

[0274] In one embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in the prevention and/or treatment of autoinflammatory diseases. In particular, the term "autoinflammatory diseases" refers to cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF) and tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Behçet's syndrome, systemic-onset juvenile idiopathic arthritis (SJIA). ) or Still's disease. More specifically, the term refers to CAPS, FMF, TRAPS, and Still's disease.

[0275] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prevention and/or treatment of autoinflammatory diseases. In particular, the term "autoinflammatory diseases" refers to cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF) and tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Behçet's syndrome, systemic-onset juvenile idiopathic arthritis (SJIA). ) or Still's disease. More specifically, the term refers to CAPS, FMF, TRAPS, and Still's disease.

[0276] In additional aspects of the method of treatment, this invention provides methods for the prevention and/or treatment of a mammal suffering from autoinflammatory diseases, where the methods include the introduction of an effective amount of the compounds according to the invention or one or more of the pharmaceutical compositions described in the invention for the treatment or prevention of the specified pathological condition. In particular, the term "autoinflammatory diseases" refers to cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF) and tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Behçet's syndrome, systemic-onset juvenile idiopathic arthritis (SJIA). ) or Still's disease. More specifically, the term refers to CAPS, FMF, TRAPS, and Still's disease.

[0277] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent. In a specific embodiment, the other therapeutic agent is an agent for the treatment of autoinflammatory diseases. In particular, the term "autoinflammatory diseases" refers to cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF) and tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Behçet's syndrome, systemic-onset juvenile idiopathic arthritis (SJIA). ) or Still's disease. More specifically, the term refers to CAPS, FMF, TRAPS, and Still's disease.

[0278] In one embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention for use in the prevention and/or treatment of autoimmune diseases. In particular, the term "autoimmune diseases" refers to COPD, asthma, bronchitis, systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), lupus nephritis, dermatomyositis, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, Sjögren's syndrome, multiple sclerosis, psoriasis, dry eyes, type I diabetes mellitus, atopic dermatitis, thyroiditis, contact dermatitis, eczematous dermatitis, inflammatory bowel disease (eg, Crohn's disease and ulcerative colitis), atherosclerosis, and amyotrophic lateral sclerosis. More specifically, the term refers to COPD, asthma, systemic lupus erythematosus, type I diabetes mellitus, and inflammatory bowel disease.

[0279] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prevention and/or treatment of autoimmune diseases. In particular, the term "autoimmune diseases" refers to COPD, asthma, bronchitis, systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), lupus nephritis, dermatomyositis, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, Sjögren's syndrome, multiple sclerosis, psoriasis, dry eyes, type I diabetes mellitus, atopic dermatitis, thyroiditis, contact dermatitis, eczematous dermatitis, inflammatory bowel disease (eg, Crohn's disease and ulcerative colitis), atherosclerosis, and amyotrophic lateral sclerosis. More specifically, the term refers to COPD, asthma, systemic lupus erythematosus, type I diabetes mellitus, and inflammatory bowel disease.

[0280] In additional aspects of the method of treatment, this invention provides methods for the prevention and/or treatment of a mammal suffering from autoimmune diseases, where the methods include the introduction of an effective amount of the compounds according to the invention or one or more of the pharmaceutical compositions described in the invention for the treatment or prevention of the specified pathological states. 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 eyes, type I diabetes mellitus, atopic dermatitis, thyroiditis, contact dermatitis, eczematous dermatitis, inflammatory bowel disease (eg, Crohn's disease and ulcerative colitis), atherosclerosis, and amyotrophic lateral sclerosis. More specifically, the term refers to COPD, asthma, systemic lupus erythematosus, type I diabetes mellitus, and inflammatory bowel disease.

[0281] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent. In a specific embodiment, the other therapeutic agent is an agent for the treatment of autoimmune diseases. In particular, the term "autoimmune diseases" refers to COPD, asthma, bronchitis, systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), lupus nephritis, dermatomyositis, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, Sjögren's syndrome, multiple sclerosis, psoriasis, dry eyes, type I diabetes mellitus, atopic dermatitis, thyroiditis, contact dermatitis, eczematous dermatitis, inflammatory bowel disease (eg, Crohn's disease and ulcerative colitis), atherosclerosis, and amyotrophic lateral sclerosis. More specifically, the term refers to COPD, asthma, systemic lupus erythematosus, type I diabetes mellitus, and inflammatory bowel disease.

[0282] In one embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in the prevention and/or treatment of proliferative diseases. In particular, the term "proliferative diseases" refers to cancer, myeloproliferative disorders, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma, or fibrosis. More specifically, the term refers to cancer, leukemia, multiple myeloma, and psoriasis.

[0283] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prevention and/or treatment of proliferative diseases. In particular, the term "proliferative diseases" refers to cancer, myeloproliferative disorders, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma, or fibrosis. More specifically, the term refers to cancer, leukemia, multiple myeloma, and psoriasis.

[0284] In additional aspects of a method of treatment, the invention provides methods for preventing and/or treating a mammal suffering from proliferative diseases, wherein the methods comprise administering an effective amount of a compound of the invention or one or more of the pharmaceutical compositions described herein for treating or preventing said pathological condition. In particular, the term "proliferative diseases" refers to cancer, myeloproliferative disorders, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma, or fibrosis. More specifically, the term refers to cancer, leukemia, multiple myeloma, and psoriasis.

[0285] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent. In a specific embodiment, the other therapeutic agent is an agent for the treatment of proliferative diseases. In particular, the term "proliferative diseases" refers to cancer, myeloproliferative disorders, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma, or fibrosis. More specifically, the term refers to cancer, leukemia, multiple myeloma, and psoriasis.

[0286] In one embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in the prevention and/or treatment of fibrotic diseases. In particular, the term "fibrotic diseases" refers to idiopathic pulmonary fibrosis (IPF), Dupuytren's disease, non-alcoholic steatohepatitis (NASH), systemic sclerosis, renal fibrosis, and cutaneous fibrosis.

[0287] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prevention and/or treatment of fibrotic diseases. In particular, the term "fibrotic diseases" refers to idiopathic pulmonary fibrosis (IPF), Dupuytren's disease, non-alcoholic steatohepatitis (NASH), systemic sclerosis, renal fibrosis, and cutaneous fibrosis.

[0288] In additional aspects of the method of treatment, this invention provides methods for the prevention and/or treatment of a mammal suffering from fibrotic diseases, where the methods include the introduction of an effective amount of the compounds according to the invention or one or more of the pharmaceutical compositions described in the invention for the treatment or prevention of the specified pathological condition. In particular, the term "fibrotic diseases" refers to idiopathic pulmonary fibrosis (IPF), Dupuytren's disease, non-alcoholic steatohepatitis (NASH), systemic sclerosis, renal fibrosis, and cutaneous fibrosis.

[0289] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent. In a specific embodiment, the other therapeutic agent is an agent for the treatment of fibrotic diseases. In particular, the term "fibrotic diseases" refers to idiopathic pulmonary fibrosis (IPF), Dupuytren's disease, non-alcoholic steatohepatitis (NASH), systemic sclerosis, renal fibrosis, and cutaneous fibrosis.

[0290] In one embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention for use in the prevention and/or treatment of transplant rejection. In particular, the term "transplant rejection" refers to the acute or chronic rejection of allo- or xenografts of cells, tissue, or a solid organ, e.g., pancreatic islets, stem cells, bone marrow, skin, muscle, corneal tissue, neuronal tissue, heart, lung , heart-lung, kidney, liver, colon, pancreas, trachea, or esophagus combinations, or graft-versus-host disease. More specifically, the term refers to graft-versus-host diseases.

[0291] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prevention and/or treatment of transplant rejection. In particular, the term "transplant rejection" refers to the acute or chronic rejection of allo- or xenografts of cells, tissue, or a solid organ, e.g., pancreatic islets, stem cells, bone marrow, skin, muscle, corneal tissue, neuronal tissue, heart, lung , heart-lung, kidney, liver, colon, pancreas, trachea, or esophagus combinations, or graft-versus-host disease. More specifically, the term refers to graft-versus-host diseases.

[0292] In additional aspects of a method of treatment, the invention provides methods for preventing and/or treating a mammal suffering from transplant rejection, wherein the methods comprise administering an effective amount of a compound of the invention or one or more of the pharmaceutical compositions described herein to treat or prevent specified pathological condition. In particular, the term "transplant rejection" refers to the acute or chronic rejection of allo- or xenografts of cells, tissue, or a solid organ, e.g., pancreatic islets, stem cells, bone marrow, skin, muscle, corneal tissue, neuronal tissue, heart, lung , heart-lung, kidney, liver, colon, pancreas, trachea, or esophagus combinations, or graft-versus-host disease. More specifically, the term refers to graft-versus-host diseases.

[0293] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent. In a specific embodiment, the other therapeutic agent is an agent for the treatment of transplant rejection. In particular, the term "transplant rejection" refers to the acute or chronic rejection of allo- or xenografts of cells, tissue, or a solid organ, e.g., pancreatic islets, stem cells, bone marrow, skin, muscle, corneal tissue, neuronal tissue, heart, lung , heart-lung, kidney, liver, colon, pancreas, trachea, or esophagus combinations, or graft-versus-host disease. More specifically, the term refers to graft-versus-host diseases.

[0294] In one embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in the prevention and/or treatment of diseases related to impaired cartilage renewal. In particular, the term "disorders related to impaired cartilage renewal" refers to osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, sympathetic reflex dystrophy, algodystrophy, Tietze's syndrome or costal chondritis, fibromyalgia, osteochondritis , neurogenic or neuropathic arthritis, arthropathy, endemic forms of arthritis such as deforming endemic osteoarthritis, Mseleni's disease, and Handigodu's disease; degeneration resulting from fibromyalgia, systemic lupus erythematosus, scleroderma and ankylosing spondylitis. More specifically, the term refers to osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus, scleroderma, and ankylosing spondylitis.

[0295] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prevention and/or treatment of diseases related to impaired cartilage renewal. In particular, the term "disorders related to impaired cartilage renewal" refers to osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, sympathetic reflex dystrophy, algodystrophy, Tietze's syndrome or costal chondritis, fibromyalgia, osteochondritis , neurogenic or neuropathic arthritis, arthropathy, endemic forms of arthritis such as deforming endemic osteoarthritis, Mseleni's disease, and Handigodu's disease; degeneration resulting from fibromyalgia, systemic lupus erythematosus, scleroderma and ankylosing spondylitis. More specifically, the term refers to osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus, scleroderma, and ankylosing spondylitis.

[0296] In additional aspects of a method of treatment, the invention provides methods for the prevention and/or treatment of a mammal suffering from a disease related to impaired cartilage renewal, wherein the methods comprise administering an effective amount of a compound of the invention or one or more of the pharmaceutical compositions described herein. for the treatment or prevention of said pathological condition. In particular, the term "disorders related to impaired cartilage renewal" refers to osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, sympathetic reflex dystrophy, algodystrophy, Tietze's syndrome or costal chondritis, fibromyalgia, osteochondritis , neurogenic or neuropathic arthritis, arthropathy, endemic forms of arthritis such as deforming endemic osteoarthritis, Mseleni's disease, and Handigodu's disease; degeneration resulting from fibromyalgia, systemic lupus erythematosus, scleroderma and ankylosing spondylitis. More specifically, the term refers to osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus, scleroderma, and ankylosing spondylitis.

[0297] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent. In a specific embodiment, the other therapeutic agent is an agent for the treatment of diseases related to impaired cartilage renewal. In particular, the term "disorders related to impaired cartilage renewal" refers to osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, sympathetic reflex dystrophy, algodystrophy, Tietze's syndrome or costal chondritis, fibromyalgia, osteochondritis , neurogenic or neuropathic arthritis, arthropathy, endemic forms of arthritis such as deforming endemic osteoarthritis, Mseleni's disease, and Handigodu's disease; degeneration resulting from fibromyalgia, systemic lupus erythematosus, scleroderma and ankylosing spondylitis. More specifically, the term refers to osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus, scleroderma, and ankylosing spondylitis.

[0298] In one embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in the prevention and/or treatment of a congenital cartilage defect. In particular, the term "congenital cartilage defect" refers to hereditary chondrolysis, chondrodysplasia and pseudochondrodysplasia, microtia, anotia, metaphyseal chondrodysplasia. More specifically, the term refers to microtia, anotia, metaphyseal chondrodysplasia.

[0299] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prevention and/or treatment of a congenital cartilage defect. In particular, the term "congenital cartilage defect" refers to hereditary chondrolysis, chondrodysplasia and pseudochondrodysplasia, microtia, anotia, metaphyseal chondrodysplasia. More specifically, the term refers to microtia, anotia, metaphyseal chondrodysplasia.

[0300] In additional aspects of a method of treatment, the invention provides methods for the prevention and/or treatment of a mammal suffering from a congenital cartilage defect, wherein the methods comprise administering an effective amount of a compound of the invention or one or more of the pharmaceutical compositions described herein to treat or prevent specified pathological condition. In particular, the term "congenital cartilage defect" refers to hereditary chondrolysis, chondrodysplasia and pseudochondrodysplasia, microtia, anotia, metaphyseal chondrodysplasia. More specifically, the term refers to microtia, anotia, metaphyseal chondrodysplasia.

[0301] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent. In a specific embodiment, the other therapeutic agent is an agent for the treatment of a congenital cartilage defect. In particular, the term "congenital cartilage defect" refers to hereditary chondrolysis, chondrodysplasia and pseudochondrodysplasia, microtia, anotia, metaphyseal chondrodysplasia. More specifically, the term refers to microtia, anotia, metaphyseal chondrodysplasia.

[0302] In one embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in the prevention and/or treatment of diseases related to impaired bone remodeling. In particular, the term "diseases related to impaired bone remodeling" refers to osteoporosis, osteopenia, hormonal deficiency, hormone excess, Paget's disease, osteoarthritis, renal osteodystrophy, osteogenesis imperfecta, and hypophosphatasia. More specifically, the term refers to osteoporosis.

[0303] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prevention and/or treatment of diseases related to impaired bone remodeling. In particular, the term "diseases related to impaired bone remodeling" refers to osteoporosis, osteopenia, hormonal deficiency, hormone excess, Paget's disease, osteoarthritis, renal osteodystrophy, osteogenesis imperfecta, and hypophosphatasia. More specifically, the term refers to osteoporosis.

[0304] In additional aspects of the method of treatment, this invention provides methods for the prevention and/or treatment of a mammal suffering from diseases related to impaired bone remodeling, where the methods include administering an effective amount of a compound of the invention or one or more of the pharmaceutical compositions described in the invention for the treatment or prevention of said pathological condition. In particular, the term "diseases related to impaired bone remodeling" refers to osteoporosis, osteopenia, hormonal deficiency, hormone excess, Paget's disease, osteoarthritis, renal osteodystrophy, osteogenesis imperfecta, and hypophosphatasia. More specifically, the term refers to osteoporosis.

[0305] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent. In a specific embodiment, the other therapeutic agent is an agent for the treatment of diseases related to impaired bone remodeling. In particular, the term "diseases related to impaired bone remodeling" refers to osteoporosis, osteopenia, hormonal deficiency, hormone excess, Paget's disease, osteoarthritis, renal osteodystrophy, osteogenesis imperfecta, and hypophosphatasia. More specifically, the term refers to osteoporosis.

[0306] In one embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in the prevention and/or treatment of diseases associated with IL-6 hypersecretion. In particular, the term "diseases associated with hypersecretion of IL-6" refers to Castleman's disease, multiple myeloma, psoriasis, Kaposi's sarcoma and/or mesangial proliferative glomerulonephritis.

[0307] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prevention and/or treatment of diseases associated with IL-6 hypersecretion. In particular, the term "diseases associated with hypersecretion of IL-6" refers to Castleman's disease, multiple myeloma, psoriasis, Kaposi's sarcoma and/or mesangial proliferative glomerulonephritis.

[0308] In additional aspects of a method of treatment, the invention provides methods for preventing and/or treating a mammal suffering from diseases associated with IL-6 hypersecretion, wherein the methods comprise administering an effective amount of a compound of the invention or one or more of the pharmaceutical compositions described herein. compositions for the treatment or prevention of said pathological condition. In particular, the term "diseases associated with hypersecretion of IL-6" refers to Castleman's disease, multiple myeloma, psoriasis, Kaposi's sarcoma and/or mesangial proliferative glomerulonephritis.

[0309] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent. In a specific embodiment, the other therapeutic agent is an agent for the treatment of diseases associated with hypersecretion of IL-6. In particular, the term "diseases associated with hypersecretion of IL-6" refers to Castleman's disease, multiple myeloma, psoriasis, Kaposi's sarcoma and/or mesangial proliferative glomerulonephritis.

[0310] In one embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention for use in the prevention and/or treatment of diseases associated with hypersecretion of TNFα, interferons, IL-12 and/or IL-23 . In particular, the term "diseases associated with hypersecretion of TNFα, interferons, IL-12 and/or IL-23" refers to systemic and cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis , trisomy 21, ulcerative colitis and/or Crohn's disease. More specifically, the term refers to Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and/or Crohn's disease.

[0311] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prevention and/or treatment of diseases associated with hypersecretion of TNFα, interferons, IL-12 and/or IL‑23. In particular, the term "diseases associated with hypersecretion of TNFα, interferons, IL-12 and/or IL-23" refers to systemic and cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis , trisomy 21, ulcerative colitis and/or Crohn's disease. More specifically, the term refers to Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and/or Crohn's disease.

[0312] In additional aspects of the method of treatment, this invention provides methods for the prevention and/or treatment of a mammal suffering from diseases associated with hypersecretion of TNFα, interferons, IL-12 and/or IL-23, where the methods include administering an effective amount of the compound at of the invention or one or more of the pharmaceutical compositions described herein for the treatment or prevention of said pathological condition. In particular, the term "diseases associated with hypersecretion of TNFα, interferons, IL-12 and/or IL-23" refers to systemic and cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis , trisomy 21, ulcerative colitis and/or Crohn's disease. More specifically, the term refers to Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and/or Crohn's disease.

[0313] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent. In a specific embodiment, the other therapeutic agent is an agent for the treatment of diseases associated with hypersecretion of TNFα, interferons, IL-12 and/or IL-23. In particular, the term "diseases associated with hypersecretion of TNFα, interferons, IL-12 and/or IL-23" refers to systemic and cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis , trisomy 21, ulcerative colitis and/or Crohn's disease. More specifically, the term refers to Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and/or Crohn's disease.

[0314] In one embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in the prevention and/or treatment of respiratory diseases. In particular, the term "respiratory disease" refers to asthma, adult acute respiratory distress syndrome, isocapnic hyperventilation, seasonal asthma, seasonal allergic rhinitis, chronic allergic rhinitis, chronic obstructive pulmonary disease, emphysema, pulmonary hypertension, interstitial pulmonary fibrosis, cystic fibrosis, or hypoxia. More specifically, the term refers to pulmonary hypertension or interstitial pulmonary fibrosis.

[0315] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prevention and/or treatment of respiratory diseases. In particular, the term "respiratory disease" refers to asthma, adult acute respiratory distress syndrome, isocapnic hyperventilation, seasonal asthma, seasonal allergic rhinitis, chronic allergic rhinitis, chronic obstructive pulmonary disease, emphysema, pulmonary hypertension, interstitial pulmonary fibrosis, cystic fibrosis, or hypoxia. More specifically, the term refers to pulmonary hypertension or interstitial pulmonary fibrosis.

[0316] In additional aspects of the method of treatment, this invention provides methods for the prevention and/or treatment of a mammal suffering from respiratory diseases, where the methods include the introduction of an effective amount of the compound according to the invention or one or more of the pharmaceutical compositions described in the invention for the treatment or prevention of the specified pathological condition. In particular, the term "respiratory disease" refers to asthma, adult acute respiratory distress syndrome, isocapnic hyperventilation, seasonal asthma, seasonal allergic rhinitis, chronic allergic rhinitis, chronic obstructive pulmonary disease, emphysema, pulmonary hypertension, interstitial pulmonary fibrosis, cystic fibrosis, or hypoxia. More specifically, the term refers to pulmonary hypertension or interstitial pulmonary fibrosis.

[0317] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent. In a specific embodiment, the other therapeutic agent is an agent for the treatment of respiratory diseases. In particular, the term "respiratory disease" refers to asthma, adult acute respiratory distress syndrome, isocapnic hyperventilation, seasonal asthma, seasonal allergic rhinitis, chronic allergic rhinitis, chronic obstructive pulmonary disease, emphysema, pulmonary hypertension, interstitial pulmonary fibrosis, cystic fibrosis, or hypoxia. More specifically, the term refers to pulmonary hypertension or interstitial pulmonary fibrosis.

[0318] In one embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention for use in the prevention and/or treatment of endocrine and/or metabolic diseases. In particular, the term "endocrine and/or metabolic diseases" refers to hypothyroidism, congenital adrenal hyperplasia, parathyroid disease, diabetes mellitus, 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 specifically, the term refers to obesity and/or type II diabetes.

[0319] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prevention and/or treatment of endocrine and/or metabolic diseases. In particular, the term "endocrine and/or metabolic diseases" refers to hypothyroidism, congenital adrenal hyperplasia, parathyroid disease, diabetes mellitus, 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 specifically, the term refers to obesity and/or type II diabetes.

[0320] In additional aspects of the method of treatment, this invention provides methods for the prevention and/or treatment of a mammal suffering from endocrine and/or metabolic diseases, where the methods include administering an effective amount of a compound of the invention or one or more of the pharmaceutical compositions described in the invention for treatment or prevention of said pathological condition. In particular, the term "endocrine and/or metabolic diseases" refers to hypothyroidism, congenital adrenal hyperplasia, parathyroid disease, diabetes mellitus, 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 specifically, the term refers to obesity and/or type II diabetes.

[0321] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent. In a specific embodiment, the other therapeutic agent is an agent for the treatment of endocrine and/or metabolic diseases. In particular, the term "endocrine and/or metabolic diseases" refers to hypothyroidism, congenital adrenal hyperplasia, parathyroid disease, diabetes mellitus, 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 specifically, the term refers to obesity and/or type II diabetes.

[0322] In one embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in the prevention and/or treatment of cardiovascular disease. In particular, the term "cardiovascular disease" refers to arrhythmia (atrial or ventricular, or both); atherosclerosis and its complications; angina; heart rhythm disturbances; myocardial ischemia; myocardial infarction; aneurysm of the heart or blood vessels; vasculitis, stroke; peripheral obstructive arteriopathy of a limb, organ or tissue; reperfusion injury after ischemia of the brain, heart, kidney or other organ or tissue; endotoxic, operational or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; shock vasoconstriction (including vasoconstriction associated with migraines); vascular disorders, inflammation, insufficiency, related to only one organ or tissue. More specifically, the term refers to atherosclerosis.

[0323] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prevention and/or treatment of cardiovascular disease. In particular, the term "cardiovascular disease" refers to arrhythmia (atrial or ventricular, or both); atherosclerosis and its complications; angina; heart rhythm disturbances; myocardial ischemia; myocardial infarction; aneurysm of the heart or blood vessels; vasculitis, stroke; peripheral obstructive arteriopathy of a limb, organ or tissue; reperfusion injury after ischemia of the brain, heart, kidney or other organ or tissue; endotoxic, operational or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; shock vasoconstriction (including vasoconstriction associated with migraines); vascular disorders, inflammation, insufficiency, related to only one organ or tissue. More specifically, the term refers to atherosclerosis.

[0324] In additional aspects of the method of treatment, this invention provides methods for the prevention and/or treatment of a mammal suffering from cardiovascular diseases, where the methods include the introduction of an effective amount of the compounds according to the invention or one or more of the pharmaceutical compositions described in the invention for the treatment or prevention of this pathological condition. In particular, the term "cardiovascular disease" refers to arrhythmia (atrial or ventricular, or both); atherosclerosis and its complications; angina; heart rhythm disturbances; myocardial ischemia; myocardial infarction; aneurysm of the heart or blood vessels; vasculitis, stroke; peripheral obstructive arteriopathy of a limb, organ or tissue; reperfusion injury after ischemia of the brain, heart, kidney or other organ or tissue; endotoxic, operational or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; shock vasoconstriction (including vasoconstriction associated with migraines); vascular disorders, inflammation, insufficiency, related to only one organ or tissue. More specifically, the term refers to atherosclerosis.

[0325] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent. In a specific embodiment, the other therapeutic agent is an agent for the treatment of cardiovascular diseases. In particular, the term "cardiovascular disease" refers to arrhythmia (atrial or ventricular, or both); atherosclerosis and its complications; angina; heart rhythm disturbances; myocardial ischemia; myocardial infarction; aneurysm of the heart or blood vessels; vasculitis, stroke; peripheral obstructive arteriopathy of a limb, organ or tissue; reperfusion injury after ischemia of the brain, heart, kidney or other organ or tissue; endotoxic, operational or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; shock vasoconstriction (including vasoconstriction associated with migraines); vascular disorders, inflammation, insufficiency, related to only one organ or tissue. More specifically, the term refers to atherosclerosis.

[0326] In one embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in the prevention and/or treatment of dermatological diseases. In particular, the term "dermatological diseases" refers to atopic dermatitis, bullous disorders, collagenosis, psoriasis, psoriatic lesions, dermatitis, contact dermatitis, eczema, vitiligo, pruritus, urticaria, acne rosacea, scleroderma, wound healing, scarring, hypertrophic scarring, keloid scarring, Kawasaki disease, rosacea, Sjögren-Larsson syndrome, or urticaria. More specifically, the term refers to atopic dermatitis, scleroderma, Sjögren-Larsson syndrome, or urticaria.

[0327] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prevention and/or treatment of dermatological diseases. In particular, the term "dermatological diseases" refers to atopic dermatitis, bullous disorders, collagenosis, psoriasis, psoriatic lesions, dermatitis, contact dermatitis, eczema, vitiligo, pruritus, urticaria, acne rosacea, scleroderma, wound healing, scarring, hypertrophic scarring, keloid scarring, Kawasaki disease, rosacea, Sjögren-Larsson syndrome, or urticaria. More specifically, the term refers to atopic dermatitis, scleroderma, Sjögren-Larsson syndrome, or urticaria.

[0328] In additional aspects of a method of treatment, the invention provides methods for preventing and/or treating a mammal suffering from a dermatological disease, wherein the methods comprise administering an effective amount of a compound of the invention or one or more of the pharmaceutical compositions described herein for treating or preventing said pathological condition. In particular, the term "dermatological diseases" refers to atopic dermatitis, bullous disorders, collagenosis, psoriasis, psoriatic lesions, dermatitis, contact dermatitis, eczema, vitiligo, pruritus, urticaria, acne rosacea, scleroderma, wound healing, scarring, hypertrophic scarring, keloid scarring, Kawasaki disease, rosacea, Sjögren-Larsson syndrome, or urticaria. More specifically, the term refers to atopic dermatitis, scleroderma, Sjögren-Larsson syndrome, or urticaria.

[0329] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent. In a specific embodiment, the other therapeutic agent is an agent for the treatment of dermatological diseases. In particular, the term "dermatological diseases" refers to atopic dermatitis, bullous disorders, collagenosis, psoriasis, psoriatic lesions, dermatitis, contact dermatitis, eczema, vitiligo, pruritus, urticaria, acne rosacea, scleroderma, wound healing, scarring, hypertrophic scarring, keloid scarring, Kawasaki disease, rosacea, Sjögren-Larsson syndrome, or urticaria. More specifically, the term refers to atopic dermatitis, scleroderma, Sjögren-Larsson syndrome, or urticaria.

[0330] In one embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention for use in the prevention and/or treatment of diseases associated with abnormal angiogenesis. In particular, the term "diseases associated with abnormal angiogenesis" refers to atherosclerosis, hypertension, tumor growth, inflammation, rheumatoid arthritis, wet macular degeneration, choroidal neovascularization, retinal neovascularization, and diabetic retinopathy. More specifically, the term refers to atherosclerosis, hypertension, or diabetic retinopathy.

[0331] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prevention and/or treatment of diseases associated with abnormal angiogenesis. In particular, the term "diseases associated with abnormal angiogenesis" refers to atherosclerosis, hypertension, tumor growth, inflammation, rheumatoid arthritis, wet macular degeneration, choroidal neovascularization, retinal neovascularization, and diabetic retinopathy. More specifically, the term refers to atherosclerosis, hypertension, or diabetic retinopathy.

[0332] In additional aspects of the method of treatment, this invention provides methods for the prevention and/or treatment of a mammal suffering from diseases associated with abnormal angiogenesis, where the methods include administering an effective amount of a compound of the invention or one or more of the pharmaceutical compositions described in the invention for treatment or prevention of said pathological condition. In particular, the term "diseases associated with abnormal angiogenesis" refers to atherosclerosis, hypertension, tumor growth, inflammation, rheumatoid arthritis, wet macular degeneration, choroidal neovascularization, retinal neovascularization, and diabetic retinopathy. More specifically, the term refers to atherosclerosis, hypertension, or diabetic retinopathy.

[0333] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent. In a specific embodiment, the other therapeutic agent is an agent for the treatment of diseases associated with abnormal angiogenesis. In particular, the term "diseases associated with abnormal angiogenesis" refers to atherosclerosis, hypertension, tumor growth, inflammation, rheumatoid arthritis, wet macular degeneration, choroidal neovascularization, retinal neovascularization, and diabetic retinopathy. More specifically, the term refers to atherosclerosis, hypertension, or diabetic retinopathy.

[0334] Injectable dose levels range from about 0.1 mg/kg/hour to 10 mg/kg/hour, all administered over about 1 to about 120 hours, and in particular over 24 to 96 hours . A bolus of about 0.1 mg/kg to about 10 mg/kg or higher may also be pre-bolused to achieve adequate steady state levels. It is assumed that the maximum total dose should not exceed 1 g / day for a patient with a body weight of 40 to 80 kg.

[0335] For the prevention and/or treatment of long-term pathological conditions, such as degenerative conditions, the treatment process is usually extended over many months or years, so oral administration is preferred for the patient in terms of convenience and tolerability. When administered orally, typical treatment regimens are regular administration of one to four (1-4) doses daily, in particular one to three (1-3) doses daily, usually one to two (1-2) doses daily. and, most often, one (1) dose daily. Alternatively, in the case of oral administration of long acting drugs, typical treatment regimens are once every two weeks, once a week and once a day. In particular, the dosage regimen may be every 1-14 days, more specifically 1-10 days, even more specifically 1-7 days, and most specifically 1-3 days.

[0336] Using these dosing regimens, each dose provides from about 1 to about 1000 mg of a compound of the invention, with each specific dose providing from about 10 to about 500 mg, and in particular from about 30 to about 250 mg.

[0337] Transdermal doses are typically chosen to provide similar or lower blood drug concentrations than those achieved with injectable doses.

[0338] In the case of use to prevent the occurrence of a pathological condition, a compound of the invention may be administered to a patient at risk of developing a pathological condition, usually on the advice and under the supervision of a physician, at the dose levels described above. Patients at risk of developing a particular condition generally include patients who have a family history of that condition or those patients who have been identified by genetic testing or screening to be particularly predisposed to developing the condition.

[0339] The compound of the invention may be administered as monotherapy, or it may be administered in combination with other therapeutic agents, including another compound of the invention, that exhibit the same or similar therapeutic activity and have been found to are safe and effective in case of such combined administration. In a specific embodiment, the co-administration of two (or more) agents can significantly reduce the dose of each of the agents used, thereby reducing the observed side effects.

[0340] In one embodiment, a compound of the invention or a pharmaceutical composition comprising a compound of the invention is administered as a drug. In a particular embodiment, said pharmaceutical composition further comprises an additional active ingredient.

[0341] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of a disease involving inflammation, wherein the specific agents include, but are not limited to, immunoregulatory agents, e.g., azathioprine, corticosteroids (e.g., prednisolone or dexamethasone), cyclophosphamide, cyclosporine A, tacrolimus, mycophenolate mofetil, muromonab-CD3 (OKT3, eg ^orthocolon® ), ATG, aspirin, acetaminophen, ibuprofen, naproxen, and piroxicam.

[0342] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of arthritis (e.g., rheumatoid arthritis), the specific agents including, but not limited to, analgesics, nonsteroidal anti-inflammatory drugs (NSAIDS ), steroids, synthetic DMARDs (for example, but not limited to, methotrexate, leflunomide, sulfasalazine, auranofin, sodium aurothiomalate, penicillamine, chloroquine, hydroxychloroquine, azathioprine, tofacitinib, baricitinib, fostamatinib, and cyclosporine), and biological DMARDS (eg, but not limited to, infliximab, etanercept, adalimumab, rituximab, and abatacept).

[0343] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of proliferative disorders, wherein particular agents include, but are not limited to, methotrexate, leucovorin, adriamycin, prednisone, bleomycin, cyclophosphamide, 5-fluorouracil, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, doxorubicin, tamoxifen, toremifene, megestrol acetate, anastrozole, goserelin, anti-HER2 monoclonal antibody (eg, ^Herceptin® ), capecitabine, raloxifene hydrochloride, EGFR inhibitors (eg, ^Iressu® , Tarceva ^® , Erbitux ^® ), VEGF inhibitors (eg Avastin ^® ), proteasome inhibitors (eg Velcade ^® ), Gleevec ^® and hsp90 inhibitors (eg 17-AAG). In addition, the compound of the invention corresponding to formula I may be administered in combination with other therapies, including, but not limited to, radiation therapy or surgery. In a particular embodiment, the proliferative disorder is selected from cancer, myeloproliferative disease, or leukemia.

[0344] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of autoimmune diseases, wherein the particular agents include, but are not limited to, glucocorticoids, cytostatics (e.g., purine analogs), alkylating agents , (e.g., nitrogen mustards (cyclophosphamide), nitrosoureas, platinum compound of the inventions, and others), antimetabolites (e.g., methotrexate, azathioprine, and mercaptopurine), cytotoxic antibiotics (e.g., dactinomycin, anthracyclines, mitomycin C, bleomycin, and mithramycin), antibodies ( e.g. anti-CD20, anti-CD25 or anti-CD3 (OTK3) monoclonal antibodies, Atgam ^® and Thymoglobuline ^® antithymocyte globulin), cyclosporine, tacrolimus, rapamycin (sirolimus), interferons (eg IFN-β), TNF binding proteins (eg infliximab , etanercept, or adalimumab), mycophenolate, fingolimod, and myriocin.

[0345] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of transplant rejection, the specific agents including, but not limited to, calcineurin inhibitors (e.g., cyclosporine or tacrolimus (FK506)) , mTOR inhibitors (eg, sirolimus, everolimus), antiproliferatives (eg, azathioprine, mycophenolic acid), corticosteroids (eg, prednisolone, hydrocortisone), antibodies (eg, anti-IL-2Rα receptor monoclonal antibodies, basiliximab, daclizumab), polyclonal antibodies against T cells (eg antithymocyte globulin (ATG), antilymphocyte globulin (ALG)).

[0346] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of asthma and/or rhinitis and/or COPD, the specific agents including, but not limited to, beta2-adrenoceptor agonists ( eg salbutamol, levosalbutamol, terbutaline, and bitolterol), epinephrine (inhaled or tablet), anticholinergics (eg, ipratropium bromide), glucocorticoids (oral or inhaled). Long-acting β2-agonists (eg, salmeterol, formoterol, bambuterol, and extended-release oral albuterol), combinations of inhaled steroids and long-acting bronchodilators (eg, fluticasone/salmeterol, budesonide/formoterol), leukotriene antagonists and inhibitors (eg, montelukast, zafirlukast and zileitone), inhibitors of mediator release (eg, chromoglycate and ketotifen), biological regulators of the IgE response (eg, omalizumab), antihistamines (eg, cetirizine, cinnarizine, fexofenadine), and vasoconstrictors (eg, oxymetazoline, xylometazoline, naphazoline, and tramazolin ).

[0347] Additionally, a compound of the invention may be administered in combination with rescue therapies for asthma and/or COPD, such therapies including administration of oxygen or helium-oxygen mixture, nebulized salbutamol, or terbutaline (optionally in combination with an anticholinergic agent ( eg, ipratropium), systemic steroids (oral or intravenous, eg, prednisone, prednisolone, methylprednisolone, dexamethasone, or hydrocortisone), intravenous salbutamol, injectable or inhaled non-specific beta-agonists (eg, epinephrine, isoetarine, isoproterenol, metaproterenol), anticholinergics ( intravenously or sprayed, for example, glycopyrrolate, atropine, ipratropium), methylxanthines (theophylline, aminophylline, bamiphylin), inhalation anesthetics that have a bronchodilatory effect (for example, isoflurane, halothane, enflurane), ketamine and intravenous magnesium sulfate.

[0348] In one embodiment, a compound of the invention is administered in combination with another therapeutic agent for the treatment and/or prevention of inflammatory bowel disease (IBD), the specific agents including, but not limited to, glucocorticoids (e.g., prednisone, budesonide ), disease-modifying synthetic immunomodulating agents (eg, methotrexate, leflunomide, sulfasalazine, mesalazine, azathioprine, 6-mercaptopurine, and cyclosporine), and disease-modifying biological immunomodulating agents (infliximab, adalimumab, rituximab, and abatacept).

[0349] In one embodiment, a compound of the invention is administered in combination with another therapeutic agent for the treatment and/or prevention of systemic lupus erythematosus (SLE), the specific agents including, but not limited to, human monoclonal antibodies (belimumab (benlysta) ), disease-modifying antirheumatic drugs (DMARDs), such as antimalarials (eg, plaquenil, hydroxychloroquine), immunosuppressants (eg, methotrexate and azathioprine), cyclophosphamide, and mycophenolic acid, immunosuppressants, and analgesics such as non-steroidal anti-inflammatory drugs, opiates ( eg dextropropoxyphene and co-codamol), opioids (eg hydrocodone, oxycodone, controlled release morphine sulfate or methadone) and fentanyl transdermal patch.

[0350] In one embodiment, a compound of the invention is administered in combination with another therapeutic agent for the treatment and/or prevention of psoriasis, the specific agents including, but not limited to, topical treatments such as baths, moisturizers, medicinal creams and ointments containing tar, dithranol (anthralin), corticosteroids such as deoxymethasone (topicort™), fluocinonide, vitamin D3 analogs (eg calcipotriol), argan oil and retinoids (etretinate, acitretin, tazarotene), systemic therapies such as as the use of methotrexate, cyclosporine, retinoids, thioguanine, hydroxyurea, sulfasalazine, mycophenolate mofetil, azathioprine, tacrolimus, fumaric acid esters, or biologics such as ameviv™, enbrel™, humira™, remicade™, raptiva™ and ustekinumab (an IL-blocker). 12 and IL-23). Additionally, a compound of the invention may be administered in combination with other therapies, including, but not limited to, phototherapy or photochemotherapy (eg, psoralen and ultraviolet A (PUVA) phototherapy).

[0351] In one embodiment, a compound of the invention is administered in combination with another therapeutic agent for the treatment and/or prevention of an allergic reaction, wherein particular agents include, but are not limited to, antihistamines (e.g., cetirizine, diphenhydramine, fexofenadine, levocetirizine), glucocorticoids (eg, prednisone, betamethasone, beclomethasone, dexamethasone), epinephrine, theophylline, or antileukotrienes (eg, montelukast or zafirlukast), anticholinergics, and decongestants.

[0352] For a specialist in the field of medicine, it is obvious that the joint introduction means any means of delivering two or more therapeutic agents to a patient within the same treatment regimen. Although two or more drugs can be administered simultaneously in one dosage form, that is, as part of one pharmaceutical composition, but this is not a fundamentally important point. Medicines can be administered in different dosage forms and at different times.

CHEMICAL SYNTHESIS TECHNIQUES

General information

[353] The compound of the invention can be prepared from readily available starting materials using the following general methods and techniques. It should be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, reaction times, molar ratios of reactants, solvents, pressures, and the like) are given, other process conditions may be used if not otherwise specified. Optimum reaction conditions may vary depending on the particular reagents or solvent used, but such conditions can be determined by one skilled in the art by applying conventional optimization techniques.

[0354] In addition, for specialists in this field it is obvious that the use of traditional protective groups may be required to prevent the occurrence of undesired reactions involving certain functional groups. The selection of an appropriate protecting group for a particular functional group, as well as suitable conditions for protection and deprotection, are well known (Wuts & Greene 2006).

[0355] The following are detailed methods for preparing the above-described compound of the invention and comparative examples. The compound of the invention can be synthesized from known or commercially available starting materials and reagents by any person skilled in the art of organic synthesis.

[0356] All reagents are commercial grade and are used as received, without further purification, unless otherwise noted. Commercially available anhydrous solvents are used for reactions carried out in an inert atmosphere. In all other cases, analytical grade solvents are used unless otherwise noted. Column chromatography was performed on silica gel 60 (35-70 µm) on 15 µm Interchim® normal phase spherical silica gel columns or using Biotage® SNAP KP-NH or Biotage® SNAP Ultra flash chromatography cartridges. Thin layer chromatography was carried out using pre-coated F-254 silica gel plates (thickness 0.25 mm). ¹ H NMR spectra were recorded on a Bruker DPX 400 NMR spectrometer (400 MHz) or a Bruker Advance 300 NMR spectrometer (300 MHz). Chemical shifts (δ) for ¹ H NMR spectra are given in parts per million (ppm) relative to tetramethylsilane (δ) (0.00) or the corresponding residual solvent peak, i.e. CHCl ₃ (7.27), as an internal standard. The multiplicities are given in the form of a singlet (s), doublet (d), triplet (t), quartet (q), quintet (quintet), multiplet (m), and broadening (br). Mass spectra were recorded in electrospray ionization mode on a Waters liquid chromatomass spectrometer or on a Waters Acquity H-Class UPLC spectrometer connected to a Waters Mass 3100 detector. Columns used: Waters Acquity UPLC BEH C18 1.7 µm, 2.1 mm id x 50 mm length, Waters Acquity UPLC BEH C18 1.7 µm, 2.1 mm ID x 30 mm length, or Waters Xterra MS 5 µm C18, 100 x 4.6 mm. The methods use either ACN/H ₂ O gradients (H ₂ O contains either 0.1% TFA or 0.1% NH ₃ ) or MeOH/H ₂ O gradients (H ₂ O contains 0.05% TFA). Microwave heating is carried out using a Biotage Initiator microwave synthesis unit.

Table I. List of abbreviations used in the experimental section

Reduction Definition µl microliter AcOH acetic acid ACOK potassium acetate ACN acetonitrile water. water ATP adenosine 5'-triphosphate BBBPY 4,4'-ditretbutyl-2,2'-dipyridyl Boc tert-butyloxy-carbonyl B ₂ pin ₂ 4,4,5,5-tetra-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxa-borolan br.s wide singlet BrettPhos 2-(dicyclohexylphosphino)3,6-di-methoxy-2',4',6'-triisopropyl-1,1'-biphenyl Calc. calculated d doublet DBU 1,8-diazabicyclo-[5,4,0]undec-7-ene dd doublet of doublets DCM dichloromethane DIPEA N,N-diisopropyl-ethylamine DMAC dimethylacetamide DMF N,N-dimethyl-formamide DMSO dimethyl sulfoxide DPPF 1,1'-bis(diphenylphosphino)ferrocene _Et2O diethyl ether EtOAc ethyl acetate EtOH ethanol equiv. equivalent G gram h hour HATU 1-[bis(dimethyl-amino)methylene]-1H-1,2,3-triazolo-[4,5-b]pyridinium 3-oxide hexafluorophosphate HPLC high performance liquid chromatography i-PrOH isopropanol [Ir(OMe)(COD)] ₂ (1,5-cyclo-octadiene)-(methoxy)iridium(I) dimer LiHMDS lithium hexamethyldisilazane LCMS Liquid Chromatography - Mass Spectrometry m multiplet MeOH methanol MeONa sodium methoxide mg milligram min minute ml milliliter mmol millimole MS mass spectrometry MTBE methyl tert-butyl ether MW Molecular mass MW (nab) observed molecular weight MW (calc) calculated molecular weight NA no data n-BuOH butan-1-ol NMP N-methyl-2-pyrrolidone obsd observable Pd(dppf)Cl ₂ DCM complex of 1,1'-bis-[(diphenylphosphino)-ferrocene]dichloro-palladium(II) with dichloromethane Pd(OAc) ₂ palladium(II) acetate Pd(PPh ₃ ) ₄ tetrakis(triphenylphosphine)palladium(0) Pd ₂ (dba) ₃ tris(dibenzylidene-acetone)-dipalladium(0) ppm parts per million to quadruplet RT Room temperature With singlet us. saturated SM raw material t triplet t-BuXPhos 2-ditretbutyl-phosphino-2',4',6'-triisopropyl-biphenyl Et ₃ N triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

SYNTHESIS OF THE COMPOUNDS OF THE INVENTION

General synthesis methods

Overview of synthesis methods

General methods B: Nucleophilic aromatic substitution reaction (S _N Ar) of a trisubstituted aniline on a halonitrophenyl derivative or a pyridine derivative

Method B1: S _N Ar reaction of a disubstituted aminobenzoate on a halonitrophenyl derivative

Method B2: S _N Ar reaction of a disubstituted aminobenzoate on a halonitrophenyl derivative

Method B3: S _N Ar reaction of a disubstituted aminobenzoate or benzoate on a halonitrophenyl derivative

Common C Methods: Reduction and Cyclization Reaction

Method C1: SnCl ₂ , 2H ₂ O/SnCl ₂ /trimethylorthoformate

Method C2: Zn/AcOH/HC(OCH3) ₃

General Methods E: Aryl Coupling Reaction with Peptide Coupling Reaction

Method E1: Suzuki reaction (3 steps in interchangeable order)

Method E2: Buchwald reaction (3 steps)

Method E3: Copper catalyzed amination reaction (3 steps)

Method E4: Borylation reaction then Suzuki reaction (3 steps)

Method E5: Cyanidation reaction, then cycling reaction (4 steps)

General Methods F: Heteroaryl compound iodination reaction

Common H Methods: C-H Link Activation

General methods I: deprotection of phenol (demethylation)

General Methods J: Phenol Alkylation

Method J1: K ₂ CO ₃ /alkyl iodide

Method J2: KOH/diethyl(bromodifluoromethyl)phosphonate

General methods K: Amine deprotection

General methods L: amine functionalization

Method L1: reductive amination

Method L2: N-alkylation of an amine

General methods M: Nucleophilic aromatic substitution reaction (S _N Ar)

Method M1: Reaction of S _N Ar with an amine

Method M2: reaction of S _N Ar with alcohol

General methods N: pyrazole alkylation

Method N1: Alkylation with an alkyl halide

Method N2: alkylation with haloacetate

General Methods O: Amide Alkylation

General methods P: tert-butyl ether cleavage

General Methods Q: Carboxylic Acid Esterification

Method Q1: HATU

Method Q2: SOCl ₂

Method Q3: alkyl bromide/Cs ₂ CO ₃

General Methods R: Interesterification of tert-butyl ether

General Methods

Methods B: SNAr reaction of a trisubstituted aniline on a halonitrophenyl derivative or a pyridine derivative

Method B1: SNAr reaction of disubstituted aminobenzoate on a halonitrophenyl derivative

[0357] A solution of methyl 4-amino-2,6-dimethoxybenzoate (1 eq) and 4-bromo-1-fluoro-2-nitrobenzene (1 eq) in THF is cooled at 0°C under N ₂ atmosphere. LiHMDS (1 M solution in THF, 2.3 eq) is then added dropwise over 2 hours. The reaction is stopped by adding water. The THF is evaporated and the remaining reaction mixture is stirred at 3° C. overnight. To the reaction mixture was slowly added with rapid stirring 2 M HCl, and the mixture was stirred for 1 hour at 3°C. The precipitate is filtered off, then dried in a vacuum oven at 45°C and 0.002 MPa for 5 hours to obtain the desired intermediate.

Illustrative Synthesis of Intermediate Int 59

[0358] A solution of methyl 4-amino-2,6-dimethoxybenzoate (40 g, 189.4 mmol, 1 eq) and 4-bromo-1-fluoro-2-nitrobenzene (23.3 ml, 189.4 mmol, 1 eq) in THF (1000 ml) is cooled at 0°C in an atmosphere of N ₂ . LiHMDS (1 M solution in THF, 435.6 ml, 435.6 mmol, 2.3 eq) is then added dropwise over 2 hours. The reaction is stopped by adding water (800 ml). The THF is evaporated and the remaining reaction mixture is stirred at 3° C. overnight. 2 M HCl (600 ml) was slowly added to the reaction mixture with rapid stirring, and the mixture was stirred for 1 hour at 3°C. The precipitate is filtered off, then dried in a vacuum oven at 45° C. and 0.002 MPa for 5 hours to obtain the desired compound.

Method B2: SNAr reaction of a disubstituted aminobenzoate on a halonitrophenyl derivative

[0359] To a solution of the disubstituted aminobenzamide (1 to 1.1 eq) in anhydrous THF or DMF (DMF is used in the case of the CN substituent) under argon, the fluoronitro derivative (1 to 1.7 eq) is added. The mixture is cooled at 0°C and NaH (3 eq) is added in portions. The mixture is stirred at 0°C for 10 minutes, then at room temperature overnight, or heated to 100°C for 3 hours (when W=-CN). The mixture is cooled to 0°C, quenched with water or saturated NH ₄ Cl solution, diluted with EtOAc or DCM and water, saturated NH ₄ Cl solution or brine, extracted with EtOAc or DCM. The combined organic layers are dried or washed with brine, then dried (Na ₂ SO ₄ or MgSO ₄ ), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel gives the desired compound.

Illustrative Synthesis of Intermediate Int 61

[0360] To a solution of Int 12 (3.90 g, 14.98 mmol, 1 eq) in anhydrous THF (30 ml), degassed with N _2, then placed under argon, was added 4-bromo-1-fluoro- 2-nitro-benzene (3.95 g, 17.97 mmol, 1.2 eq). The mixture is cooled at 0° C. and NaH (1.79 g, 44.94 mmol, 3 eq) is added portionwise. The mixture is warmed to room temperature and stirred at room temperature overnight. The mixture is cooled to 0°C, quenched with cold water, diluted with EtOAc, water and saturated NH ₄ Cl solution, extracted with EtOAc. The combined organic layers are dried, filtered and concentrated in vacuo. The residue is purified by flash chromatography on silica gel (eluting with DCM/MeOH 95/5) to give the desired product.

Illustrative synthesis of 4-(4-cyano-2-nitroanilino)-2-(difluoromethoxy)-N-ethyl-6-methoxybenzamide

[0361] To a stirred solution of Int 12 (1.00 g, 3.84 mmol, 1 eq) and the fluoronitro derivative (0.79 g, 4.77 mmol, 1.1 eq) in anhydrous DMF (15 ml), cooled to 0°C, NaH (0.46 g, 11.52 mmol, 3 eq) is added. The mixture was stirred at 0°C for 1 hour, then at room temperature for 1 hour, then at 100°C for 3 hours. The mixture is carefully added to the ice/water mixture. Brine is added and the aqueous layer is extracted with EtOAc. The combined organic layers are dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with DCM/MeOH 100/0 to 98/2) to give the desired product.

LCMS: MW (calculated): 406.3; m/z MW (detected): 407.3 (M+H).

Method B3: SNAr reaction of a disubstituted aminobenzoate or benzoate on a halonitrophenyl derivative

[0362] Et ₃ N (5 eq). The mixture is stirred at 80°C overnight. After cooling to room temperature, the mixture is concentrated in vacuo (the reaction is carried out only with DMF as solvent), diluted with EtOAc or DCM, water or NaCl solution, extracted with EtOAc or DCM. The combined organic layers are dried, filtered or dried by filtration through a hydrophobic column and concentrated in vacuo. The residue is purified by silica gel flash chromatography to give the desired product.

Illustrative Synthesis of Intermediate Int 73

[0363] To a solution of methyl 4-amino-2,6-dimethoxybenzoate (232 mg, 1.1 mmol, 1.2 eq) and 5-bromo-2-chloro-3-nitropyridine (250 mg, 0.914 mmol, 1 eq ) in anhydrous DMSO (0.5 ml), stirred at 80°C for 5 minutes, add Et ₃ N (0.64 ml, 4.57 mmol, 5 eq). The mixture was stirred at 80°C, then anhydrous DMSO (1 ml) was added and the mixture was stirred at 80°C overnight. After cooling to room temperature, the mixture is diluted with EtOAc, water and brine. The aqueous layer is extracted with EtOAc. The combined organic layers are dried, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with heptane/EtOAc 80/20) to give the desired product.

Method C: reduction and cyclization reaction

Method C1: SnCl ₂ , 2H ₂ O/SnCl ₂ /trimethylorthoformate

[0364] A mixture of nitroaniline derivative (1 eq), tin(II) chloride dihydrate (2.3 eq) and tin(II) chloride (1.7 eq) in EtOH was stirred at reflux for 2 hours. After completion of the reduction to the amine, which was confirmed by continuous monitoring by ultra high performance liquid chromatography (UPLC), trimethylorthoformate (4 eq) was slowly added to the mixture and stirring was continued at reflux for 2 hours. The mixture is cooled to room temperature and concentrated to dryness. The residue is taken up in EtOAc and washed with 2 M NaOH. The resulting suspension (stannous chloride) is filtered. The layers are separated. A saturated aqueous solution of NaHCO ₃ was added to the organic layer. Again a suspension is formed. A 20% NaOH solution is added to the suspension (heat generation). The mixture separates overnight. The organic layer is dried over K ₂ CO ₃ and filtered. All filter cakes are washed with EtOAc, combined with the aqueous layers, and the layers are separated. The organic layers are combined and concentrated to dryness under reduced pressure. The residue is suspended in Et ₂ O, stirred for 30 minutes and filtered. The filter cake of the funnel is kept under vacuum for 20 minutes to obtain the desired product.

Illustrative Synthesis of Intermediate Int 45

[0365] A mixture of Int 59 (148.2 g, 360.4 mmol, 1 eq), tin(II) chloride dihydrate (188 g, 833.1 mmol, 2.3 eq) and tin(II) chloride (116, 2 g, 612.8 mmol, 1.7 eq) in EtOH (1800 ml) was stirred at reflux for 2 hours. After completion of the reduction to the amine, which was confirmed by continuous monitoring by ultra high performance liquid chromatography (UPLC), trimethyl orthoformate (157.7 mL, 1441.5 mmol, 4 eq) was slowly added to the mixture and stirring was continued at reflux for 2 hours. The mixture is cooled to room temperature and concentrated to dryness. The residue was taken up in EtOAc (1400 ml) and washed with 2 M NaOH (600 ml). The resulting suspension (stannous chloride) is filtered (overnight). The layers are separated. Saturated aqueous NaHCO ₃ solution (1000 ml) was added to the organic layer. Again a suspension is formed. A 20% NaOH solution (2000 ml) was added to the suspension (heat development). The mixture exfoliates over night. The organic layer is dried over K ₂ CO ₃ and filtered. All filter cakes are washed with EtOAc, combined with the aqueous layers, and the layers are separated. The organic layers are combined and concentrated to dryness under reduced pressure. The residue is suspended in Et ₂ O (500 ml), stirred for 30 minutes and filtered. The filter cake of the funnel is kept under vacuum for 20 minutes to obtain the desired product Int 45 (82.1 g).

Method C2: Zn/AcOH/HC(OCH ₃ ) ₃

[0366] Zinc dust (5 to 11.1 eq) is added in portions to a solution of the nitroamino derivative (1 eq) in glacial acetic acid, stirred at room temperature or at reflux. The resulting mixture is stirred (75° C. or reflux) for 10 minutes to 1 hour (completion of the reaction is confirmed by continuous monitoring by TLC and/or UPLC-MS). The reaction mixture is cooled to room temperature, after dilution in EtOAc or toluene or without dilution, filtered through a pad of Clarcel diatomaceous earth, washed with EtOAc or toluene or AcOH or EtOAc and toluene. The filtrate is evaporated to dryness and either the diamino derivative is used without further purification in the next step, or the residue is purified by flash chromatography on a ^Biotage® SNAP KP-NH cartridge and used in the next step.

[0367] To a solution of the diamino derivative (1 eq) in MeOH is added p-toluenesulfonic acid or p-toluenesulfonic acid monohydrate (0.2 to 0.6 eq) or AcOH (0.2 eq) and trimethyl orthoformate (3 to 5 equiv). The resulting mixture was stirred at 75° C. - at reflux (30 minutes to overnight) and cooled to room temperature. The reaction mixture was concentrated in vacuo, purified by silica gel flash chromatography or extracted with water/EtOAc and purified by silica gel flash chromatography to give the desired product.

Illustrative Synthesis of Intermediate Int 42

[0368] To a solution of Int 60 (313 mg, 0.663 mmol, 1 eq) in glacial acetic acid, stirred at reflux, zinc dust (330 mg, 5.047 mmol, 7.6 eq) was added in portions. The resulting mixture was stirred at reflux, then zinc dust (150 mg, 2.294 mmol, 3.5 eq) was added again and the mixture was stirred at reflux (completion of the reaction was monitored by TLC). The reaction mixture is cooled to room temperature, filtered through a pad of Clarcel, washed with EtOAc and toluene. The filtrate is concentrated in vacuo and 4-(2-amino-4-bromanilino)-N-cyclopropyl-2-(difluoromethoxy)-6-methoxybenzamide, an o-phenylene diamine derivative, is used without further purification in the next step.

[0369] To a solution of the o-phenylenediamine derivative (0.663 mmol, 1 eq) in MeOH (7 mL) was added p-toluenesulfonic acid monohydrate (25 mg, 0.133 mmol, 0.2 eq) and trimethyl orthoformate (218 μL, 1.988 mmol , 3 equiv). The resulting mixture was stirred at 90°C for 30 minutes and at room temperature overnight. The reaction mixture is concentrated in vacuo and purified by silica gel flash chromatography (eluting with DCM/MeOH 100/0 to 90/10) to give the desired product.

Method E

Method E1: Suzuki reaction (3 steps in interchangeable order)

[0370] Method E1: sequence E1.1+E1.2+E1.3

1.1.2.0.1 E1.1: saponification of ether

[0371] A mixture of methyl ester derivative (1 eq), mixtures of MeOH/THF or MeOH and 2 M NaOH (2 to 20 eq), or a mixture of methyl ester derivative (1 eq), MeOH and NaOH granules (excess) is stirred at 65 -90°C for 5 hours to a period of time during the night. After cooling to ambient temperature, the organic solvents are removed under reduced pressure. The residue is diluted with water, the pH is adjusted to an acidic value with HCl (2 N or 6 N). The resulting suspension is filtered, washed with either pentane and Et ₂ O or water, and dried in a vacuum oven, or the suspension is extracted with a mixture of CHCl ₃ /n-BuOH (9/1), the combined organic layers are dried, filtered and concentrated under vacuum to obtain the required product.

Illustrative Synthesis of Intermediate Int 44

[0372] A mixture of methyl 4-(5-bromobenzimidazol-1-yl)-2,6-dimethoxybenzoate (Int 45) (82.1 g, 209.8 mmol, 1 eq), MeOH (450 ml), THF (550 ml) and 2 M NaOH (550 ml, 1100 mmol, 5.2 eq) stirred at 75°C overnight. After cooling to ambient temperature, the organic solvents are removed under reduced pressure. The residue is diluted with water (800 ml). The pH is adjusted from 12.4 to 1.6 with 6 M aqueous HCl. The resulting suspension is stirred at 2°C for 30 minutes and then filtered. The filter cake was washed with water (800 ml) and kept on the funnel filter under vacuum for 20 minutes to give a dark red solid. The solid is dried in a vacuum oven at 45° C. for 2 hours to give 4-(5-bromobenzimidazol-1-yl)-2,6-dimethoxybenzoic acid as a purple powder.

1.1.2.0.2 E1.2: peptide coupling reaction

[0373] The flask is loaded with carboxylic acid derivative (1 eq), anhydrous DMF, HATU (1.0 to 2 eq), DIPEA (2 to 10 eq). The mixture is stirred for 5 to 20 minutes at room temperature, then amine or amine hydrochloride (1.2 to 4.8 eq) is added. The mixture is stirred at room temperature for 1 hour to 96 hours, the precipitate is either filtered after adding water to the mixture to give the desired amide derivative, or the mixture is optionally concentrated in vacuo, water or saturated NaHCO ₃ solution is added and then extracted with EtOAc, EtOAc/MeOH, EtOAc/i-PrOH or DCM. The combined organic layers are then either dried on a hydrophobic column or washed with 0.1 N HCl, then brine or brine alone and dried over anhydrous Na ₂ SO ₄ (or MgSO ₄ ), filtered, concentrated in vacuo. The residue is purified by flash chromatography on silica gel or on a ^Biotage® SNAP KP-NH cartridge, or triturated in ACN or DCM to give the desired amide derivative. Alternative product isolation method: The mixture is concentrated in vacuo, purified by flash chromatography on a ^Biotage® SNAP KP-NH cartridge to give the desired amide derivative.

Illustrative Synthesis of Intermediate Int 39

[0374] The flask is charged with Int 44 (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 equiv). The mixture was stirred at room temperature for 10 minutes, then 2,2,2-trifluoroethanamine hydrochloride (216 mg, 1.6 mmol, 2 eq) was added. The mixture is stirred at room temperature overnight. After evaporation of the DMF, the residue is partitioned between EtOAc and water. The aqueous layer is extracted with EtOAc. The combined organic layers are dried over anhydrous Na ₂ SO ₄ , filtered, concentrated in vacuo and purified by flash chromatography on silica gel (eluting with DCM/MeOH 100/0 to 95/5) to give Int 39.

1.1.2.0.3 E1.3: Suzuki reaction

[0375] A high pressure reactor or an open round-bottom flask equipped with a condenser is charged with a heteroaryl bromide derivative (1 eq), boronic acid or boronic acid pinacol ester (1.1 to 1.5 eq), base (Cs ₂ CO ₃ , Na ₂ CO ₃ or KF, 2 to 3 eq) and solvent mixture dioxane/water: 4/1 or 3/1, or solvent mixture DMF/water: 4/1, or THF/water mixture: 9/1, or DME/water: 10/1). The mixture is either heated to 50°C or refluxed, degassed with N ₂ , then palladium catalyst (Pd(Ph ₃ ) ₄ or Pd(dppf)Cl ₂ DCM adduct (0.07 to 0.2 eq), or degassed with N ₂ or Ar at room temperature, then the catalyst is added, or the solvent is degassed before it is added to the mixture, and finally the catalyst is added. hours.Either the reaction mixture is concentrated in vacuo and the residue is dissolved in EtOAc or DCM and water, or the reaction mixture is quenched with water or saturated NaHCO ₃ solution.The reaction mixture is then extracted with EtOAc or DCM.The combined organic layers are optionally washed with brine, dried over anhydrous Na ₂ SO ₄ or MgSO ₄ , filter, concentrate in vacuo and purify by flash chromatography on silica gel or/and ^Biotage® SNAP KP-NH cartridge to give the desired compound. door to rubbing in ACN and filtered.

Illustrative synthesis of the compound Cpd 25

[0376] The flask was charged with 4-(5-bromobenzimidazol-1-yl)-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)benzamide, Int 39 (450 mg, 0.982 mmol, 1 eq), Cs ₂ CO ₃ (961 mg, 2.95 mmol, 3 eq) 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (CAS# 761446 -44-0; 306 mg, 1.47 mmol, 1.5 eq) and solvent mixture dioxane/water: 4/1 (20 ml). The mixture is heated to 100° C., degassed with N ₂ for 5 minutes, then Pd(PPh ₃ ) ₄ (173 mg, 0.15 mmol, 0.15 eq) is added. The mixture is stirred at 100°C for 2 hours. The reaction mixture is concentrated under vacuum. The residue is taken up in EtOAc and water and the aqueous layer is extracted with EtOAc. The combined organic layers are dried over anhydrous Na ₂ SO ₄ , filtered, concentrated in vacuo and purified by flash chromatography on silica gel (eluting with DCM/MeOH 95/5) to give the desired compound.

Illustrative synthesis of the compound Cpd 51

[0377] 4-(5-Bromobenzimidazol-1-yl)-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)benzamide (Int 39) (40 mg, 0.09 mmol, 1 eq), KF (16 mg, 0.27 mmol, 3 eq), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (CAS# 928664-98- 6; 26 mg, 0.135 mmol, 1.5 eq) and solvent mixture DMF/water: 4/1 (2 ml). The mixture is heated to 50°C, degassed with N ₂ for 3 minutes, then add Pd(dppf)Cl ₂ ·DCM (8 mg, 0.009 mmol, 0.1 eq). The mixture is stirred at 50°C for 2 hours. The mixture was partitioned into EtOAc and water and the aqueous layer was extracted with EtOAc. The combined organic layers are dried over anhydrous Na ₂ SO ₄ , filtered, concentrated in vacuo and purified by silica gel flash chromatography (eluting with DCM/MeOH 95/5) followed by preparative HPLC to give the desired compound.

Illustrative synthesis of the compound Cpd 55

[0378] The flask was charged with Int 42 (50 mg, 0.11 mmol, 1 eq), Cs ₂ CO ₃ (107 mg, 0.33 mmol, 3 eq) 2-(4-(4.4.5.5 -tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetonitrile (CAS# 1093307-35-7; 33 mg, 0.14 mmol, 1.3 eq) and solvent mixture THF/water: 9/1 (3 ml). The mixture is refluxed, degassed with N ₂ for 5 minutes, then add Pd(dppf)Cl ₂ ·DCM (9 mg, 0.01 mmol, 0.1 eq). The mixture is stirred at reflux for 1 hour. The mixture is partitioned into DCM and water and the aqueous layer is extracted with DCM. The combined organic layers are dried by filtration through a hydrophobic column, concentrated in vacuo and purified by flash chromatography on silica gel (eluting with DCM/MeOH 95/5). Trituration in isopropyl ether with a few drops of ACN, then filtration gives the desired compound.

Illustrative synthesis of the compound Cpd 124

[0379] To a pre-degassed solution of Int 37 (90 mg, 0.19 mmol, 1 eq), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )pyrazole (47 mg, 0.23 mmol, 1.2 eq) Cs ₂ CO ₃ (124 mg, 0.38 mmol, 2 eq) and Pd(dppf)Cl ₂ DCM complex (15.5 mg, 0.019 mmol, 0.1 equiv). The solution is stirred at 105-110°C for 2 hours. The reaction mixture is diluted in DCM, washed with water and brine. The organic layer is separated, dried over MgSO ₄ , filtered, concentrated under vacuum. The residue is purified by flash chromatography on silica gel (eluting with DCM/MeOH 100/0 to 95/5), then triturated in Et ₂ O and concentrated in vacuo to give the desired compound.

1.1.2.0.4 E1.3a: Suzuki reaction without water

Illustrative synthesis of the compound Cpd 284

[0380] The flask was charged with Int 37 (50 mg, 0.110 mmol, 1 eq), 1-(ethoxycarbonylmethyl)-1H-pyrazole-4-boronic acid pinacol ester (CAS# 864754-16-5; 34 mg, 0.12 mmol, 1.1 eq), Cs ₂ CO ₃ (72 mg, 0.22 mmol, 2 eq), dioxane degassed with N ₂ (1 ml), and Pd(dppf)Cl ₂ DCM adduct (6, 3 mg, 0.008 mmol, 0.07 eq). The flask is sealed and the mixture is heated to 90°C for 6.5 hours. Add 1-(ethoxycarbonylmethyl)-1H-pyrazole-4-boronic acid pinacol ester, (CAS# 864754-16-5; 10 mg, 0.04 mmol, 0.3 eq) and Pd(dppf)Cl ₂ DCM adduct (6.3 mg, 0.008 mmol, 0.07 eq) and the mixture was stirred at 90° C. for 2 hours. The solvent is evaporated and the residue is taken up in EtOAc and water, extracted with EtOAc. The combined organic layers are washed with brine, dried over anhydrous MgSO ₄ , filtered, concentrated in vacuo and purified by flash chromatography on silica gel (eluting with heptane/EtOAc 100/0 to 0/100 followed by EtOAc/MeOH 100/0 to 90 /ten). After evaporation, ACN is added to the residue and the resulting solid is filtered to give the desired compound

Illustrative Synthesis of Intermediate Int 3

[0381] The flask is charged with 7-bromimidazo[1,2-a]pyridine (476 mg, 2.42 mmol, 1 eq), dioxane degassed with N ₂ (15 ml), pinacol ether 1-(ethoxycarbonylmethyl)- 1H-pyrazole-4-boronic acid (CAS# 864754-16-5; 745 mg, 2.66 mmol, 1.1 eq), Cs ₂ CO ₃ (1.58 g, 4.84 mmol, 2 eq) and adduct Pd(dppf)Cl ₂ DCM (138 mg, 0.17 mmol, 0.07 eq). The flask is sealed, purged with N ₂ and the mixture is heated at 90°C for 3 hours. EtOAc, water and brine are added to the mixture, then extracted with EtOAc, then with DCM. The insoluble matter is removed by filtration and the organic layers are separately dried by filtration through a hydrophobic column, then combined, concentrated in vacuo and purified by flash chromatography on silica gel (eluting with heptane/EtOAc from 100/0 to 0/100, then DCM/MeOH from 100 /0 to 90/10) to obtain the desired product.

1.1.2.0.5 E1.3b: Suzuki reaction with nitrile hydrolysis

[0382] General method: the appropriate derivative (1 eq) and a 4/1 dioxane/water solvent mixture are charged into the flask. The mixture is degassed with N ₂ , then boronic ether (1.2 to 1.5 eq), Cs ₂ CO ₃ (2 eq) and palladium catalyst (Pd(dppf)Cl ₂ DCM 0.1 eq or Pd( PPh ₃ ) ₄ 0.15 eq). The flask is sealed and the mixture is heated at 90°C-100°C for 1 hour to 1.5 hours. The reaction mixture is quenched with water or saturated NaHCO ₃ solution, extracted with EtOAc or DCM. The combined organic layers are dried over anhydrous Na ₂ SO ₄ , filtered or washed with brine and dried by filtration through a hydrophobic column, then concentrated under vacuum, purified by flash chromatography on silica gel and optionally dissolved in DCM, and subjected to SPM32 (supported on 3-mercaptopropylethyl sulfide silica gel) to give the desired compound.

Illustrative synthesis of the compound Cpd 259 and Cpd 258

[0383] The flask was charged with Int 46 (50 mg, 0.110 mmol, 1 eq), dioxane/water solvent mixture, degassed with N ₂ : 4/1 (1 mL), 3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridine-4-carbonitrile (CAS# 878194-91-3; 38 mg, 0.164 mmol, 1.5 eq), Cs ₂ CO ₃ (83 mg, 0.218 mmol, 2 eq) and Pd(dppf)Cl ₂ DCM (9 mg, 0.011 mmol, 0.1 eq). The flask is sealed and the mixture is heated at 90° C. for 1 hour. The reaction mixture is quenched with water, extracted with EtOAc. The combined organic layers are dried over anhydrous Na ₂ SO ₄ , filtered, concentrated in vacuo and purified by silica gel flash chromatography (eluting with DCM/MeOH 99/1 to 97/3) to give the desired nitrile compound (Cpd 258) LCMS: MW (calculated): 481.4; m/z MW (detected): 482.0 (M+H). Elution is carried out from 97/3 to 90/10 to obtain the desired carboxamide compound (Cpd 259).

LCMS: MW (calculated): 499.4; m/z MW (detected): 500.2 (M+H)

1.1.2.0.6 E1.3c: Suzuki reaction with ether splitting

Illustrative synthesis of the compound Cpd 255

[0384] The flask is charged with Int 46 (100 mg, 0.218 mmol, 1 eq), Cs ₂ CO ₃ (142 mg, 0.44 mmol, 2 eq), methyl 4-[4-(4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]butanoate (Int 72) (71 mg, 0.24 mmol, 1.1 eq) and dioxane/water solvent mixture, degassed with N ₂ : 4/1 (4 ml). Add Pd(dppf)Cl ₂ ·DCM (12 mg, 0.015 mmol, 0.07 eq), the flask is sealed, and the mixture is heated at 90°C for 2 hours, then at 50°C during the night. Add 1 ml of water, and the mixture is stirred at 90°C for 4 hours. The mixture is concentrated in vacuo and the residue partitioned between Et ₂ O and water. The organic layer is extracted with water. The combined aqueous layers were acidified to pH 5-6 with 2N HCl and extracted with EtOAc. The combined organic layers are washed with brine, dried over anhydrous MgSO ₄ , filtered, concentrated in vacuo and purified by flash chromatography on silica gel (eluting with DCM/MeOH 100/0 to 90/10). The precipitate formed as a result of evaporation of the fractions is filtered, washed with Et ₂ O to obtain the desired compound.

Method E1: sequence E1.1+E1.3+E1.2

1.1.2.1.1 E1.1: saponification of ether

[0385] See E1.1 sequences E1.1+E1.2+E1.3

1.1.2.1.2 E1.3: Suzuki coupling reaction

[0386] The flask was charged with the appropriate intermediate (1 eq), boronic ether (1.3 eq), Cs ₂ CO ₃ (3 eq), and dioxane/water: 4/1 solvent mixture. The mixture is degassed with N ₂ then Pd(PPh ₃ ) ₄ (0.15 eq) is added. The mixture is stirred at reflux for 2 hours, then concentrated in vacuo, diluted with EtOAc and water, basified to pH 9-10 with NaOH (2 N). The aqueous phase is separated, acidified to pH 2-3 with HCl (1 N), then a mixture of chloroform/n-BuOH: 4/1 is added. The resulting solid is filtered, dissolved in a mixture of DCM/MeOH: 50/50. The solution is dried, filtered, concentrated under vacuum. Trituration in isopropyl ether and ACN, then concentration in vacuo gives the desired compound.

Illustrative Synthesis of Intermediate Int 50

[0387] The flask was charged with Int 44 (2.5 g, 6.62 mmol, 1 eq), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrazole (CAS# 761446-44-0; 1.79 g, 8.61 mmol, 1.3 eq), Cs ₂ CO ₃ (6.5 g, 19.9 mmol, 3 eq) and dioxane solvent mixture /water: 4/1 (100 ml). The mixture is degassed with N ₂ then Pd(PPh ₃ ) ₄ (1.14 g, 0.99 mmol, 0.15 eq) is added. The mixture is stirred at reflux for 2 hours, then concentrated in vacuo, diluted with EtOAc and water, basified to pH 9-10 with NaOH (2 N). The aqueous phase is separated, acidified to pH 2-3 with HCl (1 N), then a mixture of CHCl ₃ /n-BuOH 4/1 is added. The resulting solid is filtered, dissolved in a mixture of DCM/MeOH: 50/50. The solution is dried, filtered, concentrated under vacuum. Trituration in isopropyl ether and ACN, then concentration in vacuo gives the desired compound.

1.1.2.1.3 E1.2: peptide combination

[0388] The carboxylic acid derivative (1 eq), HATU (1.1 to 1.2 eq), anhydrous DMF or DMSO, and DIPEA (3 eq) are charged into the flask. The mixture was stirred at room temperature for 5 minutes, then amine (3 eq) was added. The mixture is stirred at room temperature for 1 hour to overnight. The mixture is either purified by preparative LCMS (if reacting in DMSO and DMF solvent) to give the desired amide, or concentrated in vacuo, taken up in EtOAc and water, extracted with EtOAc (if reacted in DMF) or diluted in DCM or EtOAc, washed with water and/or brine (if reaction is carried out in DMF). The combined organic layers are then dried and filtered, or dried by filtration on a hydrophobic column, concentrated in vacuo and purified by flash chromatography on silica gel to give the desired amide.

Illustrative synthesis of the compound Cpd 86

[0389] The flask is charged with Int 50 (1.4 g, 3.69 mmol, 1 eq), HATU (1.54 g, 4.06 mmol, 1.1 eq), anhydrous DMF (4 ml) and DIPEA ( 1.92 ml, 11.07 mmol, 3 eq). The mixture was stirred at room temperature for 5 minutes then cyclopropylamine (free base) (632 mg, 11.07 mmol, 3 eq) was added. The mixture is stirred at room temperature for 2 hours. The mixture was concentrated in vacuo, the residue was taken up in EtOAc, washed with water then brine. The aqueous layer is extracted with EtOAc. The combined organic layers are dried, filtered, concentrated in vacuo and purified by silica gel flash chromatography (eluting with DCM/MeOH 100/0 to 95/5) to give the desired amide derivative.

1.1.2.1.4 E1.2 with polymer coated Mukayama reagent

[0390] The carboxylic acid derivative (1 eq) deposited on the polymer is loaded into the flask Mukayama's reagent (2 eq), amine (0.9 eq), anhydrous DCM and Et₃N (3 equiv). The mixture is stirred at room temperature for 40-48 hours. The reaction mixture is diluted in DCM, filtered, concentrated in vacuo and purified by preparative LCMS to give the desired amide compound.

Illustrative synthesis of the compound Cpd 70

[0391] The flask is loaded with Int 50 (50 mg, 0.131 mmol, 1 eq) coated on the polymer Mukayama's reagent (Aldrich, Cat# 657182; 223 mg, 1.7-2.5 eq), 5-methylpyrazine-2-amine (CAS# 5521-58-4; 13 mg, 0.118 mmol, 0.9 eq), Et₃N (55 µl, 0.393 mmol, 3 eq) and anhydrous DCM (3 ml). The mixture is stirred at room temperature for 40 hours. The reaction mixture is diluted in DCM, filtered, concentrated in vacuo and purified by preparative LCMS to give the desired amide compound.

Method E1: sequence E1.3+E1.1+E1.2

1.1.2.2.1 E1.3: Suzuki coupling reaction

[0392] See E1.3 sequences E1.1+E1.2+E1.3

Illustrative Synthesis of Intermediate Int 51

[0393] The flask was charged with Int 35 (2.26 g, 0.006 mol, 1 eq), solvent mixture dioxane/water: 4/1 (25 mL), 1-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (CAS# 761446-44-0; 1.44 g, 0.007 mol, 1.2 eq), Cs ₂ CO ₃ (3.76 g, 0.012 mol , 2 eq) and Pd(dppf)Cl ₂ DCM (0.47 g, 0.001 mol, 0.1 eq). The mixture is stirred at 80°C for 3 hours, then quenched with water. Add DCM and saturated solution of NaHCO ₃ , the aqueous layer is extracted with DCM. The combined organic layers are washed with saturated NaHCO ₃ then brine, dried over anhydrous Na ₂ SO ₄ , filtered, concentrated in vacuo and purified by silica gel flash chromatography (eluting with DCM/MeOH 100/0 to 91/9).

Illustrative Synthesis of Intermediate Int 27

[0394] The flask was charged with Int 26 (99 mg, 0.285 mmol, 1 eq), solvent mixture dioxane/water: 4/1 (25 ml), N ₂ was sparged, then 1-methyl-4-(4.4, 5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)pyrazole (CAS# 761446-44-0; 71 mg, 0.342 mmol, 1.2 eq), Cs ₂ CO ₃ (186 mg, 0.570 mol, 2 eq) and Pd(PPh ₃ ) ₄ (49 mg, 0.043 mmol, 0.15 eq). The mixture is stirred at 100°C for 3 hours, then at room temperature overnight, quenched with saturated NaHCO ₃ solution, extracted with DCM. The combined organic layers are washed with brine, dried on a hydrophobic column, concentrated in vacuo and purified by silica gel flash chromatography (eluting with DCM/MeOH 100/0 to 96/4) to give the desired intermediate.

1.1.2.2.2 Method E1,3 for administering a trisubstituted benzoate or benzamide

Illustrative Synthesis of Intermediate Int 37

[0395] The flask was charged with 7-bromo-3-iodo-imidazo[1,2-a]pyridine (2 g, 6.19 mmol, 1 eq), N-cyclopropyl-2-(difluoromethoxy)-6-methoxy- 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (2.37 g, 6.19 mmol, 1 eq) (Int 17), Cs ₂ CO ₃ ( 4.04 g, 12.39 mmol, 2 eq) and degassed with N ₂ solvent mixture dioxane/water: 4/1 (70 ml). Pd(PPh ₃ ) ₄ (537 mg, 0.46 mmol, 0.075 eq) is added and the system is purged with N ₂ , then the mixture is stirred at 90° C. for 20 hours. The dioxane is evaporated, water is added and the mixture is extracted with EtOAc or DCM. The combined organic layers are washed with water and brine, dried over anhydrous MgSO ₄ , filtered and concentrated under vacuum to a residual volume of approximately 100 ml EtOAc, resulting in the precipitation of a solid. The solid is filtered, washed with EtOAc, then Et ₂ O to obtain the desired bromo derivative.

1.1.2.2.3 Method E1.3 for introducing heteroaryl

Illustrative Synthesis of Intermediate Int 1

[0396] 7-bromimidazo[1,2-a]pyridine (100 g, 507.54 mmol, 1 eq), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyrazole (CAS# 761446-44-0; 116.18 g, 558.29 mmol, 1.1 eq), Na ₂ CO ₃ (161.37 g, 1522.61 mmol, 3 eq) dioxane/water: 3/1 (1 L) was added to the solvent mixture. The mixture was degassed with N ₂ , then the Pd(dppf)Cl ₂ ·DCM adduct (2.07 g, 2.54 mmol, 0.005 eq) was added and the mixture was stirred at 100° C. for 6 hours. The mixture is cooled to room temperature, filtered through a pad of ^Celite® , washed with DCM and the filtrate concentrated in vacuo. The residue was dissolved in DCM/n-BuOH (9/1, 1 L) and water (1 L) was added. The organic layer is separated and the aqueous layer is extracted with DCM (1 L) then DCM/n-BuOH (9/1, 0.5 L). The combined organic layer was washed with brine (0.5 L), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue is triturated in MTBE (0.3 L) at room temperature, the suspension is filtered and the solid is washed with MTBE, then dried under vacuum to obtain the desired intermediate.

Illustrative Synthesis of Intermediate Int 2

[0397] 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine (CAS# 908268-52-0; 0.5 g, 2.05 mmol, 1 eq), 3-chloro-6-methylpyridazine (CAS# 1121-79-5; 316 mg, 2.46 mmol, 1.2 eq), Cs ₂ CO ₃ (1.34 g, 4.10 mmol, 2 eq), Pd(dppf)Cl ₂ ·DCM (167 mg, 0.20 mmol, 0.1 eq) and dioxane/water solvent mixture degassed with N ₂ : 4 /1 (10 ml). The system was purged with N ₂ , then the mixture was stirred at 90° C. for 1 hour. The reaction mixture is cooled to room temperature, diluted in EtOAc, filtered through a layer of Celite ^® . The filtrate is concentrated in vacuo and used in the next step without further purification.

1.1.2.2.4 E1.1: ester saponification

[0398] See E1.1 sequences E1.1+E1.2+E1.3.

Illustrative Synthesis of Intermediate Int 52

[0399] A mixture of Int 51 (1.92 g, 0.005 mol, 1 eq), MeOH (10 ml), THF (10 ml) and 2 M NaOH (15 ml, 0.029 mol 6 eq) was stirred at 70°C for 18 hours. After cooling to ambient temperature, the organic solvents are removed under reduced pressure. To the residue is added 2 N HCl, then water and ACN, the suspension is triturated, filtered, washed with water, then ACN, then ACN/DCM to give Int 52.

Illustrative synthesis of 2,6-dimethoxy-4-[7-(1-methylimidazol-4-yl)imidazo[1,2-a]pyridin-3-yl]benzoic acid

[0400] A mixture of methyl 2,6-dimethoxy-4-[7-(1-methylimidazol-4-yl)imidazo[1,2-a]pyridin-3-yl]benzoate (116 mg, 0.296 mmol, 1 eq) , MeOH (5 ml), THF (5 ml) and 2 M NaOH (0.89 ml, 1.774 mmol, 6 eq) were stirred at 70°C for 16 hours. Then 2 M NaOH (45 μl, 0.090 mmol, 0.3 eq) was added and the mixture was stirred at 90° C. for 4 hours, then at room temperature for 48 hours. After cooling to ambient temperature, the organic solvents are removed under reduced pressure, and 2 N HCl is added to the residue, followed by water. The mixture was concentrated in vacuo, taken up in DCM and a small amount of MeOH, filtered. The filtrate is concentrated in vacuo to give the carboxylic acid compound.

LCMS: MW (calculated): 378.4; m/z MW (detected): 379.3 (M+H).

Illustrative Synthesis of Intermediate Int 28

[0401] A mixture of Int 27 (43 mg, 0.109 mmol, 1 eq), MeOH (4 ml), THF (2 ml) and 2 M NaOH (2 ml, 1.088 mmol, 10 eq) was stirred at 70°C for 3 .5 hours, then at 90°C for 3 hours, then at room temperature overnight. The mixture is taken up in DCM and water. The aqueous layer was washed with DCM, then acidified with 2 N HCl and extracted with DCM. The combined organic layers are dried on a hydrophobic column and concentrated to give the carboxylic acid compound.

Illustrative synthesis of 2-chloro-6-methoxy-4-[7-(1-methyl-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl]benzoic acid

[0402] A mixture of methyl 2-chloro-6-methoxy-4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl]benzoate (80 mg, 0.20 mmol , 1 eq), MeOH (2 ml) and 2 N NaOH (200 μl, 0.40 mmol, 2 eq) were stirred at reflux for 48 hours. After cooling to room temperature, organic solvents are removed under reduced pressure. The residue is diluted with water. The pH was adjusted to 6 with 2 N HCl aqueous solution. The resulting suspension is filtered and dried under vacuum to obtain a carboxylic acid derivative.

LCMS: MW (calculated): 382.8; m/z MW (detected): 383.3-385.2 (M+H).

Illustrative synthesis of 4-[6-(1-ethylpyrazol-4-yl)imidazo[4,5-b]pyridin-3-yl]-2,6-dimethoxybenzoic acid

[0403] A mixture of methyl 4-[6-(1-ethylpyrazol-4-yl)imidazo[4,5-b]pyridin-3-yl]-2,6-dimethoxybenzoate (150 mg, 0.368 mmol, 1 eq), MeOH (5 ml) and NaOH (5 beads, excess) were stirred at 65° C. overnight. organic solvents are removed under reduced pressure. The residue is diluted with water. The pH value is adjusted to 1-2 with 2 N HCl aqueous solution. The resulting mixture is extracted with n-BuOH/MeOH (9/1), dried, filtered and concentrated in vacuo to give the carboxylic acid derivative.

LCMS: MW (calculated): 393.4; m/z MW (detected): 394.4 (M+H).

1.1.2.2.5 Method E1.1 (saponification of pyrazol acetate)

Illustrative synthesis of the compound Cpd 228

[0404] A mixture of Cpd 230 (80 mg, 0.151 mmol, 1 eq), EtOH (2.4 ml) and 2 N NaOH (90.3 μl, 0.18 mmol, 1.2 eq) was stirred at 60°C in within 20 minutes. Organic solvents are removed under vacuum. The residue was diluted with water and Et ₂ O. The aqueous layer was separated, acidified to pH 5 with 2 N aqueous HCl. The resulting suspension is stirred, filtered and the resulting solid is purified by preparative HPLC to give the desired compound.

1.1.2.2.6 E1.2: peptide combination

[0405] See E1.2 of method E1: sequence E1.1+E1.2+E1.3.

Illustrative synthesis of the compound Cpd 88

[0406] Int 52 (4.66 g, 0.012 mol, 1 eq) is suspended in anhydrous DMF (45 ml), then HATU (5.62 g, 0.015 mol, 1.2 eq) and DIPEA (6.44 ml , 0.037 mol, 3 eq). The mixture was stirred at room temperature for 5 minutes, then 2,2,2-trifluoropentanamine (CAS# 753-90-2; 1.93 ml, 0.025 mol, 2 eq) was added to the solution. The reaction mixture is stirred at room temperature for 16 hours, quenched with water. Add EtOAc and saturated NaHCO ₃ solution, the aqueous layer is extracted with EtOAc. Brine is added to the combined organic layers and the resulting solid is filtered, washed with EtOAc and dichloromethane.

[0407] The aqueous layer is separated, again extracted with EtOAc. The combined organic layers and previous layers are dried over anhydrous Na ₂ SO ₄ , filtered, concentrated. The residue is taken up in ACN, triturated, sonicated and filtered. The two solids obtained are combined, purified by silica gel flash chromatography (eluting with DCM/MeOH 100/0 to 96/4) to give the desired amide derivative.

LCMS: MW (calculated): 459.4; m/z MW (detected): 460.4 (M+H).

Illustrative synthesis of the compound Cpd 52

[0408] The vial is loaded with Int 28 (18.5 mg, 0.049 mmol, 1 eq), anhydrous DMF (1.5 ml) followed by DIPEA (26 µl, 0.146 mmol, 3 eq) and HATU (20 mg, 0.054 mmol, 1.1 eq). The mixture was stirred at room temperature for 20 minutes, then 2,2,2-trifluoropentamine hydrochloride (13 mg, 0.098 mol, 2 eq) was added. The reaction mixture was stirred at room temperature for 16 hours, quenched with saturated NaHCO ₃ solution, extracted with EtOAc. The combined organic layers are dried on a hydrophobic column, concentrated under vacuum. The residue is taken up in DCM, dispersed by sonication, filtered, washed with Et ₂ O to give the desired compound.

Illustrative synthesis of the compound Cpd 29

[0409] 4-[6-(1-Ethylpyrazol-4-yl)-imidazo[4,5-b]pyridin-3-yl]-2,6-dimethoxybenzoic acid (58 mg, 0.147 mmol, 1 eq), HATU (61 mg, 0.161 mmol, 1.1 eq), anhydrous DMF (3 ml) and DIPEA (77 µl, 0.441 mmol, 3 eq). The mixture was stirred at room temperature for 10 minutes, then 2,2,2-trifluoropentamine hydrochloride (60 mg, 0.441 mmol, 3 eq) was added. The reaction mixture was stirred at room temperature for 16 hours. EtOAc and brine are added, the aqueous layer is extracted with EtOAc. The combined organic layers are dried, filtered, concentrated in vacuo, purified by silica gel flash chromatography (eluting with DCM/MeOH 100/0 to 95/5), then preparative LCMS to give the desired amide derivative.

Illustrative synthesis of the compound Cpd 206

[0410] The vial is loaded with 2-methoxy-6-methyl-4-[7-(1-methyl-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl]benzoic acid (60 mg, 0.16 mmol, 1 eq), HATU (69 mg, 0.18 mmol, 1.1 eq), anhydrous DMF (1 ml) and DIPEA (56 µl, 0.32 mmol, 2 eq). The mixture was stirred at room temperature for 10 minutes, then 2,2,2-trifluoropentamine (15 μl, 0.19 mmol, 1.2 eq) was added. The reaction mixture was stirred at room temperature for 96 hours. The mixture was concentrated in vacuo, purified by flash chromatography on a ^Biotage® SNAP KP-NH cartridge (eluting with DCM/MeOH 100/0 to 98/2) to give the desired amide derivative.

Method E2: Buchwald reaction (3 steps)

1.1.2.3.1 E2.1: ester saponification

[0411] See E1.1 method E1 section E1.1+E1.2+E1.3.

1.1.2.3.2 E2.2: peptide combination

[0412] See E1.2 of method E1 of section E1.1+E1.2+E1.3.

1.1.2.3.3 E2.3: Buchwald reaction

[0413] To a stirred solution of haloaryl derivative (1 eq) and amine derivative (1.5 eq) in dioxane, previously degassed with N ₂ , add t-BuOK (3 eq), t-BuXPhos (0.2 eq) and Pd ₂ (dba) ₃ (0.1 equiv). The mixture is heated at 110°C overnight, then at 120°C for 96 hours, then purified by preparative LCMS to obtain the desired compound.

Illustrative synthesis of the compound Cpd 154

[0414] To a stirred solution of Int 39 (46 mg, 0.10 mmol, 1 eq) and 3-methylpyrazole (CAS# 1453-58-3; 12 μl, 0.15 mmol, 1.5 eq) in dioxane (2 ml), previously degassed with N ₂ , add t-BuOK (34 mg, 0.30 mmol, 3 eq), t-BuXPhos (9 mg, 0.02 mmol, 0.2 eq) and Pd ₂ (dba) ₃ (9 mg, 0.01 mmol, 0.1 eq). The mixture is heated at 110°C overnight, then at 120°C for 96 hours, then purified by preparative LCMS to obtain the desired compound.

Method E3: Copper catalyzed amination reaction (3 steps)

1.1.2.4.1 E3.1: saponification of ester

[0415] See E1.1 method E1 section E1.1+E1.2+E1.3.

1.1.2.4.2 E3.2: peptide combination

[0416] See E1.2 method E1 section E1.1+E1.2+E1.3.

1.1.2.4.3 E3.3: copper-catalyzed amination reaction

[0417] To a stirred solution of haloaryl derivative (1 eq) and amine derivative (1 eq) in DMF, previously degassed with N ₂ , Cs ₂ CO ₃ (2.5 eq), CuI (0.4 eq) and N , N'-dimethylethylenediamine (CAS# 110-70-3; 0.2 eq). The mixture is heated at 140° C. for 20 hours, then purified by preparative LCMS to give the desired compound.

Illustrative synthesis of the compound Cpd 155

[0418] To a stirred solution of Int 39 (92 mg, 0.20 mmol, 1 eq) and 4(5)-methylimidazole (CAS# 822-36-6; 17 mg, 0.20 mmol, 1 eq) in DMF ( 1 ml), previously degassed with N ₂ , add Cs ₂ CO ₃ (163 mg, 0.50 mmol, 2.5 eq), CuI (15 mg, 0.08 mmol, 0.4 eq) and N, N '-dimethylethylenediamine (CAS# 110-70-3; 5 µl, 0.04 mmol, 0.2 eq). The mixture is heated at 140° C. for 20 hours, then purified by preparative LCMS to give the desired compound as an 85/15 mixture of regioisomers.

Method E4: Borylation reaction then Suzuki reaction (3 steps)

1.1.2.5.1 E4.1: ester saponification

[0419] See E1.1 method E1 section E1.1+E1.2+E1.3.

1.1.2.5.2 E4.2: peptide combination

[0420] See E1.2 method E1 section E1.1+E1.2+E1.3.

1.1.2.5.3 E4.3: borylation reaction then Suzuki reaction

1.1.2.5.3.1. E4.3i: 2 stages in one (in one flask):

[0421] The flask was charged with haloaryl derivative (1 eq), dioxane previously degassed with N ₂ , B ₂ pin ₂ (1.1 to 1.5 eq), potassium acetate (3 to 4 eq), and Pd( dppf)Cl ₂ ·DCM (0.1 to 0.12 eq). The mixture is stirred at 90°C-110°C for 1.5-20 hours, cooled to room temperature or to 50°C and used without further purification in a Suzuki coupling reaction (see E1.3 using 0.9 to 1.4 equivalents of aryl bromide or aryl chloride).

Illustrative synthesis of the compound Cpd 273

[0422] The flask is charged with Int 37 (100 mg, 0.22 mmol, 1 eq), dioxane (4 ml), previously degassed with N ₂ , B ₂ pin ₂ (67 mg, 0.26 mmol, 1.2 eq), potassium acetate (65 mg, 0.66 mmol, 3 eq) and Pd(dppf)Cl ₂ DCM (11 mg, 0.013 mmol, 0.06 eq). The mixture is stirred at 90°C for 20 hours. Add Pd(dppf)Cl ₂ DCM (11 mg, 0.013 mmol, 0.06 eq), B ₂ pin ₂ (17 mg, 0.065 mmol, 0.3 eq), potassium acetate (22 mg, 0.22 mmol, 1 eq) and the mixture was stirred at 90°C for 3 hours, cooled to room temperature and used without further purification in the next step.

[0423] Suzuki coupling reaction (E1.3 equivalent of step): Transfer an appropriate amount of the previously prepared boronic ester/boronic acid solution mixture (2.1 ml, 0.11 mmol, 1 eq) to a flask, add dioxane and water (C= 0.037 M, dioxane/water: 4/1), then 6-methylchloropyridazine (13 mg, 0.099 mmol, 0.9 eq), Cs ₂ CO ₃ (72 mg, 0.22 mmol, 2 eq) and Pd( dppf)Cl ₂ DCM (4.5 mg, 0.006 mmol, 0.05 eq). The mixture is stirred at 90°C for 3 hours. The dioxane is evaporated, the remaining aqueous layer is extracted with DCM using a SPE separator. The combined organic layers are concentrated in vacuo, purified by preparative LCMS to give the desired compound.

1.1.2.5.3.2. E4.3ii: 2 stages

[0424] The flask is charged with haloaryl derivative (1 eq), dioxane previously degassed with N ₂ , B ₂ pin ₂ (1.5 to 2 eq), potassium acetate (3 eq) and Pd(dppf)Cl ₂ · DCM (from 0.1 to 0.2 eq). The mixture is degassed with N ₂ if it has not been degassed before. The mixture is stirred at 100-110° C. overnight, cooled to room temperature, and either directly concentrated in vacuo or filtered through a pad of ^Clarcel® , washed with EtOAc/MeOH and the filtrate concentrated in vacuo. The residue is taken up in either EtOAc and saturated NaHCO ₃ solution or DCM and water. The mixture is extracted with EtOAc or DCM. The combined organic layers are dried over anhydrous Na ₂ SO ₄ , filtered, concentrated in vacuo and either purified by flash chromatography on silica gel or used without further purification in a Suzuki coupling reaction (see E1.3 using 1 to 1.1 eq of a mixture of boron ester and boronic acid and 1 equivalent of aryl bromide or aryl chloride).

Illustrative synthesis of the compound Cpd 137

[0425] Borylation reaction: Int 39 (458 mg, 1 mmol, 1 eq), B ₂ pin ₂ (381 mg, 1.5 mmol, 1.5 eq), dioxane (5 ml), previously degassed with using N ₂ , potassium acetate (295 mg, 3 mmol, 3 eq) and Pd(dppf)Cl ₂ ·DCM (82 mg, 0.10 mmol, 0.1 eq). The mixture is stirred at 100°C overnight, concentrated under vacuum. The residue is diluted in DCM and water. The organic layer is separated and concentrated in vacuo, purified by silica gel flash chromatography (eluting with DCM/MeOH 100/0 to 95/5) to give the desired mixture of boronic ester and boronic acid.

LCMS: MW (calculated): 505.3; m/z MW (detected): 506.3 (M+H).

LCMS: MW (calculated): 423.1; m/z MW (detected): 424.1 (M+H).

[0426] Suzuki coupling reaction: to a stirred solution of a mixture of boronic ester and boronic acid (51 mg, 0.10 mmol, 1 eq) and 4-bromo-1-methylimidazole (CAS# 25676-75-9; 10 μl, 0. 10 mmol, 1 eq) in dioxane (2 ml) add Cs ₂ CO ₃ (65 mg, 0.20 mmol, 2 eq), Pd(PPh ₃ ) ₄ (12 mg, 0.01 mmol, 0.1 eq) in water (0.5 ml). The mixture is heated at 90°C for 1 hour, then concentrated under vacuum. The residue is diluted in DCM and water. The organic layer was separated and concentrated in vacuo, purified by flash chromatography on a ^Biotage® SNAP KP-NH cartridge (eluting with DCM/MeOH 100/0 to 98/2) to give the desired compound.

Method E5: Cyanidation reaction, then cycling reaction

1.1.2.6.1 E5.1: ester saponification

[0427] See E1.1 method E1 section E1.1+E1.2+E1.3.

1.1.2.6.2 E5.2: peptide combination

[0428] See E1.2 method E1 section E1.1+E1.2+E1.3.

1.1.2.6.3 E5.3: cyanidation reaction

[0429] To a stirred solution of an aryl bromide derivative (1 eq) in degassed N,N-dimethylacetamide add ZnCN ₂ (2 eq), Pd ₂ (dba) ₃ (0.03 eq), DPPF (0.07 eq), and zinc dust (0.04 equiv). The mixture is degassed with argon for 5 minutes and stirred at 125° C. for 3 hours. The reaction mixture is filtered. Add DCM and water. The organic layer is separated and concentrated under vacuum. The residue is purified by silica gel flash chromatography to give the desired nitrile intermediate.

Illustrative synthesis of 4-(5-cyanobenzimidazol-1-yl)-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)benzamide

[0430] To a stirred solution of Int 39 (458 mg, 1.00 mmol, 1 eq) in degassed N,N-dimethylacetamide (5 mL) was added ZnCN ₂ (235 mg, 2.00 mmol, 2 eq), Pd ₂ ( dba) ₃ (27 mg, 0.03 mmol, 0.03 eq), DPPF (39 mg, 0.07 mmol, 0.07 eq) and zinc dust (3 mg, 0.04 mmol, 0.04 eq) . The mixture is degassed with argon for 5 minutes and stirred at 125° C. for 3 hours. The reaction mixture is filtered. Add DCM and water. The organic layer is separated and concentrated under vacuum. The residue is purified by flash chromatography on silica gel (eluting with DCM/MeOH 100/0 to 96/4) to give the desired nitrile intermediate.

LCMS: MW (calculated): 404.3; m/z MW (detected): 405.3 (M+H).

1.1.2.6.4 E5.4: ring formation reaction

1.1.2.6.4.1. E5.4i: 1,2,4-oxadiazole ring formation

[0431] To a stirred solution of the nitrile derivative (1.0 eq) in EtOH was added Et ₃ N (3.0 eq) and hydroxylamine hydrochloride (1.1 eq). The reaction mixture is stirred at 80°C (for 4 to 5 hours) and concentrated under vacuum. The residue is either used in the next step without further purification or purified on a ^Biotage® SNAP KP-NH cartridge to give the N-hydroxycarboximidamide intermediate.

[0432] Acetic anhydride was added to the N-hydroxy-carboximidamide intermediate (1 eq) and the resulting mixture was stirred for 1 hour to 2 hours at 100° C., then concentrated in vacuo. The residue is either purified by silica gel flash chromatography followed by preparative LCMS or purified on a ^Biotage® SNAP KP-NH cartridge to give the desired compound.

Illustrative synthesis of the compound Cpd 126

[0433] To a stirred solution of 4-(5-cyanobenzimidazol-1-yl)-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)benzamide (37 mg, 0.09 mmol, 1 eq) in EtOH (2 ml) add Et ₃ N (37 μl, 0.27 mmol, 3.0 eq) and hydroxylamine hydrochloride (7 mg, 0.10 mmol, 1.1 eq). The reaction mixture is stirred at 80°C for 5 hours and concentrated under vacuum. The N-hydroxycarboximidamide intermediate was used in the next step without further purification.

[0434] Acetic anhydride (1 ml) was added to the N-hydroxy-carboximidamide intermediate (39 mg, 0.09 mmol, 1.0 eq) and the resulting mixture was stirred for 1 hour at 100° C., then concentrated in vacuo . The residue is purified by flash chromatography on silica gel (eluting with DCM/MeOH 100/0 to 97/3) to give the desired compound.

1.1.2.6.4.2. E5.4ii: 1,2,4-triazole ring formation

[0435] To a stirred solution of the nitrile derivative (1.0 eq) in DMSO add copper(I) bromide (0.05 eq), Cs ₂ CO ₃ (3.0 eq) and acetamidine hydrochloride (CAS# 124-42-5 ; 1.5 eq). The reaction mixture was stirred overnight at 125° C., then purified by preparative LCMS to give the desired compound.

Illustrative synthesis of the compound Cpd 127

[0436] To a stirred solution of 4-(5-cyanobenzimidazol-1-yl)-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)benzamide (41 mg, 0.10 mmol, 1.0 eq) copper(I) bromide (1 mg, 0.005 mmol, 0.05 eq), Cs ₂ CO ₃ (98 mg, 0.30 mmol, 3.0 eq) and acetamidine hydrochloride (CAS # 124-42-5; 14 mg, 0.15 mmol, 1.5 eq). The reaction mixture was stirred overnight at 125° C., then purified by preparative LCMS to give the desired compound.

Method F: Iodization of a Bromoheteroaryl Compound

[0437] To a solution of 6-bromopyrazolo[1,5-a]pyridine (CAS# 1264193-11-4; 1 eq) in ACN under N ₂ was added N-iodosuccinimide (1.05 eq). The resulting solution was stirred at room temperature overnight. The reaction mixture is filtered and the solid is washed with a few milliliters of ACN to give the desired bromoiodoheteroaryl compound.

Illustrative Synthesis of Intermediate Int 15

[0438] N- _{iodosuccinimide} (780 mg, 3.46 mmol, 1.05 eq). The resulting solution was stirred at room temperature overnight.

[0439] The reaction mixture is filtered and the solid is washed with a few milliliters of ACN to give 6-bromo-3-iodopyrazolo[1,5-a]pyridine, which is used without further purification in the next step.

Method H: C-H bond activation

[0440] The nitrogen-containing heterocycle (1 eq) is dissolved in DMAC previously degassed with N ₂ . Aryl bromide (1.0 to 1.6 eq) and potassium acetate (2 to 3 eq) are added. The mixture is degassed with N ₂ then Pd(dppf)Cl ₂ ·DCM (0.005 to 0.05 eq) is added. The mixture is heated at 105-130° C. for 2.5 hours to overnight.

[0441] Isolation Method: The mixture is cooled to room temperature, then either diluted in DCM/MeOH, filtered through a pad of ^Celite® and the filtrate concentrated in vacuo, or the reaction mixture is quenched with sat. NaHCO ₃ , extracted with EtOAc, then combined organic the layers are dried (anhydrous Na ₂ SO ₄ ) or washed with water then brine and dried (anhydrous MgSO ₄ ), filtered and concentrated in vacuo. The residue, obtained in one way or another, is purified by flash chromatography on silica gel or on a ^Biotage® SNAP KP-NH cartridge to obtain the desired product.

[0442] Alternative extraction method 1: the mixture is cooled to room temperature, then filtered through a layer of Celite ^® . The solid is triturated in EtOAc and n-BuOH to give the first batch of the crude compound. Water is added to the filtrate and the mixture is extracted with DCM. Water is added to the combined organic layers and the resulting solid is filtered to give a second crop of the crude compound. The two batches of the compound are combined and triturated with ACN to give the desired compound.

[0443] Alternate isolation method 2: The mixture is cooled to room temperature, then filtered. Water is added to the filtrate and the suspension is filtered. The solid is washed with water, filtered, then triturated with MTBE. The solid is taken up in water and DCM and the mixture is extracted with DCM. The combined organic layers are washed with water, purified by silica gel flash chromatography to give the desired compound.

Illustrative synthesis of the compound Cpd 275

[0444] Int 2 (47 mg, 0.22 mmol, 1 eq) is dissolved in DMAC (2 ml), Int 7 (113 mg, 0.34 mmol, 1.5 eq), potassium acetate (66 mg, 0 ,67 mmol, 3 eq), Pd(dppf)Cl ₂ ·DCM (9 mg, 0.01 mmol, 0.05 eq) and the mixture was stirred at 110° C. overnight. The mixture is then cooled to room temperature, quenched with saturated NaHCO ₃ , extracted with EtOAc. The combined organic layers are dried over anhydrous Na ₂ SO ₄ , filtered, concentrated in vacuo. The residue was purified twice by flash chromatography on a ^Biotage® SNAP KP-NH cartridge (eluting first with DCM/EtOAc 100/0 to 90/10, then with heptane/EtOAc 90/10 to 0/100) to give the desired compound.

Method I: Deprotection of Phenol (Demethylation)

[0445] To a stirred mixture of the methoxy derivative (1 eq) in DCM, cooled to 0°C - -15°C, was added dropwise a 1 M solution of BCl ₃ in DCM (2.2 eq). The mixture is stirred at 0°C for 2 hours, or at 0°C for 45 minutes and at room temperature for 3 hours. The reaction mixture is poured into ice/water and acidified with HCl (2 N), or poured into HCl (0.1 N)/ice, then extracted with DCM and a few drops of MeOH, or with DCM, then with EtOAc, then CHCl ₃ /n-BuOH (90/10 or 80/20 mixture). The combined organic layers are dried (filtered on a hydrophobic column or over Na ₂ SO ₄ ) and concentrated in vacuo. The residue is either used without further purification in the next step or purified by silica gel flash chromatography to give the desired phenolic compound.

Illustrative synthesis of the compound Cpd 233

[0446] To a stirred mixture of Cpd 88 (100 mg, 0.218 mmol, 1 eq) in DCM (3 ml) cooled to 0°C, was added dropwise a solution of 1 M BCl ₃ in DCM (479 μl, 0.479 mmol, 2, 2 equiv). The mixture is stirred at 0°C for 2 hours. The reaction mixture is poured into a mixture of 0.1 N HCl and ice, extracted with DCM and a few drops of MeOH, then the combined organic layers are dried on a hydrophobic column and concentrated in vacuo. The residue is purified by flash chromatography on silica gel (eluting with DCM/MeOH 100/0 to 90/10) to give the desired compound.

Method J: Phenol Alkylation

Method J1: K ₂ CO ₃ /alkyl iodide

[447] An alkyl halide (1.3 eq) was added dropwise to a stirred mixture of phenol derivative (1 eq) in an ACN/THF 1/1 mixture. The mixture is stirred at 80°C for 50 hours. The mixture is taken up in DCM and the organic layer is washed with water, dried on a hydrophobic column and concentrated in vacuo. The residue is purified by preparative HPLC to give the desired compound.

Illustrative synthesis of the compound Cpd 119

[0448] To a stirred mixture of N-cyclopropyl-2-hydroxy-6-methoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzamide (30 mg, 0.074 mmol, 1 eq) in ACN/THF 1/1 mixture (4 ml) was added dropwise with 2-iodopropane (16.3 mg, 0.096 mmol, 1.3 eq). The mixture is stirred at 80°C for 50 hours. The mixture is taken up in DCM and the organic layer is washed with water, dried on a hydrophobic column and concentrated in vacuo. The residue is purified by preparative HPLC to give the desired compound.

Method J2: KOH/diethyl(bromodifluoromethyl)phosphonate

[0449] KOH pellets (10 eq) were added to a stirred mixture of phenol derivative (1 eq) in ACN/water 1/1 (2 ml). The mixture was stirred at -40° C. for 15 minutes, then diethyl(bromodifluoromethyl)phosphonate (CAS# 65094-22-6; 3 eq) was added. The reaction mixture was stirred at - 40°C for 1 hour, then warmed to room temperature and stirred overnight at room temperature. Then KOH (excess) and diethyl(bromodifluoromethyl)phosphonate (3 eq) are added and the mixture is stirred at room temperature for 4 hours, then at 90°C for 2 hours, then at room temperature for 48 hours. The mixture was quenched with sat. NaHCO ₃ , extracted with DCM. The combined organic layers are washed with brine, dried by filtration through a hydrophobic column and concentrated in vacuo. The residue is purified by silica gel flash chromatography to give the desired compound.

Illustrative synthesis of the compound Cpd 17

[0450] To a stirred mixture of Cpd 23 (36 mg, 0.089 mmol, 1 eq) in ACN/water 1/1 (2 ml) was added KOH pellets (50 mg, 0.888 mmol, 10 eq). The mixture was stirred at -40° C. for 15 minutes, then diethyl(bromodifluoromethyl)phosphonate (47 μl, 0.266 mmol, 3 eq) was added. The reaction mixture was stirred at - 40°C for 1 hour, then warmed to room temperature and stirred overnight at room temperature. Then KOH (excess) and diethyl-(bromodifluoromethyl)phosphonate (47 μl, 0.266 mmol, 3 eq) are added and the mixture is stirred at room temperature for 4 hours, then at 90°C for 2 hours, then at room temperature in within 48 hours. The mixture was quenched with sat. NaHCO ₃ , extracted with DCM. The combined organic layers are washed with brine, dried by filtration through a hydrophobic column and concentrated in vacuo. The residue is purified by flash chromatography on silica gel (eluting with DCM/MeOH 100/0 to 96/4) to give the desired compound.

Method K: Amine deprotection

[0451] To a stirred solution of the N-Boc protected amine derivative (1 eq) in DCM is added TFA (DCM/TFA mixture: 90/10 to 50/50). The reaction mixture is stirred at room temperature for 18 to 72 hours. Then either the reaction mixture is diluted with DCM, cooled to 0°C, diluted with water, basified with NaOH (2 N) (pH 10-11), extracted, the combined organic layers are dried, filtered and concentrated under vacuum to obtain the desired compound, either the reaction mixture is diluted in toluene, concentrated in vacuo, diluted with DCM, a few drops of MeOH, and saturated Na ₂ CO ₃ solution, and the organic layer is separated, washed with brine, dried over anhydrous MgSO ₄ , filtered, concentrated in vacuo, purified flash chromatography on a Biotage ^® SNAP KP-NH cartridge to give the desired compound, or the reaction mixture is evaporated to dryness, then diluted with DCM and saturated Na ₂ CO ₃ solution, then the organic layer is separated, concentrated under vacuum, purified by flash chromatography on a cartridge ^Biotage® SNAP KP-NH, treated with activated charcoal and filtered to obtain, after concentration in vacuo, the desired compound either the reaction mixture was concentrated in vacuo, taken up in water, the aqueous layer was washed with EtOAc, then basified with NaOH solution (1 N) to pH 10, extracted with EtOAc, and the combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered , concentrated under vacuum. The resulting residue is triturated in Et ₂ O and filtered to give the desired compound.

Illustrative synthesis of the compound Cpd 94

[0452] To a stirred solution of tert-butyl 3-[4-[1-[3,5-dimethoxy-4-(2,2,2-trifluoroethylcarbamoyl)phenyl]benzimidazol-5-yl]pyrazol-1-yl]azetidine-1 -carboxylate (235 mg, 0.39 mmol, 1 eq) in DCM (4 ml) add TFA (0.4 ml). The reaction mixture was stirred at room temperature for 72 hours. The reaction mixture was evaporated to dryness, then diluted with DCM and saturated Na₂CO₃. The organic layer is separated and concentrated under vacuum. The residue is purified by flash chromatography on a Biotage cartridge.^® SNAP KP-NH (eluting with DCM/MeOH 100/0 to 97/3), treated with activated charcoal (50 mg), filtered to give, after concentration in vacuo, the desired compound.

Method L: amine functionalization

Method L1: reductive amination

1.1.8.0.1 Method L1i: reductive amination using formaldehyde/NaBH(OAc) ₃ /AcOH

[0453] To a stirred solution of the amine derivative or TFA salt of the amine (1 eq) in ACN or DCM are added formaldehyde (37% in water) (3 eq) and AcOH (0.1 to 1 eq). The reaction mixture was stirred at room temperature and NaBH(OAc) ₃ (3 eq) was added. The reaction mixture is stirred overnight at room temperature. Thereafter, it is either concentrated in vacuo, diluted with DCM and saturated NaHCO ₃ solution, then the organic layer is separated, concentrated in vacuo and the residue is purified by flash chromatography on a Biotage ^® SNAP KP-NH cartridge to give the desired compound, or the reaction mixture quench by adding saturated Na ₂ CO ₃ solution, extracted with DCM and a few milliliters of MeOH, the organic layer is then separated, washed with brine, dried over anhydrous MgSO ₄ , filtered, concentrated under vacuum, and the residue is purified by flash chromatography on a Biotage ^® cartridge SNAP KP-NH to give the desired compound.

Illustrative synthesis of the compound Cpd 98

[0454] To a stirred solution of Cpd 94 (50 mg, 0.10 mmol, 1 eq) in ACN (2 ml) was added formaldehyde (37% in water) (24 μl, 0.30 mmol, 3 eq) and AcOH (12 µl, 0.01 mmol, 0.1 eq). The reaction mixture was stirred at room temperature for 5 minutes and NaBH(OAc) ₃ (64 mg, 0.30 mmol, 3 eq) was added. The reaction mixture is stirred overnight at room temperature, concentrated in vacuo, diluted with DCM and saturated NaHCO ₃ solution. The organic layer is separated and concentrated under vacuum. The residue was purified by flash chromatography on a ^Biotage® SNAP KP-NH cartridge (eluting with DCM/MeOH 100/0 to 97/3) to give the desired compound.

1.1.8.0.2 Method L1ii: reductive amination using formaldehyde/NaBH _four

[0455] To a stirred solution of the amine derivative (1 eq) in MeOH at 0° C. under N ₂ was added formaldehyde (37% in water) (11 eq) followed by NaBH ₄ (20 eq). The reaction mixture is warmed to room temperature and stirred for 1 hour. NaOH solution (2 N) is added, the resulting solid is filtered, then purified by flash chromatography on silica gel to give the desired compound.

Illustrative synthesis of the compound Cpd 46

[ ₀₄₅₆ ] Formaldehyde (37% in water) (47 μl, 1.24 mmol , 11 eq), then NaBH ₄ (85 mg, 2.26 mmol, 20 eq). The reaction mixture is warmed to room temperature and stirred for 1 hour. NaOH solution (2 N) is added, the resulting solid is filtered and purified by flash chromatography on silica gel (eluting with DCM/MeOH 90/10) to give the desired compound.

Method L2: N-alkylation of an amine

1.1.8.1.1 Method L2i: Alkylation using 2-bromoacetonitrile

[0457] To a stirred solution of the amine derivative (1 eq) in ACN was added K ₂ CO ₃ (2 eq) and 2-bromoacetonitrile (1.1 eq). The reaction mixture was stirred at room temperature from overnight to 72 hours. The reaction mixture is either concentrated in vacuo, diluted with DCM and water and the organic layer separated, concentrated in vacuo, or NaHCO ₃ solution is added and the mixture is extracted with EtOAc, the combined organic layers are dried over anhydrous Na ₂ SO ₄ , filtered, concentrated under vacuum. The residue, obtained in one way or the other, is purified by flash chromatography on silica gel to obtain the desired compound.

Illustrative synthesis of the compound Cpd 100

[0458] To a stirred solution of Cpd 94 (41 mg, 0.08 mmol, 1 eq) in ACN (2 ml) was added K ₂ CO ₃ (22 mg, 0.16 mmol, 2 eq) and 2-bromoacetonitrile (6 μl , 0.09 mmol, 1.1 eq). The reaction mixture is stirred at room temperature for 72 hours. The reaction mixture is concentrated under vacuum, diluted with DCM and water. The organic layer is separated and concentrated under vacuum. The residue is purified by flash chromatography on silica gel (eluting with DCM/MeOH 100/0 to 95/5) to give the desired compound.

1.1.8.1.2 Method L2ii: Alkylation using prop-2-enenitrile

[0459] To a stirred mixture of amine derivative (1 eq) in MeOH was added DIPEA (5 eq) and prop-2-enenitrile (1.1 eq). The reaction mixture was stirred at room temperature for 1 hour, then ACN was added and the mixture was stirred at room temperature overnight. Add a saturated solution of NaHCO ₃ and the mixture is extracted with EtOAc. The combined organic layers are dried over Na ₂ SO ₄ , filtered, concentrated in vacuo, purified by silica gel flash chromatography to give the desired compound.

Illustrative synthesis of the compound Cpd 264

[0460] To a stirred mixture of 4-[7-[1-(azetidin-3-yl)-pyrazol-4-yl]imidazo[1,2-a]pyridin-3-yl]-2,6-dimethoxy-N -(2,2,2-trifluoroethyl)benzamide (50 mg, 0.10 mmol, 1 eq) in MeOH (0.5 ml) DIPEA (83 μl, 0.50 mmol, 5 eq) and prop-2- ennitrile (7 µl, 0.11 mmol, 1.1 eq). The reaction mixture was stirred at room temperature for 1 hour, then ACN (0.2 ml) was added and the mixture was stirred at room temperature overnight. Add a saturated solution of NaHCO ₃ and the mixture is extracted with EtOAc. The combined organic layers are dried over Na ₂ SO ₄ , filtered, concentrated in vacuo, purified by flash chromatography on silica gel (eluting with DCM/MeOH 99/1 to 95/5) to give the desired compound.

Method M: SNAr reaction

Method M1: Reaction of SNAr with an amine

[0461] In a sealed flask, potassium carbonate (3 eq) and an amine derivative (20 to 50 eq) are added to a stirred solution of the aryl fluoride derivative (1 eq) in THF. The mixture is stirred at 90°C for 48 hours. If complete conversion is not achieved at this stage, potassium carbonate (3 eq) and an amine derivative (50 eq) are added and the mixture is stirred at 90°C, then the mixture is concentrated in vacuo, the amine derivative (excess) is added, and the mixture stirred at 90°C for 18 hours, the amine derivative (excess) was added three times again, and the mixture was stirred at 65°C for 32 hours and at 75°C for 3 days. The mixture is concentrated under vacuum. Purification by silica gel flash chromatography or preparative LCMS gives the desired compound.

Illustrative synthesis of the compound Cpd 204

[0462] In a sealed flask, to a stirred solution of Cpd 203 (55 mg, 0.12 mmol, 1 eq) in THF (3 mL) was added potassium carbonate (50 mg, 0.36 mmol, 3 eq) and 2 M methylamine in THF (1.2 ml, 2.40 mmol, 20 eq). The mixture is stirred at 90°C for 48 hours. The mixture is concentrated under vacuum. Purification by flash chromatography on silica gel (eluting with 0 to 3% MeOH in DCM) gives the desired compound.

Method M2: reaction of SNAr with alcohol

[0463] To a mixture of t-BuOK (3 eq) and alcohol (excess), stirred for 5 minutes at room temperature, add an aryl fluoride derivative (1 eq). The reaction mixture is stirred at 80°C (for 2 hours to 26 hours) and at room temperature for 48 hours. If complete conversion is not achieved at this stage, t-BuOK (3 eq) and alcohol (excess) are added and the mixture is stirred at 80°C for 18 hours, then at 110°C for 3 hours. The mixture is extracted with DCM and purified by preparative LCMS to give the desired compound.

Illustrative synthesis of the compound Cpd 278

[0464] To a mixture of t-BuOK (33 mg, 0.30 mmol, 3 eq) and 2-methoxyethanol (0.5 ml, excess), stirred for 5 minutes at room temperature, add N-cyclopropyl-2-fluoro -6-methoxy-4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl]-benzamide (Cpd 276) (40 mg, 0.10 mmol, 1 eq ). The reaction mixture was stirred at 80°C for 2 hours and at room temperature for 48 hours, extracted with DCM and purified by preparative LCMS to give the desired compound.

Method N: pyrazole alkylation

Method N1: Alkylation with an alkyl halide

[0465] In a sealed flask, K ₂ CO ₃ (2 eq) and an alkyl halide (1.3 eq) are added to a stirred solution of the pyrazole derivative (1 eq) in ACN (2 ml). The reaction mixture is stirred at 60°C for 2 hours and at 90°C overnight or at 90°C overnight. An alkyl halide (3.0 eq) is then added and the reaction mixture is stirred at 100° C. (for 3 hours to overnight). The reaction mixture is concentrated under vacuum, diluted with DCM and water. The organic layer is separated and concentrated under vacuum. The residue is purified by silica gel flash chromatography to give the desired compound.

Illustrative synthesis of the compound Cpd 110

[0466] In a sealed flask, K ₂ CO ₃ (22 mg, 0.16 mmol, 2 eq) and 1- bromine-2-methylpropane (12 µl, 0.10 mmol, 1.3 eq). The reaction mixture was stirred at 60°C for 2 hours and at 90°C overnight. Then 1-bromo-2-methylpropane (3.0 eq) was added and the reaction mixture was stirred overnight at 100°C. The reaction mixture is concentrated under vacuum, diluted with DCM and water. The organic layer is separated and concentrated under vacuum. The residue is purified by flash chromatography on silica gel (eluting with DCM/MeOH 100/0 to 95/5) to give the desired compound.

Method N2: alkylation with haloacetate

[0467] To a stirred solution of the pyrazole derivative (1 eq) in DMF was added K ₂ CO ₃ (1.5 eq) and the haloacetate derivative (1.05 eq). The reaction mixture is stirred at 50°C for 3 hours and at 60°C for 2 hours. The reaction mixture is cooled to room temperature and water is added. The aqueous layer is extracted with EtOAc and the combined organic layers are washed with brine, dried over MgSO ₄ , filtered, concentrated in vacuo. The residue was purified by silica gel filtration, then purified by preparative LCMS, then purified by silica gel flash chromatography to give the desired compound.

Illustrative synthesis of the compound Cpd 229

[0468] To a stirred solution of Cpd 227 (262 mg, 0.588 mmol, 1 eq) in DMF (10 ml) was added K ₂ CO ₃ (122 mg, 0.882 mmol, 1.5 eq) and tert-butyl 2-chloroacetate (88 μl, 0.618 mmol, 1.05 eq). The reaction mixture is stirred at 50°C for 3 hours and at 60°C for 2 hours. The reaction mixture is cooled to room temperature and water is added. The aqueous layer is extracted with EtOAc and the combined organic layers are washed with brine, dried over MgSO ₄ , filtered, concentrated in vacuo. The residue is purified by filtration through a plug of silica gel (eluting with DCM/MeOH 100/0 to 90/10), then purified by preparative LCMS, then purified by flash chromatography on silica gel (eluting with DCM/MeOH 100/0 to 95/5) with obtaining the desired connection.

Method O: Amide alkylation

[0469] A solution of 1 N LiHMDS in THF (1.4 to 1.7 eq) was added dropwise to a stirred mixture of amide derivative (1 eq) in NMP/THF (1/1) or DMAC at 0°C. After 15 minutes of stirring, the trifluoromethanesulfonate derivative (1.4 to 1.7 eq) is added at 0°C and the reaction mixture is warmed to room temperature, then either stirred at room temperature overnight and the reaction mixture is quenched by adding a saturated solution NaHCO ₃ or stirred at 100°C for 1 hour, then at 120°C for 30 minutes. In the latter case, an additional amount of a solution of 1 N LiHMDS in THF (1.7 eq) is added, the reaction mixture is stirred for 15 minutes, 2,2,2-trifluoroethyl trifluoromethanesulfonate (3.4 eq) is added, and the reaction mixture is stirred at 120 °C for 30 minutes, and the reaction mixture is quenched by adding a saturated solution of NaHCO ₃ . The mixture is extracted with EtOAc and the combined organic layers are washed with brine, dried over Na ₂ SO ₄ or MgSO ₄ , filtered, concentrated in vacuo. The residue was purified by silica gel flash chromatography and either crystallized in hot ACN or precipitated in Et ₂ O to give the desired compound.

Illustrative synthesis of the compound Cpd 225

[0470] A solution of 1 N LiHMDS in THF (92 µl, 0.093 mmol, 1.7 eq). After 15 minutes of stirring, 2,2,2-trifluoroethyl trifluoromethanesulfonate (13.5 μl, 0.093 mmol, 1.7 eq) is added at 0°C and the reaction mixture is warmed to room temperature, then stirred at 100°C for 1 hours, then at 120°C for 30 minutes. An additional solution of 1 N LiHMDS in THF (92 µl, 0.093 mmol, 1.7 eq) is added, the reaction mixture is stirred for 15 minutes and 2,2,2-trifluoroethyl trifluoromethanesulfonate (27 µl, 0.19 mmol, 3, 4 equiv). The reaction mixture is stirred at 120°C for 30 minutes. The reaction mixture was quenched by adding saturated NaHCO ₃ solution, the mixture was extracted with EtOAc and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, concentrated in vacuo. The residue was purified twice by flash chromatography on silica gel (eluting with DCM/MeOH 100/0 to 95/5), then crystallized in hot ACN to give the desired compound.

Method P: tert-butyl ether cleavage

[0471] To a stirred solution of tert-butyl ether derivative (1 eq) in DCM was added a solution of 4 N HCl in dioxane (20 eq). The reaction mixture is stirred at room temperature for 48 hours and concentrated under vacuum. The solid is taken up in Et ₂ O, filtered, washed with Et ₂ O to give the desired compound.

Illustrative synthesis of the compound Cpd 254

[0472] To a stirred solution of Cpd 243 (29 mg, 0.050 mmol, 1 eq) in DCM (4 ml) was added a solution of 4 N HCl in dioxane (0.25 ml, 0.996 mmol, 20 eq). The reaction mixture is stirred at room temperature for 48 hours and concentrated under vacuum. The solid is taken up in Et ₂ O, filtered, washed with Et ₂ O to give the desired compound.

Method Q: Carboxylic acid esterification

Method Q1: HATU

[0473] To a stirred solution of the carboxylic acid derivative or sodium carboxylate (1 eq) in DMF is added HATU (1.1 eq) and the alcohol derivative (2.4 eq). The reaction mixture is stirred at room temperature overnight, then at 50°C for 1.5 hours. Add HATU (1.1 eq) and DIPEA (2 eq) and the reaction mixture is stirred at 50°C for 4 hours. The reaction mixture is purified by preparative LCMS to give the desired compound.

Illustrative synthesis of the compound Cpd 235

[0474] To a stirred solution of Cpd 228 (0.054 mmol, 1 eq) in DMF (1 ml) was added HATU (23 mg, 0.06 mmol, 1.1 eq) and 2-fluoroethanol (8 μl, 0.13 mmol, 2.4 equiv). The reaction mixture is stirred at room temperature overnight, then at 50°C for 1.5 hours. Add HATU (23 mg, 0.06 mmol, 1.1 eq), DIPEA (19 μl, 0.11 mmol, 2 eq) and the reaction mixture is stirred at 50°C for 4 hours. The reaction mixture is purified by preparative LCMS to give the desired compound.

Method Q2: SOCl ₂

1.1.13.1.1 Method Q2i: SOCl ₂ / room temperature

[0475] To a stirred solution of a carboxylic acid derivative (1 eq) in an alcohol derivative (1 ml) was added SOCl ₂ (1.5 to 6 eq, once or twice over 18 hours) and the reaction mixture was stirred at room temperature ( within 18 hours to 70 hours). The mixture is either concentrated in vacuo, dissolved in DCM/MeOH, neutralized with NaHCO ₃ , purified by silica gel flash chromatography to give the desired compound, or water and NaHCO ₃ are added, volatiles are concentrated in vacuo, the mixture is extracted with DCM by filtration through a hydrophobic column, concentrated under vacuum. The residue is either purified by flash chromatography on silica gel to give the desired compound, or ACN is added before complete evaporation, evaporation is carried out until a small amount of solvent remains, and the solid is filtered to obtain the desired compound.

Illustrative synthesis of the compound Cpd 236

[0476] To a stirred solution of Cpd 228 (23 mg, 0.046 mmol, 1 eq) in MeOH (1 ml) was added SOCl ₂ (5 μl, 0.068 mmol, 1.5 eq) and the reaction mixture was stirred at room temperature overnight . SOCl ₂ (5 μl, 0.068 mmol, 1.5 eq) was added and the reaction mixture was stirred at room temperature for 48 hours, concentrated in vacuo, dissolved in DCM/MeOH, neutralized with NaHCO ₃ , purified by flash chromatography on silica gel (eluting with DCM/MeOH 100/0 to 95/5) to give the desired compound.

1.1.13.1.2 Method Q2ii: SOCl ₂ /60°C

[0477] In a screw cap flask, SOCl ₂ (3 eq) and an alcohol derivative (2 eq) were added to a stirred mixture of carboxylic acid derivative (1 eq) in DCM, and the reaction mixture was stirred at room temperature overnight. Then an alcohol derivative (excess) is added and the reaction mixture is stirred at 40° C. for 1 hour. The DCM is evaporated and SOCl ₂ (6 eq) is added in four portions over 5.5 days with stirring at 60°C. The reaction mixture is concentrated in vacuo, neutralized with NaHCO ₃ , purified by silica gel flash chromatography, optionally crystallized in DCM/Et ₂ O to give the desired compound.

Illustrative synthesis of the compound Cpd 237

[0478] In a screw cap flask, to a stirred mixture of Cpd 228 (2o mg, 0.040 mmol, 1 eq) in DCM (1 ml) was added SOCl ₂ (8.6 μl, 0.12 mmol, 3 eq) and tetrahydrofuran- 3-ol (6.4 μl, 0.08 mmol, 2 eq) and the reaction mixture was stirred at room temperature overnight. Then add tetrahydrofuran-3-ol (0.2 ml, excess) and the reaction mixture is stirred at 40°C for 1 hour. The DCM is evaporated, SOCl ₂ (4.3 µl, 0.06 mmol, 1.5 eq) is added and the mixture is stirred at 60° C. for 24 hours. Add SOCl ₂ (4.3 μl, 0.06 mmol, 1.5 eq) and the mixture is stirred at 60°C for 24 hours and at room temperature for 3 days. Add SOCl ₂ (4.3 μl, 0.06 mmol, 1.5 eq) and the mixture is stirred at 50°C for 4 hours. Add SOCl ₂ (4.3 μl, 0.06 mmol, 1.5 eq) and the mixture is stirred at 60°C for 3 hours. The reaction mixture is concentrated in vacuo, neutralized with NaHCO ₃ , purified by flash chromatography on silica gel (eluting with DCM/MeOH 100/0 to 90/10), crystallized in DCM/Et ₂ O to give the desired compound.

Method Q3: alkyl bromide/Cs ₂ CO ₃

[0479] To a stirred mixture of carboxylic acid derivative (1 eq) in DMF was added Cs ₂ CO ₃ (2 eq) and an alkyl bromide derivative (1.2 eq). The reaction mixture is stirred at 60°C for 2 hours. An alkyl bromide derivative (1.8 eq) and Cs ₂ CO ₃ (1 eq) are added and the reaction mixture is stirred at 60° C. for 20 hours. The reaction mixture was purified by preparative LCMS and silica gel flash chromatography to give the desired compound.

Illustrative synthesis of the compound Cpd 238

[0480] To a stirred mixture of Cpd 228 (24 mg, 0.048 mmol, 1 eq) in DMF (1 ml) was added Cs ₂ CO ₃ (31 mg, 0.095 mmol, 2 eq) and bromomethylcyclobutane (6.4 μl, 0.057 mmol, 1.2 eq). The reaction mixture is stirred at 60°C for 2 hours. Bromomethylcyclobutane (9.6 μl, 0.087 mmol, 1.8 eq) and Cs ₂ CO ₃ (15 mg, 0.047 mmol, 1 eq) are added and the reaction mixture is stirred at 60° C. for 20 hours. The reaction mixture was purified by preparative LCMS followed by silica gel flash chromatography (eluting with DCM/MeOH 100/0 to 95/5) to give the desired compound.

Method R: Interesterification of tert-butyl ether

[0481] To a stirred solution of a tert-butyl ether derivative (1 eq) in an alcohol derivative is added 4 N HCl in dioxane (100 eq) and the reaction mixture is stirred at room temperature for 24 hours or at 60°C (for 0.5 up to 1.5 hours). The reaction mixture was concentrated in vacuo and either dissolved in DMSO, neutralized with NaHCO ₃ and purified by preparative LCMS to give the desired compound, or taken up in DCM and aqueous NaHCO ₃ , extracted with DCM, dried by filtration through a hydrophobic column, concentrated under vacuum, purified by silica gel flash chromatography to give the desired compound, or taken up in DCM and aqueous NaHCO ₃ , the mixture was extracted with DCM, dried by filtration through a hydrophobic column, concentrated in vacuo after addition of Et ₂ O, and the resulting solid was taken up in Et ₂ O and filtered to give the desired compound.

Illustrative synthesis of the compound Cpd 231

[0482] To a stirred solution of Cpd 229 (20 mg, 0.036 mmol, 1 eq) in propan-2-ol (1 ml) was added 4 N HCl in dioxane (0.89 ml, 3.6 mmol, 100 eq), and the reaction mixture is stirred at 60°C for 1.5 hours. The reaction mixture was concentrated in vacuo, dissolved in DMSO, neutralized with NaHCO ₃ and purified by preparative LCMS to give the desired compound.

Obtaining compounds according to the invention.

Int 1

[0483] 7-bromimidazo[1,2-a]pyridine (CAS# 808744-34-5; 100 g, 507.54 mmol, 1 eq), 1-methylpyrazole-4-boronic acid pinacol ester (CAS# 761446- 44-0; 116.18 g, 558.29 mmol, 1.1 eq), Na ₂ CO ₃ (161.37 g, 1522.61 mmol, 3 eq) is added to dioxane/water solvent mixture: 3/1 ( 1 l). The mixture was degassed with N ₂ , then the Pd(dppf)Cl ₂ ·DCM adduct (2.07 g, 2.54 mmol, 0.005 eq) was added and the mixture was stirred at 100° C. for 6 hours. The mixture is cooled to room temperature, filtered through a pad of ^Celite® , washed with DCM and the filtrate concentrated in vacuo. The residue was dissolved in DCM/n-BuOH (9/1, 1 L) and water (1 L) was added. The organic layer is separated and the aqueous layer is extracted with DCM (1 L) then with DCM/n-BuOH (9/1, 0.5 L). The combined organic layer was washed with brine (0.5 L), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue is triturated in MTBE (0.3 L) at room temperature, the suspension is filtered and the solid is washed with MTBE, then dried under vacuum to obtain the desired intermediate.

int 2

[0484] 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine (CAS# 908268-52-0; 0.5 g, 2.05 mmol, 1 eq), 3-chloro-6-methylpyridazine (CAS# 1121-79-5; 316 mg, 2.46 mmol, 1.2 eq), Cs ₂ CO ₃ (1 .34 g, 4.10 mmol, 2 eq.), Pd(dppf)Cl ₂ DCM (167 mg, 0.20 mmol, 0.1 eq.) and solvent mixture dioxane/water 4/1 (10 ml), degassed using N ₂ . The system was purged with N ₂ , then the mixture was stirred at 90° C. for 1 hour. The reaction mixture is cooled to room temperature, diluted in EtOAc, filtered through a layer of Celite ^® . The filtrate is concentrated in vacuo and used in the next step without further purification.

int 4

[0485] 4-Bromo-2,6-difluorobenzoic acid (90.5 g, 381.86 mmol, 1.0 eq) was added to SOCl ₂ (181 mL, 2 vols, 6.5 eq). The reaction mixture is stirred at the boil under reflux. After refluxing for 6 hours, heating is stopped and the reaction mixture is cooled to room temperature and then concentrated under vacuum. The residue was diluted with toluene (181 ml, 2 volumes) and concentrated to give residual thionyl chloride.

[0486] The liquid residue is diluted with DCM (453 ml, 5 volumes). Trifluoroethylamine hydrochloride (54.34 g, 400.95 mmol, 1.05 eq) was added to the reaction mixture under N ₂ atmosphere and then cooled to 5°C. Et ₃ N (117.09 mL, 840.08 mmol, 2.2 eq) is then added dropwise while maintaining the temperature of the reaction mixture below 27°C. The reaction mixture was then stirred under N ₂ at room temperature for 14 hours. The suspension is diluted with DCM (1000 ml, 10 volumes). The organic phase is washed with water (500 ml, 5 volumes) and saturated NaHCO ₃ solution (500 ml, 5 volumes). The organic phase is dried over Na ₂ SO ₄ (100 g), filtered, concentrated and triturated with heptane (500 ml, 6 volumes). The suspension is filtered and washed with heptane (500 ml, 6 volumes) and the solid is dried under reduced pressure to give Int 4.

int 5

[0487] To a solution of Int 4,4-bromo-2,6-difluoro-N-(2,2,2-trifluoroethyl)benzamide (110.20 g, 346.50 mmol, 1.0 eq) in NMP (551 ml, 5 volumes) under N ₂ atmosphere, sodium methoxide (56.15 g, 1.04 mol, 3 eq) is added. The reaction mixture is heated to 90°C. After heating for 1.5 hours at 90°C, the reaction mixture is cooled to room temperature and water (1100 ml, 10 volumes) is added and a precipitate forms. The suspension is filtered and the filter cake washed with water (3 x 1100 ml). The solid is dried at 55°C under vacuum (for 3 days) to obtain Int 5.

int 6

[0488] A mixture of Int 62 (1 g, 3.62 mmol, 1 eq) and sodium methoxide (0.23 g, 4.35 mmol, 1.2 eq) in DMSO (5 ml) is heated at 60°C for 24 hours. The reaction mixture was cooled to room temperature and poured into water (50 ml). The resulting solid is filtered, washed with water and dried to give the desired compound Int 6.

int 7

Stage i: 6-bromo-8-methoxy-3,4-dihydro-2H-isoquinolin-1-one

[0489] To a stirred solution of 6-bromo-8-fluoro-3,4-dihydro-2H-isoquinolin-1-one (CAS# 1242157-15-8; 3 g, 12.29 mmol, 1 eq) in THF ( 30 ml) is added dropwise a solution of MeONa 25 wt.% in MeOH (3.35 ml, 14.75 mmol, 1.2 eq). Then add THF (10 ml) in the process of adding a solution of sodium methoxide. The reaction mixture was stirred at room temperature for 2 hours, quenched with saturated aqueous NH ₄ Cl and the THF was evaporated. The resulting solid in the remaining water is filtered to give the desired compound

LCMS: MW (calculated): 256.1; m/z MW (detected): 256.1-258.1.

Step ii: 6-bromo-8-methoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one

[0490] To a stirred solution of 6-bromo-8-methoxy-3,4-dihydro-2H-isoquinolin-1-one (1.95 g, 7.61 mmol, 1 eq) in THF (45 ml) at 0° C add dropwise a solution of 1 N LiHMDS in THF (11.4 ml, 11.4 mmol, 1.5 eq). The resulting mixture was stirred for 15 minutes at 0°C and 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.64 ml, 11.4 mmol, 1.5 eq) was added at 0°C. The reaction mixture is slowly warmed to room temperature and stirred at room temperature overnight, then at 65°C for 2.5 hours, then to 80°C for 2 hours. The reaction mixture is quenched with water. The THF is evaporated and the aqueous layer is extracted with EtOAc. The combined organic layers are washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with DCM/MeOH 100/0 to 95/5) to give Int 7.

Int 8

[0491] To a solution of CD ₃ OD (2.36 ml, 58.00 mmol, 3.0 eq) in NMP (26.35 ml, 5 volumes) cooled to 0° C. in an ice bath, under N ₂ was added portions of NaH (1.99 g, 60% in oil, 3 eq.). The reaction mixture was stirred at room temperature for 30 minutes and then Int 4 (5.27 g, 16.57 mmol, 1.0 eq) was added to the mixture. The reaction mixture is heated to 90°C for 1.5 hours. The reaction mixture was cooled to room temperature and water (60 ml, 10 vols) was added. The suspension is filtered and the filter cake is washed with water (3 x 60 ml) and heptane (3 x 60 ml due to oil from NaH). The solid is dried at 40° C. under vacuum to give Int 8.

Int 9

[0492] In a 15 L single jacket reactor, potassium hydroxide (10 eq, 243 g) is added to a solution of Int 64 (1 eq, 124 g) in ACN/water (ACN/H ₂ O 1/1, 10 volumes, 1240 ml). The reaction mixture is cooled to 5°C (jacket temperature from 20°C to 0°C after 40 minutes). Pure diethyl (bromodifluoromethyl)phosphonate (2 eq, 154 mL) is added to the solution over 1 hour at 5°C (at 0°C jacket temperature), keeping the reaction temperature below 18°C. At the end of the addition, the reaction mixture is heated to 20°C and stirred at 20°C for 30 minutes.

[0493] The aqueous phase is extracted three times with EtOAc (3 x 650 ml, 3 x 5 volumes). The organic phases are combined and washed once with 20% NaCl (5 volumes, 650 ml) and concentrated.

[0494] The crude material is resuspended in MTBE (3 volumes/theoretical weight, 400 ml) for 30 minutes at 20°C. The suspension is filtered and the solid is washed with MTBE (140 ml). The solid is dried to give Int 9.

Int 9 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.31 (1H, br. s), 7.34-6.98 (3H, m), 3.84 (3H, s), 2 .74 (1H, m), 0.66 (2H, m), 0.43 (2H, m).

Int 10

Stage i: methyl 4-amino-2-hydroxy-6-methoxybenzoate

[0495] ₁ M BCl ₃ in DCM (91 ml, 91 mmol, 2.2 eq) at 0°C, stirred for 45 minutes and at room temperature overnight. Add 2 N HCl and ice-water, and the mixture is extracted twice with DCM. The combined organic layers are washed with water, brine, dried over anhydrous Na ₂ SO ₄ and evaporated under vacuum to obtain the desired product.

LCMS: MW (calculated): 197.1; m/z MW (detected): 198.2 (M+H).

Stage ii: methyl 4-(2,5-dimethylpyrrol-1-yl)-2-hydroxy-6-methoxybenzoate

[0496] 2,5-Hexadione (5.62 ml, 48 mmol, 2 eq) and stirred at 110°C for 15 minutes, then at room temperature for 1.5 hours. The mixture is evaporated in vacuo and purified by silica gel column chromatography (heptane/EtOAc, 50/50 v/v) to give the desired product.

LCMS: MW (calculated): 275.3; m/z MW (detected): 276.3 (M+H).

Step iii: 4-(2,5-dimethylpyrrol-1-yl)-2-hydroxy-6-methoxybenzoic acid

[0497] To a solution of methyl 4-(2,5-dimethylpyrrol-1-yl)-2-hydroxy-6-methoxybenzoate (6.10 g, 22 mmol) in MeOH (100 ml) was added a solution of 2 N NaOH (133 ml , 266 mmol, 12 equiv). Then the reaction mixture is stirred at 100°C for 18 hours. The MeOH was concentrated in vacuo, then the aqueous layer was acidified with 2 N HCl (140 ml) and extracted three times with DCM. The combined organic layers are dried over Na ₂ SO ₄ , filtered and concentrated under vacuum to obtain the desired product.

LCMS: MW (calculated): 261.2; m/z MW (detected): 262.2 (M+H).

Step iv: N-cyclopropyl-4-(2,5-dimethylpyrrol-1-yl)-2-hydroxy-6-methoxybenzamide

[0498] To a stirred solution of 4-(2,5-dimethylpyrrol-1-yl)-2-hydroxy-6-methoxybenzoic acid (10 g, 38.27 mmol, 1 eq) and HATU (16.01 g, 42. 10 mmol, 1.1 eq) in anhydrous DMF (200 ml) was added with DIPEA (13.34 ml, 76.54 mmol, 2 eq). The mixture was stirred at room temperature for 10 minutes and cyclopropylamine (3.18 ml, 45.92 mmol, 1.2 eq) was added. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture is evaporated to dryness and then diluted with EtOAc and water. The organic layer is separated, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue is purified by silica gel chromatography eluting with 0-30% EtOAc in heptanes. The product fractions are combined and evaporated to dryness to give the title compound.

LCMS: MW (calculated): 300.3; m/z MW (detected): 301.3 (M+H).

Stage v: N-cyclopropyl-2-(difluoromethoxy)-4-(2,5-dimethyl-pyrrol-1-yl)-6-methoxybenzamide

[0499] To a stirred solution of N-cyclopropyl-4-(2,5-dimethylpyrrol-1-yl)-2-hydroxy-6-methoxybenzamide (6.33 g, 21.07 mmol, 1 eq) in ACN (100 ml ) at -10°C, KOH (23.65 g, 421.40 mmol, 20 eq) in H ₂ O (100 ml) was added dropwise. The resulting mixture was stirred at -10° C. for 25 minutes and diethyl(bromodifluoromethyl)phosphonate (7.49 ml, 44.14 mmol, 2 eq) in ACN (15 ml) was added dropwise. The mixture was quenched by adding ice/H ₂ O and extracted twice with DCM. The organic layers are dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified on a 2×100 g HP column (Biotage), eluted with 0-2% MeOH in DCM. The product fractions are combined and evaporated to dryness to give the title compound.

LCMS: MW (calculated): 350.3; m/z MW (detected): 351.5 (M+H).

Stage vi: Int 10

[0500] To a stirred solution of N-cyclopropyl-2-(difluoro-methoxy)-4-(2,5-dimethylpyrrol-1-yl)-6-methoxybenzamide (6.78 g, 19.35 mmol, 1 eq) in EtOH (100 ml) at room temperature is added hydroxylamine hydrochloride (13.45 g, 193.51 mmol, 10 eq) in H ₂ O (50 ml). The resulting mixture was stirred overnight at 110°C. Hydroxylamine hydrochloride (5 eq) and Et ₃ N (2 eq) are added. The resulting mixture was stirred at 110°C for 3 hours 30 minutes. The EtOH is concentrated in vacuo. The aqueous phase is adjusted to pH 9 with 2N NaOH and extracted twice with EtOAc. The organic layers are dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue is purified by silica gel chromatography eluting with 0-5% MeOH in DCM. Product fractions are combined and concentrated under vacuum. The solid is triturated with Et ₂ O and filtered to give the title compound.

LCMS: MW (calculated): 272.2; m/z MW (detected): 273.2 (M+H).

Int 11

Step i: N-tert-butyl-4-(2,5-dimethylpyrrol-1-yl)-2-hydroxy-6-methoxybenzamide

[0501] To a stirred solution of 4-(2,5-dimethylpyrrol-1-yl)-2-hydroxy-6-methoxybenzoic acid (see Synthesis Int 10, examples 0) (5.6 g, 21.4 mmol, 1, 0 eq) and HATU (10.6 g, 27.8 mmol, 1.3 eq) in anhydrous DMF (25 ml) DIPEA (7.3 ml, 42.8 mmol, 2.0 eq) is added. The mixture was stirred at room temperature for 10 minutes and tert-butylamine (4.5 ml, 42.8 mmol, 2.0 eq) was added. The reaction mixture is evaporated to dryness and then diluted with EtOAc and water. The organic layer is separated, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel (eluting with DCM/heptane 2/1, 4/1, 9/1) gives the desired compound.

LCMS: MW (calculated): 316.4; m/z MW (detected): 317.7 (M+H).

Step ii: N-tert-butyl-2-(difluoromethoxy)-4-(2,5-dimethyl-pyrrol-1-yl)-6-methoxybenzamide

[0502] KOH (5.3 g, 94.8 mmol, 20 eq) in H ₂ O (20 ml). The resulting mixture was stirred at -10° C. for 10 minutes and diethyl(bromodifluoromethyl)phosphonate (1.5 ml, 9.5 mmol, 2.0 eq) was added dropwise. The mixture is stirred for 30 minutes at 0°C. The mixture was quenched with ice/H ₂ O and extracted twice with DCM. ACN is concentrated under reduced pressure. The desired product is filtered and washed with water.

LCMS: MW (calculated): 366.4; m/z MW (detected): 367.8 (M+H).

Stage iii: Int 11

[0503] To a stirred solution of N-tert-butyl-2-(difluoro-methoxy)-4-(2,5-dimethylpyrrol-1-yl)-6-methoxybenzamide (1.5 g, 4.1 mmol, 1 eq) in EtOH (50 ml) and H ₂ O (25 ml) Et ₃ N (1.2 ml, 8.2 mmol, 2.0 eq) and hydroxylamine hydrochloride (2.9 g, 41 mmol, 10 eq) are added at room temperature ). The resulting mixture was stirred overnight at 100°C. The EtOH is evaporated. The aqueous phase is adjusted to pH 9 with 2 N NaOH and extracted twice with DCM. The organic layers are dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel (eluting with DCM, then with DCM/MeOH 95/5) gives the desired compound.

Int 12

Stage i: 4-(2,5-dimethylpyrrol-1-yl)-N-ethyl-2-hydroxy-6-methoxybenzamide

[0504] To a solution of 4-(2,5-dimethylpyrrol-1-yl)-2-hydroxy-6-methoxybenzoic acid (see Synthesis Int 10, examples 0) (5.57 g, 21 mmol, 1 eq) in dried DMF (50 ml) was added with HATU (8.92 g, 23 mmol, 1.1 eq) and DIPEA (29.71 ml, 171 mmol, 8 eq). The mixture is stirred for 30 minutes at room temperature, then ethylammonium chloride (10.43 g, 128 mmol, 6 eq) is added and stirred at room temperature overnight. The reaction mixture was quenched with saturated NaHCO ₃ solution and extracted twice with EtOAc. The combined organic layers are washed with saturated NaHCO ₃ , brine and dried over Na ₂ SO ₄ and evaporated under reduced pressure. The crude material was purified by silica gel column chromatography (heptane/EtOAc 80/20) to give the desired product.

LCMS: MW (calculated): 288.3; m/z MW (detected): 289.4 (M+H)

Step ii: 2-(difluoromethoxy)-4-(2,5-dimethylpyrrol-1-yl)-N-ethyl-6-methoxybenzamide

[0505] To a solution of 4-(2,5-dimethylpyrrol-1-yl)-N-ethyl-2-hydroxy-6-methoxybenzamide (4.78 g, 17 mmol, 1 eq) in ACN (100 ml), chilled to -15°C, add KOH (18.60 g, 332 mmol, 20 eq) in water (100 ml). Then, diethyl(bromodifluoromethyl)phosphonate (5.89 ml, 33 mmol, 2 eq) dissolved in ACN was slowly added to the mixture, and stirred at -10° C. for 45 minutes. The reaction mixture was quenched with sat. NaHCO ₃ and ice-water and extracted twice with DCM. The combined organic layers are dried over Na ₂ SO ₄ and evaporated under reduced pressure to obtain the desired product.

LCMS: MW (calculated): 338.3; m/z MW (detected): 339.4 (M+H)

Stage iii: Int 12

[0506] To a stirred solution of 2-(difluoromethoxy)-4-(2,5-dimethylpyrrol-1-yl)-N-ethyl-6-methoxybenzamide (17 g, 50.2 mmol, 1 eq) in EtOH (200 ml ) at room temperature, add hydroxylamine hydrochloride (34.9 g, 502.4 mmol, 10 eq) in H ₂ O (100 ml) in Et ₃ N (13.9 ml, 100.5 mmol, 2 eq). The resulting mixture was stirred overnight at 110°C. The EtOH is evaporated. The aqueous phase is adjusted to pH 9 with 2N NaOH and extracted twice with DCM. The aqueous phase is adjusted to pH 10 using saturated aqueous Na ₂ CO ₃ and extracted with DCM. The organic layers are combined and dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The solid is triturated with DCM and Et ₂ O and filtered. Purification by flash chromatography eluting with 0-5% MeOH in DCM gave the desired product.

Int 13

[0507] SOCl ₂ (3.08 ml, 42.19 mmol, 5 equiv). The reaction mixture is stirred at the boil under reflux. After refluxing for 4 hours, complete conversion is achieved. Heating is stopped and the reaction mixture is cooled to room temperature and then concentrated under vacuum. The residue was diluted with toluene (20 ml, 10 volumes) and concentrated to remove residual thionyl chloride.

[0508] The yellow remaining liquid is diluted with DCM (5 ml, 5 volumes) under N ₂ . The reaction mixture is cooled in an ice bath. Slowly add Et ₃ N, then cyclopropylamine-d ₅ . The reaction mixture was then stirred under N ₂ at room temperature overnight. The reaction mixture is then diluted with DCM and water is added. The organic phase is washed successively with aqueous solutions of NaHCO ₃ 20% NaCl. The organic phase is dried over MgSO ₄ , filtered and concentrated. The residue is triturated with heptane (500 ml, 6 volumes). The suspension is filtered and washed with heptane (20 ml, 10 volumes) at room temperature for 30 minutes. The suspension is filtered and the filter cake is washed with a minimum amount of heptane to give Int 13.

Int 14: methyl 2,6-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate/(3,5-dimethoxy-4-methoxycarbonylphenyl) mixture )boronic acid

[0509] Methyl 2,6-dimethoxybenzoate (CAS# 2065-27-2; 96.6 g, 492 mmol, 1 eq) B ₂ pin ₂ (312.6 g, 1.23 mol, 2.5 eq) , [Ir(OMe)(COD)] ₂ (6.5 g, 9.8 mmol, 0.02 eq) and 3,4,7,8-tetramethyl-1,10-phenanthroline (Activate Scientific, Cat# AS21433 ; 4.7 g, 20 mmol, 0.04 eq) are dissolved in THF (1 L). The mixture is degassed with nitrogen and then refluxed. The reaction mixture is stirred at 65°C overnight. The solvent is concentrated under vacuum and the residue is triturated in diisopropyl ether (400 ml). The resulting solid is dried in a vacuum oven at 40° C. overnight to give the desired compound.

Int 16

Stage i: N-ethyl-2,6-dimethoxybenzamide

[0510] In an inert atmosphere, 2,6-dimethoxybenzoic acid (2 g, 11 mmol, 1 eq) is dissolved in DMF (200 ml), then Et ₃ N (31 ml, 220 mmol, 20 eq) and HATU (6 .3 g, 16.47 mmol, 1.5 eq), stirring at room temperature for 30 minutes, then ethylammonium chloride (9 g, 111 mmol, 10 eq) is added. Reaction time: 18 hours at room temperature. The mixture is concentrated under vacuum. Add water and EtOAc. The mixture is extracted three times with EtOAc and then the organic phases are combined and dried over Na ₂ SO ₄ , filtered and concentrated under vacuum. Purification by flash chromatography on silica gel (eluting with DCM/MeOH 99/1 to 97/3) gives the desired compound.

LCMS: MW (calculated): 209.2; m/z MW (detected): 210.4 (M+H)

Stage ii: N-ethyl-2-hydroxy-6-methoxybenzamide

[0511] Boron trichloride (1 M in DCM, 25 ml, 24 .15 mmol, 2.2 equiv). The mixture is stirred at 0°C for 30 minutes. The crude mixture is poured onto ice, water and concentrated ammonium hydroxide. The product is extracted 3 times with DCM. The organic layers are dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The obtained crude material is refluxed for 1 hour in an aqueous solution of 2 N HCl. The compound is extracted 3 times with EtOAc. The organic phases are dried over Na ₂ SO ₄ , filtered and concentrated under vacuum. Purification by flash chromatography on silica gel (eluting with 90/10 to 85/15 heptane/EtOAc) gives the desired compound.

LCMS: MW (calculated): 195.2; m/z MW (detected): 196.4 (M+H)

Step iii: 2-(difluoromethoxy)-N-ethyl-6-methoxybenzamide

[0512] Water (1.5 ml) and KOH (861 mg, 15.3 mmol, 10 eq). Diethyl(bromodifluoromethyl)phosphonate (CAS# 65094-22-6; 0.546 ml, 3.06 mmol, 2 eq) is added dropwise at -40°C. The mixture is stirred at -40°C for 10 minutes, then at room temperature for 30 minutes. The mixture is cooled to -40° C. and diethyl (bromodifluoromethyl)phosphonate (0.546 ml, 3.06 mmol, 2 eq) is added dropwise. The mixture is stirred at -40°C for 10 minutes, then overnight at room temperature. Water is added and the compound is extracted 3 times with EtOAc. The combined organic layers are dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Purification by flash chromatography on silica gel (eluting with 90/10 to 60/40 heptane/EtOAc) gives the desired compound.

LCMS: MW (calculated): 245.2; m/z MW (detected): 246.3 (M+H)

Stage iv: Int 16

[0513] In an inert atmosphere, 2-(difluoromethoxy)-N-ethyl-6-methoxybenzamide (690 mg, 2.8 mmol, 1 eq), B ₂ pin ₂ (2.15 g, 8.4 mmol, 3 eq ), [Ir(OMe)(COD)] ₂ (93 mg, 0.1 mmol, 0.05 eq) and BBBPY (30 mg; 0.11 mmol, 0.04 eq) are dissolved in THF (12 ml). The mixture is stirred at 70°C overnight. The mixture is concentrated under vacuum. Purification by flash chromatography on silica gel (eluting with 90/10 to 30/70 heptane/EtOAc) gives the desired compound.

Int 17

Stage i: N-cyclopropyl-2-hydroxy-6-methoxybenzamide

[0514] 6-Methoxysalicylic acid (CAS# 3147-64-6; 10 g, 0.06 mmol, 1 eq) is dissolved in DMF (50 ml), HATU (33.93 g, 0.09 mmol, 1, 5 eq), then after 15 minutes cyclopropylamine (CAS# 765-30-0; 10.18 g, 0.18 mmol, 3 eq) and DIPEA (34.55 g, 0.26 mmol, 4.5 eq). The reaction mixture is stirred at room temperature for 18 hours, then add 1 eq HATU, 2 eq cyclopropylamine and 2 eq DIPEA. The reaction mixture is stirred at room temperature for 68 hours. The reaction mixture is concentrated under vacuum. Purification is carried out by flash chromatography on silica gel (eluting with 100/0 to 50/50 heptane/EtOAc). The collected fractions are concentrated in vacuo and triturated twice with MeOH/Et ₂ O. The filtrate is concentrated in vacuo to give the desired product.

LCMS: MW (calculated): 207.2; m/z MW (detected): 208.4 (M+H)

Step ii: N-cyclopropyl-2-(difluoromethoxy)-6-methoxybenzamide

[0515] Under an inert atmosphere, N-cyclopropyl-2-hydroxy-6-methoxybenzamide (2.80 g, 0.013 mmol, 1 eq) is dissolved in ACN (20 ml) and cooled to -20°C. A solution of KOH (7.57 g, 0.13 mmol, 10 eq) in water (20 mL) was added and the mixture was stirred for 10 minutes, then diethyl (bromodifluoromethyl)phosphonate (CAS# 65094-22-6) was added slowly; 10.9 g, 0.04 mmol, 3.1 eq). The reaction mixture is stirred at -20°C for 30 minutes, then at room temperature for another 30 minutes. Water is added and three extractions are carried out with EtOAc. The organic layers are dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Purification by flash chromatography on silica gel (eluting with a 100/0 to 0/100 heptane/EtOAc gradient) gave the desired product.

LCMS: MW (calculated): 257.2; m/z MW (detected): 258.4 (M+H)

Stage iii: Int 17: mixture of N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzamide and 4 -(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxyphenylboronic acid

[0516] In an inert atmosphere, N-cyclopropyl-2-(difluoromethoxy)-6-methoxybenzamide (2.80 g, 10.89 mmol, 1 eq), B ₂ pin ₂ (8.30 g, 32.68 mmol, 3 eq), [Ir(OCH3)(COD)] (360 mg, 0.54 mmol, 0.05 eq) and BBBPY (120 mg, 0.45 mmol, 0.04 eq) are dissolved in degassed THF (70 ml ). The reaction mixture was stirred at 70° C. under N ₂ for 3 hours, then at room temperature overnight. Purification by flash chromatography on silica gel (eluting with a gradient of heptane/EtOAc from 100/0 to 30/70) gave the desired product in admixture with the appropriate boronic acid.

Int 18

Stage i: 5-bromo-2-ethyl-7-fluoroisoindolin-1-one:

[0517] To a stirred mixture of 5-bromo-7-fluoroisoindolin-1-one (CAS# 957346-37-1; 0.8 g, 3.48 mmol, 1 eq) in THF (2 ml) and DMF (25 ml ) add NaH 60% in oil (153 mg, 3.83 mmol, 1.1 eq). The reaction mixture was stirred at room temperature for 45 minutes and iodoethane (308 μl, 3.83 mmol, 1.1 eq) was added, the reaction mixture was stirred at room temperature for 1 hour. The mixture is then quenched with aqueous NaHCO ₃ , DMF and THF are concentrated, water is added again and the mixture is extracted with EtOAc. The combined organic layers are washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with 100/0 to 50/50 heptane/EtOAc) to give 5-bromo-2-ethyl-7-fluoroisoindolin-1-one.

LCMS: MW (calculated): 258.1; m/z MW (detected): 258.1-260.1

Step ii: 5-bromo-2-ethyl-7-methoxyisoindolin-1-one

[0518] A solution of 25 wt% MeONa in MeOH (106 µl, 0.465 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 5 minutes, quenched with saturated aqueous NH ₄ Cl. The mixture is extracted with EtOAc. The combined organic layers are washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo to give 5-bromo-2-ethyl-7-methoxyisoindolin-1-one.

LCMS: MW (calculated): 270.1; m/z MW (detected): 270.1-272.1

Stage iii: Int 18: mixture of 2-ethyl-7-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one/(2-ethyl -7-methoxy-1-oxo-isoindolin-5-yl)boronic acid

[0519] Charge the flask with 5-bromo-2-ethyl-7-methoxyisoindolin-1-one (0.387 mmol, 1 eq), B ₂ pin ₂ (118 mg, 0.46 mmol, 1.2 eq), AcOK ( 114 mg, 1.16 mmol, 3 eq), degassed dioxane (2 ml) and Pd(dppf)Cl ₂ ·DCM complex (19 mg, 0.02 mmol, 0.06 eq). The flask is sealed and the reaction mixture is stirred at 90°C for 1 hour. Add water and NaHCO ₃ and the mixture is extracted with EtOAc. The combined organic layers are washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with DCM/MeOH 100/0 to 90/10) to give a mixture of 2-ethyl-7-methoxy-5-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)isoindolin-1-one/(2-ethyl-7-methoxy-1-oxoisoindolin-5-yl)boronic acid.

Int 19

Stage i: 5-bromo-2-ethyl-7-fluoroisoindolin-1-one

[0520] See Int 18, step i.

Step ii: 5-bromo-2-ethyl-7-(2-hydroxyethylamino)isoindolin-1-one

[0521] To a stirred solution of 5-bromo-2-ethyl-7-fluoro-iso-indolin-1-one (100 mg, 0.387 mmol, 1 eq) in DMAC (2 ml) was added 2-aminoethanol (70 μl, 1 .16 mmol, 3 eq) and DIPEA (202 µl, 1.16 mmol, 3 eq). The mixture is stirred at room temperature for 1 hour, then at 100°C for 40 hours. The reaction mixture is cooled, water is added and the mixture is extracted with EtOAc. The combined organic layers are washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo to give 5-bromo-2-ethyl-7-(2-hydroxyethylamino)isoindolin-1-one.

LCMS: MW (calculated): 299.2; m/z MW (detected): 299.3-301.2.

Stage iii: Int 19

[0522] The flask is charged with 5-bromo-2-ethyl-7-(2-hydroxyethyl-amino)isoindolin-1-one (120 mg, 0.387 mmol, 1 eq), B ₂ pin ₂ (118 mg, 0.46 mmol, 1.2 eq), AcOK (114 mg, 1.16 mmol, 3 eq), degassed dioxane (2 ml) and Pd(dppf)Cl ₂ DCM complex (19 mg, 0.023 mmol, 0.06 eq) . The flask is sealed and the reaction mixture is stirred at 90°C for 1 hour. Add water and NaHCO ₃ and the mixture is extracted with EtOAc. The combined organic layers are washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with DCM/MeOH 100/0 to 95/5) to give 2-ethyl-7-(2-hydroxyethylamino)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)isoindolin-1-one.

Int 20

Stage i: 4-bromo-2-fluoro-6-methoxy-N-(2,2,2-trifluoroethyl)-benzamide

[0523] To a stirred solution of 4-bromo-2-fluoro-6-methoxy-benzoic acid (500 mg, 2 mmol, 1 eq) and HATU (841 mg, 2.2 mmol, 1.1 eq) in anhydrous DMF ( 5 ml) add DIPEA (701 μl, 4 mmol, 2 eq). The mixture was stirred at room temperature for 10 minutes and trifluoroethylamine (189 μl, 2.4 mmol, 1.2 eq) was added. The resulting mixture was stirred overnight at room temperature. The reaction mixture is concentrated under vacuum and diluted with DCM and water. The product is extracted with DCM and the organic layers are dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Purification by flash chromatography on silica gel (eluting with DCM) gives the desired compound.

LCMS: MW (calculated): 330.1; m/z MW (detected): 330.1-332.1 (M+H)

Step ii: Int 20: mixture of 2-fluoro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(2,2,2- trifluoroethyl)-benzamide and 3-fluoro-5-methoxy-4-[(2,2,2-trifluoroethyl)carbamoyl]-phenylboronic acid

[0524] To a stirred solution of 4-bromo-2-fluoro-6-methoxy-N-(2,2,2-trifluoroethyl)benzamide (165 mg, 0.5 mmol, 1 eq) and B ₂ pin ₂ (190 mg , 0.75 mmol, 1.5 eq) in degassed dioxane (2.5 ml) add KOAc (147 mg, 1.5 mmol, 3 eq) and Pd(dppf)Cl ₂ DCM (41 mg, 0.05 mmol, 0.1 equiv). The reaction mixture is stirred for 2 hours at 90°C. The reaction mixture is concentrated under vacuum and then diluted with DCM and water. The organic layer is separated and concentrated under reduced pressure. Purification by flash chromatography on silica gel (eluting with 0-2% MeOH in DCM) gives the desired compound mixed with the appropriate boronic acid.

Int 21

[0525] To a stirred solution of methyl 2-methoxy-6-methyl-benzoate (180 mg, 1 mmol, 1 eq) in degassed THF (3 ml) was added [Ir(OMe)(COD)] ₂ (33 mg, 0 05 mmol, 0.05 eq), BBBPY (13 mg, 0.05 mmol, 0.05 eq) and B ₂ pin ₂ (330 mg, 1.3 mmol, 1.3 eq). The reaction mixture is stirred for 2 hours at 70°C. additional amounts of [Ir(OMe)(COD)] ₂ (33 mg, 0.05 mmol, 0.05 eq), BBBPY (13 mg, 0.05 mmol, 0.05 eq) are added and the reaction mixture is stirred for 4 hours at 70°C. The reaction mixture is stirred overnight at 70°C. Additional amounts of [Ir(OMe)(COD)] ₂ (33 mg, 0.05 mmol, 0.05 eq), BBBPY (13 mg, 0.05 mmol, 0.05 eq) and B ₂ pin ₂ (120 mg, 0.47 mmol, 0.5 eq) and the reaction mixture was stirred for 4 hours at 70°C. The reaction mixture is concentrated under vacuum. Purification by flash chromatography on silica gel (eluting with 0-1% MeOH in DCM) gives the desired compound.

Int 22

[0526] B ₂ pin ₂ (330 mg, 1.3 mmol, 1.3 eq), BBBPY (13 mg, 0.05 mmol, 0.05 eq) and [Ir(OMe)(COD)] ₂ (33 mg, 0.05 mmol, 0.05 eq). The reaction mixture is stirred for 1 hour at 70°C. The reaction mixture is concentrated under vacuum. Purification by flash chromatography on silica gel (eluting with DCM) gives the desired compound.

Int 23: mixture of 8-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-isoquinolin-1-one and (8 -methoxy-1-oxo-3,4-dihydro-2H-isoquinolin-6-yl)boronic acid

[0527] The flask is charged with 6-bromo-8-methoxy-3,4-dihydro-2H-isoquinolin-1-one (100 mg, 0.39 mmol, 1 eq), B ₂ pin ₂ (119 mg, 0. 47 mmol, 1.2 eq), AcOK (115 mg, 1.17 mmol, 3 eq), degassed dioxane (2 ml), Pd(dppf)Cl ₂ DCM complex (19 mg, 0.023 mmol, 0.06 eq ). The flask is sealed and the reaction mixture is stirred at 90°C for 1 hour, at room temperature overnight and at 90°C for another 1 hour. Then purified by flash chromatography on silica gel (eluting with DCM/MeOH+1% AcOH from 100/0/1% to 80/20/1%) to give a mixture of 8-methoxy-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-isoquinolin-1-one/(8-methoxy-1-oxo-3,4-dihydro-2H-isoquinoline-6- yl) boronic acid.

Int 24

Stage i: 6-bromo-2-cyclopropyl-8-methoxy-3,4-dihydroiso-quinolin-1-one

[0528] To a stirred solution of 6-bromo-8-methoxy-3,4-dihydro-2H-isoquinolin-1-one (223 mg, 0.87 mmol, 1 eq) in THF (5 mL) at 0°C was added dropwise solution of LiHMDS 1 N in THF (1.25 ml, 1.25 mmol, 1.4 eq). After 15 minutes of stirring, cyclopropyl trifluoromethanesulfonate (0.15 ml, 1.25 mmol, 1.4 eq) is added at 0° C. and the reaction mixture is stirred at room temperature overnight, then at 100° C. for 8 hours. The reaction mixture was quenched with saturated NaHCO ₃ solution, extracted with EtOAc. The combined organic layers are washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with 100/0 to 0/100 heptane/EtOAc) to give 6-bromo-2-cyclopropyl-8-methoxy-3,4-dihydroisoquinolin-1-one.

LCMS: MW (calculated): 296.2; m/z MW (detected): 296.1-298.1.

Step ii: mixture of 2-cyclopropyl-8-methoxy-6-(4,4,5,5-tetra-methyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1-one and (2-cyclopropyl-8-methoxy-1-oxo-3,4-dihydroisoquinolin-6-yl)-boronic acid

[0529] The flask is charged with 6-bromo-2-cyclopropyl-8-methoxy-3,4-dihydroisoquinolin-1-one (106 mg, 0.358 mmol, 1 eq), B ₂ pin ₂ (109 mg, 0.429 mmol, 1 .2 eq), AcOK (105 mg, 1.074 mmol, 3 eq), degassed dioxane (2 ml), Pd(dppf)Cl ₂ DCM complex (17 mg, 0.021 mmol, 0.06 eq). The flask is sealed and the reaction mixture is stirred at 90°C for 2 hours. Then purified by flash chromatography on silica gel (eluting with DCM/MeOH 100/0 to 90/10) to give a mixture of 2-cyclopropyl-8-methoxy-6-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1-one/(2-cyclopropyl-8-methoxy-1-oxo-3,4-dihydroisoquinolin-6-yl)-boronic acid.

Int 25

Stage i: 5-bromo-7-methoxyisoindolin-1-one

[0530] A solution of 25 wt.% MeONa in MeOH (0.6 ml, 2.61 mmol, 1.2 eq). THF (5 ml) is then added. The reaction mixture was stirred at room temperature for 24 hours, then at 60°C for 30 minutes, quenched with saturated aqueous NH ₄ Cl, extracted with EtOAc. The combined organic layers are washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with heptane/EtOAc 100/0 to 0/100, then EtOAc/[DCM/MeOH (90/10)] 100/0 to 0/100) to give 5-bromo- 7-methoxyisoindolin-1-one.

LCMS: MW (calculated): 242.1; m/z MW (detected): 242.1-244.1

Step ii: Int 25: mixture of 7-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one and (7-methoxy-1-oxo -isoindolin-5-yl)boronic acid

[0531] The flask is charged with 5-bromo-7-methoxyisoindolin-1-one (90 mg, 0.37 mmol, 1 eq), B ₂ pin ₂ (113 mg, 0.45 mmol, 1.2 eq), AcOK (109 mg, 1.12 mmol, 3 eq), degassed dioxane (2 ml) and Pd(dppf)Cl ₂ ·DCM complex (18 mg, 0.022 mmol, 0.06 eq). The flask is sealed and the reaction mixture is stirred at 90°C for 1 hour and at room temperature overnight. Then purified by flash chromatography on silica gel (eluting with DCM/MeOH 100/0 to 80/20, then DCM/MeOH/AcOH 80/20/2%) to give 7-methoxy-5-(4,4,5 ,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)isoindolin-1-one/(7-methoxy-1-oxo-isoindolin-5-yl)boronic acid.

Int 62

[0532] In a 15 L jacketed reactor, 4-bromo-2,6-difluorobenzoic acid (900 g, 3.80 mol, 1 eq) is added to SOCl ₂ (5 eq, 1385 ml, 19.07 mol, 5 eq) in toluene (2 volumes, 1800 ml) in a stream of N ₂ at 20°C (jacket temperature). The suspension is then heated to 80° C. for 17 hours (jacket temperature 80° C.).

[0533] The reaction mixture is cooled to 40°C and concentrated (200 ml of toluene is used to wash the reactor). Toluene (1 vol, 900 ml) was added to the residue and the solution was concentrated.

[0534] The liquid residue (940 g) was dissolved in DCM (5 volumes, 4.5 L) under N ₂ and placed in a 15 L reactor. The reaction mixture is cooled to 13°C (jacket temperature: 5°C) and a mixture of Et ₃ N (582.22 ml, 4.18 mol, 1.1 eq) and cyclopropylamine (276.21 ml, 3.99 mol, 1.1 eq) for 1.3 hours keeping the temperature below 25°C (jacket temperature 5°C during addition). The reaction mixture was stirred under N ₂ at 20° C. for 14 hours.

[0535] Water (2.2 volumes, 2 L) is added to the suspension. The biphasic solution is stirred (200 rpm) for 15 minutes. The organic phase is then washed successively with a solution of 5% NaHCO ₃ (1.1 vol, 1 L) and 20% NaCl (1.1 vol, 1 L). The DCM layer is collected and transferred to a 15 L reactor.

[0536] In a 15 L reactor, a solvent change is carried out: 1 L of heptane is added to the DCM layer. The mixture is progressively heated at a jacket temperature of 65°C and the DCM is removed between 43°C and 50°C. After removing 2 L of DCM, 1 L of heptane is added. After removing a total of 4 l of solvent, add 1 l of heptane, and the mixture is cooled to 20°C for 20 minutes. Finally, 1 L of heptane is added (4 L of heptane added in total) and the mixture is stirred at 20° C. for 45 minutes.

[0537] The suspension is filtered and the filter cake is washed with 1.5 L of heptane.

[0538] The solid is dried at 50° C. under vacuum overnight to give Int 62.

Int 63

[0539] In a 15 L jacketed reactor, add 4 N NaOH (2155 mL, 8.62 mol, 2.5 eq) in one portion to a solution of Int 62 (952 g, 3.45 mol, 1 eq) in DMSO ( 2 volumes, 1.9 l). The suspension is heated to 90°C (jacket temperature from 50°C to 90°C for 20 minutes, then maintained at 90°C for 2 hours).

[0540] The reaction mixture is then cooled to 25°C (jacket temperature from 90°C to 5°C for 45 minutes) and 2 N HCl (2.7 L, 5.4 mol, 0.63 eq/NaOH) is added until the pH value reaches 3. The temperature is maintained below 30°C during the addition of HCl (addition over 20 minutes and the jacket temperature is 5°C). The suspension is stirred at 200 rpm for 2 hours, while the temperature is reduced to 20°C (jacket temperature is 5°C). The suspension is then filtered. The wet filter cake is washed with water (twice 2 L, 2 x 2 volumes) and the solid is dried on a sintered glass filter overnight.

[0541] The solid is dried in a vacuum oven at 50°C for 3 days to obtain Int 63.

int 64

[0542] In a 15 L single jacket reactor, NaOMe (717 g, 13.27 mol, 3.5 eq) is added over 20 minutes to a solution of Int 63 (1040 g, 3.79 mol, 1 eq) in DMSO (5 volumes, 5200 ml) under N ₂ atmosphere. The reaction mixture is heated to 100°C (jacket temperature from 20°C to 100°C for 30 minutes) and stirred at 250 rpm overnight.

[0543] The reaction mixture is cooled to 20°C (jacket temperature drops from 100°C to 10°C over 45 minutes) and after 2 hours 2 N HCl (5.3 L, 10.6 mol, 0.8 eq) is added /NaOMe) while maintaining the temperature range below 30°C. The suspension is cooled to 20°C, stirred for 15 minutes and filtered. The filter cake is washed with water (2 x 2 L, 2 x 2 volumes). The solid is dried in a vacuum oven at 50°C.

[0544] In a 15 L reactor, the crude solid (1040 g) was dissolved in acetone (3 L, 3 volumes). The solution is cooled at 15°C (jacket temperature from 20°C to 10°C after 20 minutes) and gradually add water (3 l, 3 volumes) over 30 minutes. The crystallization process begins after adding 800 ml of water. At the end of the addition, the suspension is cooled to 15°C and stirred for 15 minutes. The suspension is filtered and the filter cake washed with water (2 x 3 L, 2 x 3 volumes). The solid is dried in a vacuum oven at 50° C. to give Int 64.

Int 64 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 13.14 (1H, br.s), 8.38 (1H, br.s), 6.72 (2H, m), 3.86 (3H, s), 2.81 (1H, m), 0.70 (2H, m), 0.59 (2H, m).

Int 65

[0545] To a solution of Int 13 (2 g, 7 mmol, 1.0 eq) in DMSO (4 ml, 2 volumes) was added an aqueous solution of 4 M NaOH (4.4 ml) in one portion. The reaction mixture is stirred at 90°C. After 4 hours of stirring at 90°C, the reaction mixture is cooled to 25°C and an aqueous solution of 2 M HCl (5.7 ml, 11.34 mmol, 0.63 eq/NaOH) is added until a pH of approximately 3 is reached while maintaining the temperature below 30°C (addition after 1 minute). The suspension is stirred for 30 minutes, while the temperature drops to 20°C. The suspension is then filtered. The wet filter cake is washed with water (2 x 4 ml, 2 x 2 volumes) and the solid is dried on a fritted glass filter overnight to give Int 65.

int 66

[0546] A solution of CD ₃ OD (0.52 ml, 13.00 mmol, 4.5 eq) in DMSO (2 ml, 2.5 volumes) under N ₂ is cooled to 0° C. in an ice bath and NaH is added in portions (0.310 g, 60% in oil, 4.5 eq). The reaction mixture was stirred at room temperature for 30 minutes. Then a solution of Int 65 (0.8 g, 2.9 mmol, 1.0 eq) in DMSO (2 ml, 2.5 vols) was slowly added to the mixture. The reaction mixture is heated at 100°C for 2.5 hours. The reaction mixture is cooled to 20°C and an aqueous solution of 2 M HCl (5.2 ml, 10.4 mmol, 0.8 eq/NaOMe) is added. The suspension is stirred for 15 minutes at 20°C and then filtered. The filter cake is washed with water (2 x 2 ml, 2 x 2 volumes) to give the crude material, which is dissolved in acetone. The reaction mixture is cooled at 10°C (ice bath) and water is added. The suspension is cooled to 10°C and stirred for 15 minutes at this temperature. The suspension is filtered and washed with water to give Int 66.

Int 67

[0547] Int 66 (1.59 g, 5.40 mmol, 1.0 eq) is suspended in ACN (8 ml, 5 volumes) at 5°C. After 2 minutes, a solution of KOH (3.03 g, 54.05 mmol, 10.0 eq) in cold water (8 ml, 5 vols) is added. After 1.5 hours, diethyl (bromodifluoromethyl)phosphonate (CAS# 65094-22-6; 1.34 ml, 7.57 mmol, 1.4 eq) is added to the solution at 5°C while maintaining the temperature below 20°C. After completion of the addition (2.2 hours), after 10 minutes the temperature of the reaction mixture was raised to 20°C. EtOAc (8 ml, 5 vols) was added to the reaction mixture and then the aqueous phase was extracted. Perform another extraction with EtOAc (2 ml, 2 volumes). The organic phases are combined and washed once with a solution of 20% NaCl (6 ml, 5 volumes) and concentrated. This crude mixture is suspended in MTBE (6 ml, 3 volumes) for 30 minutes at room temperature. The suspension is filtered and the solid is washed with MTBE (2 ml, 1 vol). The solid is dried at 40° C. in a vacuum oven to give Int 67.

Int 68

[0548] To a solution of Int 67 (1.45 g, 4.21 mmol, 1.0 eq) and Int 56 (1.01 g, 4.63 mmol, 1.1 eq) in dioxane (9 ml, 6 volumes ) in an atmosphere of N ₂ add K ₃ PO ₄ . (1.79 g, 8.43 mmol, 2.0 eq), Pd(OAc) ₂ (9.5 mg, 0.04 mmol, 0.010 eq) and XantPhos (48.8 mg, 0.08 mmol, 0.020 eq). The reaction mixture is heated at 100°C for 1 hour. The reaction mixture is then cooled to room temperature. Water (6 ml, 4 volumes) was added to stop the reaction, and then additional water (12 ml, total 18 ml, 12 volumes) was slowly added while the reaction temperature was lowered. The suspension is stirred for 1 hour. The suspension is filtered and the filter cake washed with water (9 ml, 6 volumes). The filter cake is purified on a SiO ₂ column (25 g ^Biotage® SNAP Ultra, solid deposit) using a gradient from 100% DCM to 98/2 DCM/MeOH to give Int 68.

Int 69

[0549] To a solution of Int 68 (1.2 g, 2.49 mmol, 1.0 eq) and NH ₄ Cl (0.8 g, 14.95 mmol, 6.0 eq) in THF/MeOH (4/ 4 ml, 6 volumes) at 20° C. Zn (0.65 g, 9.97 mmol, 4.0 eq) is added in portions. The reaction mixture is heated at 60° C. for 1 hour, then NH ₄ Cl (70 mg, 1.31 mmol, 0.5 eq) is added. The reaction mixture is cooled to 25°C and filtered through a pad of Dicalite 4158 RE (Carlo Erba Reagents, Cat# P8880017). The filter cake is washed with THF (10 ml). The filtrate is concentrated. The crude material was triturated in EtOAc (6 ml) at room temperature for 10 minutes and filtered. The filter cake is washed with EtOAc (3 ml). The solid is dried at 45° C. under vacuum overnight to give Int 69.

Int 70

Stage i: 4-bromo-N-cyclopropyl-2-hydroxy-6-(trideuteriomethoxy)benzamide

[0550] An oven-dried flask (25 ml) under N ₂ was charged with MeOH-d ₄ (10 g, 12.63 ml). Sodium metal (1.452 g, 63.15 mmol) is weighed in heptane and cut into 6 approximately equal portions. MeOH-d ₄ cooled in an ice bath, and add portions of sodium over 40 minutes. The mixture is cooled to room temperature over several hours and then stirred overnight. The solution was used without further purification and without any analysis.

[0551] Int 63 (1.55 g, 1 eq) was dissolved in DMSO (8 ml). NaOMe-d ₃ (3.96 ml, 5 M, 3.5 eq) was added to the mixture with a syringe and the mixture was heated to 100° C. for 3 hours. The mixture was cooled to room temperature and 2 M HCl (7.92 ml, 2.8 eq) was added over 10 minutes. The mixture is stirred for 1 hour and filtered. The filter cake was washed with water (2 x 6 ml) and dried under vacuum at 40° C. overnight to give 4-bromo-N-cyclopropyl-2-(difluoromethoxy)-6-(trideuteriomethoxy)benzamide.

Stage II: Int 70

[0552] 4-Bromo-N-cyclopropyl-2-hydroxy-6-(trideuteriomethoxy)benzamide (1.386 g, 1 eq) was dissolved in ACN (7 ml) and cooled to 0-5°C. Prepare a solution of KOH (3.13 ml, 10 eq) in water (7 ml), cool, and add to the mixture, resulting in a biphasic mixture. Diethyl(bromodifluoromethyl)phosphonate (CAS# 65094-22-6; 1.192 ml, 1.4 eq) was added with stirring over 15 minutes, keeping the temperature below 10°C. The mixture is stirred for another 15 minutes and then warmed to room temperature. EtOAc (14 ml) was added, the phases were separated and the aqueous phase was extracted with EtOAc (5 ml). The combined organic layers are washed with brine (5 ml), dried over Na ₂ SO ₄ and concentrated in vacuo. The solid is triturated with MTBE (4 ml) for 1 hour, filtered, the filter cake is washed with MTBE (1.4 ml) and dried under vacuum to give Int 70.

Int 72

[0553] To a stirred solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (CAS# 269410-08-4; 200 mg, 1.03 mmol, 1 eq) in DMF (6 ml) add tert-butyl 2-bromopropanoate (180 μl, 1.08 mmol, 1.05 eq), K ₂ CO ₃ (150 mg, 1.08 mmol, 1.05 eq), and the reaction mixture was stirred at room temperature for 4 hours. tert-Butyl 2-bromopropanoate (17 μl, 0.1 mmol, 0.1 eq), K ₂ CO ₃ (14 mg, 0.1 mmol, 0.1 eq) is added and the reaction mixture is stirred at room temperature for 4 days . The mixture is concentrated under vacuum, add water and DCM. The mixture is extracted with DCM, dried by filtration through a hydrophobic column and concentrated under vacuum to obtain the desired product.

Int 73

[0554] To a stirred solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (200 mg, 1.03 mmol, 1 eq) in ACN ( 5 ml) add methyl 4-bromobutanoate (143 μl, 1.13 mmol, 1.1 eq), Cs ₂ CO ₃ (440 mg, 1.33 mmol, 1.3 eq) and the reaction mixture is stirred at 120°C for 20 minutes (microwave heating), then at 130°C for 10 minutes. Add methyl 4-bromobutanoate (26 μl, 0.21 mmol, 0.2 eq) and the reaction mixture was stirred at 120°C for 1 hour, then at room temperature overnight. The mixture is concentrated under vacuum, add water and DCM. The mixture is extracted with DCM, dried by filtration through a hydrophobic column and concentrated under vacuum to obtain the desired product.

Int 76

Stage i: tert-butyl 4-imidazo[1,2-a]pyridin-7-ylpyrazole-1-carboxylate

[0555] Degassed solution of tert-butyl 4-(4,4,5,5-tetra-methyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate (CAS# 552846-17-0; 1.50 g, 4.99 mmol, 1.10 eq), potassium phosphate, K ₃ PO ₄ (2.91 g, 3.0 eq), 7-bromimidazo[1,2-a]pyridine (CAS# 808744-34- 5; 920 mg, 1.0 eq) and Pd(dppf)Cl ₂ ·DCM complex (190 mg, 0.23 mmol, 0.05 eq) in dried THF (18 ml) were placed under argon and stirred at 70° C within 3 hours. The mixture is cooled to room temperature and diluted with 100 ml EtOAc. The organic layer is then washed with 200 ml of water, then with 100 ml of brine. After drying over Na ₂ SO ₄ and filtering, the solvent is evaporated. The residue was purified by silica gel flash chromatography (eluting with 0 to 50% (10% MeOH in EtOAc) in EtOAc) to give tert-butyl 4-imidazo[1,2-a]pyridin-7-ylpyrazole-1-carboxylate.

LCMS: MW (calculated): 284.3; m/z MW (detected): 285.6

Stage II: Int 76

[0556] To a solution of tert-butyl 4-imidazo[1,2-a]pyridin-7-yl-pyrazole-1-carboxylate (0.88 g, 2.94 mmol, 1.0 eq) in 40 ml of dried DCM is added TFA (4.55 ml, 20.0 eq). The resulting mixture was stirred at room temperature for 16 hours. The volatiles are evaporated and the residue is loaded into DCM on a 20 g MeOH-conditioned ^Agilent® Mega BOND-ELUT SCX column eluting with NH ₄ OH/MeOH solution and the product is isolated as the free base. The volatiles are evaporated and the residue is triturated with Et ₂ O to give Int 76.

Int 77

Stage i: 7-chloro-6-methoxyimidazo[1,2-a]pyridine

[0557] 4-chloro-5-methoxypyridine-2-amine (CAS# 867131-26-8; 1.0 g, 6.1 mmol, 1 eq) and NaHCO ₃ (1.04 g, 12.2 mmol, 2 eq) in EtOH (8 ml) is heated to 60°C and chloroacetaldehyde (50 wt% solution in water, 1.17 ml, 9.2 mmol, 1.5 eq) is added dropwise. The reaction mixture is then heated to 80°C for 1 hour. The reaction medium is cooled to room temperature and concentrated to dryness. The residue is poured into water and extracted with EtOAc. The combined organic layers are dried over MgSO ₄ , filtered and evaporated to dryness. The residue is taken up in 20 ml of water/aqueous HCl (3N). The aqueous layer was washed with Et ₂ O, then basified with K ₂ CO ₃ and extracted with EtOAc. The EtOAc layers are dried over MgSO ₄ , filtered and evaporated to dryness to give the desired product.

LCMS: MW (calculated): 182.6; m/z MW (detected): 183.0 (M+H)

Stage II: Int 77

[0558] _{BBr 3 (} 1 N solution in DCM, 11.55 ml, 11.5 mmol, 5 eq). The mixture is warmed to room temperature and stirred for 6 hours. The reaction medium is then cooled to 0° C., MeOH (10 ml) is added and the mixture is stirred at room temperature for 2 hours. The volatiles are concentrated and the residue is taken up in EtOH (10 ml). The solvent is evaporated to dryness to obtain the desired product.

cpd 48

Stage i: Method E1.3. Int 58

[0559] A round bottom flask was charged with 1-bromo-4-fluoro-3-nitrobenzene (CAS# 364-73-8; 10 g, 45.45 mmol, 1 eq), 1-methyl-4-(4.4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (CAS# 761446-44-0; 11.34 g, 54.54 mmol, 1.2 eq), Pd(PPh ₃ ) ₄ (5.3 g, 4.54 mmol, 0.1 eq), Cs ₂ CO ₃ (44.5 g, 136.4 mmol, 3 eq) and a degassed solution of dioxane (100 ml) and water (25 ml). The mixture is stirred at 100°C for 2 hours. The mixture is cooled to room temperature and the solvents are evaporated under vacuum. Water (200 ml) and brine (50 ml) are added. The mixture is extracted three times with DCM (200 ml, 100 ml, 100 ml). The organic phase is dried over Na ₂ SO ₄ , filtered and concentrated under vacuum. Purification by flash chromatography on silica gel eluting with DCM then DCM/AcOEt 4/1 gives the desired product.

Stage ii: Method B2, Int 57

[0560] Hydride sodium (60% dispersion in mineral oil; 3.53 g, 88.29 mmol, 3 eq) at 0°C. The reaction mixture is stirred for 1 hour at 0°C, and at room temperature for 1.5 hours. The reaction mixture was carefully added to ice/H ₂ O and the resulting solid was filtered to remove remaining Int 12 and DMF. The residue is diluted with EtOAc and washed successively with H ₂ O and brine. The organic layer is dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Purification by flash chromatography on silica gel (eluting with 0 to 2% MeOH in DCM) gives the desired compound, which is triturated with acetone/Et ₂ O and filtered to give the title Int 57.

Step iii: Method C2, Cpd 48

[0561] Zinc dust (2.83 g, 43.3 mmol, 5 eq) was added to a stirred solution of Int 57 (4 g, 8.66 mmol, 1 eq) in AcOH (40 ml) at room temperature. The resulting mixture was stirred for 1 hour at 75°C. The reaction mixture was diluted with EtOAc and filtered through a pad of Dicalite 4158 RE (Carlo Erba Reagents, Cat# P8880017) with EtOAc. The filtrate is concentrated under vacuum. Purification by flash chromatography on silica gel (eluting with 0 to 2% MeOH in DCM) gives the desired compound.

LCMS: MW (calculated): 431.4; m/z MW (detected): 432.3 (M+H).

[0562] The resulting compound (2.91 g, 6.74 mmol, 1 eq) was dissolved in MeOH (30 mL). Then acetic acid (50 µl) and trimethylorthoformate (3.68 ml, 33.70 mmol, 5 eq) are added. The resulting mixture was stirred for 1 hour at 75°C. The reaction mixture is concentrated under vacuum. Purification by flash chromatography on a ^Biotage® SNAP KP-NH column (eluting with DCM) gave a residue which was again purified by flash chromatography on silica gel (eluting with 0 to 5% MeOH in DCM) to give the desired compound. Trituration with Et ₂ O (and a few drops of MeOH) and filtration gave the title compound after drying under vacuum.

cpd 53

Step i: Method E1,3: 4-(4-fluoro-3-nitrophenyl)-1-methyl-pyrazole, Int 56

[0563] In a 15 L single jacket reactor, Na ₂ CO ₃ (488 g, 2.0 eq) was added to a degassed dioxane/water 4:1 mixture (4 L, 8 volumes). 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (CAS# 761446-44-0; 550 g, 1.15 eq) and 4-bromo-2-nitroaniline (CAS# 875-51-4; 500 g, 1.0 eq). Add one portion of Pd(PPh ₃ ) ₄ (26.6 g, 1.0 mol%), and the reaction mixture is heated from 20°C to 95°C for 40 minutes, and then boiled under reflux for 3 hours. The reaction mixture was concentrated to remove dioxane and the crude residue was poured into water/ice (4 L, 8 vols). The suspension is stirred at room temperature for 18 hours and then filtered. The filter cake is washed with water (2 x 2 L, 2 x 4 volumes). The crude residue is triturated in i-PrOH (1.5 L, 3 volumes). The suspension is filtered and the solid is washed with i-PrOH (500 ml, 1 vol). The solid is dried in a vacuum oven at 50° C. to give Int 56.

Int 56 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.08 (2H, m), 7.80 (1H, s), 7.64 (1H, dd), 7.41 (2H, br .s), 7.04 (1H, d), 3.84 (3H, s).

Step ii: Method E2.3: 2-(difluoromethoxy)-N-ethyl-6-methoxy-4-[4-(1-methylpyrazol-4-yl)-2-nitroanilino]benzamide, Int 55

[0564] In a 15 L single jacket reactor, Pd(OAc) ₂ (3.6 g, 1.0 mol%) and XantPhos (18.6 g, 2.0 mol%) are added to a solution of Int 9 (540 g, 1.0 eq), Int 56 (385 g, 1.1 eq) and K ₃ PO ₄ (682 g, 2.0 eq) in dioxane (2.7 l, 5 volumes) under N ₂ atmosphere. The reaction mixture is refluxed (jacket temperature from 20°C to 100°C after 1 hour, then the temperature is maintained).

[0565] After 1 hour and 20 minutes at 98-101°C, the jacket temperature is lowered from 100°C to 15°C over 1 hour. At the start of cooling, water (2 L, 3.7 volumes) was added to stop the reaction.

[0566] Then slowly add the remaining water (3.4 l, total 5.4 l, 10 volumes) over 2 hours while lowering the reaction temperature from 60°C to 20°C. After the addition of 3.5 L, a precipitate begins to form. Most of the precipitation falls when the temperature drops below 25°C. After completion of the addition, the suspension is subjected to aging for 30 minutes. The suspension is filtered and the solid is washed with water (2 L, 4 volumes). The solid is dried in a vacuum oven at 60° C. for 2 days.

[0567] The crude solid (740 g) was triturated in EtOAc/MTBE (1500/1500 mL, 2 vol/2 vol) for 1 hour. The suspension is filtered and the solid washed with 700 ml MTBE (1 vol). The solid is dried under vacuum at 50°C for 4 days to obtain Int 55.

Int 55 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.20 (1H, br.s), 8.24 (3H, br.s), 7.93 (1H, s), 7.82 (1H, dd), 7.44 (1H, d), 7.24 (0.4 H, s), 7.06 (0.6H, s), 6.87 (1H, s), 6.70 (1H, s), 3.87 (3H, s), 3.76 (3H, s), 2.77 (1H, m), 0.67 (2H, m), 0.46 (2H, m) .

Step iii: Method C3: N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]benzamide (Cpd 53)

[0568] In a 5 L single jacket reactor equipped with baffles, Int 55 (525 g, 1.0 eq) and ammonium chloride (326 g, 5.5 eq) are added to a 1:1 tetrahydrofuran/MeOH solution (2. 5 l, 5 volumes) under N ₂ atmosphere. Stirring is carried out at 300 rpm, and zinc dust (<10 μm, 290 g, 4.0 eq) (15 to 40 g) is added in portions while maintaining the reaction temperature below 50°C (jacket temperature is 20°C during additions). Additions are carried out within 1 hour.

[0569] The reaction mixture is heated at 60°C (jacket temperature) for 15 minutes. The reaction mixture is cooled to room temperature and filtered through a pad of Dicalite 4158 RE (Carlo Erba Reagents, Cat# P8880017). The filter cake is washed with THF (1500 ml, 3 volumes) and the filtrate is concentrated. After removing 2 L, add EtOAc (2 L, 4 vol) to co-evaporate with MeOH. At the end of evaporation, add 1 L of EtOAc.

[0570] The suspension is triturated at room temperature for 30 minutes and filtered. The filter cake is washed with EtOAc (200 ml). The solid is dried at 45° C. under vacuum overnight to give 4-[2-amino-4-(1-methyl-pyrazol-4-yl)anilino]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy -benzamide.

[0571] LCMS: MW (calculated): 443.4; m/z MW (detected): 444.6 (M+H)

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.04 (1H, d), 7.96 (1H, s), 7.70 (1H, s), 7.57 (1H, s), 7.06-6.69 (3H, m), 6.78 (1H, dd), 6.23 (1H, s), 6.06 (1H, s), 4.79 (2H, br.s) , 3.86(3H, s), 3.66(3H, s), 2.72(1H, m), 0.63(2H, m), 0.44(2H, m).

[0572] In a 5 L single jacket reactor, 4-[2-amino-4-(1-methylpyrazol-4-yl)anilino]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxybenzamide (660 g, 1.0 eq) was suspended in trimethylorthoformate (2640 ml, 4 volumes). The reaction mixture is then refluxed (jacket temperature is 110° C.) for 1.5 hours. The reactor was equipped with a solvent spray head and half of the solvents in the reaction mixture were removed (1350 ml of solvents removed after 2.5 hours). The reaction temperature is raised from 87°C to 100°C, and as MeOH is removed, a precipitate begins to precipitate. The jacket temperature is programmed to drop from 110°C to 20°C after 1 hour. When the reaction temperature reaches 60° C., MTBE (1.35 L, 2 volumes, 1 eq/trimethylorthoformate) is added slowly. The suspension is stirred at room temperature overnight.

[0573] The suspension is filtered. The filter cake is washed with MTBE (1 L). The solid is dried at 45° C. under vacuum to give Cpd 53.

cpd 165

Stage i: mixture of tert-butyl N-amino-N-[1-[3,5-dimethoxy-4-(2,2,2-trifluoroethylcarbamoyl)phenyl]benzimidazol-5-yl]carbamate and tert-butyl N-[[1-[ 3,5-dimethoxy-4-(2,2,2-trifluoroethylcarbamoyl)-phenyl]benzimidazol-5-yl]amino]carbamate

[0574] To a stirred solution of Int 39 (92 mg, 0.2 mmol, 1 eq) and tert-butylcarbazate (CAS# 870-46-2; 40 mg, 0.3 mmol, 1.5 eq) in degassed dioxane (2 ml ) add Cs ₂ CO ₃ (196 mg, 0.6 mmol, 3 eq), BrettPhos (11 mg, 0.02 mmol, 0.1 eq) and Pd ₂ (dba) ₃ (19 mg, 0.02 mmol, 0.1 equiv). The reaction mixture is stirred at 110°C for 3 hours. The reaction mixture was concentrated in vacuo and then diluted with EtOAc and water. The organic phase is separated, dried over MgSO ₄ , filtered and concentrated under vacuum. Purification by flash chromatography on silica gel (eluting with 0-5% MeOH in DCM) gives the desired products (mixture of both regioisomers). Purification by flash chromatography on silica gel (eluting with 0-3% MeOH in DCM) gives the desired regioisomers.

LCMS: Rt=0.64 min, MW (calculated): 509.5; m/z MW (detected): 510.3 (M+H).

LCMS: Rt=0.58 min, MW (calculated): 509.5; m/z MW (detected): 510.3 (M+H).

Step ii: 4-(5-hydrazinobenzimidazol-1-yl)-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)benzamide

[0575] To a stirred solution of one N-Boc regioisomer of a protected arylhydrazine (Rt=0.64 min, step i) (40 mg, 0.078 mmol, 1 eq) in dioxane (2 ml) was added 12 N HCl (65 μl, 0. 78 mmol, 10 eq). The reaction mixture is stirred overnight at room temperature. The residue is concentrated under vacuum to give the desired product in the form of the hydrochloride salt.

LCMS: MW (calculated): 409.4; m/z MW (detected): 410.3 (M+H).

Stage iii: Cpd 165

[0576] A solution of 4-(5-hydrazinobenzimidazol-1-yl)-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)benzamide (32 mg, 0.078 mmol, 1 eq) in EtOH (1 ml) treated with acetylacetone (CAS# 123-54-2; 8 μl, 0.078 mmol, 1 eq) at room temperature and stirred for 1 hour at reflux. The reaction mixture is concentrated under vacuum. Purification by flash chromatography on silica gel (eluting with 0-1% MeOH in DCM) gives the desired product.

cpd 166

Preparation of ethanimidothionic acid methyl ester:

[0577] Methyl iodide (249 µl, 4 mmol, 2 eq) is added dropwise to a solution of thioacetamide (150 mg, 2 mmol, 1 eq) in acetone (3 ml) at 0°C. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture is concentrated in vacuo and the residue is filtered and washed with Et ₂ O to give the title compound.

cpd 166

[0578] To a stirred solution of 4-(5-hydrazino-benzimidazol-1-yl)-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)benzamide (see Synthesis of Cpd 165 example 0 step ii) ( 30 mg, 0.074 mmol, 1 eq) in MeOH (1 ml) was added freshly prepared ethanimidothionic acid methyl ester. The reaction mixture is stirred at room temperature for 30 minutes and the solvent is removed under reduced pressure. Toluene (1 ml), trimethylorthoformate (41 μl, 0.370 mmol, 5 eq) and pyridine (1 ml) are added and the reaction mixture is stirred overnight at 110°C. The reaction mixture is concentrated under vacuum. The residue is diluted with saturated aqueous NaHCO₃ and extracted with DCM with Biotage phase separator^® ISOLUTE^®. The organic layer is concentrated under vacuum. Purification by flash chromatography on silica gel (eluting with 0-8% MeOH in DCM) gives the desired product.

cpd 167

Stage i: methyl 1-[3,5-dimethoxy-4-(2,2,2-trifluoroethyl-carbamoyl)phenyl]benzimidazole-5-carboxylate

[0579] Mo(CO) ₆ , [(t-Bu) ₃ PH]BF ₄ (12 mg, 0.04 mmol, 0.2 eq), Herrmann's catalyst (CAS# 172418-32-5; 19 mg, 0.02 mmol, 0.1 eq) and DBU (45 µl, 0.3 mmol , 0.1 equiv). The reaction mixture is stirred for 1 hour at 150°C under microwave radiation. The reaction mixture is concentrated under vacuum. Purification by flash chromatography on silica gel (eluting with 0-4% MeOH in DCM) gives the desired product.

LCMS: MW (calculated): 437.4; m/z MW (detected): 438.5 (M+H)

Step ii: 4-[5-(hydrazinecarbonyl)benzimidazol-1-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)benzamide

[0580] A solution of methyl 1-[3,5-dimethoxy-4-(2,2,2-trifluoroethyl-carbamoyl)phenyl]benzimidazole-5-carboxylate (100 mg, 0.23 mmol, 1 eq) in EtOH (2 ml) is treated with hydrazine hydrate (112 μl, 2.3 mmol, 10 eq) at room temperature and stirred for 4 hours at 120°C. The reaction mixture is stirred for 2 hours at 150°C under microwave radiation. The reaction mixture is concentrated under vacuum. The residue is washed with DCM and then diluted with MeOH. The mixture is filtered and the filtrate concentrated in vacuo to give the desired product.

LCMS: MW (calculated): 437.4; m/z MW (detected): 438.2 (M+H)

Stage iii: Cpd 167

[0581] AcOH (1 drop) is added to a solution of 4-[5-(hydrazine-carbonyl)benzimidazol-1-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)-benzamide (50 mg , 0.11 mmol, 1 eq) in trimethylorthoacetate (1 ml). The reaction mixture was stirred overnight at 110° C. in a sealed flask. The reaction mixture is concentrated under vacuum. Purification by flash chromatography on silica gel (eluting with 0-5% MeOH in DCM) gave the desired product.

cpd 168

[0582] AcOH is added to a solution of 4-[5-(hydrazinecarbonyl)-benzimidazol-1-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)benzamide (see Example 0 Cpd 167 step ii ; 50 mg, 0.11 mmol, 1 eq), trimethylorthocetate (44 µl, 0.35 mmol, 1.5 eq) and methylamine 2 M in THF (345 µl, 0.69 mmol, 3 eq) in dioxane (1 ml). The reaction mixture was stirred overnight at 120° C. in a sealed flask. The reaction mixture is concentrated under vacuum. Purification by flash chromatography on ^Biotage® SNAP KP-NH (eluting with 0-2% MeOH in DCM) gave the desired product.

cpd 169

[0583] Sodium hydride (60% dispersion in mineral oil) (3 mg, 0.082 mmol, 1 eq) at room temperature. The reaction mixture is stirred for 1 hour at 60°C and then cooled to 0°C, after which a solution of methyl 1-[3,5-dimethoxy-4-(2,2,2-trifluoroethylcarbamoyl)phenyl]-benzimidazole-5 is added -carboxylate (see example 0 Cpd 167, step i; 30 mg, 0.068 mmol, 1 eq) in anhydrous THF (1 ml). The reaction mixture is stirred for 1 hour at 60°C. Add saturated aqueous NH_fourCl and the aqueous layer was extracted twice with DCM with Biotage phase separator^® ISOLUTE^®. The organic layer is concentrated under vacuum. Purification by flash chromatography on silica gel (eluting with 0-3% MeOH in DCM) gives the desired product.

cpd 173

[0584] To a suspension of Int 52 (160 mg, 0.42 mmol, 1 eq) in DMF (1.5 ml) is added HATU (239 mg, 0.63 mmol, 1.5 eq) followed by DIPEA (220 μl, 1.26 mmol, 3 eq) and 3,3-difluoroazetidine hydrochloride (CAS# 288315-03-7; 66 mg, 0.51 mmol, 1.2 eq). The solution is stirred at room temperature overnight. The mixture is diluted with DCM, washed with water and brine. The organic phase is separated, dried over MgSO ₄ , filtered and concentrated under vacuum. Purification by flash chromatography on silica gel (eluting with 0 to 5% MeOH in DCM). A second flash chromatography purification on a ^Biotage® SNAP KP-NH column (eluting with 0 to 5% MeOH in DCM) gave the desired compound.

Cpd 174 (Method E1.2)

[0585] To a suspension of Int 52 (650 mg, 1.72 mmol, 1 eq) in DMF (5 ml) was added DIPEA (955 μl, 6.87 mmol, 4 eq), (2R)-1,1,1- trifluoropropane-2-amine (CAS# 779303-24-1; 514 mg, 3.44 mmol, 2 eq) and HATU (718 mg, 1.89 mmol, 1.1 eq). The mixture is stirred at room temperature overnight. HATU (460 mg, 0.6 eq) and (2R)-1,1,1-trifluoropropan-2-amine (0.7 eq) are added and the mixture is stirred at room temperature for 3 hours. Add a saturated solution of NaHCO ₃ and water, the mixture is extracted with EtOAc. The combined organic layers are washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified twice by flash chromatography on silica gel (eluting with DCM/MeOH 100/0 to 95/5) to give the desired compound.

cpd 175

Step i: Method E1.3: 5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazole

[0586] A flask equipped with an air condenser is charged with 5-bromo-1H-benzimidazole (CAS# 4887-88-1; 1.052 g, 5.34 mmol, 0.95 eq), 1-methyl-4-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (CAS# 761446-44-0; 1.17 g, 5.62 mmol, 1 eq), Cs ₂ CO ₃ (3 .67 g, 11.26 mmol, 2 eq) and dioxane/water 4/1 solvent mixture (50 ml) degassed with N ₂ . Pd(dppf)Cl ₂ ·DCM (344 mg, 0.42 mmol, 0.075 eq) is added and the system is placed under N ₂ atmosphere. The reaction mixture is stirred at 115°C for 2 hours, then at room temperature overnight. The reaction mixture was degassed with N ₂ then a degassed solvent mixture of dioxane/water 4/1 (10 ml), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)pyrazole (CAS# 761446-44-0; 117 mg, 0.562 mmol, 0.1 eq) and Pd(dppf)Cl ₂ DCM (162 mg, 0.198 mmol, 0.035 eq) and the mixture was stirred at 115° C for 3.5 hours. Finally, using the same protocol, add 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (CAS# 761446-44-0; 117 mg , 0.562 mmol, 0.1 eq) and Pd(dppf)Cl ₂ ·DCM (162 mg, 0.198 mmol, 0.035 eq) and the mixture was stirred at 115° C. for 3 hours. The mixture is filtered through a pad of ^Celite® . The filtrate is concentrated in vacuo and purified by silica gel flash chromatography (eluting with DCM/MeOH 100/0 to 90/10) to give the desired 5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazole.

LCMS: MW (calculated): 198.2; m/z MW (detected): 199.2 (M+H)

Step ii: Method E2.3: Cpd 175

[0587] A microwave flask was charged with 5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazole (80 mg, 0.40 mmol, 1 eq) and K ₃ PO ₄ (171 mg, 0.81 mmol, 2 eq). The flask is sealed, then evacuated and filled with argon (this process is repeated three times). Add by syringe a degassed solution of anhydrous toluene and anhydrous dioxane (5/1, 0.4 ml).

[0588] The second flask was charged with Pd ₂ dba ₃ (22 mg, 0.024 mmol, 6 mol %) and Me ₄ t-BuXPhos (CAS# 857356-94-6; 23 mg, 0.048 mmol, 12 mol %). The flask is sealed, then evacuated and filled with argon (this process is repeated three times). Add by syringe a degassed solution of anhydrous toluene and anhydrous dioxane (5/1, 0.4 ml). The resulting mixture was stirred at 120°C for 5 minutes. Then 5-bromo-2-ethyl-7-fluoro-isoindolin-1-one (see Synthesis Int 19, example 0, step i; 104 mg, 0.40 mmol, 1 eq) and the pre-mixed catalyst solution are added to the first flask. . The reaction mixture is heated to 120°C for 18 hours.

[0589] Water is added and the mixture is extracted with DCM. The combined organic layers are washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (eluting with DCM/EtOAc/EtOH 60/35/5 then 60/30/10) and preparative TLC (eluting with DCM/EtOAc/EtOH 60/30/10) to give Cpd 175.

cpd 202

[0590] A microwave reaction flask was charged with Cpd 175 (39 mg, 0.104 mmol, 1 eq), DMAC (0.9 ml), ethanolamine (19 μl, 0.311 mmol, 3 eq) and DIPEA (54 μl, 0.311 mmol, 3 eq). The reaction mixture is stirred at 100°C for 30 hours. The mixture is concentrated under vacuum, water and NaHCO ₃ are added and the mixture is extracted with DCM. The combined organic layers are washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with DCM/MeOH 100/0 to 95/5) to give Cpd 202.

Cpd 266 (method H)

[0591] Load Int 1 (2.5 g, 12.61 mmol, 1.0 eq), Int 8 (4.32 g, 12.61 mmol, 1.0 eq), KOAc (2.5 g, 25 .22 mmol, 2.0 eq) and DMAC (25 ml, 10 volumes). The reaction mixture is degassed with N ₂ with stirring. Add Pd(dppf)Cl ₂ ·DCM (0.051 g, 0.063 mmol, 0.005 eq). The mixture is heated at 130°C for 21 hours. The mixture is cooled to room temperature and then filtered. Water (60 ml, 24 volumes) was added to the filtrate and the resulting suspension was filtered. The solid is washed with water (60 ml, 24 volumes), filtered and triturated with MTBE (60 ml, 24 volumes). The solid is taken up in water and DCM and the mixture is extracted with DCM. The combined organic layers are washed with water, purified by silica gel flash chromatography eluting with DCM/MeOH (100/0 to 95/05) to give Cpd 266.

cpd 291

[0592] Int 69 (0.787 g, 1.74 mmol, 1.0 eq) is suspended in trimethyl orthoformate (3 ml, 4 volumes). The reaction mixture is refluxed (110°C) for 50 minutes. The reaction mixture is cooled to 25°C, and then add MTBE (3 ml). The reaction mixture was stirred at room temperature for 1 hour. The suspension is filtered. The filter cake is washed with MTBE (5 ml). The solid was purified on a silica gel column eluting with DCM/ACN to 100% ACN to give Cpd 291.

cpd 292

Step i: Method E2.3: N-cyclopropyl-2-(difluoromethoxy)-4-[4-(1-methylpyrazol-4-yl)-2-nitro-anilino]-6-(trideuteriomethoxy)-benzamide

[0593] The experiment is carried out in an atmosphere free of oxygen and water (glove box). Int 70 (1.4 g, 4.13 mmol, 1 eq), Int 56 (0.99 g, 4.54 mmol, 1.1 eq), K ₃ PO ₄ (1.75 g, 8.26 mmol , 2 eq), XantPhos (48 mg, 0.083 mmol, 0.02 eq) and Pd(OAc) ₂ (9 mg, 0.041 mmol, 0.01 eq) are suspended in dioxane (5V). The mixture is heated at 100°C for 90 minutes. The mixture is cooled to room temperature. During the cooling process, water is added to the mixture. The mixture is stirred for 1 hour. The mixture is filtered and the filter cake is washed with water then MTBE. The resulting filter cake is dried under vacuum and then suspended in MTBE (10 ml) and triturated overnight. The mixture is filtered and the filter cake is washed with MTBE (2 x 5 ml). The resulting solid is dried under vacuum at 50° C. for 3 hours to give the desired nitroaniline compound.

LCMS: MW (calculated): 476.5; m/z MW (detected): 477.2

Step ii: Method C3: Cpd 292

[0594] N-cyclopropyl-2-(difluoromethoxy)-4-[4-(1-methylpyrazol-4-yl)-2-nitroanilino]-6-(trideuteriomethoxy)benzamide (1.68 g, 1 eq) was dissolved in THF (9 ml) and MeOH (9 ml). NH ₄ Cl (2.075 g, 11 eq) was added followed by zinc (2.075 g, 9 eq). The mixture is heated to 30°C and add zinc portions of ~0.1 g over 15 minutes, maintaining the temperature in the range of 30-40°C. Additional Zn (0.231 g, 1 eq) and NH ₄ Cl (0.207 g, 1.1 eq) are added. The mixture is stirred at 50° C. until its color changes from orange to pale brown. The mixture is filtered through a pad of ^Celite® and the filter cake is washed with THF (3 x 5 ml) and the filtrate is concentrated in vacuo. The resulting solid is suspended in trimethylorthoformate (7.72 ml, 20 eq) and refluxed for 40 minutes. The mixture is cooled to 50°C, then add MTBE (15 ml), and then the mixture is cooled to room temperature with stirring. Add EtOAc and continue mixing. The mixture is concentrated in vacuo and the crude material is purified by flash chromatography, the residue is evaporated and the resulting solid is triturated in MTBE for 30 minutes. The mixture is filtered and the solid is dried under vacuum. The solid is then dissolved in a mixture of i-PrOH and cyclohexane 1:1 (40 ml) at the boil under reflux. After cooling, the mixture is kept for 1 hour and filtered. The filtrate is collected and kept for 72 hours. The mixture is filtered and the solid is dried under vacuum at 40° C. to give Cpd 292.

cpd 293

Stage i: ethyl 3-(4-imidazo[1,2-a]pyridin-7-ylpyrazol-1-yl)-2-methylpropanoate

[0595] Ethyl methacrylate (327 μl, 5.0 eq) was added to a suspension of Int 76 (100 mg, 0.52 mmol, 1.0 eq) in 3 ml of dried ACN followed by DBU (40 μl, 0.5 eq). The resulting mixture was stirred at 80°C in a sealed flask for 16 hours. The reaction mixture is cooled to room temperature and diluted with 20 ml EtOAc. The organic layers are washed with 2×30 ml aqueous saturated NaHCO ₃ , 30 ml brine. After drying over Na ₂ SO ₄ , the solvent is evaporated. The residue was purified by silica gel flash chromatography (eluting with 5 to 100% (10% MeOH in EtOAc) in EtOAc) to give ethyl 3-(4-imidazo[1,2-a]pyridin-7-ylpyrazol-1-yl) -2-methylpropanoate.

LCMS: MW (calculated): 298.3; m/z MW (detected): 299.6 (M+H)

Stage ii: Cpd 293

[0596] Degassed solution of Int 5 (262 mg, 1.6 eq), KOAc (138 mg, 3.0 eq), ethyl 3-(4-imidazo[1,2-a]pyridin-7-ylpyrazol-1- yl)-2-methylpropanoate (140 mg, 0.464 mmol, 1.0 eq) and Pd(dppf)Cl ₂ DCM (19 mg, 0.05 eq) in dried DMAC (2.0 ml) were placed under argon and stirred at 115°C for 8 hours. The reaction mixture is cooled to room temperature and poured into 30 ml of water. Add 5 ml of a saturated aqueous solution of Na ₂ CO ₃ . Next, extraction is carried out with 3 × 15 ml of EtOAc. The combined organic layers are washed with 20 ml of saline and dried over Na ₂ SO ₄ . After filtration, the solvent is evaporated. The residue was purified by flash chromatography on silica gel (eluting with 0 to 80% (10% MeOH in DCM) in DCM, then 100% (10% MeOH in DCM)). After evaporation of the solvent from the collected fractions, the residue is dissolved in 10 ml of DCM. Evaporation gives the desired product.

cpd 294

Stage i: ethyl 2-[(4-imidazo[1,2-a]pyridin-7-ylpyrazol-1-yl)methyl]-3-methylbutanoate

[0597] Ethyl 3-methyl-2-methylenebutanoate (327 µl, 5.0 eq) was added to a suspension of Int 76 (100 mg, 0.52 mmol, 1.0 eq) in 3 ml of dried ACN followed by DBU (40 µl , 0.5 equiv). The resulting mixture was stirred at 80°C in a sealed flask for 16 hours. The reaction mixture is cooled to room temperature and diluted with 30 ml of EtOAc. The organic layers are washed with 2×30 ml of saturated aqueous NaHCO ₃ , then with 30 ml of brine. After drying over Na ₂ SO ₄ , the solvent is evaporated. The residue was purified by silica gel flash chromatography (eluting with 5 to 100% (10% MeOH in EtOAc) in EtOAc) to give ethyl 2-[(4-imidazo[1,2-a]pyridin-7-ylpyrazol-1-yl )methyl]-3-methylbutanoate.

LCMS: MW (calculated): 326.4; m/z MW (detected): 327.2 (M+H)

Stage ii: Cpd 294

[0598] Degassed solution of Int 5 (238 mg, 1.6 eq), KOAc (138 mg, 3.0 eq), ethyl 2-[(4-imidazo[1,2-a]pyridin-7-ylpyrazol-1 -yl)methyl]-3-methylbutanoate (145 mg, 0.464 mmol, 1.0 eq) and Pd(dppf)Cl ₂ ·DCM (18 mg, 0.05 eq) in dried DMAC (2.0 ml) were placed in an argon atmosphere and stirred at 115°C for 8 hours. The reaction mixture is cooled at room temperature and poured into 30 ml of a saturated aqueous solution of NaHCO ₃ . Extraction is then carried out with 3 x 15 ml EtOAc. The combined organic layers are washed with 2×20 ml saturated aqueous NaHCO ₃ , 20 ml brine, and dried over Na ₂ SO ₄ . After filtration, the solvent is evaporated. The residue was purified by flash chromatography on silica gel (eluting with 0 to 45% (10% MeOH in DCM) in DCM). After evaporation of the solvent from the collected fractions, the residue is dissolved in 10 ml of DCM. Evaporation gives the desired product.

cpd 295

Stage i: ethyl 2-(4-imidazo[1,2-a]pyridin-7-ylpyrazol-1-yl)-2-methylpropanoate

[0599] K ₂ CO ₃ (139 mg , 1.7 eq). The resulting mixture was stirred at 90°C in a sealed flask for 16 hours. The reaction mixture was cooled to room temperature and poured into 30 ml of a saturated aqueous NaHCO ₃ solution. Extraction is then carried out with 2 x 20 ml EtOAc. The combined organic layers are washed with brine and the solvent is evaporated. The residue was purified by flash chromatography on silica gel (eluting with EtOAc/10% MeOH(DCM), 5-100% 10% MeOH(DCM)) to give ethyl 2-(4-imidazo[1,2-a]pyridine-7- ylpyrazol-1-yl)-2-methylpropanoate.

LCMS: MW (calculated): 298.3; m/z MW (detected): 299.1 (M+H)

Stage ii: Cpd 295

[0600] Degassed solution of Int 5 (187 mg, 0.55 mmol, 1.6 eq), KOAc (98 mg, 3.0 eq), ethyl 2-(4-imidazo[1,2-a]pyridine-7 -ylpyrazol-1-yl)-2-methylpropanoate (101 mg, 0.331 mmol, 1.0 eq) and Pd(dppf)Cl ₂ DCM (15 mg, 0.05 eq) in dried DMAC (2.0 ml) placed in an argon atmosphere and stirred at 115°C for 4 hours. The reaction mixture is cooled at room temperature and poured into 30 ml of a saturated aqueous solution of NaHCO ₃ . Extraction is then carried out with 3 x 15 ml EtOAc. The combined organic layers are washed with 2×20 ml saturated aqueous NaHCO ₃ , 20 ml brine, and dried over Na ₂ SO ₄ . After filtration, the solvent is evaporated. The residue was purified by flash chromatography on silica gel (eluting with 0 to 45% (10% MeOH in DCM) in DCM). After evaporation of the solvent from the collected fractions, the residue is dissolved in 10 ml of DCM. Evaporation gives the desired product.

cpd 296

Stage i: ethyl 2-(4-imidazo[1,2-a]pyridin-7-ylpyrazol-1-yl)-3-methylbutanoate

[0601] K ₂ CO ₃ (139 mg , 1.7 eq). The resulting mixture was stirred at 70°C for 8 hours. The reaction mixture was cooled to room temperature and poured into 30 ml of a saturated aqueous NaHCO ₃ solution. Extraction is then carried out with 2 x 20 ml EtOAc. The combined organic layers are washed with brine and the solvent is evaporated. The residue was purified by silica gel flash chromatography (eluting with 0 to 85% (10% MeOH in DCM) in DCM) to give ethyl 2-(4-imidazo[1,2-a]-pyridin-7-ylpyrazol-1-yl )-3-methylbutanoate.

LCMS: MW (calculated): 312.4; m/z MW (detected): 313.2 (M+H)

Stage ii: Cpd 296

[0602] Degassed solution of Int 5 (187 mg, 0.55 mmol, 1.6 eq), KOAc (98 mg, 3.0 eq), ethyl 2-(4-imidazo[1,2-a]pyridine-7 -ylpyrazol-1-yl)-3-methylbutanoate (105 mg, 0.331 mmol, 1.0 eq) and Pd(dppf)Cl ₂ DCM (15 mg, 0.05 eq) in dried DMAC (2.0 ml) placed in an argon atmosphere and stirred at 115°C for 4 hours. The reaction mixture is cooled at room temperature and poured into 30 ml of a saturated aqueous solution of NaHCO ₃ . Extraction is then carried out with 3 x 15 ml EtOAc. The combined organic layers are washed with 2×20 ml saturated aqueous NaHCO ₃ , 20 ml brine, and dried over Na ₂ SO ₄ . After filtration, the solvent is evaporated. The residue was purified by flash chromatography on silica gel (eluting with 0 to 45% (10% MeOH in DCM) in DCM). After evaporation of the solvent from the collected fractions, the residue is dissolved in 10 ml of DCM. Evaporation gives the desired product.

cpd 297

[0603] To a solution of Cpd 228 (100 mg, 0.196 mmol, 1.0 eq) in 1.2 ml of dried DMF is added 1,1'-carbonyldiimidazole (49 mg, 1.5 eq) and the mixture is stirred at 50°C within 1 hour. A mixture of tetrahydrofuran-2-ylmethanol (39 µl, 2.0 eq) and DBU (45 µl, 1.5 eq) in 400 µl of dried DMF is then added n drops. The mixture is stirred at 50°C for 2 hours and cooled to room temperature. The mixture is poured into 25 ml of an aqueous solution of 5% NaHCO ₃ . Extraction is then carried out with 3 x 15 ml DCM (10% isopropanol). The combined organic layers are dried over Na ₂ SO ₄ and after filtration the solvent is evaporated. The residue was purified by flash chromatography (eluting with 0 to 55% (10% MeOH in DCM) in DCM) to give the desired product.

cpd 298

Stage i: ethyl 2-(4-imidazo[1,2-a]pyridin-7-ylpyrazol-1-yl)-3-methylbutanoate

[0604] Int 77 (575 mg, 2.3 mmol, 1 eq) and K ₂ CO ₃ (370 mg, 2.8 mmol, 1.15 eq) are suspended in DMF (9 ml) and the mixture is heated to 60° C. At this temperature, a solution of ethyl bromoacetate (272 μl, 2.43 mmol, 1.05 eq) in DMF (1 ml) is added dropwise. After the addition was completed, the suspension was heated at 60° C. for 90 minutes, then the reaction medium was cooled to room temperature and poured into 120 ml of 5% aqueous NaHCO ₃ solution. The mixture is extracted with EtOAc (3 times) and the combined organic layers are dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel flash chromatography (eluting with 0 to 50% (10% MeOH in EtOAc) in MeOH) to give the desired compound.

LCMS: MW (calculated): 254.7; m/z MW (detected): 255.3 (M+H)

Step ii: Ethyl 2-[7-(1-methylpyrazol-4-yl)imidazo[1,2-a]-pyridin-6-yl]oxyacetate

[0605] Degassed solution of 1-methyl-pyrazole-4-boronic acid pinacol ester (CAS# 761446-44-0; 105 mg, 0.49 mmol, 1.25 eq), K ₃ PO ₄ (250 mg, 1. 2 mmol, 3 eq), ethyl 2-(7-chloroimidazo[1,2-a]pyridin-6-yl)oxyacetate (100 mg, 0.39 mmol, 1 eq) and Pd(dppf)Cl ₂ DCM ( 33 mg, 0.04 mmol, 0.1 eq) in a mixture of dried 1,4-dioxane and EtOH (2 ml/2 ml) was stirred in a sealed flask at 80° C. under argon for 4 hours. The reaction mixture is cooled to room temperature and diluted with 50 ml of DCM. The resulting suspension is filtered through a pad of celite and the filtrate is concentrated. The residue was purified by silica gel flash chromatography (eluting with 0 to 80% (10% MeOH in DCM) in DCM) to give the desired product.

LCMS: MW (calculated): 300.3; m/z MW (detected): 301.1 (M+H)

Stage iii: Cpd 298

[0606] A mixture of Int 9 (128 mg, 0.37 mmol, 1.6 eq), KOAc (69 mg, 0.69 mmol, 3 eq), ethyl 2-[7-(1-methylpyrazol-4-yl) imidazo[1,2-a]pyridin-6-yl]oxyacetate (73 mg, 0.23 mmol, 1 eq) and Pd(dppf)Cl ₂ DCM (13 mg, 0.02 mmol, 0.07 eq) in dried DMAC (1.5 ml) stirred at 115°C for 4 hours under argon. The reaction medium is then cooled to room temperature and poured into 20 ml of 5% NaHCO ₃ aqueous solution. The mixture is extracted with EtAOc (3 times) and the combined organic layers are washed with 5% aqueous NaHCO ₃ (2 times) and brine. The organic layer is dried over Na ₂ SO ₄ , filtered and concentrated. Purify the crude mixture by flash chromatography on silica gel (eluting with 0 to 80% (10% MeOH in DCM) in DCM) to give a residue which is dissolved in 10 ml of DCM. Concentration to dryness gives the desired compound.

cpd 299

[0607] Lithium hydroxide (6.5 mg, 0.27 mmol, ₅ eq.) ), and the reaction mixture was stirred at room temperature for 1 hour. The volatiles are evaporated off and the residue is taken up in 10 ml of water and 1.5 ml of 1 N NaOH aqueous solution. The resulting suspension is stirred for 15 minutes and the pH is adjusted to ≈3 using 4 N aqueous HCl. A precipitate forms, the solid is collected by filtration and washed with 3 ml of HCl solution at pH=3. Drying the solid in a vacuum oven at 40°C for 3 hours gives the desired product.

cpd 300

Step i: 6-benzyloxy-7-chloroimidazo[1,2-a]pyridine

[ ₀₆₀₈ ] Benzyl chloride (117 µl, ₁ mmol , 1 eq), and the mixture was stirred at room temperature for 3 hours. The reaction medium is poured into 120 ml of a 5% NaHCO ₃ aqueous solution and the mixture is extracted with EtOAc. The combined organic layers are dried over Na ₂ SO ₄ , filtered and evaporated. Purify the crude mixture by silica gel flash chromatography (eluting with 0 to 50% (10% MeOH in EtOAc) in EtOAc) to give the desired product.

LCMS: MW (calculated): 258.7; m/z MW (detected): 259.1 (M+H)

Step ii: 6-benzyloxy-7-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridine

[0609] Degassed solution of 1-methyl-pyrazole-4-boronic acid pinacol ester (CAS#761446-44-0; 96 mg, 0.45 mmol, 1.25 eq), K ₃ PO ₄ (231 mg, 1. 1 mmol, 3 eq), 6-benzyloxy-7-chloro-imidazo[1,2-a]pyridine (105 mg, 0.36 mmol, 1 eq) and Pd(dppf)Cl ₂ DCM (30 mg, 0 04 mmol, 0.1 eq) in a mixture of dried 1,4-dioxane and EtOH (2 ml/2 ml) was stirred in a sealed flask at 80° C. under argon for 4 hours. The reaction mixture is cooled to room temperature and diluted with 50 ml of DCM. The resulting suspension is filtered through Celite and the filtrate is concentrated. The residue was purified by silica gel flash chromatography (eluting with 0 to 80% (10% MeOH in DCM) in DCM) to give the desired product.

LCMS: MW (calculated): 304.4; m/z MW (detected): 305.2 (M+H)

Stage iii: Cpd 300

[0610] Degassed mixture of Int 9 (81 mg, 0.24 mmol, 1.6 eq), KOAc (44 mg, 0.44 mmol, 3 eq), 6-benzyloxy-7-(1-methylpyrazol-4-yl )imidazo[1,2-a]pyridine (47 mg, 0.15 mmol, 1 eq) and Pd(dppf)Cl ₂ DCM (8 mg, 0.01 mmol, 0.07 eq) in dried DMAC (1 ml) stirred at 115°C for 4 hours in an argon atmosphere. The reaction medium is then cooled to room temperature and poured into 20 ml of 5% NaHCO ₃ aqueous solution. The mixture is extracted with EtOAc (3 times) and the combined organic layers are washed with 5% aqueous NaHCO ₃ (2 times) and brine. The organic layer is dried over Na ₂ SO ₄ , filtered and concentrated. Purify the crude mixture by flash chromatography on silica gel (eluting with 0 to 80% (10% MeOH in DCM) in DCM) to give a residue which is dissolved in 10 ml of DCM. Concentration to dryness gives the desired compound.

cpd 301

Stage i: 5-bromo-4-chloro-N, N-bis[(4-methoxyphenyl)methyl]-pyridine-2-amine

[0611] Sodium hydride is added to a solution of 5-bromo-4-chloropyridine-2-amine (CAS# 942947-94-6; 3.0 g, 14 mmol, 1 eq) in dried DMF (30 ml) at 0°C (60% dispersion in mineral oil, 1.46 g, 36.5 mmol, 2.6 eq) and the resulting mixture was stirred at 0° C. for 15 minutes. Then add 1-(chloromethyl)-4-methoxy-benzene (4.08 ml, 29.5 mmol, 2.2 eq) and the mixture is stirred at 0°C for 90 minutes. The reaction medium is poured into a mixture of Et ₂ O (300 ml)/water (400 ml) and the layers are separated. The aqueous phase is extracted with Et ₂ O (twice) and the combined organic layers are washed with water and brine, then dried over Na ₂ SO ₄ . After filtration, the solvents are concentrated. The residue was purified by flash chromatography on silica gel (eluting with 0 to 15% EtOAc in cyclohexane) to give the desired product.

LCMS: MW (calculated): 447.8; m/z MW (detected): 447.1/449.1 (M+H)

Step ii: 6-[bis[(4-methoxyphenyl)methyl]amino]-4-chloro-pyridin-3-ol

[0612] To a solution of 5-bromo-4-chloro-N,N-bis[(4-methoxyphenyl)-methyl]pyridine-2-amine (3.2 g, 7.07 mmol, 1 eq) in dried THF ( 80 ml) at -78°C, n-butyllithium (2.5 M in hexanes, 3.54 ml, 8.84 mmol, 1.25 eq) is added dropwise. The mixture was stirred for 90 minutes at -78°C, then 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAS# 61676-62-8, 2.94 ml, 14 ,14 mmol, 2.0 eq) and the reaction mixture was stirred at -78°C for 45 minutes. The mixture is warmed to -10°C after 30 minutes and hydrogen peroxide (30% aqueous solution, 2.89 ml, 28.28 mmol, 4.0 eq) is added. The reaction mixture was then stirred at room temperature for 30 minutes, then diluted with 250 ml EtOAc and poured into 250 ml water/brine. The layers are separated and the aqueous phase is extracted with EtOAc. The combined organic layers are dried over Na ₂ SO ₄ , filtered and concentrated. The residue is suspended in 400 ml of 1 N aqueous NaOH solution and the aqueous phase is washed with Et ₂ O. The pH of the aqueous layer is adjusted to ≈6 using concentrated HCl, then extracted with EtOAc (3 times). The combined organic layers are dried over Na ₂ SO ₄ , filtered and concentrated to obtain the desired product.

LCMS: MW (calculated): 384.9; m/z MW (detected): 385.2 (M+H)

Step iii: 2-[[6-[bis[(4-methoxyphenyl)methyl]amino]-4-chloro-3-pyridyl]oxy]propanenitrile

[0613] To a suspension of 6-[bis[(4-methoxyphenyl)methyl]amino]-4-chloropyridin-3-ol (500 mg, 1.24 mmol, 1.0 eq) and Cs ₂ CO ₃ (612 mg, 1.86 mmol, 1.5 eq) in dried DMF (7 ml) was added 2-bromopropionitrile (133 μl, 1.5 mmol, 1.2 eq). The resulting mixture was stirred at 75°C for 45 minutes and then cooled to room temperature, poured into a mixture of EtOAc (70 ml)/water (45 ml)/brine (45 ml). The layers are separated and the aqueous phase is extracted with EtOAc. The combined organic layers are washed with 50 ml brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel flash chromatography (eluting with 0 to 25% EtOAc in cyclohexane) to give the desired product.

LCMS: MW (calculated): 437.9; m/z MW (detected): 438.2 (M+H)

Step iv: 2-[[6-[bis[(4-methoxyphenyl)methyl]amino]-4-(1-methylpyrazol-4-yl)-3-pyridyl]oxy]propanenitrile

[0614] 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (CAS# 761446-44-0; 271 mg, 1.26 mmol, 1.5 eq), K ₃ PO ₄ (541 mg, 2.52 mmol, 3 eq), 2-[[6-[bis[(4-methoxyphenyl)methyl]-amino]-4-chloro-3-pyridyl ]hydroxy]propanenitrile (372 mg, 0.84 mmol, 1 eq) and Pd(dppf)Cl ₂ DCM (70.8 mg, 0.084 mmol, 0.1 eq) in dried 1,4-dioxane (6 ml) stirred in a sealed flask at 115°C in an argon atmosphere for 16 hours. The reaction mixture is cooled to room temperature and diluted with 50 ml EtOAc, 70 ml water and 50 ml brine. The layers are separated and the aqueous phase is extracted with EtOAc (2×30 ml). The combined organic layers are washed with brine, filtered through a pad of celite, and the filtrate is concentrated. The residue was purified by silica gel flash chromatography (eluting with 0 to 35% EtOAc in DCM) to give the desired product.

LCMS: MW (calculated): 483.6; m/z MW (detected): 484.3 (M+H)

Step v: 2-[7-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridin-6-yl]oxypropanenitrile

[0615] To a stirred solution of 2-[[6-[bis[(4-methoxy-phenyl)methyl]amino]-4-(1-methylpyrazol-4-yl)-3-pyridyl]oxy]-propanenitrile (270 mg , 0.54 mmol, 1 eq) in dried DCM (7 ml) was added with TFA (1.25 ml, 16.1 mmol, 30 eq) and the mixture was stirred at room temperature for 16 hours. The solvents are then evaporated, the residue is dissolved in DCM (30 ml) and saturated aqueous NaHCO ₃ (30 ml) is added. The resulting mixture was vigorously stirred for 5 minutes and the layers were separated. The aqueous phase is extracted with DCM and the combined organic layers are dried over Na ₂ SO ₄ , filtered and evaporated. The residue is suspended in EtOH (6 ml), the mixture is heated to 60°C and 2-chloroacetaldehyde (50% aqueous solution, 0.12 ml, 0.97 mmol, 1.8 eq) is added dropwise. The reaction medium is stirred at reflux for 3.5 hours, then the volatiles are evaporated and the residue is taken up in DCM (40 ml) and saturated aqueous Na ₂ CO ₃ (30 ml). The layers are separated and the aqueous phase is extracted with DCM (twice). The combined organic layers are dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel flash chromatography (eluting with 0 to 35% (10% MeOH in DCM) in DCM) to give the desired product.

LCMS: MW (calculated): 267.3; m/z MW (detected): 268.1 (M+H)

Stage vi: Cpd 301

[0616] Degassed mixture of Int 9 (99 mg, 0.29 mmol, 1.6 eq), KOAc (53 mg, 0.54 mmol, 3 eq), 2-[7-(1-methylpyrazol-4-yl) imidazo[1,2-a]pyridin-6-yl]oxypropanenitrile (50 mg, 0.18 mmol, 1 eq) and Pd(dppf)Cl ₂ DCM (11 mg, 0.01 mmol, 0.07 eq) in dried DMAC (1.2 ml) stirred at 119°C for 2 hours under argon. The reaction mixture was then cooled to room temperature and poured into 20 ml of 5% NaHCO ₃ aqueous solution. The mixture is extracted with EtOAc (3 times) and the combined organic layers are washed with 5% aqueous NaHCO ₃ (2 times) and brine. The organic layer is dried over Na ₂ SO ₄ , filtered and concentrated. Purify the crude mixture by flash chromatography on silica gel (eluting with 0 to 80% (10% MeOH in DCM) in DCM) to give a residue which is dissolved in 2 ml of DCM. Concentration to dryness gives the desired compound.

cpd 302

[0617] HCl (1.25 M in EtOH, 1.08 ml, 1.34 mmol, 6 eq). The resulting mixture was stirred in a sealed flask at 90°C for 60 hours and then poured into 100 ml of ice. The mixture was stirred for 15 minutes, diluted with 50 ml saturated aqueous NaHCO ₃ and extracted with 2×40 ml EtOAc. The combined organic layers are dried over Na ₂ SO ₄ , filtered and concentrated. Purify the crude mixture by flash chromatography on silica gel (eluting with 0 to 100% (10% MeOH in EtOAc) in EtOAc) to give a residue which is dissolved in DCM/Et ₂ O. Concentration of the solvents gives the desired compound.

cpd 303

[ ₀₆₁₈ ] Lithium hydroxide (6.1 mg, 0.25 mmol, 5 eq) and the reaction mixture was stirred at room temperature for 1 hour. The volatiles are evaporated off and the residue is taken up in 20 ml of water and 1 ml of an aqueous 1 N NaOH solution. The solution is washed with Et ₂ O. Then, with stirring, the pH of the aqueous phase is adjusted to ≈3 using an aqueous solution of 4 N HCl. The resulting solution was extracted with 20% isopropanol in DCM (3 x 15 ml). The combined organic layers are dried over Na ₂ SO ₄ , passed through a phase separator cartridge and concentrated to give the desired compound.

cpd 304

[0619] To a stirred suspension of Cpd 295 (22.0 mg, 0.0381 mmol) in 1,4-dioxane (2.0 ml) was slowly added 1 N aqueous NaOH, (3.00 ml, 3.00 mmol) , and the mixture was stirred at room temperature for 2 hours. The mixture is transferred to a flask and the 1,4-dioxane is evaporated. The residue is diluted with 3 ml of water. The pH of the solution was adjusted to ≈4 using an aqueous solution of 4 N HCl. A precipitate formed, which was collected by filtration and washed with 2×3 ml aqueous HCl solution (pH≈4). Drying in a vacuum oven at 40° C. for 3 hours gives the desired compound.

cpd 305

[0620] The reaction mixture of Cpd 304 (40.0 mg, 0.0730 mmol), KOAc (50.4 mg, 0.365 mmol) and 2-chloroethyl(diethyl)ammonium chloride (62.8 mg, 0.365 mmol) was vigorously stirred in sealed flask at room temperature for 16 hours. The reaction mixture is diluted with 5 ml of EtOAc, then with 5 ml of water, and after vigorous shaking, the mixture is allowed to separate into two layers. The organic layer is dried over Na ₂ SO ₄ . After filtration, the solvent is evaporated to give crude material which is purified by silica gel flash chromatography (eluting with 10% isopropanol in DCM, then 10% isopropanol in 1,4-dioxane). The solvent from the collected fractions is evaporated to give a residue which is dissolved in DCM/Et ₂ O. Concentration of the solvents gives the desired compound.

Table II. Intermediates used for the synthesis of the compounds of the invention.

SM=Source material, Mtd=Method, MS Mes'd=Measured mass

int
No. Structure Name SM mtd MW MS Mes'd one

7-(1-methyl-pyrazol-4-yl)-imidazo[1,2-a]-pyridine CAS#
808744-34-5
+
CAS#
761446-44-0 E1.3 198.2 199.0 2

7-(6-methyl-pyridazin-3-yl)imidazo-[1,2-a]pyridine CAS#
908268-52-0
+
CAS#
1121-79-5 E1.3 210.2 211.2 3

ethyl 2-(4-imidazo[1,2-a]-pyridin-7-yl-pyrazol-1-yl)-acetate CAS#
6188-23-4
+
CAS#
864754-16-5 E1.3a 270.3 271.9 four

4-bromo-2,6-difluoro-N-(2,2,2-trifluoro-ethyl)benzamide CAS#
183065-68-1 Ex.2.3 318.0 317.8
+
319.8 5

4-bromo-2,6-dimethoxy-N-(2,2,2-trifluoro-ethyl)benzamide Int 4 Ex.2.4 342.1 341.8
+
343.8 6

4-bromo-N-cyclopropyl-2-fluoro-6-methoxy-benzamide Int 62 Ex.2.5 288.1 287.8
+
289.8 7

6-bromo-8-methoxy-2-(2,2,2-trifluoro-ethyl)-3,4-dihydro-isoquinolin-1-one CAS#
1242157-15-8 Ex.2.6 338.1 338.1
+
340.1 eight

4-bromo-2,6-bis-(trideuterio-methoxy)-N-(2,2,2-trifluoro-ethyl)benzamide Int 4 Ex.2.7 348.1 347.9
+
349.9 9

4-bromo-N-cyclo-propyl-2-(di-fluoromethoxy)-6-methoxybenzamide CAS#
183065-68-1 Ex.2.8 336.1 336.3
+
338.3 ten

4-amino-N-cyclopropyl-2-(difluoro-methoxy)-6-methoxybenzamide CAS#
3956-34-1 Ex.2.9 272.2 273.2 eleven

4-amino-N-tert-butyl-2-(difluoro-methoxy)-6-methoxybenzamide CAS#
3956-34-1 Ex.2.10 288.3 289.6 12

4-amino-2-(difluoro-methoxy)-N-ethyl-6-methoxy-benzamide CAS#
3956-34-1 Ex.2.11 260.2 261.2 13

4-bromo-2,6-difluoro-N-(1,2,2,3,3-pentadeuterio-cyclopropyl)-benzamide CAS#
183065-68-1 Ex.2.12 281.1 281.3
+
283.3 fourteen

methyl 2,6-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate/ (3,5-dimethoxy-4-methoxy-carbonylphenyl)-boronic mixture acid CAS#
2065-27-2 Ex.2.13 322.2
+
240.0 323.1
+
241.1 fifteen

6-bromo-3-iodine-pyrazolo[1,5-a]pyridine CAS#
1264193-11-4 F 322.9 NA 16

2-(difluoro-methoxy)-N-ethyl-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide CAS#
1466-76-8 Ex.2.14 371.2 372.4 17

N-cyclopropyl-2-(difluoro-methoxy)-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)-benzamide/4-(cyclopropyl -carbamoyl)-3-(difluoro-methoxy)-5-methoxyphenyl-boronic acid CAS#
3147-64-6 Ex.2.15 383.2
+
301.1 384.4
+
302.2 eighteen

A mixture of 2-ethyl-7-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-isoindolin-1-one / (2-ethyl-7-methoxy- 1-oxo-isoindolin-5-yl)boronic acid CAS#
957346-37-1 Ex.2.16 317.2
+
235.1 318.4
+
236.3 19

2-ethyl-7-(2-hydroxyethyl-amino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)-isoindolin-1-one CAS#
957346-37-1 Ex.2.17 346.2 347.5 twenty

2-fluoro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)-N-(2,2,2-trifluoroethyl)-benzamide/ 3-fluoro-5-methoxy-4-[(2,2,2-trifluoroethyl)-carbamoyl]-phenylboronic acid CAS#
1472104-49-6 Ex.2.18 377.1
+
295.0 378.4
+
296.1 21

methyl 2-methoxy-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)-benzoate CAS#
79383-44-1 Ex.2.19 306.2 307.3 22

methyl 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)-benzoate CAS#
936479-46-8 Ex.2.20 326.6 327.2 23

mixture of 8-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)-3,4-dihydro-2H-isoquinolin-1-one / (8- methoxy-1-oxo-3,4-dihydro-2H-iso-quinolin-6-yl)-boronic acid CAS#
1242157-15-8 Ex.2.21 303.2
+
221.0 304.4
+
222.3 24

2-cyclo-propyl-8-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxa-bororan-2-yl)-3,4-dihydro-isoquinolin-1-one mixture / (2-cyclo-propyl-8-methoxy-1-oxo-3,4-dihydro-isoquinolin-6-yl)boronic acid CAS#
1242157-15-8 Ex.2.22 343.2
+
261.1 344.3
+
262.2 25

a mixture of 7-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)-isoindolin-1-one / (7-methoxy-1-oxo-iso- indolin-5-yl)-boronic acid CAS#
957346-37-1 Ex.2.23 289.1
+
207.0 290.3
+
208.3 26

methyl 4-(6-chloropyrazolo-[1,5-a]-pyrimidin-3-yl)-2,6-dimethoxy-benzoate CAS#
1314893-92-9
+
Int 14 E1.3 347.8 348.3
+
350.3 27

methyl 2,6-dimethoxy-4-[6-(1-methyl-pyrazol-4-yl)-pyrazolo[1,5-a]pyrimidin-3-yl]benzoate CAS#
761446-44-0
+
Int 26 E1.3 393.4 394.2 28

2,6-dimethoxy-4-[6-(1-methyl-pyrazol-4-yl)-pyrazolo[1,5-a]pyrimidin-3-yl]benzoic acid Int 27 E1.1 379.4 380.4 29

4-[6-(1-ethyl-pyrazol-4-yl)-pyrazolo[1,5-a]pyrimidin-3-yl]-2,6-dimethoxy-benzoic acid CAS#
847818-70-6
+
Int 26 E1.3 407.4 408.4 thirty

4-[6-(1-ethyl-pyrazol-4-yl)-pyrazolo[1,5-a]pyrimidin-3-yl]-2,6-dimethoxy-benzoic acid Int 29 E1.1 393.4 394.4 31

methyl 4-(7-chloroimidazo-[1,2-b]-pyridazin-3-yl)-2,6-dimethoxy-benzoate CAS#
1383481-13-7 E1.3 347.8 348.2
+
350.2 32

methyl 2,6-dimethoxy-4-[7-(1-methyl-pyrazol-4-yl)-imidazo[1,2-b]-pyridazin-3-yl]benzoate CAS#
761446-44-0
+
Int 31 E1.3 393.4 394.4 33

2,6-dimethoxy-4-[7-(1-methyl-pyrazol-4-yl)-imidazo[1,2-b]-pyridazin-3-yl]benzoic acid Int 32 E1.1 379.4 NA 34

methyl 4-(6-bromopyrazolo-[1,5-a]pyridin-3-yl)-2,6-dimethoxy-benzoate Int 15
+
Int 14 E1.3 391.2 391.1
+
393.0 35

methyl 4-(7-bromimidazo-[1,2-a]pyridin-3-yl)-2,6-dimethoxy-benzoate CAS#
1246184-55-3
+
Int 14 E1.3 391.2 391.2
+
393.2 36

4-(7-bromimidazo-[1,2-a]pyridin-3-yl)-2-(difluoromethoxy)-N-ethyl-6-methoxybenzamide CAS#
1246184-55-3
+
Int 16 E1.3 440.2 NA 37

4-(7-bromo-imidazo[1,2-a]-pyridin-3-yl)-N-cyclopropyl-2-(difluoromethoxy)-6-methoxybenzamide CAS#
1246184-55-3
+
Int 17 E1.3 452.2 452.1
+
454.1 38

4-(5-bromo-benzimidazol-1-yl)-2-(difluoro-methoxy)-N-ethyl-6-methoxy-benzamide CAS#
364-73-8
+
Int 12 B2
+
C2 440.2 NA 39

4-(5-bromo-benzimidazol-1-yl)-2,6-dimethoxy-N-(2,2,2-trifluoro-ethyl)benzamide Int 44 E1.2 458.2 458.3
+
460.2 40

4-(5-bromo-benzimidazol-1-yl)-N-(2,2-difluoroethyl)-2,6-dimethoxybenzamide Int 44 E1.2 440.2 438.1
+
440.1 41

4-(5-bromo-benzimidazol-1-yl)-N-cyclopropyl-2,6-dimethoxy-benzamide Int 44 E1.2 416.3 416.1
+
417.9 42

4-(7-bromo-imidazo[1,2-a]-pyridin-3-yl)-N-cyclopropyl-2-(difluoromethoxy)-6-methoxybenzamide Int 60 C2 452.2 452.4
+
454.4 43

4-(5-bromo-benzimidazol-1-yl)-N-ethyl-2,6-dimethoxy-benzamide Int 44 E1.2 404.3 404.3
+
406.2 44

4-(5-bromo-benzimidazol-1-yl)-2,6-dimethoxy-benzoic acid Int 45 E1.1 377.2 377.0
+
379.0 45

methyl 4-(5-bromobenz-imidazol-1-yl)-2,6-dimethoxy-benzoate Int 59 C1 391.2 391.1
+
393.1 46

4-(7-bromo-imidazo[1,2-a]-pyridin-3-yl)-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)-benzamide Int 48 E1.2 458.2 458.4
+
460.3 48

4-(7-bromo-imidazo[1,2-a]-pyridin-3-yl)-2,6-dimethoxybenzoic acid Int 35 E1.1 377.2 377.2
+
379.2 fifty

2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]benzoic acid Int 44 E1.3 378.4 379.5 51

methyl 2,6-dimethoxy-4-[7-(1-methyl-pyrazol-4-yl)-imidazo[1,2-a]-pyridin-3-yl]-benzoate Int 35 E1.3 392.4 393.9 52

2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]benzoic acid Int 51 E1.1 378.4 379.3 53

methyl 2,6-dimethoxy-4-[7-(3-methyliso-xazol-5-yl)-imidazo[1,2-a]-pyridin-3-yl]-benzoate CAS#
1346808-44-3
+
Int 35 E1.3 393.4 394.3 54

2,6-dimethoxy-4-[7-(3-methyl-isoxazol-5-yl)imidazo-[1,2-a]pyridin-3-yl]benzoic acid Int 53 E1.1 379.4 380.3 55

N-cyclopropyl-2-(difluoro-methoxy)-6-methoxy-4-[4-(1-methyl-pyrazol-4-yl)-2-nitro-anilino]-benzamide Int 9
+
int 56 E2.3 473.4 474.4 56

4-(1-methyl-pyrazol-4-yl)-2-nitroaniline CAS#
875-51-4
+
CAS#
761446-44-0 E1.3 218.2 219.0 57

2-(difluoro-methoxy)-N-ethyl-6-methoxy-4-[4-(1-methyl-pyrazol-4-yl)-2-nitro-anilino]-benzamide Int 58
+
Int 12 B2 461.4 462.2 58

4-(4-fluoro-3-nitrophenyl)-1-methylpyrazole CAS#
364-73-8
+
CAS#
761446-44-0 E1.3 221.2 222.2 59

methyl 4-(4-bromo-2-nitro-anilino)-2,6-dimethoxy-benzoate CAS#
364-73-8
+
CAS#
3956-34-1 B1 411.2 411.1
+
413.0 60

4-(4-bromo-2-nitroanilino)-N-cyclopropyl-2-(difluoromethoxy)-6-methoxybenzamide CAS#
364-73-8
+
Int 10 B2 472.3 472.1
+
474.0 61

4-(4-bromo-2-nitroanilino)-N-cyclopropyl-2-(difluoromethoxy)-6-methoxybenzamide CAS#
364-73-8
+
Int 12 B2 460.2 460.1
+
462.1 62

4-bromo-N-cyclopropyl-2,6-difluoro-benzamide CAS#
183065-68-1 Ex.2.24 276.1 276.1
+
278.1 63

4-bromo-N-cyclopropyl-2-fluoro-6-hydroxy-benzamide Int 62 Ex.2.25 274.1 273.8
+
275.8 64

4-bromo-N-cyclopropyl-2-hydroxy-6-methoxy-benzamide Int 63 Ex.2.26 286.1 286.3
+
288.2 65

4-bromo-2-fluoro-6-hydroxy-N-(1,2,2,3,3-pentadeuterio-cyclopropyl)-benzamide Int 13 Ex.2.27 279.1 279.3
+
281.1 66

4-bromo-2-hydroxy-N-(1,2,2,3,3-pentadeuterio-cyclopropyl)-6-(trideuteriomethoxy)-benzamide Int 65 Ex.2.28 294.1 293.9
+
295.9 67

4-bromo-2-(difluoro-methoxy)-N-(1,2,2,3,3-pentadeuterio-cyclopropyl)-6-(trideuterio-methoxy)-benzamide int 66 Ex.2.29 344.2 343.9
+
345.9 68

2-(difluoro-methoxy)-4-[4-(1-methyl-pyrazol-4-yl)-2-nitro-anilino]-N-(1,2,2,3,3-pentadeuterio-cyclopropyl)- 6-(trideuterio-methoxy)-benzamide int 56
+
Int 67 E2.3 481.5 482.1 69

4-[2-Amino-4-(1-methyl-pyrazol-4-yl)-anilino]-2-(difluoro-methoxy)-N-(1,2,2,3,3-pentadeuterio-cyclopropyl)- 6-(trideuterio-methoxy)-benzamide Int 68 Ex.2.31 451.5 452.1 70

4-bromo-N-cyclo-propyl-2-(di-fluoromethoxy)-6-(trideuteriomethoxy)-benzamide Int 63 Ex.2.32 339.1 339.0
+
341.0 71

tert-butyl 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)-pyrazol-1-yl]-propanoate CAS#
269410-08-4
+
CAS#
39149-80-9 Ex.2.33 322.2 323.4 72

methyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)-pyrazol-1-yl]-butanoate CAS#
269410-08-4
+
CAS#
4897-84-1 Ex.2.34 294.2 NA 73

methyl 4-[(5-bromo-3-nitro-2-pyridyl)amino]-2,6-dimethoxybenzoate CAS#
67443-38-3
+
CAS#
3956-34-1 B3 412.2 412.3
+
414.3 74

methyl 4-[6-(1-ethylpyrazol-4-yl)imidazo-[4,5-b]pyridin-3-yl]-2,6-dimethoxy-benzoate Int 74
+
CAS#
847818-70-6 C2
+
E1.3 407.4 408.6 75

8-methoxy-6-[7-(1-methyl-pyrazol-4-yl)-imidazo[1,2-a]-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one CAS#
1246184-55-3
+
Int 23
+
CAS#
761446-44-0 E1.3
+
E1.3 373.4 374.3 76

7-(1H-pyrazol-4-yl)imidazo-[1,2-a]pyridine CAS#
552846-17-0
+
CAS#
808744-34-5 Ex.2.35 184.2 185.5 77

7-chloroimidazo-[1,2-a]pyridin-6-ol, hydrobromide salt CAS#
867131-26-8 Ex.2.36 158.6 NA

Table III. Exemplary Compounds of the Invention.

SM=Source material, Mtd=Method, MS Mes'd=Measured mass

cpd
No. Structure Name SM mtd MW MS Mes'd one

N-ethyl-4-[5-(1-ethyl-pyrazol-4-yl)-benzimidazol-1-yl]-2,6-dimethoxybenzamide Int 43
+
CAS#
847818-70-6 E1.3 419.5 420.5 2

N-ethyl-2,6-dimethoxy-4-[5-(3-pyridyl)-benzimidazol-1-yl]benzamide Int 43
+
CAS#
1692-25-7 E1.3 402.4 403.3 3

N-ethyl-2,6-dimethoxy-4-[5-(6-morpholino-3-pyridyl)-benzimidazol-1-yl]benzamide Int 43
+
CAS#
485799-04-0 E1.3 487.6 488.4 four

N-ethyl-2,6-dimethoxy-4-[5-[1-(2-morpholino-ethyl)pyrazol-4-yl]benz-imidazol-1-yl]benzamide Int 43
+
CAS#
864754-18-7 E1.3 504.6 505.4 5

4-[5-(1-ethyl-pyrazol-4-yl)-benzimidazol-1-yl]-N-(2-hydroxyethyl)-2,6-dimethoxybenzamide Int 44
+
CAS#
141-43-5
+
CAS#
847818-70-6 E1.2
+
E1.3 435.5 436.4 6

4-[5-(1-ethyl-pyrazol-4-yl)-benzimidazol-1-yl]-2,6-dimethoxy-N-methylbenzamide Int 44
+
methylamine
+
CAS#
847818-70-6 E1.2
+
E1.3 405.4 406.5 7

N-ethyl-2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]benzamide Int 43
+
CAS#
761446-44-0 E1.3 405.4 406.6 eight

4-[5-(1,3-dimethyl-pyrazol-4-yl)-benzimidazol-1-yl]-N-ethyl-2,6-dimethoxy-benzamide Int 43
+
CAS#
1046832-21-6 E1.3 419.5 420.5 9

N-ethyl-4-[6-(1-ethyl-pyrazol-4-yl)-pyrazolo[1,5-a]pyrimidin-3-yl]-2,6-dimethoxybenzamide Int 30
+
CAS#
557-66-4 E1.2 420.5 421.3 ten

4-[5-(1-ethyl-pyrazol-4-yl)-benzimidazol-1-yl]-N-(2-fluoroethyl)-2,6-dimethoxybenzamide Int 44
+
CAS#
460-08-2
+
CAS#
847818-70-6 E1.2
+
E1.3 437.5 438.5 eleven

N-(2,2-difluoro-ethyl)-4-[5-(1-ethylpyrazol-4-yl)benz-imidazol-1-yl]-2,6-dimethoxybenzamide Int 40
+
CAS#
847818-70-6 E1.3 455.5 456.4 12

4-[5-(1-ethyl-pyrazol-4-yl)-benzimidazol-1-yl]-2,6-dimethoxy-N-(2,2,2-trifluoro-ethyl)benzamide Int 44
+
CAS#
373-88-6
+
CAS#
847818-70-6 E1.2
+
E1.3 473.4 474.6 13

N-ethyl-2,6-dimethoxy-4-[5-[1-(2-methoxyethyl)-pyrazol-4-yl]-benzimidazol-1-yl]benzamide Int 43
+
CAS#
847818-71-7 E1.3 449.5 450.7 fourteen

N-ethyl-2,6-dimethoxy-4-[5-(1-tetra-hydropyran-4-ylpyrazol-4-yl)benz-imidazol-1-yl]benzamide Int 43
+
CAS#
1040377-03-4 E1.3 475.5 476.3 fifteen

4-[5-[1-(cyanomethyl)-pyrazol-4-yl]-benzimidazol-1-yl]-N-ethyl-2,6-dimethoxybenzamide Int 43
+
CAS#
1093307-35-7 E1.3b 430.5 431.2 16

N-ethyl-4-[5-[1-(2-hydroxyethyl)-pyrazol-4-yl]-benzimidazol-1-yl]-2,6-dimethoxybenzamide Int 43
+
CAS#
1040377-08-9 E1.3 435.5 436.3 17

2-(difluoro-methoxy)-N-ethyl-4-[5-(1-ethylpyrazol-4-yl)benz-imidazol-1-yl]-6-methoxybenzamide cpd 23 J2 455.5 456.2 eighteen

4-[5-[1-(2-Amino-2-oxo-ethyl)pyrazol-4-yl]benz-imidazol-1-yl]-N-ethyl-2,6-dimethoxybenzamide Int 43
+
CAS#
1093307-35-7 E1.3b 448.5 449.2 19

N-cyclopropyl-4-[5-(1-ethyl-pyrazol-4-yl)-benzimidazol-1-yl]-2,6-dimethoxybenzamide Int 41
+
CAS#
847818-70-6 E1.3 431.5 432.6 twenty

4-[6-(1-ethyl-pyrazol-4-yl)-pyrazolo[1,5-a]pyrimidin-3-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)- benzamide Int 30
+
CAS#
373-88-6 E1.2 474.4 475.4 21

N-(2,2-difluoro-ethyl)-4-[6-(1-ethylpyrazol-4-yl)pyrazolo-[1,5-a]-pyrimidin-3-yl]-2,6-dimethoxybenzamide Int 30
+
CAS#
430-67-1 E1.2 456.4 457.2 22

4-[5-(1-ethyl-pyrazol-4-yl)-benzimidazol-1-yl]-2,6-dimethoxy-N-propyl-benzamide Int 44
+
CAS#
107-10-8
+
CAS#
847818-56-8 E1.2
+
E1.3 433.5 434.5 23

N-ethyl-4-[5-(1-ethyl-pyrazol-4-yl)-benzimidazol-1-yl]-2-hydroxy-6-methoxy-benzamide cpd 1 I 405.4 406.3 24

N-(2,2-difluoroethyl)-2,6-dimethoxy-4-[6-(1-methyl-pyrazol-4-yl)-pyrazolo[1,5-a]pyrimidin-3-yl]benzamide Int 28
+
CAS#
430-67-1 E1.2 442.4 443.3 25

2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)-benzamide Int 39
+
CAS#
761446-44-0 E1.3 459.4 460.6 26

N-cyclobutyl-4-[5-(1-ethyl-pyrazol-4-yl)-benzimidazol-1-yl]-2,6-dimethoxybenzamide Int 44
+
CAS#
2516-34-9
+
CAS#
847818-70-6 E1.2
+
E1.3 445.5 446.7 27

4-[5-(1-ethyl-pyrazol-4-yl)-benzimidazol-1-yl]-2,6-dimethoxy-N-(2-methoxy-ethyl)-N-methyl-benzamide Int 44
+
CAS#
38256-93-8
+
CAS#
847818-70-6 E1.2
+
E1.3 463.5 464.7 28

4-[5-(1-ethyl-pyrazol-4-yl)-benzimidazol-1-yl]-N-isobutyl-2,6-dimethoxy-N-methylbenzamide Int 44
+
CAS#
625-43-4
+
CAS#
847818-70-6 E1.2
+
E1.3 461.6 462.7 29

4-[6-(1-ethyl-pyrazol-4-yl)-imidazo[4,5-b]pyridin-3-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)- benzamide Int 74
+
CAS#
373-88-6 E1.1
+
E1.2 474.4 475.3 thirty

N-cyclopropyl-4-[5-(1-ethyl-pyrazol-4-yl)-benzimidazol-1-yl]-2,6-dimethoxy-N-methylbenzamide Int 44
+
CAS#
5163-20-2
+
CAS#
847818-70-6 E1.2
+
E1.3 445.5 446.6 31

N-(cyano-methyl)-4-[5-(1-ethyl-pyrazol-4-yl)-benzimidazol-1-yl]-2,6-dimethoxy-N-methylbenzamide Int 44
+
CAS#
25808-30-4
+
CAS#
847818-70-6 E1.2
+
E1.3 444.5 445.5 32

2,6-dimethoxy-4-[5-(6-morpholino-3-pyridyl)-benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)-benzamide Int 39
+
CAS#
485799-04-0 E1.3 541.5 542.5 33

4-[5-[1-(2-Hydroxyethyl)-pyrazol-4-yl]-benzimidazol-1-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)-benzamide Int 39
+
CAS#
1040377-08-9 E1.3 489.4 490.3 34

2,6-dimethoxy-4-[5-(6-pyrrolidin-1-yl-3-pyridyl)-benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)-benzamide Int 39
+
CAS#
933986-97-1 E1.3 525.5 526.6 35

2,6-dimethoxy-4-[5-(5-methoxy-3-pyridyl)benz-imidazol-1-yl]-N-(2,2,2-trifluoroethyl)-benzamide Int 39
+
CAS#
445264-60-8 E1.3 486.4 487.6 36

4-[5-(6-cyano-3-pyridyl)-benzimidazol-1-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)-benzamide Int 39
+
CAS#
741709-63-7 E1.3 481.4 482.5 37

4-[5-[6-(dimethylamino)-3-pyridyl]-benzimidazol-1-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)-benzamide Int 39
+
CAS#
1036991-24-8 E1.3 499.5 500.6 38

4-[5-(6-Amino-3-pyridyl)-benzimidazol-1-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)-benzamide Int 39
+
CAS#
827614-64-2 E1.3 471.4 472.4 39

2,6-dimethoxy-4-[5-(3-pyridyl)-benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)-benzamide Int 39
+
CAS#
329214-79-1 E1.3 456.4 457.6 40

4-[5-[1-(cyanomethyl)-pyrazol-4-yl]-benzimidazol-1-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)-benzamide Int 39
+
CAS#
1093307-35-7 E1.3 484.4 485.6 41

2,6-dimethoxy-4-[5-[1-(2-morpholinoethyl)pyrazol-4-yl]-benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)-benzamide Int 39
+
CAS#
864754-18-7 E1.3 558.6 559.5 42

2,6-dimethoxy-4-[5-[1-(4-piperidyl)-pyrazol-4-yl]-benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)-benzamide Int 39
+
CAS#
877399-74-1 E1.3
+
K 528.5 529.4 43

N-tert-butyl-4-[5-(1-ethyl-pyrazol-4-yl)-benzimidazol-1-yl]-2,6-dimethoxybenzamide Int 44
+
CAS#
75-64-9
+
CAS#
847818-70-6 E1.2
+
E1.3 447.5 448.6 44

4-[5-(1-ethyl-pyrazol-4-yl)-benzimidazol-1-yl]-2,6-dimethoxy-N-(3,3,3-tri-fluoropropyl)-benzamide Int 44
+
CAS#
460-39-9
+
CAS#
847818-70-6 E1.2
+
E1.3 487.5 488.5 45

N-cyclopentyl-4-[5-(1-ethyl-pyrazol-4-yl)-benzimidazol-1-yl]-2,6-dimethoxybenzamide Int 44
+
CAS#
1003-03-8
+
CAS#
847818-70-6 E1.2
+
E1.3 459.5 460.6 46

2,6-dimethoxy-4-[5-[1-(1-methyl-4-piperidyl)-pyrazol-4-yl]-benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)- benzamide cpd 42 L1ii 542.6 543.4 47

2,6-dimethoxy-4-[5-(1H-pyrazol-4-yl)-benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)-benzamide Int 39
+
CAS#
269410-08-4 E1.3 445.4 446.5 48

2-(difluoro-methoxy)-N-ethyl-6-methoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]benzamide Int 57 C2 441.4 442.3 49

4-[5-(1-ethylpyrazol-4-yl)benzimidazol-1-yl]-2,6-dimethoxy-N-[(2R)-2-methyl-cyclopropyl]-benzamide Int 44
+
CAS#
97291-66-2
+
CAS#
847818-70-6 E1.2
+
E1.3 445.5 446.4 fifty

N-(cyano-methyl)-4-[5-(1-ethyl-pyrazol-4-yl)-benzimidazol-1-yl]-2,6-dimethoxybenzamide Int 44
+
CAS#
540-61-4
+
CAS#
847818-70-6 E1.2
+
E1.3 430.5 431.5 51

4-(5-iso-xazol-4-yl-benzimidazol-1-yl)-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)-benzamide Int 39
+
CAS#
928664-98-6 E1.3 446.4 447.3 52

2,6-dimethoxy-4-[6-(1-methyl-pyrazol-4-yl)-pyrazolo[1,5-a]pyrimidin-3-yl]-N-(2,2,2-trifluoroethyl)- benzamide Int 28
+
CAS#
373-88-6 E1.2 460.4 461.3 53

N-cyclopropyl-2-(difluoro-methoxy)-6-methoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]benzamide Int 55 C3 453.4 454.5 54

N-cyclopropyl-2-(difluoro-methoxy)-4-[5-(1-ethyl-pyrazol-4-yl)-benzimidazol-1-yl]-6-methoxybenzamide Int 42
+
CAS#
847818-70-6 E1.3 467.5 468.5 55

4-[5-[1-(cyanomethyl)-pyrazol-4-yl]-benzimidazol-1-yl]-N-cyclopropyl-2-(difluoro-methoxy)-6-methoxy-benzamide Int 42
+
CAS#
1093307-35-7 E1.3 478.5 479.3 56

N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[5-[1-(2-morpholino-ethyl)pyrazol-4-yl]benz-imidazol-1-yl]benzamide Int 42
+
CAS#
864754-18-7 E1.3 552.6 553.4 57

2-(difluoro-methoxy)-N-ethyl-6-methoxy-4-[5-[1-(2-morpholino-ethyl)pyrazol-4-yl]benz-imidazol-1-yl]benzamide Int 38
+
CAS#
864754-18-7 E1.3 540.6 541.3 58

2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]-N-[(1R)-2,2,2-trifluoro-1-methylethyl]- benzamide Int 50
+
CAS#
125278-10-6 E1.2 473.4 474.6 59

N-(2-cyano-ethyl)-2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]benzamide Int 50
+
CAS#
151-18-8 E1.2 430.5 431.4 60

2,6-dimethoxy-N-(3-methoxy-propyl)-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]benzamide Int 50
+
CAS#
5332-73-0 E1.2 449.5 450.4 61

2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]-N-[(1-methylpyrazol-3-yl)methyl]-benzamide Int 50
+
CAS#
612511-81-6 E1.2 471.5 472.4 62

2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)benz-imidazol-1-yl]-N-(2-pyridylmethyl)-benzamide Int 50
+
CAS#
3731-51-9 E1.2 468.5 469.3 63

N-(3-hydroxy-propyl)-2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]benzamide Int 50
+
CAS#
156-87-6 E1.2 435.5 436.5 64

N-(1,1-dioxo-thietan-3-yl)-2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]benzamide Int 50
+
CAS#
88511-13-1 E1.2 481.5 482.5 65

2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]-N-(2-methylsulfonyl-ethyl)benzamide Int 50
+
CAS#
49773-20-8 E1.2 483.5 484.6 66

N-(1,1-dioxo-thiolan-3-yl)-2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]benzamide Int 50
+
CAS#
6338-70-1 E1.2 495.6 496.6 67

N-[[(2R)-1,4-dioxan-2-yl]-methyl]-2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl ]benzamide Int 50
+
CAS#
1449010-18-7 E1.2 477.5 478.4 68

2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]-N-(2,2,2-trifluoro-1,1-dimethylethyl)-benzamide Int 50
+
CAS#
812-18-0 E1.2 487.5 488.7 69

N-[[(2S)-1,4-dioxan-2-yl]methyl]-2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl] benzamide Int 50
+
CAS#
1337470-52-6 E1.2 477.5 478.4 70

2,6-dimethoxy-N-(5-methyl-pyrazin-2-yl)-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]benzamide Int 50
+
CAS#
5521-58-4 E1.2 469.5 470.3 71

2,6-dimethoxy-N-[(1-methyl-imidazol-2-yl)methyl]-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]benzamide Int 50
+
CAS#
124312-73-8 E1.2 471.5 472.3 72

N-isoxazol-3-yl-2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]benzamide Int 50
+
CAS#
1750-42-1 E1.2 444.4 445.4 73

2,6-dimethoxy-N-(2-methyl-pyrazol-3-yl)-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]benzamide Int 50
+
CAS#
1192-21-8 E1.2 457.5 458.2 74

N-(cyano-methyl)-2,6-dimethoxy-N-methyl-4-[5-(1-methylpyrazol-4-yl)benz-imidazol-1-yl]benzamide Int 50
+
CAS#
5616-32-0 E1.2 430.5 431.3 75

N-(cyano-methyl)-2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]benzamide Int 50
+
CAS#
540-61-4 E1.2 416.4 417.3 76

N-tert-butyl-2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]benzamide Int 50
+
CAS#
75-64-9 E1.2 433.5 434.4 77

N-cyclobutyl-2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]benzamide Int 50
+
CAS#
2516-34-9 E1.2 431.5 432.4 78

N-(2,2-difluoroethyl)-2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]benzamide Int 50
+
CAS#
430-67-1 E1.2 441.4 442.3 79

N-(2-fluoro-ethyl)-2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]benzamide Int 50
+
CAS#
406-34-8 E1.2 423.4 424.3 80

2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]-N-[(1S)-2,2,2-trifluoro-1-methylethyl]- benzamide Int 50
+
CAS#
779303-24-1 E1.2 473.4 474.3 81

2,6-dimethoxy-N-(1-methyl-pyrazol-3-yl)-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]benzamide Int 50
+
CAS#
1904-31-0 E1.2 457.5 458.3 82

2,6-dimethoxy-N-(1-methyl-imidazol-4-yl)-4-[5-(1-methylpyrazol-4-yl)benz-imidazol-1-yl]benzamide Int 50
+
CAS#
79578-98-6 E1.2 457.5 458.3 83

2,6-dimethoxy-N-(1-methyl-pyrazol-4-yl)-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]benzamide Int 50
+
CAS#
69843-13-6 E1.2 457.5 458.3 84

2,6-dimethoxy-4-[5-[1-(2-methoxyethyl)pyrazol-4-yl]-benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)-benzamide Int 39
+
CAS#
847818-71-7 E1.3 503.5 504.3 85

2,6-dimethoxy-4-[5-[1-(oxetan-3-yl)pyrazol-4-yl]benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)-benzamide Int 39
+
CAS#
1339890-99-1 E1.3 501.5 502.3 86

N-cyclopropyl-2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]benzamide Int 50
+
CAS#
765-30-0 E1.2 417.5 418.3 87

N-(1-cyano-ethyl)-2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)benz-imidazol-1-yl]benzamide Int 50
+
CAS#
72187-91-8 E1.2 430.5 431.3 88

2,6-dimethoxy-4-[7-(1-methyl-pyrazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]-N-(2,2,2-trifluoroethyl)- benzamide Int 52
+
CAS#
753-90-2 E1.2 459.4 460.4 89

2,6-dimethoxy-4-[5-(1-methyl-pyrazol-3-yl)-benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)-benzamide Int 39
+
CAS#
1020174-04-2 E1.3 459.4 460.3 90

N-(2,2-difluoro-cyclopentyl)-2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]benzamide Int 50
+
CAS#
921753-24-4 E1.2 481.5 482.3 91

N-(2,2-difluoro-1-methylethyl)-2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]benzamide Int 50
+
CAS#
1384427-90-0 E1.2 455.5 456.3 92

2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]-N-(oxetan-3-yl)benzamide Int 50
+
CAS#
21635-88-1 E1.2 433.5 434.3 93

2,6-dimethoxy-4-(5-pyridazin-4-ylbenz-imidazol-1-yl)-N-(2,2,2-trifluoroethyl)-benzamide Int 39
+
CAS#
863422-41-7 E1.3 457.4 458.4 94

4-[5-[1-(azetidin-3-yl)pyrazol-4-yl]benz-imidazol-1-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)-benzamide Int 39
+
CAS#
877399-35-4 E1.3
+
K 500.5 501.3 95

4-[5-(1-isopropyl-pyrazol-4-yl)-benzimidazol-1-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)-benzamide Int 39
+
CAS#
879487-10-2 E1.3 487.5 488.5 96

4-[5-(1-cyclopropyl-pyrazol-4-yl)-benzimidazol-1-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)-benzamide Int 39
+
CAS#
1151802-22-0 E1.3 485.5 486.4 97

4-[5-[1-(difluoromethyl)-pyrazol-4-yl]-benzimidazol-1-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)-benzamide Int 39
+
CAS#
1206640-82-5 E1.3 495.4 496.5 98

2,6-dimethoxy-4-[5-[1-(1-methylazetidin-3-yl)pyrazol-4-yl]benz-imidazol-1-yl]-N-(2,2,2-trifluoroethyl)- benzamide cpd 94 L1i 514.5 515.3 99

2,6-dimethoxy-4-[6-(1-methyl-pyrazol-4-yl)-pyrazolo[1,5-a]pyridin-3-yl]-N-(2,2,2-trifluoroethyl)- benzamide Int 34
+
CAS#
761446-44-0
+
CAS#
753-90-2 E1.3
+
E1.1
+
E1.2 459.4 460.3 100

4-[5-[1-[1-(cyanomethyl)-azetidin-3-yl]pyrazol-4-yl]benz-imidazol-1-yl]-2,6-dimethoxy-N-(2,2,2 -trifluoroethyl)-benzamide cpd 94
+
CAS#
590-17-0 L2i 539.5 540.5 101

2,6-dimethoxy-4-[5-(3-methyl-1H-pyrazol-5-yl)benz-imidazol-1-yl]-N-(2,2,2-trifluoroethyl)-benzamide Int 39
+
CAS#
1888441-67-5 E1.3 459.4 460.3 102

N-cyclopropyl-2,6-dimethoxy-4-[7-(1-methyl-pyrazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]benzamide Int 52
+
CAS#
765-30-0 E1.2 417.5 418.3 103

2,6-dimethoxy-4-[5-(1-propylpyrazol-4-yl)benz-imidazol-1-yl]-N-(2,2,2-trifluoroethyl)-benzamide Int 39
+
CAS#
827614-69-7 E1.3 487.5 488.6 104

2,6-dimethoxy-4-(5-pyrimidin-5-ylbenz-imidazol-1-yl)-N-(2,2,2-trifluoroethyl)-benzamide Int 39
+
CAS#
109299-78-7 E1.3 457.4 458.6 105

2,6-dimethoxy-4-[5-(2-methoxy-pyrimidin-5-yl)benz-imidazol-1-yl]-N-(2,2,2-trifluoroethyl)-benzamide Int 39
+
CAS#
628692-15-9 E1.3 487.4 488.3 106

2,6-dimethoxy-4-[5-(2-methoxy-4-pyridyl)benz-imidazol-1-yl]-N-(2,2,2-trifluoroethyl)-benzamide Int 39
+
CAS#
762262-09-9 E1.3 486.4 487.3 107

2,6-dimethoxy-4-[7-(1-methyl-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-yl]-N-(2,2,2-trifluoroethyl)- benzamide Int 33
+
CAS#
753-90-2 E1.2 460.4 461.2 108

2,6-dimethoxy-4-[5-(3-methyl-isoxazol-4-yl)benz-imidazol-1-yl]-N-(2,2,2-trifluoroethyl)-benzamide Int 39
+
CAS#
1421846-79-8
+
CAS#
1346808-44-3 E1.3 460.4 461.3 109

2,6-dimethoxy-4-[5-(3-methyl-isoxazol-5-yl)benz-imidazol-1-yl]-N-(2,2,2-trifluoroethyl)-benzamide Int 39
+
CAS#
1346808-44-3 E1.3 460.4 461.4 110

4-[5-(1-isobutyl-pyrazol-4-yl)-benzimidazol-1-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)-benzamide cpd 47
+
CAS#
78-77-3 N1 501.5 502.3 111

2,6-dimethoxy-4-[5-[1-(tetrahydro-furan-2-yl-methyl)pyrazol-4-yl]benz-imidazol-1-yl]-N-(2,2,2-trifluoroethyl )-benzamide cpd 47
+
CAS#
1192-30-9 N1 529.5 530.4 112

N-cyclopropyl-2,6-dimethoxy-4-[7-(1-methyl-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-yl]benzamide Int 33
+
CAS#
765-30-0 E1.2 418.4 419.3 113

N-isobutyl-2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]benzamide Int 44
+
CAS#
78-81-9
+
CAS#
761446-44-0 E1.2
+
E1.3 433.5 434.7 114

2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]-N-sec-butylbenzamide Int 44
+
CAS#
13952-84-6
+
CAS#
761446-44-0 E1.2
+
E1.3 433.5 434.7 115

N-isopropyl-2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]benzamide Int 44
+
CAS#
75-31-0
+
CAS#
761446-44-0 E1.2
+
E1.3 419.5 420.7 116

2-(difluoro-methoxy)-N-ethyl-6-methoxy-4-[7-(1-methyl-pyrazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]benzamide Int 36
+
CAS#
761446-44-0 E1.3 441.4 442.6 117

2-(difluoro-methoxy)-N-ethyl-6-methoxy-4-[6-(1-methyl-pyrazol-4-yl)-pyrazolo[1,5-a]pyridin-3-yl]benzamide Int 15
+
Int 16
+
CAS#
761446-44-0 E1.3
+
E1.3 441.4 442.5 118

2-(difluoro-methoxy)-N-ethyl-6-methoxy-4-[7-(1-methyl-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-yl]benzamide Int 16
+
CAS#
1383481-13-7
+
CAS#
761446-44-0 E1.3
+
E1.3 442.4 443.2 119

N-cyclopropyl-2-isopropoxy-6-methoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]benzamide cpd 86
+
CAS#
75-30-9 I
+
J1 445.5 446.8 120

2,6-dimethoxy-4-[5-[2-(4-methylpiperazin-1-yl)-4-pyridyl]benz-imidazol-1-yl]-N-(2,2,2-trifluoroethyl)-benzamide Int 39
+
CAS#
832114-09-7 E1.3 554.6 555.4 121

2,6-dimethoxy-4-[5-(6-methyl-pyridazin-4-yl)benz-imidazol-1-yl]-N-(2,2,2-trifluoroethyl)-benzamide Int 39
+
CAS#
1350543-95-1 E1.3 471.4 472.6 122

N-(cyano-methyl)-2,6-dimethoxy-4-[7-(1-methyl-pyrazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]benzamide Int 52
+
CAS#
6011-14-9 E1.2 416.4 417.5 123

2-(difluoro-methoxy)-N-ethyl-6-methoxy-4-[7-(3-methyl-isoxazol-5-yl)imidazo-[1,2-a]-pyridin-3-yl]-benzamide Int 36
+
CAS#
1346808-44-3 E1.3 442.4 443.3 124

N-cyclopropyl-2-(difluoro-methoxy)-6-methoxy-4-[7-(1-methyl-pyrazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]benzamide Int 37
+
CAS#
761446-44-0 E1.3 453.4 454.3 125

N-(3,3-difluoro-cyclobutyl)-2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]benzamide Int 44
+
CAS#
637031-93-7
+
CAS#
761446-44-0 E1.2
+
E1.3 467.5 468.3 126

2,6-dimethoxy-4-[5-(5-methyl-1,2,4-oxa-diazol-3-yl)-benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)- benzamide Int 39 E5.3
+
E5.4i 461.4 462.2 127

2,6-dimethoxy-4-[5-(5-methyl-4H-1,2,4-triazol-3-yl)-benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)- benzamide Int 39 E5.3
+
E5.4ii 460.4 461.3 128

2,6-dimethoxy-4-(5-pyrazin-2-ylbenz-imidazol-1-yl)-N-(2,2,2-trifluoroethyl)-benzamide Int 39
+
CAS#
762263-64-9 E1.3 457.4 458.3 129

N-isobutyl-2,6-dimethoxy-4-[7-(1-methyl-pyrazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]benzamide Int 52
+
CAS#
78-81-9 E1.2 433.5 434.4 130

N-(1,1-dioxothietan-3-yl)-2,6-dimethoxy-4-[7-(1-methyl-pyrazol-4-yl)-imidazo[1,2-a]pyridin-3-yl ]benzamide Int 52
+
CAS#
151-18-8 E1.2 481.5 482.3 131

2,6-dimethoxy-N-(2-methoxy-ethyl)-N-methyl-4-[7-(1-methyl-pyrazol-4-yl)-imidazo[1,2-a]pyridin-3-yl ]benzamide Int 52
+
CAS#
38256-93-8 E1.2 449.5 450.4 132

2,6-dimethoxy-4-[7-(1-methyl-pyrazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]-N-[(1S)-2,2,2 -trifluoro-1-methylethyl]-benzamide Int 52
+
CAS#
125278-10-6 E1.2 473.4 474.3 133

N-(2,2-difluoroethyl)-2,6-dimethoxy-4-[7-(1-methyl-pyrazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]benzamide Int 52
+
CAS#
79667-91-7 E1.2 441.4 442.4 134

2,6-dimethoxy-4-[5-(1-methyl-imidazol-2-yl)benz-imidazol-1-yl]-N-(2,2,2-trifluoroethyl)-benzamide Int 39
+
CAS#
16681-59-7 E4.3ii 459.4 460.3 135

2,6-dimethoxy-4-[5-(3-methyl-imidazol-4-yl)benz-imidazol-1-yl]-N-(2,2,2-trifluoroethyl)-benzamide Int 39
+
CAS#
1003-21-0 E4.3ii 459.4 460.3 136

2-(difluoro-methoxy)-N-ethyl-6-methoxy-4-[5-(5-methyl-1,2,4-oxadiazol-3-yl)benz-imidazol-1-yl]benzamide Int 12
+
CAS#
1009-35-4 B2
+
C2
+
E5.4i 443.4 444.5 137

2,6-dimethoxy-4-[5-(1-methyl-imidazol-4-yl)benz-imidazol-1-yl]-N-(2,2,2-trifluoroethyl)-benzamide Int 39
+
CAS#
25676-75-9 E4.3ii 459.4 460.3 138

4-[5-(2,3-dimethyl-imidazol-4-yl)benz-imidazol-1-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)-benzamide Int 39
+
CAS#
24134-09-6 E4.3ii 473.4 474.3 139

N-[(1R,2R)-2-aminocyclohexyl]-2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]benzamide Int 50
+
CAS#
21436-03-3 E1.2 474.6 475.4 140

N-[(1R,2R)-2-hydroxycyclopentyl]-2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]benzamide Int 50
+
CAS#
31775-67-4 E1.2 461.5 462.3 141

N-[(1R,2S)-2-hydroxy-cyclopentyl]-2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]benzamide Int 50
+
CAS#
137254-03-6 E1.2 461.5 462.3 142

(3,3-difluoro-azetidin-1-yl)-[2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]phenyl]-methanone Int 50
+
CAS#
288315-03-7 E1.2 453.4 454.4 143

N-[(1R,2R)-2-hydroxycyclopentyl]-2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]benzamide Int 50
+
CAS#
68327-11-7 E1.2 461.5 462.4 144

N-[(1R,2S)-2-fluorocyclo-propyl]-2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]benzamide Int 50
+
CAS#
143062-84-4 E1.2 435.5 436.4 145

2-(difluoro-methoxy)-N-ethyl-6-methoxy-4-(7-pyridazin-4-ylimidazo-[1,2-a]-pyridin-3-yl)-benzamide Int 36
+
CAS#
863422-41-7 E1.3 439.4 440.4 146

4-[7-(6-cyano-3-pyridyl)-imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-N-ethyl-6-methoxybenzamide Int 36
+
CAS#
741709-63-7 E1.3 463.4 464.4 147

tert-butyl 4-[4-[3-[3-(di-fluoromethoxy)-4-(ethyl-carbamoyl)-5-methoxy-phenyl]imidazo-[1,2-a]-pyridin-7-yl]-pyrazole -1-yl]-piperidine-1-carboxylate Int 36
+
CAS#
877399-74-1 E1.3 610.7 611.3 148

2-(Difluoro-methoxy)-N-ethyl-6-methoxy-4-[7-[1-(1-methyl-4-piperidyl)-pyrazol-4-yl]-imidazo[1,2-a]pyridine -3-yl]benzamide cpd 149 L1i 524.6 525.3 149

2-(difluoro-methoxy)-N-ethyl-6-methoxy-4-[7-[1-(4-piperidyl)-pyrazol-4-yl]-imidazo[1,2-a]pyridin-3-yl ]benzamide cpd 147 K 510.5 511.3 150

2-(Difluoro-methoxy)-N-ethyl-6-methoxy-4-[5-(5-methyl-4H-1,2,4-triazol-3-yl)benz-imidazol-1-yl]benzamide Int 12
+
CAS#
1009-35-4 B2
+
C2
+
E5.4ii 442.4 443.6 151

2-(difluoro-methoxy)-4-[7-[1-(difluoro-methyl)pyrazol-4-yl]imidazo-[1,2-a]-pyridin-3-yl]-N-ethyl-6- methoxy benzamide Int 36
+
CAS#
1206640-82-5 E1.3 477.4 478.6 152

2,6-dimethoxy-4-[5-(2-methyl-1H-imidazol-5-yl)benz-imidazol-1-yl]-N-(2,2,2-trifluoroethyl)-benzamide Int 39
+
CAS#
16265-11-5 E4.3ii 459.4 460.2 153

4-[5-(1H-imidazol-4-yl)benz-imidazol-1-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)-benzamide Int 39
+
CAS#
2302-25-2 E4.3ii 445.4 446.3 154

2,6-dimethoxy-4-[5-(3-methyl-pyrazol-1-yl)-benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)-benzamide Int 39
+
CAS#
1453-58-3 E2.3 459.4 460.3 155

2,6-dimethoxy-4-[5-(4-methyl-imidazol-1-yl)benz-imidazol-1-yl]-N-(2,2,2-trifluoroethyl)-benzamide Int 39
+
CAS#
822-36-6 E3.3 459.4 460.3 156

N-[(1R,2R)-2-(hydroxy-methyl)cyclo-propyl]-2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl] benzamide Int 50
+
CAS#
873537-21-4 E1.2 447.5 448.4 157

N-[(1R,2R)-2-(difluoromethyl)-cyclopropyl]-2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]benzamide Int 50
+
CAS#
2059915-48-7 E1.2 467.5 468.1 158

N-[(1R,2S)-2-(difluoromethyl)-cyclopropyl]-2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]benzamide Int 50
+
CAS#
1909288-67-0 E1.2 467.5 468.7 159

N-[(1R,2R)-2-hydroxycyclo-butyl]-2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]benzamide Int 50
+
CAS#
1609406-69-0 E1.2 447.5 448.7 160

2,6-dimethoxy-4-[5-(1-methyl-triazol-4-yl)-benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)-benzamide Int 39
+
CAS#
13273-53-5 E4.3ii 460.4 461.5 161

2,6-dimethoxy-N-(2-methoxy-cyclohexyl)-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]benzamide Int 50
+
CAS#
4342-43-2 E1.2 489.6 490.8 162

azetidin-1-yl-[2,6-di-methoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]phenyl]-methanone Int 50
+
CAS#
503-29-7 E1.2 417.5 418.7 163

N-(2-amino-ethyl)-2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]benzamide Int 50
+
CAS#
107-15-3 E1.2 420.5 421.5 164

N-[(1S,2S)-2-hydroxycyclo-hexyl]-2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]benzamide Int 50
+
CAS#
13374-30-6 E1.2 475.5 476.8 165

4-[5-(3,5-dimethyl-pyrazol-1-yl)-benzimidazol-1-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)-benzamide Int 39 Ex.2.39 473.4 474.3 166

2,6-dimethoxy-4-[5-(3-methyl-1,2,4-triazol-1-yl)benz-imidazol-1-yl]-N-(2,2,2-trifluoroethyl)-benzamide Int 39 Ex.2.40 460.4 461.3 167

2,6-dimethoxy-4-[5-(5-methyl-1,3,4-oxa-diazol-2-yl)-benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)- benzamide Int 39 Ex.2.41 461.4 462.7 168

4-[5-(4,5-dimethyl-1,2,4-triazol-3-yl)-benzimidazol-1-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)- benzamide Int 39 Ex.2.42 474.4 475.7 169

2,6-dimethoxy-4-[5-(3-methyl-1,2,4-oxa-diazol-5-yl)-benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)- benzamide Int 39 Ex.2.43 461.4 462.6 170

N-[(1S,2S)-2-hydroxycyclo-butyl]-2,6-dimethoxy-4-[7-(1-methyl-pyrazol-4-yl)-imidazo[1,2-a]pyridine-3 -yl]benzamide Int 52
+
CAS#
1820572-14-2 E1.2 447.5 448.3 171

N-isopropyl-2,6-dimethoxy-4-[7-(1-methyl-pyrazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]benzamide Int 52
+
CAS#
75-31-0 E1.2 419.5 420.4 172

N-[(1S,2S)-2-(difluoromethyl)-cyclopropyl]-2,6-dimethoxy-4-[7-(1-methyl-pyrazol-4-yl)-imidazo[1,2-a]pyridine -3-yl]benzamide Int 52
+
CAS#
2059915-48-7 E1.2 467.5 468.3 173

(3,3-difluoro-azetidin-1-yl)-[2,6-dimethoxy-4-[7-(1-methyl-pyrazol-4-yl)-imidazo[1,2-a]pyridine-3- yl]phenyl]-methanone Int 52
+
CAS#
288315-03-7 E1.2 453.4 454.3 174

2,6-dimethoxy-4-[7-(1-methyl-pyrazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]-N-[(1R)-2,2,2 -trifluoro-1-methylethyl]-benzamide Int 52
+
CAS#
779303-24-1 E1.2 473.4 474.3 175

2-ethyl-7-fluoro-5-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]iso-indolin-1-one CAS#
4887-88-1
+
CAS#
761446-44-0
+
5-bromo-2-ethyl-7-fluoro-isoindolin-1-one (cf. Ex. 0) Ex.2.46 375.4 376.7 176

2-ethyl-7-methoxy-5-[7-(1-methyl-pyrazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]isoindolin-1-one CAS#
1246184-55-3
+
Int 18
+
CAS#
761446-44-0 E1.3
+
E1.3 387.4 388.8 177

2-(difluoro-methoxy)-N-ethyl-6-methoxy-4-[6-(1-methyl-pyrazol-4-yl)-imidazo[4,5-b]pyridin-3-yl]benzamide CAS#
886372-98-1
+
Int 12
+
CAS#
761446-44-0 B3
+
C2
+
E1.3 442.4 443.7 178

2-(difluoro-methoxy)-N-ethyl-6-methoxy-4-[7-(1-methyl-imidazol-4-yl)imidazo-[1,2-a]-pyridin-3-yl]-benzamide CAS#
1246184-55-3
+
Int 16
+
CAS#
1083180-01-1 E1.3
+
E1.3 441.4 443.3 179

[2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]phenyl]-(3,3-dimethyl-azetidin-1-yl)methanone Int 50
+
CAS#
89381-03-3 E1.2 445.5 446.4 180

[2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]phenyl]-(3-phenyl-azetidin-1-yl)methanone Int 50
+
CAS#
4363-13-7 E1.2 493.6 495.0 181

[2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]phenyl]-(2,4-dimethyl-azetidin-1-yl) methanone Int 50
+
CAS#
1803606-22-5 E1.2 445.5 447.0 182

[2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]phenyl]-(2-methyl-azetidin-1-yl)methanone Int 50
+
CAS#
1152113-37-5 E1.2 431.5 432.9 183

[2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]phenyl]-[3-(hydroxy-methyl)-azetidin-1-yl]methanone Int 50
+
CAS#
928038-44-2 E1.2 447.5 449.0 184

[2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]phenyl]-(3-hydroxy-azetidin-1-yl)methanone Int 50
+
CAS#
18621-18-6 E1.2 433.5 434.9 185

[2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]phenyl]-[3-(dimethyl-amino)-azetidin-1-yl]methanone Int 50
+
CAS#
935670-07-8 E1.2 460.5 461.9 186

(3-benzyl-oxyazetidin-1-yl)-[2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]phenyl]-methanone Int 50
+
CAS#
897086-95-2 E1.2 523.6 525.1 187

[2,6-dimethoxy-4-[5-(1-methylpyrazol-4-yl)benz-imidazol-1-yl]phenyl]-(2-phenylazetidin-1-yl)methanone Int 50
+
CAS#
22610-18-0 E1.2 493.6 495.0 188

[2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]phenyl]-(3-morpholino-azetidin-1-yl) methanone Int 50
+
CAS#
302355-79-9 E1.2 502.6 503.9 189

[2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]phenyl]-(2,2,4-trimethyl-azetidin-1-yl)methanone Int 50
+
CAS#
1197627-45-4 E1.2 459.5 461.0 190

[2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]phenyl]-(3-methoxy-azetidin-1-yl)methanone Int 50
+
CAS#
110925-17-2 E1.2 447.5 448.9 191

[2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]phenyl]-(3-tetrahydro-pyran-4-yl-azetidin-1-yl) methanone Int 50
+
CAS#
550369-51-2 E1.2 501.6 503.1 192

1-[2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]benzoyl]-azetidine-3-carbonitrile Int 50
+
CAS#
345954-83-8 E1.2 442.5 443.3 193

[2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]phenyl]-[2-(hydroxy-methyl)-azetidin-1-yl]methanone Int 50
+
CAS#
250274-91-0 E1.2 447.5 448.9 194

[2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]phenyl]-(2-oxa-6-azaspiro-[3,3]heptan-6 -yl) methanone Int 50
+
CAS#
1045709-32-7 E1.2 459.5 461.0 195

[2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]phenyl]-(2,2-dioxo-2λ ⁶ -thia-6-azaspiro[3 ,3]-heptan-6-yl)-methanone Int 50
+
CAS#
1427388-39-3 E1.2 507.6 509.0 196

[2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]phenyl]-(3-phenyl-pyrrolidin-1-yl)methanone Int 50
+
CAS#
857281-02-8 E1.2 507.6 509.0 197

[2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]phenyl]-(4-fluoro-1-piperidyl)-methanone Int 50
+
CAS#
57395-89-8 E1.2 463.5 464.9 198

[2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]phenyl]-[4-(trifluoromethoxy)-1-piperidyl]-methanone Int 50
+
CAS#
1612172-50-5 E1.2 529.5 531.0 199

N-tert-butyl-2-(difluoro-methoxy)-6-methoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]benzamide Int 58
+
Int 11 B2
+
C2 469.5 470.8 200

2,6-dimethoxy-4-[7-(1-methyl-pyrazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]-N-[2-methyl-1-(trifluoro- methyl)-propyl]-benzamide Int 52
+
CAS#
1582-18-9 E1.2 501.5 502.8 201

2-ethyl-7-(2-hydroxyethylamino)-5-[7-(1-methylpyrazol-4-yl)imidazo-[1,2-a]-pyridin-3-yl]-isoindolin-1-one CAS#
1246184-55-3
+
Int 19
+
CAS#
761446-44-0 E1.3
+
E1.3 416.5 417.4 202

2-ethyl-7-(2-hydroxyethylamino)-5-[5-(1-methylpyrazol-4-yl)benz-imidazol-1-yl]isoindolin-1-one cpd 175
+
CAS#
141-43-5 Ex.2.47 416.5 417.4 203

2-fluoro-6-methoxy-4-[7-(1-methyl-pyrazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]-N-(2,2,2-trifluoroethyl )-benzamide CAS#
1246184-55-3
+
Int 20
+
CAS#
761446-44-0 E1.3
+
E1.3 447.4 448.3 204

2-methoxy-6-(methylamino)-4-[7-(1-methyl-pyrazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]-N-(2,2,2 -trifluoroethyl)-benzamide cpd 203
+
CAS#
74-89-5 M1 458.4 459.4 205

2-(2-hydroxy-ethylamino)-6-methoxy-4-[7-(1-methyl-pyrazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]-N-(2 ,2,2-trifluoroethyl)-benzamide cpd 203
+
CAS#
141-43-5 M1 488.5 489.4 206

2-methoxy-6-methyl-4-[7-(1-methylpyrazol-4-yl)imidazo-[1,2-a]-pyridin-3-yl]-N-(2,2,2-trifluoroethyl) -benzamide CAS#
1246184-55-3
+
Int 21
+
CAS#
761446-44-0
+
CAS#
753-90-2 E1.3
+
E1.3
+
E1.1
+
E1.2 443.4 444.4 207

2-chloro-6-methoxy-4-[7-(1-methyl-pyrazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]-N-(2,2,2-trifluoroethyl )-benzamide CAS#
1246184-55-3
+
Int 22
+
CAS#
761446-44-0
+
CAS#
753-90-2 E1.3
+
E1.3
+
E1.1
+
E1.2 463.8 464.3 208

[2,6-dimethoxy-4-[7-(1-methyl-pyrazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]phenyl]-(3,3-dimethyl-azetidine- 1-yl) methanone Int 52
+
CAS#
89381-03-3 E1.2 445.5 446.4 209

1-[2,6-dimethoxy-4-[7-(1-methyl-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl]benzoyl]azetidine-3-carbonitrile Int 52
+
CAS#
345954-83-8 E1.2 442.5 443.4 210

1-[2,6-dimethoxy-4-[7-(1-methyl-pyrazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]benzoyl]-pyrrolidin-3-carbonitrile Int 52
+
CAS#
1187930-86-4 E1.2 456.5 457.4 211

(3,3-difluoro-pyrrolidin-1-yl)-[2,6-dimethoxy-4-[7-(1-methyl-pyrazol-4-yl)-imidazo[1,2-a]pyridin-3- yl]phenyl]-methanone Int 52
+
CAS#
163457-23-6 E1.2 467.5 468.4 212

(4,4-difluoro-1-piperidyl)-[2,6-dimethoxy-4-[7-(1-methyl-pyrazol-4-yl)-imidazo[1,2-a]pyridin-3-yl] phenyl]-methanone Int 52
+
CAS#
144230-52-4 E1.2 481.5 482.4 213

[2,6-dimethoxy-4-[7-(1-methyl-pyrazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]phenyl]-[3-(trifluoro-methyl)- azetidin-1-yl] methanone Int 52
+
CAS#
1221272-90-7 E1.2 485.5 486.8 215

2,6-dimethoxy-4-[7-(1-methylimidazol-4-yl)imidazo-[1,2-a]-pyridin-3-yl]-N-[(1R)-2,2,2- trifluoro-1-methylethyl]-benzamide Int 35
+
CAS#
1083180-01-1
+
CAS#
779303-24-1 E1.3
+
E1.1
+
E1.2 473.4 474.3 216

2,6-dimethoxy-4-[7-(1-methyl-imidazol-4-yl)imidazo[1,2-a]pyridin-3-yl]-N-[(1S)-2,2,2- trifluoro-1-methylethyl]-benzamide Int 35
+
CAS#
1083180-01-1
+
CAS#
125278-10-6 E1.3
+
E1.1
+
E1.2 473.4 474.3 217

[2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]phenyl]-(3-hydroxy-3-methyl-azetidin-1-yl)methanone Int 50
+
CAS#
124668-46-8 E1.2 447.5 448.3 218

[2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]phenyl]-(3-ethyl-3-hydroxy-azetidin-1-yl)methanone Int 50
+
CAS#
935668-00-1 E1.2 461.5 462.4 219

[2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]phenyl]-[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]methanone Int 50
+
CAS#
848192-96-1 E1.2 501.5 502.3 220

(3-cyclo-propyl-3-hydroxy-azetidin-1-yl)-[2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]phenyl] -methanone Int 50
+
CAS#
848192-93-8 E1.2 473.5 474.4 221

[2,6-dimethoxy-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]phenyl]-(3-ethynyl-3-hydroxy-azetidin-1-yl)methanone Int 50
+
CAS#
1408076-23-2 E1.2 457.5 458.3 222

2,6-dimethoxy-4-[7-(1H-pyrazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]-N-[(1R)-2,2,2-trifluoro -1-methylethyl]-benzamide Int 35
+
CAS#
269410-08-4
+
CAS#
779303-24-1 E1.3
+
E1.1
+
E1.2 459.4 460.3 223

2,6-dimethoxy-4-[7-(3-methyl-isoxazol-5-yl)imidazo-[1,2-a]-pyridin-3-yl]-N-[(1R)-2,2, 2-trifluoro-1-methylethyl]-benzamide Int 54
+
CAS#
779303-24-1 E1.2 474.4 475.4 224

2,6-dimethoxy-4-[7-(3-methyl-isoxazol-5-yl)imidazo[1,2-a]pyridin-3-yl]-N-[(1S)-2,2,2- trifluoro-1-methylethyl]-benzamide Int 54
+
CAS#
125278-10-6 E1.2 474.4 475.3 225

8-methoxy-6-[7-(1-methyl-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4 -dihydro-isoquinoline-1-one Int 76
+
CAS#
6226-25-1 O 455.4 456.4 226

methyl 1-[2,6-dimethoxy-4-[7-(1-methyl-pyrazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]benzoyl]azetidine-3-carboxylate Int 52
+
CAS#
100202-39-9 E1.2 475.5 476.4 227

2,6-dimethoxy-4-[7-(1H-pyrazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]-N-(2,2,2-trifluoroethyl)-benzamide int 46
+
CAS#
269410-08-4 E1.3 445.4 446.3 228

2-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethyl-carbamoyl)-phenyl]imidazo-[1,2-a]-pyridin-7-yl]-pyrazol- 1-yl]-acetic acid Cpd-230 E1.1 503.4 504.4 229

tert-butyl 2-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethyl-carbamoyl)-phenyl]imidazo-[1,2-a]-pyridin-7-yl]-pyrazole -1-yl]-acetate cpd 227
+
CAS#
107-59-5 N2 559.5 560.4 230

ethyl 2-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethyl-carbamoyl)-phenyl]imidazo-[1,2-a]-pyridin-7-yl]-pyrazole -1-yl]-acetate Int 3
+
int 5 H 531.5 532.5 231

isopropyl 2-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethyl-carbamoyl)-phenyl]imidazo-[1,2-a]-pyridin-7-yl]-pyrazole -1-yl]-acetate cpd 229
+
CAS#
67-63-0 R 545.5 546.4 232

2,6-dimethoxy-4-[7-(3-methyl-isoxazol-5-yl)imidazo-[1,2-a]-pyridin-3-yl]-N-(2,2,2-trifluoroethyl) -benzamide Int 54
+
CAS#
753-90-2 E1.2 460.4 461.3 233

2-hydroxy-6-methoxy-4-[7-(1-methyl-pyrazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]-N-(2,2,2-trifluoroethyl )-benzamide cpd 88 I 445.4 446.3 234

cyclopropyl 2-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethyl-carbamoyl)-phenyl]imidazo-[1,2-a]-pyridin-7-yl]-pyrazole -1-yl]-acetate cpd 228
+
CAS#
16545-68-9 Q1 543.5 544.4 235

2-fluoroethyl 2-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethyl-carbamoyl)-phenyl]imidazo-[1,2-a]-pyridin-7-yl] -pyrazol-1-yl]-acetate cpd 228
+
CAS#
371-62-0 Q1 549.5 550.3 236

methyl 2-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethyl-carbamoyl)-phenyl]imidazo-[1,2-a]-pyridin-7-yl]-pyrazole -1-yl]-acetate cpd 228
+
MeOH Q2i 517.5 518.3 237

tetrahydrofuran-3-yl 2-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethyl-carbamoyl)-phenyl]imidazo-[1,2-a]-pyridine-7- yl]-pyrazol-1-yl]-acetate cpd 228
+
CAS#
453-20-3 Q2ii 573.5 574.4 238

Cyclobutylmethyl 2-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethyl-carbamoyl)-phenyl]imidazo-[1,2-a]-pyridin-7-yl] -pyrazol-1-yl]-acetate cpd 228
+
CAS#
17247-58-4 Q3 571.5 572.4 239

2,6-dimethoxy-4-[7-(6-methoxy-3-pyridyl)-imidazo[1,2-a]pyridin-3-yl]-N-(2,2,2-trifluoroethyl)-benzamide int 46
+
CAS#
163105-89-3 E1.3 486.4 487.6 240

4-[7-(6-cyano-3-pyridyl)-imidazo[1,2-a]pyridin-3-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)-benzamide Int 46
+
CAS#
741709-63-7 E1.3 481.4 482.8 241

2,6-dimethoxy-4-[7-(2-methoxy-pyrimidin-5-yl)imidazo[1,2-a]pyridin-3-yl]-N-(2,2,2-trifluoroethyl)-benzamide Int 46
+
CAS#
628692-15-9 E1.3 487.4 488.7 242

2,6-dimethoxy-4-(7-pyrimidin-5-ylimidazo[1,2-a]pyridin-3-yl)-N-(2,2,2-trifluoroethyl)-benzamide Int 46
+
CAS#
109299-78-7 E1.3 457.4 458.8 243

tert-butyl 2-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethyl-carbamoyl)-phenyl]imidazo-[1,2-a]-pyridin-7-yl]-pyrazole -1-yl]-propanoate int 46
+
Int 71 E1.3 573.6 574.4 244

methyl 2-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethyl-carbamoyl)-phenyl]imidazo-[1,2-a]-pyridin-7-yl]-pyrazole -1-yl]-propanoate cpd 243
+
MeOH R 531.5 532.9 245

2,6-dimethoxy-4-[7-(5-methoxy-3-pyridyl)-imidazo[1,2-a]pyridin-3-yl]-N-(2,2,2-trifluoroethyl)-benzamide Int 46
+
CAS#
850991-69-4 E1.3 486.4 487.3 246

4-[7-(2-Aminopyrimidin-5-yl)imidazo-[1,2-a]-pyridin-3-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)-benzamide Int 46
+
CAS#
936250-22-5 E1.3 472.4 473.3 247

2,6-dimethoxy-4-(7-pyridazin-4-ylimidazo[1,2-a]pyridin-3-yl)-N-(2,2,2-trifluoroethyl)-benzamide int 46
+
CAS#
863422-41-7 E1.3 457.4 458.2 248

4-[7-(5-ethoxy-3-pyridyl)-imidazo[1,2-a]pyridin-3-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)-benzamide int 46
+
CAS#
1224436-34-3 E1.3 500.5 501.3 249

2,6-dimethoxy-4-[7-[1-methyl-3-(trifluoro-methyl)pyrazol-4-yl]imidazo-[1,2-a]-pyridin-3-yl]-N-(2 ,2,2-trifluoroethyl)-benzamide Int 46
+
CAS#
1218790-53-4 E1.3 527.4 528.3 250

2,6-dimethoxy-4-[7-(2-methoxy-3-pyridyl)-imidazo[1,2-a]pyridin-3-yl]-N-(2,2,2-trifluoroethyl)-benzamide int 46
+
CAS#
163105-90-6 E1.3 486.4 487.3 251

2,6-dimethoxy-4-[7-(6-morpholino-3-pyridyl)-imidazo[1,2-a]pyridin-3-yl]-N-(2,2,2-trifluoroethyl)-benzamide Int 46
+
CAS#
904326-93-8 E1.3 541.5 542.7 252

2,6-dimethoxy-4-[7-(6-methyl-pyridazin-4-yl)imidazo[1,2-a]pyridin-3-yl]-N-(2,2,2-trifluoroethyl)-benzamide Int 46
+
CAS#
1350543-95-1 E1.3 471.4 472.6 253

4-[7-(4-isopropylpyrimidin-5-yl)-imidazo[1,2-a]pyridin-3-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)-benzamide int 46
+
CAS#
913835-27-5 E1.3 499.5 500.8 254

2-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethyl-carbamoyl)-phenyl]imidazo-[1,2-a]-pyridin-7-yl]-pyrazol- 1-yl]-propanoic acid cpd 243 P 517.5 518.3 255

4-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethyl-carbamoyl)-phenyl]imidazo-[1,2-a]-pyridin-7-yl]-pyrazol- 1-yl]-butanoic acid int 46
+
Int 72 E1.3c 531.5 532.3 256

methyl 4-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethyl-carbamoyl)-phenyl]imidazo-[1,2-a]-pyridin-7-yl]-pyrazole -1-yl]-butanoate cpd 255
+
MeOH Q2i 545.5 546.3 257

ethyl 4-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethyl-carbamoyl)-phenyl]imidazo-[1,2-a]-pyridin-7-yl]-pyrazole -1-yl]-butanoate cpd 255
+
EtOH Q2i 559.5 560.3 258

4-[7-(4-cyano-3-pyridyl)-imidazo[1,2-a]pyridin-3-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)-benzamide int 46
+
CAS#
878194-91-3 E1.3b 481.4 482.0 259

3-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethyl-carbamoyl)-phenyl]-imidazo-[1,2-a]-pyridin-7-yl]-pyridine-4-carboxamide int 46
+
CAS#
878194-91-3 E1.3b 499.4 500.2 260

tert-butyl 3-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethyl-carbamoyl)-phenyl]imidazo-[1,2-a]-pyridin-7-yl]-pyrazole -1-yl]-azetidine-1-carboxylate int 46
+
CAS#
877399-35-4 E1.3 600.6 601.4 261

7-methoxy-5-[7-(1-methyl-pyrazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-isoindoline- 1-he CAS#
1246184-55-3
+
Int 25
+
CAS#
761446-44-0
+
CAS#
6226-25-1 E1.3
+
E1.3
+
O 441.4 442.3 262

2-cyclopropyl-8-methoxy-6-[7-(1-methyl-pyrazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]-3,4-dihydroiso-quinoline-1- he CAS#
1246184-55-3
+
Int 24
+
CAS#
761446-44-0 E1.3
+
E1.3 413.5 414.3 263

ethyl 2-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethyl-carbamoyl)-phenyl]imidazo-[1,2-a]-pyridin-7-yl]-pyrazole -1-yl]-propanoate cpd 243
+
EtOH R 545.5 546.3 264

4-[7-[1-[1-(2-cyanoethyl)-azetidin-3-yl]pyrazol-4-yl]imidazo[1,2-a]pyridin-3-yl]-2,6-dimethoxy- N-(2,2,2-trifluoroethyl)-benzamide cpd 260 K
+
L2ii 553.5 554.3 265

4-[7-[1-[1-(cyanomethyl)-azetidin-3-yl]pyrazol-4-yl]imidazo[1,2-a]pyridin-3-yl]-2,6-dimethoxy-N- (2,2,2-trifluoroethyl)-benzamide cpd 260 K
+
L2i 539.5 540.3 266

4-[7-(1-methylpyrazol-4-yl)imidazo-[1,2-a]-pyridin-3-yl]-2,6-bis(tri-deuteriomethoxy)-N-(2,2 ,2-trifluoroethyl)-benzamide Int 1
+
Int 8 H 465.5 466.1 267

N-cyclopropyl-2-(difluoro-methoxy)-6-methoxy-4-[7-(6-methoxy-3-pyridyl)imidazo[1,2-a]pyridin-3-yl]benzamide Int 37
+
CAS#
163105-89-3 E1.3 480.5 481.3 268

4-[7-(2-cyano-3-pyridyl)-imidazo[1,2-a]pyridin-3-yl]-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)-benzamide Int 46
+
CAS#
55758-02-6 E4.3ii 481.4 482.2 269

2,6-dimethoxy-4-[7-(6-methylpyridazin-3-yl)imidazo-[1,2-a]-pyridin-3-yl]-N-(2,2,2-trifluoroethyl)-benzamide Int 46
+
CAS#
1121-79-5 E4.3ii 471.4 472.2 270

N-cyclopropyl-2-(difluoro-methoxy)-6-methoxy-4-[7-(3-methyliso-xazol-5-yl)-imidazo[1,2-a]pyridin-3-yl]benzamide Int 37
+
CAS#
1346808-44-3 E1.3 454.4 455.2 271

2,6-difluoro-4-[7-(1-methyl-pyrazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]-N-(2,2,2-trifluoroethyl)- benzamide Int 1
+
Int 4 H 435.4 436.1 272

N-cyclopropyl-2-(difluoro-methoxy)-6-methoxy-4-[7-(6-methyl-pyridazin-4-yl)imidazo[1,2-a]pyridin-3-yl]benzamide Int 37
+
CAS#
1346808-44-3 E1.3 465.5 466.2 273

N-cyclopropyl-2-(difluoro-methoxy)-6-methoxy-4-[7-(6-methyl-pyridazin-3-yl)imidazo[1,2-a]pyridin-3-yl]benzamide Int 37
+
CAS#
1121-79-5 E4.3i 465.5 466.3 274

N-cyclopropyl-2-(difluoro-methoxy)-6-methoxy-4-[7-(3-methyl-imidazol-4-yl)imidazo[1,2-a]pyridin-3-yl]benzamide Int 37
+
CAS#
1003-21-0 E4.3i 453.4 454.3 275

8-methoxy-6-[7-(6-methyl-pyridazin-3-yl)imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4 -dihydro-isoquinoline-1-one int 2
+
int 7 H 467.4 468.3 276

N-cyclopropyl-2-fluoro-6-methoxy-4-[7-(1-methyl-pyrazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]benzamide Int 1
+
int 6 H 405.4 406.2 277

N-cyclopropyl-2-(isopropyl-amino)-6-methoxy-4-[7-(1-methyl-pyrazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]benzamide cpd 276
+
CAS#
75-31-0 M1 444.5 445.4 278

N-cyclopropyl-2-methoxy-6-(2-methoxy-ethoxy)-4-[7-(1-methyl-pyrazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]benzamide cpd 276
+
CAS#
109-86-4 M2 461.5 462.3 279

N-cyclopropyl-2-(2-hydroxy-ethoxy)-6-methoxy-4-[7-(1-methyl-pyrazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]benzamide cpd 276
+
CAS#
107-21-1 M2 447.5 448.4 280

N-cyclopropyl-2-(difluoro-methoxy)-6-methoxy-4-[7-(6-methoxy-pyridazin-3-yl)imidazo[1,2-a]pyridin-3-yl]benzamide Int 37
+
CAS#
17321-29-8 E4.3i 481.5 482.5 281

N-cyclopropyl-2-(difluoro-methoxy)-6-methoxy-4-[7-[6-(trifluoro-methyl)-pyridazin-3-yl]imidazo[1,2-a]pyridin-3-yl] benzamide Int 37
+
CAS#
174607-37-5 E4.3i 519.4 520.4 282

4-[7-(6-cyano-pyridazin-3-yl)imidazo-[1,2-a]-pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxybenzamide Int 37
+
CAS#
1027513-40-1 E4.3i 476.4 477.4 283

N-cyclopropyl-2-(difluoro-methoxy)-4-[7-[6-(dimethyl-amino)-pyridazin-3-yl]imidazo[1,2-a]pyridin-3-yl]-6-methoxy -benzamide Int 37
+
CAS#
14959-33-2 E4.3i 494.5 495.4 284

ethyl 2-[4-[3-[4-(cyclo-propyl-carbamoyl)-3-(difluoro-methoxy)-5-methoxy-phenyl]imidazo-[1,2-a]-pyridin-7-yl] -pyrazol-1-yl]-acetate Int 37
+
CAS#
864754-16-5 E1.3a 525.5 526.4 285

N-cyclopropyl-4-[7-(6-cyclopropylpyridazin-3-yl)-imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxybenzamide Int 37
+
CAS#
1046816-38-9 E4.3i 491.5 492.4 286

N-cyclopropyl-2-(difluoro-methoxy)-6-methoxy-4-[7-(6-morpholino-pyridazin-3-yl)imidazo[1,2-a]pyridin-3-yl]benzamide Int 37
+
CAS#
927673-86-7 E4.3i 536.5 537.4 291

2-(difluoro-methoxy)-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]-N-(1,2,2,3,3-pentadeuterio-cyclopropyl)- 6-(tri-deuterio-methoxy)-benzamide Int 69 C3 (cf. Ex.2.49) 461.5 462.1 292

N-cyclopropyl-2-(difluoro-methoxy)-4-[5-(1-methyl-pyrazol-4-yl)-benzimidazol-1-yl]-6-(trideuteriomethoxy)-benzamide Int 70
+
int 56 E2.3
+
C3
(cf. Ex.2.50) 456.4 457.2 293

ethyl 3-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethyl-carbamoyl)-phenyl]imidazo-[1,2-a]-pyridin-7-yl]-pyrazole -1-yl]-2-methyl-propanoate Int 76 Ex.2.51 559.5 560.7 294

ethyl 2-[[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethyl-carbamoyl)-phenyl]imidazo-[1,2-a]-pyridin-7-yl]- pyrazol-1-yl]-methyl]-3-methylbutanoate Int 76 Ex.2.52 587.6 588.3 295

ethyl 2-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethyl-carbamoyl)-phenyl]imidazo-[1,2-a]-pyridin-7-yl]-pyrazole -1-yl]-2-methyl-propanoate Int 76 Ex.2.53 559.5 560.2 296

ethyl 2-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethyl-carbamoyl)-phenyl]imidazo-[1,2-a]-pyridin-7-yl]-pyrazole -1-yl]-3-methyl-butanoate Int 76 Ex.2.54 573.6 574.2 297

Tetrahydro-furan-2-yl-methyl 2-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethyl-carbamoyl)-phenyl]imidazo-[1,2-a]- pyridin-7-yl]-pyrazol-1-yl]-acetate cpd 228 Ex.2.55 587.5 588.3 298

ethyl 2-[3-[4-(cyclopropylcarbamoyl)-3-(difluoro-methoxy)-5-methoxy-phenyl]-7-(1-methylpyrazol-4-yl)imidazo-[1,2-a] -pyridin-6-yl]-hydroxyacetate Int 77 Ex.2.56 555.5 556.3 299

2-[3-[4-(cyclopropyl-carbamoyl)-3-(difluoro-methoxy)-5-methoxy-phenyl]-7-(1-methylpyrazol-4-yl)imidazo-[1,2-a]- pyridin-6-yl]-hydroxyacetic acid cpd 298 Ex.2.57 527.5 528.2 300

4-[6-benzyl-oxy-7-(1-methylpyrazol-4-yl)imidazo-[1,2-a]-pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6 -methoxy-benzamide Int 77 Ex.2.58 559.6 560.3 301

4-[6-(1-cyanoethoxy)-7-(1-methyl-pyrazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoro-methoxy )-6-methoxy-benzamide CAS#
942947-94-6 Ex.2.59 522.5 523.2 302

ethyl 2-[3-[4-(cyclopropylcarbamoyl)-3-(difluoro-methoxy)-5-methoxy-phenyl]-7-(1-methylpyrazol-4-yl)imidazo-[1,2-a] -pyridin-6-yl]-hydroxypropanoate cpd 301 Ex.2.60 569.6 570.4 303

2-[3-[4-(cyclopropyl-carbamoyl)-3-(difluoro-methoxy)-5-methoxy-phenyl]-7-(1-methylpyrazol-4-yl)imidazo-[1,2-a]- pyridin-6-yl]-hydroxypropanoic acid cpd 302 Ex.2.61 541.5 542.3 304

2-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethyl-carbamoyl)-phenyl]imidazo-[1,2-a]-pyridin-7-yl]-pyrazol- 1-yl]-2-methyl-propanoic acid cpd 295 Ex.2.62 531.5 532.3 305

2-(diethyl-amino)ethyl 2-[4-[3-[3,5-dimethoxy-4-(2,2,2-trifluoroethyl-carbamoyl)-phenyl]imidazo-[1,2-a]-pyridine -7-yl]-pyrazol-1-yl]-2-methyl-propanoate cpd 304 Ex.2.63 630.7 631.7 306

N-cyclopropyl-2-(difluoro-methoxy)-6-methoxy-4-[5-(1H-pyrazol-4-yl)benz-imidazol-1-yl]benzamide Int 42
+
CAS#
269410-08-4 E1.3 439.4 440.3 307

N-cyclopropyl-2-(difluoro-methoxy)-6-methoxy-4-[7-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl]benzamide Int 37
+
CAS#
269410-08-4 E1.3 439.4 440.8

Table IV. NMR data for exemplary compounds of the invention.

cpd
No. NMR data 17 ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.23 (s, 1H), 7.98 (s, 1H), 7.83 (s, 1H), 7.72 (s, 1H), 7.57 -7.47 (m, 2H), 7.02 (s, 2H), 6.88-6.46 (m, 1H), 5.98 (t, 1H), 4.25 (q, 2H), 3.94 (s, 3H), 3.60-3.50 (m, 2H), 1.57 (t, 3H), 1.29 (t, 3H) 25 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.88 (t, 1H), 8.61 (s, 1H), 8.19 (s, 1H), 7.98 (s, 1H), 7 .93 (s, 1H), 7.71 (d, 1H), 7.58 (d, 1H), 7.02 (s, 2H), 4.07-3.96 (m, 2H), 3, 88 (s, 3H), 3.84 (s, 6H) 26 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.59 (s, 1H), 8.40 (d, 1H), 8.24 (s, 1H), 7.99 (s, 1H), 7 .93 (s, 1H), 7.68 (d, 1H), 6.98 (s, 2H), 4.38-4.26 (m, 1H), 4.16 (q, 2H), 3, 83 (s, 6H), 2.26-2.17 (m, 2H), 2.01-1.88 (m, 2H), 1.70-1.59 (m, 2H), 1.42 ( t, 3H), 1.31-1.21 (m, 1H) 48 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.99 (s, 1H), 7.94 (s, 1H), 7.69 (d, 1H), 7.59 (d, 1H), 7 .33-7.06 (m, 3H), 8.62 (s, 1H), 8.35 (t, 1H), 8.19 (s, 1H), 3.89 (s, 6H), 3, 28-3.14 (m, 2H), 1.10 (t, 3H) 52 ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.77-8.74 (m, 2H), 8.44 (s, 1H), 7.82 (s, 1H), 7.73 (s, 1H) , 7.36 (s, 2H), 6.16 (t, 1H), 4.20-4.10 (m, 2H), 4.03 (s, 3H), 3.96 (s, 6H) 53 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.62 (1H, s), 8.42 (1H, d), 8.19 (1H, s), 7.99 (1H, s), 7.94(1H, s), 7.69-7.59(2H, m), 7.46-7.10(2H, m), 7.15(1H, s), 3.91(3H, s), 3.88(3H, s), 2.81(1H, m), 0.70(2H, m), 0.48(2H, m) 86 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.64 (s, 1H), 8.22-8.18 (m, 2H), 7.98 (s, 1H), 7.93 (d, 1H), 7.69 (d, 1H), 7.59 (dd, 1H), 6.98 (s, 2H), 3.88 (s, 3H), 3.83 (s, 6H), 2, 83-2.77 (m, 1H), 0.69-0.62 (m, 2H), 0.48-0.43 (m, 2H) 88 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.81 (t, 1H), 8.62 (d, 1H), 8.35 (s, 1H), 8.08 (s, 1H), 7 .88 (s, 1H), 7.81 (s, 1H), 7.25 (d, 1H), 6.95 (s, 2H), 4.09-3.94 (m, 2H), 3, 90 (s, 3H), 3.83 (s, 6H) 124 ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.27 (d, 1H), 7.86 (s, 1H), 7.72 (s, 3H), 7.11-6.99 (m, 2H) , 7.02-6.94 (m, 1H), 6.86-6.44 (m, 1H), 6.04 (s, 1H), 4.00 (s, 3H), 3.92 (s , 3H), 3.00-2.92 (m, 1H), 0.96-0.87 (m, 2H), 0.71-0.62 (m, 2H) 173 ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.30 (d, 1H), 7.97 (s, 1H), 7.90 (s, 1H), 7.86 (s, 1H), 7.76 (s, 1H), 7.15 (d, 1H), 6.74 (s, 2H), 4.57 (t, 2H), 4.31 (t, 2H), 4.02 (s, 3H) , 3.92 (s, 6H) 174 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.69 (d, 1H), 8.60 (d, 1H), 8.35 (s, 1H), 8.08 (s, 1H), 7 .87 (s, 1H), 7.80 (s, 1H), 7.25 (d, 1H), 6.95 (s, 2H), 4.78-4.67 (m, 1H), 3, 90 (s, 3H), 3.83 (s, 6H), 1.28 (d, 3H) 203 ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.33 (s, 1H), 7.87 (s, 1H), 7.78-7.75 (m, 2H), 7.74 (s, 1H) , 7.04 (dd, 2H), 6.93 (s, 1H), 6.61 (t, 1H), 4.23-4.12 (m, 2H), 3.99 (s, 6H) 204 ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.76 (d, 1H), 8.35 (d, 1H), 8.25 (t, 1H), 7.77 (s, 1H), 7.67 (s, 1H), 7.65 (s, 2H), 6.93 (d, 1H), 6.46 (s, 1H), 6.30 (s, 1H), 4.10-3.99 ( m, 2H), 3.92 (s, 6H), 2.85 (d, 3H) 206 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.97 (t, 1H), 8.58 (d, 1H), 8.35 (s, 1H), 8.08 (s, 1H), 7 .87 (s, 1H), 7.77 (s, 1H), 7.24 (d, 1H), 7.16 (d, 2H), 4.14-4.00 (m, 2H), 3, 90 (s, 3H), 3.84 (s, 3H), 2.27 (s, 3H) 230 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.80 (t, 1H), 8.63 (d, 1H), 8.39 (s, 1H), 8.16 (s, 1H), 7 .91 (s, 1H), 7.82 (s, 1H), 7.26 (d, 1H), 6.96 (s, 2H), 5.12 (s, 2H), 4.19 (q, 2H), 4.09-3.93(m, 2H), 3.83(s, 6H), 1.23(t, 3H) 266 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.81 (t, 1H), 8.62 (d, 1H), 8.35 (s, 1H), 8.08 (s, 1H), 7 .88 (s, 1H), 7.81 (s, 1H), 7.25 (d, 1H), 6.95 (s, 2H), 4.07-3.95 (m, 2H), 3, 90 (s, 3H) 291 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.19 (s, 1H), 8.61 (s, 1H), 8.39 (s, 1H), 7.96 (s, 2H), 7 .64 (dd, 2H), 7.46-7.06 (m, 3H), 3.88 (s, 3H)

EXAMPLES OF BIOLOGICAL ACTIVITY STUDIES

Example 3 In Vitro Studies

3.1. Biochemical research

3.1.1. Kinase radioisotope analysis using ³³ P

3.1.1.1. General information

The principle of ³³ P kinase radioisotope assay is to measure the ³³ P introduced into the AMARA peptide substrate during phosphorylation by SIK1, SIK2, or SIK3 using [ ³³ P]-g-ATP, which correlates with kinase activity.

3.1.1.2. Protocol

[0622] To construct a 10-point dose-response curve, test compounds are prepared as serial dilution solutions in 100% DMSO in 1/5 dilution steps, starting with the highest concentration of 2 mM diluted 1/20 in water, and transferred over 5 µl into assay plates (Greiner, Cat# 651201).

[0623] Final concentrations of 1% DMSO and 10 μM staurosporine are used as negative and positive controls.

[0624] 11 μl of the enzyme-substrate mixture is added to the assay plates. Reactions are initiated by adding to the plates a mixture of 9 μl of ATP, consisting of unlabeled and ³³ P-labeled ATP. The plates are incubated at 30° C. for the time intervals shown in Table V.

Table V. Conditions for radioisotope analysis of human SIK kinase using ³³ P

Kinase, [Kinase] Substratum, [Substratum] ATP Analysis Buffer Incubation time SIK1 (Carna Biosciences, Cat# 02-131), 0.4 ng/mL AMARA (SignalChem, Cat# A11-58), 7 µM 10 μM ATP +
0.25 µCi/25 µL [γ- ³³ P]ATP 25 mM Tris pH 7.5
0.01% Triton X-100
0.5 mM EGTA
2.5mM DTT
10 mM MgCl ₂ 120 min SIK2 (ThermoFisher Scientific, Cat# PV4792), 0.0532 ng/mL AMARA (SignalChem, Cat# A11-58), 5 µM 10 μM ATP +
0.25 µCi/25 µL [γ- ³³ P]ATP 25 mM Tris pH 7.5
0.01% Triton X-100
0.5 mM EGTA
5 mM MgCl ₂
2.5mM DTT 120 min SIK3 (SignalChem, Cat# S12-11G-100), 0.4 ng/mL AMARA (SignalChem, Cat# A11-58), 7 µM 15 μM ATP +
0.50 µCi/25 µL [γ- ³³ P]ATP 25 mM MOPS pH 7.5
0.01% Triton X-100
0.5 mM EGTA
5 mM MgCl ₂ 80 min

[0625] Reactions are stopped by adding 25 µl of phosphoric acid (150 mM) to the reaction medium.

[0626] The products of completely interrupted kinase reactions are transferred using a collector to pre-moistened UniFilter-96 plates (UniFilter-96 GF/B, PerkinElmer Inc., Cat#6005177).

[0627] After collecting the products of kinase reactions, the filter plates are washed 6 times with phosphoric acid (75 mm). The bottom of the UniFilter-96 plates are sealed and 40 µl of MicroScint-20 (PerkinElmer Inc., Cat#6013621) is added to each well. The top of the plate is sealed with TopSeal-A. The reading is carried out on a TopCount instrument (PerkinElmer Inc.).

3.1.1.3. Data analysis and results

[0628] After reading on the TopCount instrument, the initial data for plotting dose-response curves to calculate the percent inhibition (PIN) and the average IC ₅₀ value for each SIK homologue are obtained, which are presented in the table below.

Table VI. IC ₅₀ values for exemplary compounds of the invention obtained from radioisotope analysis of SIK kinase using ³³ P

* > 500 nM ** > 100 - 500 nM *** > 10 - 100 nM **** 0.01 - 10 nM NA did not define cpd
No. SIK1 IC ₅₀ SIK2 IC ₅₀ SIK3 IC ₅₀ one *** *** *** 2 ** ** *** 3 *** *** *** four *** *** *** 5 ** *** *** 6 *** *** *** 7 *** *** *** eight ** *** ** 9 *** *** *** ten *** **** **** eleven *** **** **** 12 *** **** **** 13 *** *** *** fourteen *** **** *** fifteen *** **** **** 16 *** *** *** 17 *** **** **** eighteen *** *** *** 19 *** **** **** twenty *** **** *** 21 *** **** **** 22 *** *** *** 23 *** *** *** 24 *** **** *** 25 *** **** **** 26 *** *** *** 27 * * * 28 * * * 29 *** *** *** thirty * * * 31 ** ** *** 32 *** *** *** 33 **** **** **** 34 *** **** *** 35 ** ** *** 36 ** *** *** 37 ** ** ** 38 ** *** *** 39 ** *** *** 40 *** **** **** 41 *** **** **** 42 **** **** **** 43 * * * 44 *** *** *** 45 *** *** *** 46 **** **** **** 47 *** *** **** 48 *** **** **** 49 *** *** *** fifty *** **** **** 51 *** *** *** 52 *** **** *** 53 **** **** **** 54 *** **** **** 55 **** **** **** 56 **** **** **** 57 *** **** **** 58 *** *** *** 59 *** *** *** 60 *** *** ** 61 * ** * 62 ** ** ** 63 ** *** *** 64 ** *** *** 65 ** *** *** 66 ** ** ** 67 ** ** ** 68 * * ** 69 ** ** ** 70 ** *** ** 71 ** *** ** 72 *** *** *** 73 * ** ** 74 ** ** *** 75 *** **** **** 76 * * * 77 *** *** *** 78 *** **** **** 79 *** **** **** 80 *** **** *** 81 ** ** ** 82 ** ** ** 83 ** ** ** 84 *** **** **** 85 *** **** **** 86 *** **** **** 87 *** *** *** 88 **** **** **** 89 *** *** *** 90 *** *** *** 91 *** *** *** 92 *** *** *** 93 ** *** *** 94 **** **** **** 95 *** **** **** 96 *** **** **** 97 *** **** **** 98 *** **** **** 99 **** **** **** 100 *** **** **** 101 *** **** **** 102 **** **** **** 103 **** **** **** 104 * ** ** 105 * * ** 106 ** *** *** 107 *** **** **** 108 ** ** ** 109 *** *** *** 110 *** **** **** 111 **** **** **** 112 **** **** **** 113 *** *** *** 114 ** ** ** 115 *** *** *** 116 **** **** **** 117 **** **** **** 119 ** ** ** 120 *** *** **** 121 * ** *** 122 **** **** **** 123 *** **** **** 124 **** **** **** 125 *** *** *** 126 * * * 127 * ** ** 128 * * ** 129 *** **** **** 130 *** **** *** 131 * ** ** 132 *** *** *** 133 **** **** **** 134 * *** ** 135 * ** ** 136 * * * 137 *** **** *** 138 * ** ** 139 **** **** **** 140 *** *** *** 141 *** *** *** 142 *** *** *** 143 ** *** *** 144 **** **** **** 145 *** *** *** 146 ** *** *** 147 **** **** **** 148 **** **** **** 149 **** **** **** 150 * * * 151 **** **** **** 152 *** *** *** 153 *** *** *** 154 ** ** ** 155 ** *** *** 156 *** *** *** 157 *** *** *** 158 *** **** **** 159 *** *** *** 160 *** *** *** 161 * * * 162 ** ** *** 163 *** *** *** 164 ** ** * 165 * * * 166 * * ** 167 * * ** 168 * * * 169 * * * 170 *** **** **** 171 *** *** *** 172 *** **** **** 173 *** **** **** 174 **** **** **** 175 * ** ** 176 *** *** *** 177 *** *** *** 178 *** **** **** 179 *** *** *** 180 *** ** ** 181 * * * 182 * * * 183 ** ** ** 184 ** ** ** 185 ** ** * 186 *** ** ** 187 * * * 188 * * * 189 * * * 190 *** *** ** 191 ** ** ** 192 *** *** *** 193 * * * 194 ** *** ** 195 ** ** ** 196 * * * 197 * * * 198 ** * ** 199 * * * 200 *** *** *** 201 * *** ** 202 ** ** * 203 *** **** **** 204 **** **** **** 205 *** **** **** 206 *** *** *** 207 *** **** **** 208 **** **** **** 209 **** **** **** 210 *** *** **** 211 *** *** *** 212 ** *** ** 213 **** **** **** 215 *** **** **** 216 ** *** ** 217 *** *** *** 218 *** *** ** 219 **** **** **** 220 *** *** *** 221 *** *** *** 222 **** **** **** 223 *** *** *** 224 ** ** ** 225 *** **** **** 226 *** *** *** 227 **** **** **** 228 **** **** **** 229 **** **** **** 230 **** **** **** 231 **** **** **** 232 *** **** **** 233 *** **** **** 234 **** **** **** 235 **** **** **** 236 **** **** **** 237 **** **** **** 238 **** **** **** 239 *** **** **** 240 ** *** **** 241 ** ** *** 242 ** ** *** 243 **** **** **** 244 **** **** **** 245 *** *** **** 246 *** *** **** 247 *** *** **** 248 *** **** **** 249 ** *** *** 250 ** *** *** 251 **** **** **** 252 ** *** **** 253 * * ** 254 **** **** **** 255 **** **** **** 256 **** **** **** 257 **** **** **** 258 * * ** 259 * * ** 260 **** **** **** 261 *** **** **** 262 *** **** **** 263 **** **** ****

3.1.2. Kinase Assay with ADP-Glo™ Kinase ATP Kinase Activity Kit

3.1.2.1. General information

[0629] The kinase assay using the ADP-Glo ^TM kit is a luminescent assay that measures the ADP generated from the kinase reaction. In this specific study, kinase reactions involved phosphorylation of the peptide substrate AMARA (SignalChem, Cat#A11-58) by SIK1 (Carna Biosciences, Cat# 02-131), SIK2 (ThermoFisher Scientific, Cat# PV4792) or SIK3 (SignalChem, Cat #S12-11G-100). In the second step, the kinase reactions are interrupted and all remaining ATP is depleted. In the final step, ADP is converted to ATP and this newly synthesized ATP is measured using the luciferase/luciferin reaction. The generated radiation is measured on an Envision tablet reader, where the resulting luminescent signal positively correlates with kinase activity.

3.1.2.2. Protocol

[0630] To construct a 10-point dose-response curve, test compounds are prepared as serial dilution solutions in 100% DMSO in 1/5 dilution steps, starting with the highest concentration of 2 mM diluted 1/20 in water, and transferred over 1 µl into assay plates (PerkinElmer Inc., Cat# 6007290).

[0631] Final concentrations of 1% DMSO and 10 μM staurosporine are used as negative and positive controls.

[0632] Add 2 µl of the enzyme-substrate mixture to the assay plates.

[0633] The reaction is initiated by adding 2 μl of diluted ATP to the plates. The plates are centrifuged for a few seconds at 1000 rpm and shaken gently for 2 minutes, then incubated at room temperature for 120 minutes.

[0634] Reactions are stopped and unreacted ATP is exhausted by adding 5 μl of ADP-Glo reagent (Promega, Cat# V912B) to the reaction mixture. The plates are centrifuged for a few seconds at 1000 rpm and incubated at room temperature for 40 minutes (ATP exhausted).

[0635] ADP is converted to ATP and luciferase and luciferin are added to detect ATP by adding 10 µl of Kinase Detection Reagent (Promega, Cat# V913B+V914B) to the reaction mixture. The plates are centrifuged for a few seconds at 1000 rpm and incubated at room temperature for 40 minutes (detection of ADP).

[0636] Luminescence is measured on an Envision plate reader (PerkinElmer Inc.).

Table VII. Conditions for the Human Kinase SIK Assay Using the ADP-Glo™ Reagent Kit

Kinase, [Kinase] Substratum, [Substratum] ATP Analysis Buffer Incubation time SIK1 (Carna Biosciences, Cat# 02-131), 0.25 ng/µl AMARA (SignalChem, Cat# A11-58), 45 µM 5 µM ATP (Promega, Cat# V915B) 25 mM Tris pH 7.5
0.01% Triton X-100
0.5 mM EGTA
2.5mM DTT
5 mM MgCl ₂ 120 min SIK2 (ThermoFisher Scientific, Cat# PV4792), 0.0625 ng/µl AMARA (SignalChem, Cat# A11-58), 45 µM 5 µM ATP (Promega, Cat# V915B) 25 mM Tris pH 7.5
0.01% Triton X-100
0.5 mM EGTA
5 mM MgCl ₂
2.5mM DTT 120 min SIK3 (SignalChem, Cat# S12-11G-100), 0.5 ng/µl AMARA (SignalChem, Cat# A11-58), 45 µM 5 µM ATP (Promega, Cat# V915B) 25 mM Tris pH 7.5
0.01% Triton X-100
0.5 mM EGTA
5 mM MgCl ₂
2.5mM DTT 120 min

3.1.2.3. Data analysis and results

[0637] After reading on the TopCount instrument, the initial data for plotting dose-response curves to calculate the percent inhibition (PIN) and the average IC ₅₀ value for each SIK homologue are obtained, which are presented in the table below.

Table VIII. IC values _fifty for exemplary compounds of the invention, obtained from a SIK kinase assay using the ADP-Glo™ reagent kit.

* > 500 nM ** > 100 - 500 nM *** > 10 - 100 nM **** 0.01 - 10 nM NA did not define cpd
No. SIK1 IC ₅₀ SIK2 IC ₅₀ SIK3 IC ₅₀ 53 **** **** **** 76 * * * 88 **** **** **** 98 **** **** **** 120 *** **** **** 133 **** **** **** 142 *** *** *** 172 **** **** **** 173 **** **** **** 174 **** **** **** 175 * ** ** 176 *** **** **** 177 *** **** **** 192 *** **** **** 201 ** *** *** 202 ** ** ** 204 **** **** **** 213 **** **** **** 215 *** **** **** 216 ** *** *** 225 **** **** **** 227 **** **** **** 230 **** **** **** 252 ** *** **** 258 * * *** 259 * * *** 260 **** **** **** 261 **** **** **** 262 **** **** **** 263 **** **** **** 264 **** **** **** 265 **** **** **** 266 **** **** **** 267 **** **** **** 268 * ** *** 269 *** **** **** 270 **** **** **** 271 ** **** *** 272 *** **** **** 273 *** **** **** 274 *** **** **** 275 *** **** **** 276 *** **** **** 277 **** **** **** 278 *** **** **** 279 **** **** **** 280 **** **** **** 281 *** **** **** 282 **** **** **** 283 **** **** **** 284 **** **** **** 285 **** **** **** 286 **** **** **** 291 **** **** **** 293 **** **** **** 294 **** **** **** 295 **** **** **** 296 **** **** **** 297 **** **** **** 298 **** **** **** 299 *** **** *** 300 *** **** *** 301 **** **** **** 302 *** *** *** 303 *** *** *** 304 **** *** **** 305 **** **** **** 306 **** **** **** 307 **** **** ****

3.2. Cellular analyzes

3.2.1. Peripheral blood mononuclear cell (PBMC) assay: liposaccharide (LPS)-induced tumor necrosis factor alpha (TNFα) (ELISA method)

3.2.1.1. General information

[0638] Inhibition of SIK results in inhibition of TNFα and an increase in IL-10 release in LPS-induced monocyte-derived macrophages (MdM) and dendritic cells (MdDCs) (Clark et al. 2012; Sundberg et al. 2014; Ozanne et al. 2015) .

[0639] This assay measures test compound inhibition of LPS-induced TNFα secretion in peripheral blood mononuclear cells (PBMCs), which in turn correlates with SIK inhibition.

3.2.1.2. Protocol

[0640] Peripheral blood mononuclear cells (PBMC) are isolated from human blood samples (buffy coats). The buffy coat is transferred under sterile conditions to a 50 ml Falcon ^™ tube and diluted 1/2 in phosphate buffered saline (PBS). Falcon tubes are filled with 20 ml of Lymphoprep medium (Axis-Shield, Cat# 1001967) and 25 ml of buffy coat. The tubes are centrifuged for 35 minutes at 400×g in a temperature controlled centrifuge without a brake step at 25°C. PBMC is aspirated from the white layer at the interface between the sample and the Lymphoprep medium. PBMC is washed five times in PBS. Cells are resuspended in RPMI 1640 complete medium supplemented with 10% FBS, 1% P/S and cell density determined using a hematology analyzer (Sysmex XS-500i). Finally, PBMCs are seeded at a density of 400,000 PBMCs/160 μl/96-well plate.

[0641] Dilution of the compound on the tablet is performed using 100% DMSO with a 3-fold dilution of 10 mm stock solution of the test compound. An intermediate dilution of the compound on the plate (10x final concentration) is carried out by diluting the compound on the plate 50 times in RPMI medium.

[0642] 20 μl of 10x the final concentration of the compound is added to the cells and incubated for 1 hour at 37°C, then add the trigger (initiating reagent). Conditions in the absence of a trigger/conditions in the presence of a trigger are supplemented with equal final concentrations of DMSO of 0.2% DMSO. 20 µl of a 10x LPS solution (final concentration 1 ng/ml) is added to all wells, except for "wells without a trigger", in which 20 µl of medium is added. After 18-20 hours, the supernatant is collected for the determination of IL-10 and TNFα by ELISA (enzyme-linked immunosorbent assay).

[0643] All wash steps in the ELISA assay for both TNFα (100 μl; 384-well plate) and IL-10 (200 μl/well; 96-well plate) are performed by filling the Multidrop dispenser and venting on absorbent paper; antibody/sample additions are made using a multichannel dispenser.

3.2.1.2.1. TNFα ELISA

[0644] In a Lumitrac 600 Greiner 384-well plate, 40 μl of immobilized antibody (BD Pharmingen, Cat#551220) was layered to a final concentration of 1 μg/ml in 1x PBS and stored overnight at 4°C.

[0645] The plate is then washed once with PBST (PBS + 0.05% Tween20) and once with PBS, then 100 μl of blocking buffer (1% bovine serum albumin (BSA) - 5% sucrose) is added, and plates sealed and incubated for at least 4 hours at room temperature. After washing the plate once with PBST and once with PBS, 40 µl of standard or sample is added (standard curve for TNFα is prepared by using 1/2 serial dilutions starting at 16,000 pg/ml; dilutions are made in dilution buffer (PBS +1% BSA)). The plates are washed twice with PBST and once with PBS, after which 35 µl of identifying antibody (0.25 µg/ml final concentration, diluted in dilution buffer) is added and the plates are incubated for at least 2 hours at room temperature. The plates are washed twice with PBST and once with PBS, after which 35 μl of Strep-HRP conjugate (0.5 μg/ml final concentration, diluted in dilution buffer) is added. The plates are incubated in the dark at room temperature for at least 45 minutes, but no longer than 1 hour. The plates are washed twice with PBST and once with PBS. Following this, 50 μl of luminol substrate (prepared according to the manufacturer's instructions) is added to each well and incubated for 5 minutes at room temperature, protected from light. Chemiluminescence is measured on an Envision 2104 plate reader.

3.2.1.3 Data analysis and results

3.2.1.3.1. Calculation of TNFα inhibition

[0646] To measure the inhibition of LPS-induced TNFα, calculate the percentage of inhibition (PIN) for all test concentrations compared to controls. Unstimulated samples (no trigger/medium (0.2% DMSO)) are used as a negative control (100% inhibition). Stimulated samples (trigger/environment) are used as a positive control (0% inhibition).

[0647] Where RLU=relative chemiluminescence light units (from which the background is subtracted) and the subscripts p and n refer to the mean of the positive and negative controls, respectively.

[0648] Using PIN values, a concentration-effect curve is plotted and EC ₅₀ values are calculated using GraphPad Prism Software using a fit (sigmoidal) curve fitting based on a four-parameter non-linear regression model. Due to the fact that no clear lower fee has been obtained, the lower part of the curve is assumed to be zero.

3.2.1.3.2. Data and results

[0649] The data obtained for typical compounds of the invention are presented in the table below.

Table IX. Inhibition of TNFα in PBMC using representative compounds of the invention.

* > 5000 nM ** > 1000 - 5000 nM *** > 100 - 1000 nM **** 0.01 - 10 nM NA did not define

3.2.2. Analysis of macrophages of monocytic origin (MdM): LPS-induced TNFα/IL-10 (ELISA method)

3.2.2.1. General information

[0650] SIK inhibition results in TNFα inhibition and increased IL-10 release in LPS-induced monocyte-derived macrophages (MdM) and dendritic cells (MdDCs) (Clark et al. 2012; Sundberg et al. 2014; Ozanne et al. 2015) . This assay evaluates the ability of exemplary compounds of the invention to inhibit LPS-induced TNFα and LPS-triggered IL-10 secretion in macrophages of monocytic origin.

3.2.2.2. Protocols

[0651] Peripheral blood mononuclear cells (PBMC) are isolated from human blood samples (buffy coats). The buffy coat is transferred under sterile conditions to a 50 ml Falcon ^™ tube and diluted 1/2 in phosphate buffered saline (PBS). Falcon tubes are filled with 20 ml of Lymphoprep medium, on top of which 25 ml buffy coat is carefully added, the tubes are centrifuged for 35 minutes at 400 xg in a temperature controlled centrifuge without a brake step at 25°C. The PBMC is aspirated from the white layer at the interface between the sample and the Lymphoprep™ medium. PBMC is washed five times in PBS. Cells are resuspended in RPMI 1640 complete medium supplemented with 10% FBS, 1% P/S and cell density determined using a hematology analyzer (Sysmex XS-500i).

[0652] PBMC centrifuged at 300 x g for 10 minutes and resuspended at a density of 1 x 10 ⁷ cells/80 μl of Miltenyi buffer (PBS, pH 7.4, 1% FBS, 2 mM EDTA).

3.2.2.2.1. Labeling positive CD14+ monocytes.

[0653] From this stage of the protocol, all stages are carried out on ice. Add 20 μl microspheres CD14+ 1.0·10 ⁷ cells, the contents of the tube are mixed and incubated for 15 minutes in a refrigerator at 4°C. The volume of the cell suspension is adjusted to a total volume of 100 ml using Miltenyi buffer, mixed gently, and then centrifuged for 10 minutes at 300×g. The supernatant is discarded and the cell pellet is resuspended in 12 ml of Miltenyi buffer.

3.2.2.2.2. Magnetic cell sorting

[0654] Four LS cell separation columns are placed in a Miltenyi Biotec MACS separator (magnetic) and pre-wetted by washing with 3 ml of MACS buffer per column. Three ml of cell suspension is added to the column (maximum 1 x 10 ⁸ labeled cells/column) and the columns are washed successively 3 times with 3 ml of Miltenyi buffer.

[0655] The columns are removed from the magnets and 5 ml of Miltenyi buffer is added to the column to flush out the CD14+ fraction by pushing the plunger in the column. The eluted fractions are collected in a fresh 50 ml Falcon tube and the volume is adjusted to 30 ml with Miltenyi buffer, the cells are centrifuged for 10 minutes at 300×g. The resulting cell pellet was resuspended in 10 ml of RPMI without FBS and the cell density was determined on a hematology analyzer (Sysmex XS-500i). 100,000 cells per well of a 96-well MdM differentiation plate are seeded in RPMI 1640 medium supplemented with 10% FBS, 1% P/S and 100 ng/ml rhM-CSF. On day 5, the medium is refreshed with 100 µl of RPMI 1640 medium supplemented with 10% FBS, 1% P/S and 100 ng/ml rhM-CSF.

[0656] On day 10, MdMs are initiated and a compound is added.

[0657] Dilution of the compound on the tablet is performed using 100% DMSO with a 3-fold dilution of 10 mm stock solution of the test compound. An intermediate dilution of the compound on the plate (10x final concentration) is carried out by diluting the compound on the plate 50 times in RPMI medium.

[0658] The medium is carefully removed from the cell plates using a multichannel pipette and replaced with 80 µl of fresh medium. Add 10 µl of 10x final compound concentration to cells and incubate for 1 hour at 37° C., then add trigger. Conditions in the absence of a trigger/conditions in the presence of a trigger are supplemented with equal final concentrations of DMSO of 0.2% DMSO. 10 µl of a 10x LPS solution (final concentration 200 ng/ml) is added to all wells, except for "wells without trigger", in which 10 µl of medium is added. After 2 hours, the supernatant was collected (IL-10 determination), and after 20 hours, LPS stimulation was performed (TNFα determination).

3.2.2.2.3. TNFα ELISA

[0659] In a Lumitrac 600 Greiner 384-well plate, 40 μl of immobilized antibody (BD Pharmingen, Cat#551220) was layered to a final concentration of 1 μg/ml in 1x PBS and stored overnight at 4°C.

[0660] The plate is then washed once with PBST (PBS + 0.05% Tween20) and once with PBS, then 100 μl of blocking buffer (1% bovine serum albumin (BSA) - 5% sucrose) is added, and plates sealed and incubated for at least 4 hours at room temperature. After washing the plate once with PBST and once with PBS, 40 µl of standard or sample is added (standard curve for TNFα is prepared by using 1/2 serial dilutions starting at 16,000 pg/ml; dilutions are made in dilution buffer (PBS +1% BSA)). The plates are washed twice with PBST and once with PBS, after which 35 µl of identifying antibody (0.25 µg/ml final concentration, diluted in dilution buffer) is added and the plates are incubated for at least 2 hours at room temperature. The plates are washed twice with PBST and once with PBS, after which 35 μl of Strep-HRP conjugate (0.5 μg/ml final concentration, diluted in dilution buffer) is added. The plates are incubated in the dark at room temperature for at least 45 minutes, but no longer than 1 hour. The plates are washed twice with PBST and once with PBS. Following this, 50 μl of luminol substrate (prepared according to the manufacturer's instructions) is added to each well and incubated for 5 minutes at room temperature, protected from light. Chemiluminescence is measured on an Envision 2104 plate reader.

3.2.2.2.1. IL-10 ELISA

[0661] In a 96-well Immulon 2HB plate (Thermo Electron Co., Cat#3455), a layer of 40 μl of conjugated antibody (final concentration 2 μg/ml, diluted in Tris buffer (50 mM Tris; 150 mM NaCl; pH 9) is applied (corrected with HCl)) and stored overnight at 4° C. The next day, the plate is washed three times with PBST and then 200 µl blocking buffer (1% BSA+5% sucrose in PBS-T) is added. After incubation for 30 minutes at 37°C, the plate is washed three times with PBST and 100 µl of standard or sample is added (a standard curve for IL-10 samples is prepared using a 1/2 serial dilution starting at 1000 pg/ml; dilutions are carried out in dilution buffer: PBS + 1% BSA) After 1 hour incubation at 37°C, the plates are washed three times with PBST, after which 100 μl of identification antibody (BD Pharmingen, Cat#554499) is added (final concentration 0 .25 µg/ml diluted in Tris buffer) and the plates are incubated for at least 2 hours at room temperature. The plates are washed three times with PBST, after which 100 μl of Strep-HRP conjugate (0.5 μg/ml final concentration, diluted in dilution buffer) is added. The plates are incubated in the dark at 37°C for 30 minutes. The plates are washed three times with PBST. Prepare a substrate solution with a total volume of 20 ml, mix 18 ml H ₂ O, 2 ml citrate acetate buffer, 200 μl of a mixture of TMB (tetramethylbenzidine (TMB) 101 mg, DMSO 10 ml, stored at 4°C), 2.5 µl 30% H ₂ O ₂ . Add 100 µl of substrate solution to each well and incubate until a bright blue color appears. The reaction is stopped by adding 50 μl of a 1 MH ₂ SO ₄ solution, after which the absorbance at 450 nm is measured on a SpectraMax i3 plate photometer from Molecular Devices.

3.2.2.3. Data analysis and results

3.2.2.3.1. Calculation of TNFα inhibition

[0662] To measure the inhibition of LPS-induced TNFα, calculate the percentage of inhibition (PIN) for all test concentrations compared to controls. Unstimulated samples (no trigger/medium (0.2% DMSO)) are used as a negative control (100% inhibition). Stimulated samples (trigger/environment) are used as a positive control (0% inhibition).

[0663] Where RLU=relative chemiluminescence light units (from which the background is subtracted) and the subscripts p and n refer to the mean of the positive and negative controls, respectively.

[0664] Using PIN values, a concentration-effect curve was plotted and EC ₅₀ values were calculated using GraphPad Prism Software using a fit (sigmoidal) curve fitting based on a four-parameter non-linear regression model. Due to the fact that no clear lower fee has been obtained, the lower part of the curve is assumed to be zero.

3.2.2.3.2. Calculation of IL-10 induction

[0665] After inhibition of SIK, IL-10 is induced. Numerically evaluate the fold change of these inductions (FC) compared to the case "in the presence of only LPS" for each test concentration, and calculate the maximum value of FC (IL-10 FCmax):

where ABS=absorbance measured at 450 nm.

[0666] Provides the mean maximum FC for test compounds for two or more assays performed (IL-10FCmax mean).

3.2.2.3.3. Data and results

[0667] The data obtained for typical compounds of the invention are presented in the table below.

Table X. MdM TNFα inhibition and IL-10 induction using exemplary compounds of the invention.

* > 5000 nM + ≤ 1.5 ** > 1000 - 5000 nM ++ > 1.5-4.5 *** > 100 - 1000 nM +++ > 4.5 **** 0.1 - 100 nM NA did not define

Example 4 In Vivo Studies

4.1. inflammatory bowel disease

4.1.1. Mouse model of dextran sodium sulfate (DSS)-induced inflammatory bowel disease

[0668] The dextran sodium sulfate (DSS) mouse model of inflammatory bowel disease (IBD) is a well established model for inflammatory bowel disease (Wirtz et al. 2007; Sina et al. 2009).

[0669] To induce chronic colitis, female BALB/c mice are given 4% dextran sodium sulfate (DSS) dissolved in drinking water for 4 days, followed by normal drinking water for 3 days. This cycle is repeated three times. This protocol allows the induction of severe colitis while avoiding a high mortality rate. Animals are divided into several groups:

a. intact water; Wednesday only, n=10),

b. sick (DSS; Wednesday only, n=10),

c. sulfasalazine used as reference compound (DSS; 20 mg/kg/day, po, n=10) and

d. test compound (DSS; 1, 3, 10, 30 mg/kg/day, po, n=10).

[0670] Clinical parameters are measured every other day. The disease activity index (DAI) is a composite score that combines individual scores for weight loss, stool consistency, and rectal bleeding. Mice are sacrificed on day 20 of the experiment according to the protocol introduced by Sina et al. (Sina et al. 2009). At the time of sacrifice, the colon is completely removed and washed with sterile PBS. Excised segments of the distal colon for histological analysis, measurement of gene expression and protein levels.

4.2. Model of collagen-induced arthritis (CIA)

4.2.1. materials

[0671] Complete Freund's Adjuvant (CFA) and Incomplete Freund's Adjuvant (IFA) were purchased from Difco. Bovine collagen type II (CII), lipopolysaccharide (LPS) and Enbrel were obtained from Chondrex (Isle d'Abeau, France), Sigma (P4252, L'Isle d'Abeau, France), Whyett (25 mg injection syringe, France ), respectively. All other reagents used were of "chemically pure" purity and all solvents were of "assay" purity.

4.2.2. Animals

[0672] DBA1/J mice (male, 7-8 weeks old) were purchased from Charles River Laboratories (France). Mice were kept on a 12-hour light-dark cycle (0700-1900). The temperature was maintained at 22°C, and provided access to food and water without restriction.

4.2.3. Collagen-induced arthritis (CIA)

[0673] One day before the start of the experiment, a solution of CII (2 mg/ml) was prepared with 0.05 M acetic acid and stored at 4 ºC. Immediately prior to immunization, equal volumes of adjuvant (IFA) and CII were mixed with a homogenizer in a pre-chilled glass bottle in an ice water bath. Additional adjuvant and longer homogenization may be required if emulsion formation does not occur. 0.2 ml of the emulsion was injected intradermally into the base of the tail of each mouse on day 1, and a second transdermal boost (CII solution at 2 mg/ml in CFA 0.1 ml saline) was given on day 22. This immunization method was modified from published methods (Jou et al. 2005; Sims et al. 2004).

4.2.4. Study Design

[0674] The therapeutic effects of the compounds were studied in a collagen-induced arthritis (CIA) mouse model. Mice were divided randomly into equal groups, and each group contained 10 mice. All mice were immunized on day 1 and boosted on day 22. The negative control group was injected with medium (MC 0.5%) and the positive control group was injected with Enbrel (10 mg/kg, 3 times a week, subcutaneously). The compound of interest was tested at 3 oral (p.o.) doses. On day 32, randomization was performed between groups taking into account the clinical score, and the animals were treated according to their group until day 47. Body weight and clinical score were recorded twice a week.

4.2.5. Clinical Assessment of Arthritis

[0675] Arthritis is scored according to the method described in Khachigian 2006, Lb Et al 2007 and Nishida et al. 2004 (Khachigian 2006; Lb et al. 2007; Nishida et al. 2004). Swelling in each of the four paws is ranked based on arthritis score as follows: 0, no symptoms; 1 - Mild presentation, but the presence of some redness and swelling of one type of joint, such as the ankle or wrist, or severe redness and swelling limited to individual fingers, regardless of the number of fingers affected; 2 - moderate redness and swelling of two or more types of joints; 3 - severe form of redness and swelling of the entire paw, including fingers; 4 - maximum degree of inflammation of the limb with the involvement of multiple joints (maximum cumulative clinical score of arthritis 16 points for one animal) (Nishida et al. 2004).

4.2.5.1. Change in body weight (%) after the onset of arthritis

[0676] Clinically, weight loss has been associated with arthritis (Argilés & López-Soriano 1998; Rall & Roubenoff 2004; Shelton et al. 2005; Walsmith et al. 2004). In this regard, changes in body weight after the onset of arthritis can be used as a non-specific expected manifestation to evaluate the effect of therapeutic drugs in a mouse model. The change in body weight (%) after the onset of arthritis was calculated using the following formula:

Mice:

4.2.5.2. X-ray examination

[0677] X-rays were taken of the hind legs of each individual animal. Each X-ray image was randomly blinded with an identification number, and the severity of bone erosion was ranked by two independent experts using a Larsen scoring system based on X-ray data as follows: 0 - normal condition with intact bone outlines and normal joint space ; 1 - a mild form of anomaly in any one or two of the external metatarsal bones, characterizing a slight erosion of the bone; 2 - a well-defined early anomaly of any three to five external metatarsal bones, characterizing bone erosion; 3 - the average form of a destructive anomaly of all external metatarsal bones, as well as any one or two internal metatarsal bones, characterizing well-defined bone erosions; 4 - a severe form of a destructive anomaly of all metatarsal bones, which characterizes a pronounced erosion of the bone and complete destruction of at least one of the internal metatarsal joints, with partial preservation of some contours of the bone joint; 5 - crippling anomaly without outlines of the bone. This scoring system is a modification of the scoring described in Salvemini et al., 2001; Bush et al., 2002; Sims et al., 2004; Jou et al., 2005 (Bush et al. 2002; Jou et al. 2005; Salvemini et al. 2001; Sims et al. 2004).

4.2.5.3. Pharmacokinetics at steady state

[0678] On day 42, blood samples were collected in the retroorbital cavity using lithium heparin as an anticoagulant at the following time points: before dosing, 1, 3 and 6 hours. Whole blood samples were centrifuged and the resulting plasma samples were stored at -20°C until used for analysis. Plasma concentrations of each test compound were determined by liquid chromatography with tandem mass spectrometry (LC-MS/MS), in which the mass spectrometer was operated in electrospray mode with positive ion detection.

4.2.6. results

[0679] When tested in accordance with this protocol, the following data were obtained:

Table XI. Clinical scoring in the collagen-induced arthritis (CIA) mouse model CIA-2144

Day 32 33 34 35 36 39 40 41 42 43 46 Placebo treated group 2.5 2.7 3.7 3.6 4.2 5.0 4.8 5.8 6.0 7.2 8.2 standard error of the mean 0.4 0.6 0.7 0.7 0.8 0.8 0.8 1.1 1.0 1.1 1.2 p-value ns ns ns ns ns ns ns ns ns ns ns Enbrel
(10 mg/kg 3 times a week) 2.5 2.4 2.9 2.7 2.5 3.0 2.5 2.7 2.8 2.9 2.9 standard error of the mean 0.3 0.3 0.5 0.4 0.4 0.4 0.4 0.5 0.4 0.5 0.6 p-value ns ns ns ns ns ns ns * * ** ** cpd 53
(2 mg/kg twice a day) 2.4 2.6 3.1 3.6 3.5 4.4 5.0 6.6 6.8 7.7 7.7 standard error of the mean 0.3 0.4 0.6 0.7 0.7 1.0 0.9 1.1 1.0 1.2 1.3 p-value ns ns ns ns ns ns ns ns ns ns ns cpd 53
(5 mg/kg twice a day) 2.4 2.7 2.9 3.0 3.0 3.4 3.4 3.9 4.3 5.2 5.4 standard error of the mean 0.4 0.4 0.4 0.4 0.5 0.5 0.5 0.7 0.6 0.7 1.0 p-value ns ns ns ns ns ns ns ns ns ns ns cpd 53
(30 mg/kg twice a day) 2.4 2.7 2.8 3.5 3.5 3.5 3.6 3.6 3.6 3.7 3.8 standard error of the mean 0.3 0.4 0.5 0.7 0.7 0.7 0.7 0.8 0.6 0.7 0.7 p-value ns ns ns ns ns ns ns ns ns * *

ns: insignificant | p-values: *** (<0.001) - p-values: *** (<0.01) - p-values: *** (<0.05) vs placebo treated disease group using analysis of variance (ANOVA) and Dunnett's test.

4.3. Mouse model of psoriasis-like epidermal hyperplasia induced by topical applications of imiquimod, a TLR7/8 agonist. PsoIMQ-2165

4.3.1. materials

[0680] ^Aldara® cream with 5% imiquimod was purchased from MEDA.

[0681] Purified anti-mouse IL-12/IL-23 antibody p40 (C17.8) was obtained from eBioscience (catalog number 16 7123 85).

4.3.2. Animals

[0682] Balb/cJ mice (female, body weight 18-20 g) were obtained from Janvier Labs (France). Mice are housed on a 12 hour light/dark cycle (0700-1900). The temperature is maintained at 22 ± 2°C, food and water are provided ad libitum.

4.3.3. Study design

[0683] Study design based on Van der Fits L. et al. (van der Fits et al. 2009).

[0684] On the first day, the area around the two ears is shaved in mice under light anesthesia with isoflurane.

[0685] 30 mg of a commercially available cream containing imiquimod (Aldara 5% cream) is applied to both inner and outer surfaces of each ear for 4 consecutive days, corresponding to a daily dose of 1.5 mg of the active compound. Control animals were treated with the same amount of Vaseline.

[0686] Between day 1 and day 5, mice are dosed with test compound, 10 or 30 mg/kg, orally, twice a day, in 0.5% methylcellulose, then imiquimod is applied (on day 5, mice are dosed with only one times 2 hours before painless killing).

[0687] In the positive reference group, animals receive two intraperitoneal injections of anti-mouse IL-12/IL-23 antibody p40, 10 mg/kg, on day 1 and 3 days before day 1.

4.3.4. Disease assessment

[0688] The thickness of both ears is measured daily using a thickness gauge (Mitutoyo, Absolute Digimatic, 547 321). Body weight is assessed at the start of the experiment and at sacrifice. On day 5, 2 hours after the last dosing, the mice are sacrificed. The auricles are cut off, excluding cartilage. The auricles are weighed and then immersed in a vial containing 1 ml of RNAlater® solution to evaluate gene expression.

[0689] Results are expressed as mean ± standard error of the mean (SEM), and statistical analysis is performed using one-way analysis of variance (ANOVA) with Dunnett's post hoc test when compared with the imiquimod group.

4.3.5. Gene Expression Analysis

[0690] The ears are removed from the RNAlater® solution and placed in Trizol® after grinding with 1.4 mm ceramic beads in a Precellys homogenizer. The total RNA is then purified using the NucleoSpin® RNA kit. cDNA was prepared and quantitative PCR was performed using gene-specific primers from Qiagen using SYBR Green technology on a ViiA7 real-time PCR system (Applied Biosystems). Expression levels of each gene are calculated relative to the level of expression of the constitutive cyclophilin A gene. Data are expressed as the mean value ± standard error of the mean relative value. The statistical test used is ANOVA with Dunnett's post hoc test compared to the imiquimod group.

4.4. Mouse model of psoriasis-like epidermal hyperplasia induced by intradermal injections of IL-23 PsoCyt-2142

4.4.1. materials

[0691] Carrier-free recombinant murine IL-23 (14-8231) supplied by e-Bioscience.

4.4.2. Animals

[0692] Balb/cJ mice (female, body weight 18-20 g) were obtained from CERJ (France). Mice are housed on a 12 hour light/dark cycle (0700-1900). The temperature is maintained at 22 ± 2°C, food and water are provided ad libitum.

4.4.3. Study Design

[0693] The design of the study is based on the publication of Rizzo HL. et al. (Rizzo et al. 2011).

[0694] On the first day (D1), the area around the two ears is shaved in mice.

[0695] For 4 consecutive days (D1 - D4), mice are injected intradermally with a daily dose of mouse recombinant IL-23 (1 μg/20 μl in PBS/0.1% BSA) in the right ear concha and 20 μl of PBS/0, 1% BSA in the left ear concha under anesthesia with isoflurane inhalation.

[0696] From D1 to D5, mice are treated with test compound or placebo 1 hour prior to IL-23 injection.

4.4.4. Disease assessment

[0697] The thickness of both ears is measured daily using an automatic caliper. Body weight is assessed at the start of the experiment and at sacrifice. On the fifth day, 2 hours after the last dosing, the mice are sacrificed. The auricles are cut off, excluding cartilage. The auricles are placed in a vial containing 1 ml of RNAlater® solution.

[0698] At D4, also collect blood samples from the retroorbital cavity to determine the pharmacokinetic characteristics just before dosing (T0) and 1 hour, 3 hours, 6 hours after dosing.

[0699] The group contains 8 mice. Results are expressed as mean ± standard error of the mean (SEM) and statistical analysis is performed using one-way analysis of variance (ANOVA) with Dunnett's post hoc test compared to IL-23 and placebo groups.

4.4.5. Gene Expression Analysis

[0700] Half of the ears are removed from the ^RNAlater® solution and placed in ^Trizol® after grinding with 1.4 mm ceramic beads in a Precellys homogenizer. The total RNA is then purified using the NucleoSpin® RNA kit. cDNA was prepared and quantitative PCR was performed using gene-specific primers from Qiagen using SYBR Green technology on a ViiA7 real-time PCR system (Applied Biosystems). Expression levels of each gene are calculated relative to the level of expression of the constitutive cyclophilin A gene. Data are expressed as the mean value ± standard error of the mean relative value. The statistical test used is ANOVA with Dunnett's post hoc test compared to the IL-23 and placebo group.

4.5. Mouse model of systemic lupus erythematosus induced by skin application of imiquimod

4.5.1. materials

[0701] ^Aldara® 5% imiquimod cream was obtained from MEDA.

[0702] Anti-mouse double-stranded DNA antibody ELISA kits were purchased from Alpha Diagnostic International (catalog number 5120). Mouse urine albumin ELISA kits were purchased from Abcam (catalog number ab108792). Urinary creatinine assay kits were purchased from Abnova (part number KA4344).

4.5.2. Animals

[0703] Balb/cJ mice (female, body weight 18-20 g) were obtained from Janvier Labs (France). Mice are housed on a 12 hour light/dark cycle (0700-1900). The temperature is maintained at 22 ± 2°C, food and water are provided ad libitum.

4.5.3. Study Design

[0704] Study design based on Yokogawa M. et al. (Yokogawa et al. 2014).

[0705] On the first day (D1), mice shave the area around the right ears.

[0706] Mice are skin-applied with 1.25 mg of imiquimod 3 times a week on the right pinna for 12 consecutive w weeks (D1 - D86). In the control group, the same amount of Vaseline is applied.

[0707] From D1 to D86, mice are treated with test compound (30 mg/kg, orally, once daily in 0.5% methylcellulose) or placebo (10 ml/kg).

4.5.4. Disease assessment

[0708] The thickness of the ears is measured once a week using an automatic thickness gauge (Mitutoyo, Absolute Digimatic, 547-321).

[0709] Body weight is assessed at the beginning of the experiment and once a week until the moment of sacrifice. In necropsy, the mass of the spleen is also measured. Mice are sacrificed 2 hours after the last dosing.

[0710] At various time points (eg, days D28, D56, and D84), mice are individually placed in a metabolic cage for urine testing and assessment of proteinuria (albumin to creatinine ratio).

[0711] Sera are collected at various time points (eg, on days D28, D56, and D86) to assess anti-dsDNA IgG levels.

[0712] On day D13, also collect blood samples from the retroorbital cavity to determine the pharmacokinetic characteristics just before dosing (T0) and 1 hour, 3 hours, 6 hours after dosing.

[0713] The group contains 8-19 mice. Results are expressed as mean ± standard error of the mean (SEM) and statistical analysis is performed using one-way analysis of variance (ANOVA) with Dunnett's post hoc test when compared with imiquimod and placebo groups.

4.5.5. Plasma Compound Levels Quantification

[0714] Plasma concentrations of each test compound are determined by liquid chromatography with tandem mass spectrometry (LC-MS/MS), in which the mass spectrometer operates in electrospray mode with registration of negative ions.

4.5.5.1. Histopathology

[0715] For each glomerulus, score on a scale of 0 to 2 and then summarize 4 different measures, including mesangial proliferation, endocapillary proliferation, mesangial matrix expansion, and segmental sclerosis. For each kidney, approximately 50 glomeruli are scored and then the score is averaged to give one glomerular lesion score (Yokogawa et al. 2014). Data are expressed as mean ± standard error of the mean (SEM) and statistical analysis is performed using the Kruskal-Wallis test and then Dunn's post hoc test when compared with the imiquimod and placebo group.

4.5.5.2. Cell Quantification

[0716] For each cell type, an immunohistochemical study is performed using image analysis (CaloPix software, TRIBVN Healthcare) on a histological section of whole tissue at x20 microscope magnification. Data are expressed as mean ± standard error of the mean (SEM) and statistical analysis is performed using one-way analysis of variance (ANOVA) with Dunnett's post hoc test compared to the imiquimod and placebo group.

4.5.5.3. Gene Expression Analysis

[0717] At sacrifice, one half of the left kidneys are placed in tubes containing 1.4 mm ceramic beads and milled in 1% DTT RLT lysis buffer (Qiagen, cat no. 79216) using a ^Precellys® homogenizer from Bertin Instruments. The total RNA is then purified with a QIAcube using the ^RNeasy® 96 ^QIAcube® HT Kit (Qiagen, cat no. 74171). cDNA was prepared and qPCR was performed with Qiagen gene-specific primers using SYBR Green technology on a ViiA 7 real-time PCR system (Applied Biosystems). The expression levels of each gene of interest (GOI=CD3, CD68, CD20, OAS1, Mx1, IFIT1, CXCL11 and Usp18) are calculated relative to the expression levels of cyclophilin, GAPDH and β-actin of the constitutive gene.

[0718] At sacrifice, one third of the spleen is placed in tubes containing 1.4 mm ceramic beads and ground in ^Trizol® using a ^Precellys® homogenizer from Bertin Instruments. Extract total RNA using a phenol/chloroform mixture and then purify with a QIAcube using the ^RNeasy® 96 ^QIAcube® HT Kit (Qiagen, cat. no. 74171). cDNA was prepared and qPCR was performed with Qiagen gene-specific primers using SYBR Green technology on a ViiA 7 real-time PCR system (Applied Biosystems). The expression levels of each gene of interest are calculated relative to the expression levels of cyclophilin, GAPDH, and β-actin of the constitutive gene.

4.6. Mouse Model of Psoriatic Arthritis Induced by Overexpression of IL-23

4.6.1. materials

[0719] An enhanced mouse IL-23 episomal expression vector (EEV) is available from System Biosciences (catalog number EEV651A-1). Mouse IL-23 Quantikine ELISA Kits are available from R&D Systems (part number M2300). The ProSense® 680 and ^{OsteoSense® 750EX} Fluorescent Biosensors are available from PerkinElmer (part number NEV10003 and NEV10053EX). ^RNAlater® is obtained from Ambion (cat. no. AM7021). ^Imalgene® 1000 (Merial) and ^Rompun® 2% (Bayer) are available from Centravet (part number IMA004-6827812 and ROM001-6835444).

4.6.2. Animals

[0720] B10.RIII mice (male, 8 weeks old) are purchased from Charles River (France). Mice are housed on a 12 hour light/dark cycle (0700-1900). The temperature is maintained at 22 ± 2°C, food and water are provided ad libitum.

4.6.3. Study Design

[0721] Study design based on Sherlock JP. et al. (Sherlock et al. 2012).

[0722] On the first day (D1), mice are hydrodynamically injected into the tail vein with Ringer's solution or IL-23 EEV in Ringer's solution.

[0723] Starting from day D5, clinical symptoms are scored twice a week throughout the duration of the experiment.

[0724] On day D5, blood is collected by puncture in the submandibular vein to assess the concentration of IL-23 in the blood serum.

[0725] On day D9, mice of all groups are injected with the ProSense ^® 680 biosensor (0.8 nmol/10 g, ip). On day D10, mice are anesthetized by intraperitoneal injection of imalgen and rompun. The granulocyte infiltration is then measured using in vivo molecular imaging (Bruker In-Vivo Xtreme Imaging System).

[0726] On day D11, randomization is performed based on ^ProSense® 680 molecular imaging data and scores.

[0727] Beginning on day D12, mice are treated with test compound or placebo.

[0728] On day D19, blood samples are collected at times T0, T 1 hour, T 3 hours, and T 6 hours after the last dosing. Separate plasma and store at 20°C until bioassay.

[0729] On day D36, mice from all groups are sacrificed 2 hours after the last administration of the compound.

[0730] Collect whole blood in a serum tube and mix by gently inverting 8-10 times. After coagulation, blood samples are centrifuged for 10 minutes at 1800 x g. After centrifugation, serum is stored at -80°C.

4.6.4. Disease assessment

[0731] Body weight is assessed at the beginning of the study, then twice a week and at sacrifice.

[0732] Twice a week, score clinical signs of inflammation: 0 for a normal paw; 1 - in case of swelling of one finger; 2 - in case of swelling of two or more fingers; 3 - in case of swelling of the entire paw. The scores for all limbs are summed up to obtain a total score.

[0733] On day D32, mice of all groups are injected with the ProSense ^® 680 biosensor (0.8 nmol/10 g, ip) and the OsteoSense ^® 750EX biosensor (0.8 nmol/10 g, ip). On day D33, mice are anesthetized by intraperitoneal injection of imalgen and rompun. Granulocyte infiltration and bone remodeling are measured using in vivo molecular imaging (Bruker In-Vivo Xtreme Imaging System).

[0734] The group contains 10 mice. Results are expressed as mean ± standard error of the mean (SEM) and statistical analysis is performed using one-way analysis of variance (ANOVA) with Dunnett's post hoc test when compared with placebo groups for scoring and image analysis, and when compared with the sham placebo group for body weight.

CONCLUDING REMARKS

[0735] Those skilled in the art will appreciate that the above descriptions are exemplary and explanatory in nature and are intended to illustrate the invention and its preferred embodiments. For any person skilled in the art it is obvious that as a result of ordinary experiments can be made obvious modifications and changes without deviating from the essence of the invention. It is intended that all such modifications not contrary to the appended claims are included within the scope of the invention. Thus, the invention is intended to be defined not only by the above description, but by the following claims and their equivalents.

[0736] The entire contents of all publications, including patents and patent applications, cited in the specification of this invention are incorporated herein by reference, as well as when the entire contents of each individual specifically cited publication is incorporated herein. invention by reference to it.

[0737] It should be borne in mind that factors such as the different ability of different compounds to penetrate into cells, can lead to discrepancies between the activity of compounds found in in vitro biochemical studies and cellular studies.

[0738] At least some of the chemical names of the compounds of the invention that are given and presented in the present invention could be generated automatically using a commercially available computer program for naming chemicals, and have not been independently verified. Typical programs that perform this function include the Lexichem Naming Tool supplied by Open Eye Software, Inc. and the Autonom Software Tool supplied by MDL, Inc. In the event that the indicated chemical name and the depicted structure differ, the depicted structure will take precedence.

CITATED LITERATURE

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Claims (117)

1. Compound corresponding to formula I

, where X represents N or CR ⁴ ; one of Y ₁ , Y ₂ and Y ₃ is N and the other two are C; Z represents - -NR ^5a R ^5b , - -NR ^5c -, where the atom N and R ^3b together with the atoms to which they are attached, form a fused 5-6-membered heterocycloalkenyl, including one double bond and including, in addition, zero, one or two additional heteroatoms, independently selected from N, O and S, or N-linked 4-7 membered heterocycloalkyl further comprising zero, one or two additional heteroatoms independently selected from N, O and S, optionally substituted with one, two or three R ⁶ groups; R ¹ is H, halogen, C _1-4 alkyl or C _1-4 alkoxy optionally substituted with C _1-4 alkoxy, phenyl, -CN, -C(=O)OH or -C(=O)- C _1-4 alkoxy; R ² is imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, each of which is optionally substituted with one or more independently selected R ⁷ groups; R ^3a and R ^3b are independently selected from - halogen, - C _1-4 alkyl, - C _1-4 alkoxy, optionally substituted with one or more selected halogens, -OH or C _1-4 alkoxy, - -NR ^8a R ^8b and - -OH; R ⁴ is H; R ^5a is H or C _1-4 alkyl; R ^5b choose from - C _1-6 alkyl, optionally substituted with one or more selected R ⁹ , - C _3-7 cycloalkyl, optionally substituted with one or more selected R ¹⁰ , - 4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O and S, where the heterocycloalkyl is optionally substituted with one or more oxo, and - 5-6-membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O and S, where the heteroaryl is optionally substituted with one or more independently selected C _1-4 alkyl; R ^5c is selected from C _3-7 cycloalkyl and C _1-6 alkyl optionally substituted with one or more independently selected halo; each R ⁶ is independently selected from - oxo, - halogen, - -CN, - -OH, - -NR ^11a R ^11b , - phenyl, - C _3-7 cycloalkyl, - C _2-4 alkynyl, - -C(=O)-C _1-4 alkoxy, - C _1-4 alkoxy, optionally substituted with one or more halo or phenyl, - C _1-4 alkyl optionally substituted with one or more halo, -OH or C _1-4 alkoxy, and - 4-7-membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S; each R ⁷ choose from - halogen, - -CN, - C _1-6 alkyl optionally substituted with one or more independently selected - - halogen, - - -CN, - - -OH, - - C _1-4 alkoxy, optionally substituted with one or more selected halogens, - - -NR ^11c R ^11d , - - -C(=O)R ¹² or - - 4-6-membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S, - C _1-4 alkoxy, - C _3-7 cycloalkyl, - azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl or piperazinyl, each substituted with -C(=O)C _1-4 alkoxy or C _1-4 alkyl optionally substituted with -CN, - -NR ^13a R ^13b and - -C(=O)NR ^13c R ^13d ; each R ^8a and R ^8b is independently selected from H and C _1-4 alkyl optionally substituted with one -OH or C _1-4 alkoxy; each R ⁹ is independently selected from - halogen, - -CN, - -NR ^11e R ^11f , - -OH, - C _1-4 alkoxy, - -S(=O) ₂ -C _1-4 alkyl, - 4-7-membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S, and - 5-6-membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O and S, where the heteroaryl is optionally substituted with one or more independently selected C _1-4 alkyl; each R ¹⁰ is independently selected from - halogen, - C _1-4 alkyl optionally substituted with one or more independently selected halo, -OH or C _1-4 alkoxy, - -OH, - C _1-4 alkoxy and - -NR ^11g R ^11h ; each R ^11a , R ^11b , R ^11c , R ^11d , R ^11e , R ^11f , R ^11g and R ^{11h is} independently selected from H and C _1-4 alkyl; each R ¹² represents - -NR ^14a R ^14b , where each R ^14a and R ^14b are independently selected from H and C _1-4 alkyl, - -OH, - C _1-4 alkoxy optionally substituted with one or more selected C _3-7 cycloalkyl, halogen, -NR ^15a R ^15b or 4-6 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S - -O- (4-6-membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S) or - -O-(C _3-7 monocyclic cycloalkyl); each R ^13a , R ^13b , R ^13c and R ^13d are independently selected from H and C _1-4 alkyl; each R ^15a and R ^15b is independently selected from H and C _1-4 alkyl. 2. Connection according to claim 1, where R ¹ is H, halogen, C _1-4 alkyl or C _1-4 alkoxy optionally substituted with C _1-4 alkoxy; each R ⁷ choose from - halogen, - -CN, - C _1-4 alkyl optionally substituted with one or more independently selected - - halogen, - - -CN, - - -OH, - - C _1-4 alkoxy, optionally substituted with one or more selected halogens, - - -NR ^11c R ^11d , - - -C(=O)R ¹² or - - 4-6-membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S, - C _1-4 alkoxy, - C _3-7 cycloalkyl, - azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl or piperazinyl, each substituted with -C(=O)C _1-4 alkoxy or C _1-4 alkyl optionally substituted with -CN, - -NR ^13a R ^13b and - -C(=O)NR ^13c R ^13d ; each R ¹² represents - -NR ^14a R ^14b , where each R ^14a and R ^14b are independently selected from H and C _1-4 alkyl, - -OH, - C _1-4 alkoxy, optionally substituted with one or more selected C _3-7 cycloalkyl or halogen, - -O-(4-6 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, O and S) or - -O-(C _3-7 monocyclic cycloalkyl). 3. The compound according to claim 1 or 2, where the compound corresponds to any one of the formulas Va-Vf:

4. Connection according to paragraphs. 1, 2 or 3, where R ⁷ is C _1-4 alkyl. 5. Connection according to any one of paragraphs. 1-4, where R ^3b is -O-CH ₃ , -O-CH ₂ CH ₃ , or -O-CH(CH ₃ ) ₂ , each of which is optionally substituted with one or more independently selected halo, -OH, or C _1-4 alkoxy. 6. Connection according to any one of paragraphs. 1-5, where R ^3a is halogen, -OH, C _1-4 alkoxy, C _1-4 alkoxy substituted with one or more independently selected halogen, -OH, or C _1-4 alkoxy. 7. The compound according to claim 1 or 2, where the compound corresponds to any one of the formulas VIIIa-VIIId:

8. Connection according to any one of paragraphs. 1-7, where Z is -NR ^5a R ^5b . 9. Connection according to any one of paragraphs. 1-8, where R ^5a represents H, -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . 10. Connection according to any one of paragraphs. 1-8, where R ^5b represents cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. 11. Connection according to any one of paragraphs. 1-8, where R ^5b represents -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -C(CH ₃ ) ₃ , -CH(CH ₃ )CH ₂ CH ₃ , or -CH(CH ₃ )CH(CH ₃ ) ₂ , each substituted with one or more independently selected R ⁹ . 12. The compound according to claim 11, where R ⁹ is F, Cl, -CN, -OH, -O-CH ₃ , -O-CH ₂ CH ₃ , -O-CH(CH ₃ ) ₂ , -S( =O) ₂ -CH ₃ , -S(=O) ₂ -CH ₂ CH ₃ or -S(=O) ₂ -CH(CH ₃ ) ₂ . 13. A pharmaceutical composition that inhibits salt-inducible kinases (SIK-kinases), comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound according to any one of paragraphs. 1-12. 14. Connection according to any one of paragraphs. 1-12 or a pharmaceutical composition according to claim 13 for use in medicine for the prevention and/or treatment of diseases or disorders associated with inhibition of SIK kinase. 15. Connection according to any one of paragraphs. 1-12 or a pharmaceutical composition according to claim 13 for use in the prevention and/or treatment of diseases or disorders associated with inhibition of SIK kinase selected from the group consisting of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, rejection in transplantation, diseases related to impaired cartilage renewal, congenital cartilage defect, diseases related to impaired bone remodeling, diseases associated with hypersecretion of TNFα, interferons, IL-6, IL-12 and/or IL-23, respiratory diseases, endocrine and/or metabolic diseases, cardiovascular diseases, dermatological diseases and/or diseases associated with abnormal angiogenesis.

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