RU2782743C9 - Imidazopyridine compounds as pad inhibitors - Google Patents

Abstract

FIELD: organic chemistry; pharmacology.

SUBSTANCE: group of inventions relates to the field of organic chemistry and pharmacology; it is aimed at the treatment of disorders mediated by PAD4. Heterocyclic compounds of the formula (I) are disclosed, where X is selected from O or S; Z is N; A is CR₁; B is CR₂; D is CR₃; R₁, R₂, R₃, and R₄ are independently selected from hydrogen, C_1-6alkyl, C_3-6cycloalkyl, or C₆aryl, where C_1-6alkyl is optionally substituted with C_1-6alkoxy; R₁₁ and R₁₂ can be taken together to form a 5-10-element monocyclic or bicyclic saturated heterocyclic ring, optionally with 1-3 heteroatoms selected from N, S, or O, where the 5-10-element monocyclic or bicyclic saturated heterocyclic ring is optionally substituted with substitutes selected from amino or -NH(CO)CH=CH-CH₂-N(CH₃)₂; and R₁₃ is selected from 6-element monocyclic aryl and 5-10-element monocyclic or bicyclic heteroaryl with 1-3 heteroatoms selected from N, S, or O, where 6-element monocyclic aryl and 5-10-element monocyclic or bicyclic heteroaryl are optionally substituted with 1-5 substitutes selected from halogen, C_1-6alkyl, C_1-6alkoxy, or C₆aryl, where C_1-6alkyl and C₆aryl are optionally substituted with one or several groups selected from C_1-6alkyl, C_1-6halogenalkyl, C_1-6alkoxy, C_3-6cycloalkyl, C₆aryl, 5-6-element heteroaryl containing 1-3 heteroatoms selected from N, S, and O, 5-6-element heterocyclyl containing 1 or 2 heteroatoms selected from N, S, and O, oxo, halogen and hydroxyl, where C₆aryl, heteroaryl, and heterocyclyl are optionally substituted with one or more groups selected from C_1-6alkyl, C_1-6alkoxy, oxo, halogen, -CH₂OH, and cyano. In addition, heterocyclic compounds of formulas (II) and (III), methods for the production of heterocyclic compounds of formulas (I), (II), and (III), a pharmaceutical composition with PAD4 inhibitor activity based on the above-mentioned compounds, a method for inhibition of PAD4 in a cell, as well as methods for the treatment of conditions mediated by PAD4, and the use of compounds of formulas (I), (II), and (III) for the treatment of conditions mediated by PAD4 are disclosed.

EFFECT: group of inventions provides effective inhibition of PAD4, which may be suitable for the treatment of various disorders, including rheumatoid arthritis, vasculitis, systemic lupus erythematosus, cutaneous lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, multiple sclerosis, and psoriasis.

25 cl, 1 tbl, 2 ex

Description

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

The present invention relates to imidazopyridine compounds of formula (I), (II) and (III), along with their polymorphs, stereoisomers, prodrugs based on them, their solvates, co-crystals, intermediates based on them, their pharmaceutically acceptable salts and metabolites that inhibit PAD4 enzyme.

Process for preparing the above heterocyclic compounds of formula (I), (II) and (III), their polymorphs, stereoisomers, their prodrugs, their solvates, co-crystals, their intermediates, their pharmaceutically acceptable salts, their pharmaceutical compositions and their metabolites suitable for the preparation of such compounds is also described herein and is suitable for the preparation of such compounds.

The compounds described herein inhibit the PAD4 enzyme of the PAD family and may be used to treat a variety of disorders associated with cell division or inflammation.

BACKGROUND OF THE INVENTION

PAD (protein arginine deiminase) is part of a family of enzymes that mediate the citrullination process in living tissues (J.E. Jones, et al. Curr. Opin. Drug Discov. Devel., 2009, 12, 616-627). The PAD family consists of the individual enzymes PAD1, PAD2, PAD3, PAD4, and PAD6. Enzymes of the PAD family influence and regulate various physiological and pathological processes in the human body and, therefore, are important.

Elevated levels of these enzymes have been associated with various diseases, such as cell differentiation (K. Nakashima et al., J. Biol. Chem., 1999, 274, 27786-27792), stem cell pluripotency (M.A. Christophorou et al. ., Nature, 2014, 507, 104-108), apoptosis (G.Y. Liu, Apoptosis, 2006, 11, 183-196), formation of a neutrophil extracellular trap (NET) (Y. Wang et al., J. Cell Biol., 2009, 184, 205-213), transcriptional regulation (P. Li et al., Mol. Cell Biol., 2008, 28, 4745-4758), autophagy antigen processing (J.M. Ireland et al., J. Exp. Med., 2011, 208, 2625-2632), inflammation (D. Makrygiannakis et al., Ann. Rheum. Dis., 2006, 65, 1219-1222), keratinization of the skin (E. Candi et al., Nat Rev. Mol. Cell Biol., 2005, 6, 328-340), demyelination in multiple sclerosis (F. G. Mastronardi et al., J. Neurosci., 2006, 26, 11387-11396), chemokine regulation (T. Loos et al., Blood, 2008, 112, 2648-2656), repair of spinal cord injury (S. Lange et al., Dev. Bi ol., 2011, 355, 205-214) and various normal cellular processes. An increase in the levels of the PAD enzyme becomes the direct cause of the above diseases due to the increase in the rate of the citrullination process.

et al. Int. J. Biochem. Cell Biol., 2006, 38, 1662-1677). Таким образом, эти ферменты играют ключевую роль в патогенезе вышеуказанных заболеваний.The enzymes not only catalyze citrullination, but also produce autoimmune antibodies that recognize citrullinated proteins. The introduction of citrulline, which is the result of PAD activity, changes both the structure and function of proteins. At levels of physiological activity, PADs regulate multiple cellular signaling pathways such as cell differentiation, apoptosis, and gene transcription (

et al. Int. J Biochem. Cell Biol., 2006, 38, 1662-1677). Thus, these enzymes play a key role in the pathogenesis of the above diseases.

PAD4 is also known to be involved in the formation of neutrophil extracellular traps (NETs) and more specifically in histone citrullination that occurs during netosis (J. Cedervall, A.-K. Olsson, Oncoscience, 2015, 2(11), 900- 901). Thus, the PAD4 enzyme is associated with diseases characterized by abnormal levels of neutrophil extracellular traps (NETs). The putative role of PAD4 in netosis is important in rheumatoid arthritis (RA) because NETs are defective in the absence of PAD4 and PAD4 is released extracellularly in joints affected by RA, possibly due to the pathological state of neutrophils in RA. Therefore, PAD inhibitor drugs would offer significant therapeutic potential due to the fact that NETs are associated with many diseases.

Examples of some PAD inhibitor compounds are chloramidine, fluorochloridine and their related analogs, which are known and act as irreversible inhibitors that irreversibly inactivate PAD4 and other PAD isoenzymes (H.D. Lewis et al., Nature Chemical Biology, 2015, 11 , 189-191). Such compounds are useful in rheumatoid arthritis (RA). PAD4, found in synovial tissue, has been found to be responsible for the citrullination of a variety of joint proteins. Such citrullinated protein substrates produce antibodies to citrullinated proteins that are responsible for the pathogenesis of the disease (Y. Kochi et al., Ann. Rheum. Dis., 2011, 70, 512-515).

Since compounds that inhibit PAD4 enzymatic activity are also known to reduce pathological activity in many diseases, such compounds can be used in injuries and painful pathologies. Thus, PAD4 inhibitors have a wider applicability in the treatment of diseases, especially diseases associated with NET.

US 20050159334 discloses the treatment of RA by administering a suitable PAD inhibitor, thus PAD inhibitor compounds are of direct relevance to the treatment of RA.

PAD inhibitor compounds such as chloramidin have been extensively studied to demonstrate their efficacy in several animal models of diseases such as collagen-induced arthritis (V.C. Willis et al., J. Immunol., 2011, 186(7), 4396-4404), sodium dextran sulfate (DSS) induced experimental colitis (A.A. Chumanevich et al., Am. J. Physiol. Gastrointest. Liver Physiol., 2011, 300(6), G929-G938), atherosclerosis and arterial thrombosis lupus prone MRL/lpr mouse line (J.S. Knight et al., Circ. Res., 2014, 114(6), 947-956), repair of spinal cord injury (S. Lange et al., Dev. Biol., 2011, 355(2), 205-214) and experimental autoimmune encephalomyelitis (EAE).

Like RA, the use of PAD4 inhibitors for the treatment of forms of cancer (J.L. Slack et al., Cellular and Molecular Life Sciences, 2011, 68(4), 709-720) has also been explored previously. PAD4 inhibitors are also thought to have an antiproliferative role. PAD4 deimines arginine residues in histones in promoters of target p53 genes such as p21, which are involved in cell cycle arrest and induction of apoptosis (P. Li et al., Molecular & Cell Biology, 2008, 28(15), 4745-4758).

The PAD4 inhibitory compounds described above have a wide range of applications. Therefore, the identification of a chemical residue that contributes to the inhibition of PAD is necessary. However, the use of PAD inhibitors in various other diseases in which PAD activity is dysregulated still needs to be studied. The identification and development of novel PAD4 inhibitor compounds for the treatment of PAD4 mediated disorders is essential for the effective treatment of diseases such as rheumatoid arthritis, vasculitis, systemic lupus erythematosus, cutaneous lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, multiple sclerosis, and psoriasis.

BRIEF DESCRIPTION OF THE INVENTION

The present invention discloses a compound of formula I,

X is selected from O or S; Z is N; A is selected from N or CR ₁ ;

B is selected from N or CR ₂ ; D is selected from N or CR ₃ ; R ₁ , R ₂ , R ₃ and R ₄ are independently selected from hydrogen, hydroxyl, cyano, amino, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _1-6 haloalkyl, C _{1 -6} haloalkoxy, C _1-6 acylamino, C _1-6 alkylamino, C _5-10 aryl, C _1-6 heterocyclyl, C _1-6 heteroaryl, C (O) NR ₁₅ , C (O) C _1-6 alkylamino , C(O)C _5-6 aryl, C(O)C _1-6 heteroaryl, C(O)C _1-6 alkyl, C(O)C _1-6 haloalkyl, SO ₂ C _1-6 alkyl, SO ₂ C _1-6 haloalkyl, SO ₂ C _3-6 cycloalkyl, SO ₂ NR ₁₅ , SO ₂ NC _1-6 alkylamino, SO ₂ C _5-6 aryl or SO ₂ C _1-6 heteroaryl, where C _1-6 alkyl , C _1-6 alkoxy, C _1-6 heteroaryl and C _1-6 haloalkoxy are optionally substituted with one or more groups selected from hydrogen, oxo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _1-6 aryl, C _1-6 heterocyclyl, C _1-6 heteroaryl, cyano and hydroxyl; R ₁₁ is hydrogen; R ₁₂ is selected from C _1-6 alkylamino and a 5-10 membered monocyclic or bicyclic saturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, or R ₁₁ and R ₁₂ may be taken together to form 5-10 -membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-5 heteroatoms selected from N, S or O, where the 5-10-membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring is optionally substituted with substituents selected from amino, C _1-6 alkylamino, C _1-6 acylamino, -NHC (NH) CH ₂ Cl, NH (CO) CH \u003d CH-CH ₂ -N (CH ₃ ) ₂ , C _1-6 alkyl, halogen, C _1-6 alkoxy or hydroxyl ; R ₁₃ is selected from hydrogen, 5-10 membered monocyclic or bicyclic arnl and 5-10 membered monocyclic or bicyclic heteroaryl with 1-5 hetero atoms selected from N, S or O, where 5-10 membered monocyclic or bicyclic aryl and 5-10 membered monocyclic or bicyclic heteroaryl optionally substituted with 1-5 substituents selected from hydroxyl, cyano, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 acylamino, C _1-6 alkylamino, C _5-10 aryl, C _1-10 heterocyclyl, C _1-10 heteroaryl, C (O) C _1-6 alkyl, C (O) C _1-6 haloalkyl, C(O)NR ₁₅ , C(O)C _1-6 alkylamino, C(O)C _5-6 aryl, C(O)C _1-6 heteroaryl, SO ₂ C _1-6 haloalkyl, SO ₂ C _3-6 haloalkyl, SO ₂ C _3-6 cycloalkyl, SO ₂ NR ₁₅ , SO ₂ NC _1-6 alkylamino, SO ₂ C _5-6 aryl or SO ₂ C _1-6 heteroaryl, where C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _5-10 aryl, C _1-10 heterocyclyl and C _1-10 heteroaryl are optionally substituted with one or more g groups selected from hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _5-6 aryl, C _1-6 heteroaryl, C _1-6 heterocyclyl, oxo, halogen, hydroxyl and cyano, where C _5-6 aryl, C _1-6 heteroaryl and C _1-6 heterocyclyl are optionally substituted with one or more groups selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, oxo, halogen , hydroxyl, -CH ₂ OH and cyano; and R ₁₅ is selected from the group consisting of hydrogen, C _1-6 alkyl, and combinations thereof.

The present invention also describes a compound of formula II,

X is selected from O or S; Z is N; A is selected from N or CR ₁ ; B is selected from N or CR ₂ ; D is selected from N or CR ₃ ; E is selected from N or CR ₆ ; F absent or selected from N and CR ₇ ; G is absent or selected from N and CR ₈ ; H is absent or selected from N and CR ₉ ; R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ and R ₁₀ are independently selected from hydrogen, hydroxyl, cyano, amino, halogen, C _1-6 alkyl, C _{1 -6} alkoxy, C _3-6 cycloalkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 acylamino, C _1-6 alkylamino, C _5-10 aryl, C _1-10 heterocyclyl, C _1-10 heteroaryl, C(O)C _1-6 alkyl, C(O)C _1-6 haloalkyl, C(O)NR ₁₅ , C(O)C _1-6 alkylamino, C(O)C _5-6 aryl, C (O)C _1-6 heteroaryl, SO ₂ C _1-6 alkyl, SO ₂ C _1-6 haloalkyl, SO ₂ C _3-6 cycloalkyl, SO ₂ NR ₁₅ , SO ₂ NC _1-6 alkylamino, SO ₂ C _{5 -6} aryl or SO ₂ C _1-6 heteroaryl, where C _1-6 alkyl, C _1-6 alkoxy, C _1-6 heteroaryl and C _1-6 haloalkoxy are optionally substituted with one or more groups selected from hydrogen, oxo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 alkylhydroxy, C _3-6 cycloalkyl, C _5-9 aryl, C _1-6 heterocyclyl, C _1-6 heteroaryl, cyano, halogen and hydroxyl, where C _5-9 aryl, C _1-6 heteroaryl and C _1-6 heterocyclyl are optionally substituted with one or more nim groups selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, oxo, halogen, hydroxyl, —CH ₂ OH and cyano;

R ₁₁ and R ₁₂ are taken together to form a 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-5 heteroatoms selected from N, S or O, where 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring optionally substituted with substituents selected from amino, C _1-6 alkylamino, C _1-6 acylamino, -NHC(NH)CH ₂ Cl, NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ , C _{1- 6} alkyl, halogen, C _1-6 alkoxy or hydroxyl; and R ₁₅ is selected from the group consisting of hydrogen, C _1-6 alkyl, and combinations thereof.

The present invention further describes a compound of formula III,

X is selected from O or S; Z is N; R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ and R ₁₀ are independently selected from hydrogen, hydroxyl, cyano, amino, halogen, C _1-6 alkyl, C _{1 -6} alkoxy, C _3-6 cycloalkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 acylamino, C _1-6 alkylamino, C _5-10 aryl, C _1-10 heterocyclyl, C _1-10 heteroaryl, C(O)C _1-6 alkyl, C(O)C _1-6 haloalkyl, C(O)NR ₁₅ , C(O)C _1-6 alkylamino, C(O)C _5-6 aryl, C (O)C _1-6 heteroaryl, SO ₂ C _1-6 alkyl, SO ₂ C _1-6 haloalkyl, SO ₂ C _3-6 cycloalkyl, SO ₂ NR ₁₅ , SO ₂ NC _1-6 alkylamino, SO ₂ C _{5 -6} aryl or SO ₂ C _1-6 heteroaryl, where C _1-6 alkyl, C _1-6 alkoxy, C _1-10 heteroaryl and C _1-6 haloalkoxy are optionally substituted with one or more groups selected from hydrogen, oxo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 alkylhydroxy, C _3-6 cycloalkyl, C _5-9 aryl, C _1-6 heterocyclyl, C _1-6 heteroaryl, cyano, halogen and hydroxyl, where C _5-9 aryl, C _1-6 heteroaryl and C _1-6 heterocyclyl are optionally substituted with one or more any groups selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, oxo, halogen, hydroxyl, —CH ₂ OH and cyano;

R ₁₁ and R ₁₂ are taken together to form a 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-5 heteroatoms selected from N, S or O, where 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring optionally substituted with substituents selected from amino, C _1-6 alkylamino, C _1-6 acylamino, -NHC(NH)CH ₂ Cl, NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ , C _{1- 6} alkyl, halogen, C _1-6 alkoxy or hydroxyl; and R ₁₅ is selected from the group consisting of hydrogen, C _1-6 alkyl, and combinations thereof.

The present invention further describes a method for preparing compounds of formula (I), formula (II) and formula (III), or their polymorphs, stereoisomers, prodrugs based on them, their solvates, co-crystals, intermediates based on them, their pharmaceutically acceptable salts and metabolites.

The present invention further discloses a pharmaceutical composition comprising a compound of formula (I), formula (II) and formula (III), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, optionally in combination with one or more other pharmaceutical compositions.

The present invention further discloses a method for inhibiting one or more members of the PAD family in a cell with an effective amount of a compound of the present invention.

The present invention further discloses a method for treating a condition mediated by one or more PADs, the method comprising administering to a subject suffering from a condition mediated by one or more members of the PAD family a therapeutically effective amount of a compound of formula (I), formula (II), and formula ( iii) or a pharmaceutical composition of the present invention with other clinically necessary agents or biological agents to a subject in need thereof.

The present invention further discloses a compound of formula (I), formula (II) and formula (III) for use in the treatment of rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus and psoriasis.

These and other features, aspects and advantages of the subject matter of the present invention will become more apparent with reference to the following description. This brief description is provided to present a set of concepts in a simplified form. This summary is not intended to identify key features or essential features of the invention, nor is it intended to be used to limit the scope of the subject matter of the present invention.

DETAILED DESCRIPTION

The person skilled in the art will understand that the present invention may be subject to changes and modifications other than those specifically described changes and modifications. It is to be understood that the present invention includes all such changes and modifications. The present invention also includes all such steps, features, compositions and compounds mentioned or referred to in this description, alone or together, and any and all combinations of any or more of such steps or features.

Definitions

For convenience, before further describing the present invention, some of the terms used in the description and examples are collected here. These definitions should be read in conjunction with the rest of the disclosure and should be understood by one of ordinary skill in the art. Terms used herein have the meanings recognizable and known to those skilled in the art, however, for convenience and completeness, specific terms and their meanings are set forth below.

The singular form is used to denote one or more (i.e. at least one) grammatical objects.

Throughout the description and the following claims, unless the context otherwise requires, the word "comprise", and variations such as "comprises" or "comprising", will be intended to include the stated integer or step or group of integers, without excluding any another integer or stage or group of integers or stages.

The term "including" is used in the sense of "including without limitation". "Including" and "including without limitation" are used interchangeably.

In the structural formula given in this document and throughout the present invention, the following terms have the indicated meaning, unless specifically indicated otherwise.

In addition, the compound of formula (I), formula (II) and formula (III) may be derivatives, analogs, stereoisomers, diastereomers, geometric isomers, polymorphs, solvates, co-crystals, intermediates, metabolites, prodrugs or pharmaceutically acceptable salts thereof, and compositions.

Compounds of formula (I), formula (II) and formula (III), as well as their polymorphs, stereoisomers, prodrugs based on them, their solvates, co-crystals, intermediates based on them, their pharmaceutically acceptable salts and metabolites may also be referred to as "compounds of the present invention."

The compounds according to formula (I), formula (II) and formula (III) contain one or more asymmetric centers (also called chiral centers) and may therefore exist as single enantiomers, diastereoisomers or other stereoisomeric forms, or as their mixtures. Chiral centers such as chiral carbon atoms may also be present on a substituent such as an alkyl group. Unless the stereochemistry of the chiral center present in formula (I), formula (II) and formula (III) or in any chemical structure illustrated herein is specified, the structure is intended to include any stereoisomer and all mixtures thereof. Thus, compounds according to formula (I), formula (II), and formula (III) containing one or more chiral centers can be used as racemic modifications, including racemic mixtures and racemates, enantiomerically enriched mixtures, or as enantiomerically pure individual stereoisomers. Individual stereoisomers of a compound according to formula (I), formula (II), and formula (III) that contain one or more asymmetric centers can be separated using methods known to those skilled in the art. For example, such separation can be carried out (1) through the formation of diastereomeric salts, complexes, or other derivatives; (2) via selective reaction with a stereoisomer-specific reagent, for example via enzymatic oxidation or reduction; or (3) using gas-liquid or liquid chromatography in a chiral medium, for example, on a chiral carrier such as silicon dioxide with an associated chiral ligand or in the presence of a chiral solvent. It should be understood that if the desired stereoisomer is converted to another chemical building block using one of the separation procedures described above, an additional step is required to release the desired form.

Alternatively, specific stereoisomers can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts, or solvents, or by converting one enantiomer to another via an asymmetric conversion.

It is to be understood that references herein to compounds of formula (I), formula (II) and formula (III) and their salts encompass compounds of formula (I), formula (II) and formula (III) as free bases or as their salts, for example in the form of their pharmaceutically acceptable salts. Thus, in one embodiment, the present invention is directed to compounds of formula (I), formula (II), and formula (III) in free base form. In another embodiment, the present invention is directed to compounds of formula (I), formula (II) and formula (III) and their salts. In an additional embodiment, the present invention is directed to compounds of formula (I), formula (II) and formula (III) and their pharmaceutically acceptable salts.

It should be understood that pharmaceutically acceptable salts of compounds according to formula (I, II and III) can be prepared. Indeed, in certain embodiments, the implementation of the present invention pharmaceutically acceptable salts of compounds in accordance with formula (I), formula (II) and formula (III) may be preferred over the corresponding free base, since such salts impart greater stability or solubility to the molecule, the thereby facilitating the formulation of the dosage form. Accordingly, the present invention is further directed to compounds of formula (I), formula (II) and formula (III) and their pharmaceutically acceptable salts.

"Enantiomeric excess" (ee) is the excess of one enantiomer over the other, expressed as a percentage. In a racemic modification, since both enantiomers are present in equal amounts, the enantiomeric excess is zero (0% ee). However, if one enantiomer was enriched to make up 95% of the product, then the enantiomeric excess would be 90% ee (amount of enriched enantiomer, 95%, minus the amount of other enantiomers, 5%).

"Enantiomerically enriched" refers to products whose enantiomeric excess (ee) is greater than zero. For example, the term 'enantiomerically enriched' refers to products whose enantiomeric excess is greater than 50% ee, greater than 75% ee, and greater than 90% ee. 'Enantiomerically pure' refers to products having an enantiomeric excess of 99% or more.

The scope of the 'compounds of the present invention' includes all solvates (including hydrates), complexes, polymorphs, prodrugs, radiolabeled derivatives and stereoisomers of the compounds of formula (I), formula (II) and formula (III) and their salts.

The compounds of the present invention may exist in solid or liquid form. In the solid state, the compounds of the present invention may exist in crystalline or non-crystalline form, or as a mixture thereof. For compounds of the present invention that are in crystalline form, one skilled in the art will appreciate that pharmaceutically acceptable solvates can be formed when solvent molecules are incorporated into the crystal lattice during crystallization. Solvates may include non-aqueous solvents such as ethanol, isopropyl alcohol, N,N-dimethyl sulfoxide (DMSO), acetic acid, ethanolamine, and ethyl acetate, or they may include water as a solvent that is included in the crystal lattice. Solvates in which water is the solvent that is incorporated into the crystal lattice are generally referred to as 'hydrates'. Hydrates include stoichiometric hydrates as well as compositions containing varying amounts of water. The present invention includes all such solvates.

Additionally, it should be understood that certain compounds of the present invention that exist in crystalline form, including their various solvates, may exhibit polymorphism (ie, the ability to exist in different crystal structures). These different crystalline forms are generally known as 'polymorphs'. The present invention includes such polymorphs. The polymorphs have the same chemical composition but differ in packaging, geometric arrangement, and other descriptive properties of the crystalline solid state. Therefore, polymorphs may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs are typically characterized by distinct melting points, IR spectra, and X-ray powder diffraction patterns that can be used for identification. It should be understood that various polymorphs can be obtained, for example, by changing or adjusting the reaction conditions or reagents used in the preparation of the compound. For example, changes in temperature, pressure, or solvent can lead to the formation of polymorphs. In addition, one polymorph can spontaneously transform into another polymorph under certain conditions.

The present invention also includes isotopically labeled compounds which are identical to the compounds of formula (I, II and III) and their salts, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number, most commonly found in nature. Examples of isotopes that can be included in the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen and fluorine such as ³ H, ¹¹ C, ¹⁴ C and ¹⁸ F.

The term "co-crystals" refers to solids that are crystalline single phase materials composed of two or more different molecular and/or ionic compounds, usually in a stoichiometric ratio, that are neither solvates nor simple salts.

The term "substituted" in relation to a group indicates that a hydrogen atom attached to an atom that is a member within the group has been replaced. It should be understood that the term 'substituted' includes the express provision that such substitution must correspond to the allowable valence of the substituted atom and substituent, and that the substitution results in the formation of a stable compound (i.e., a compound that does not undergo spontaneous transformation, such as a rearrangement , cyclization or elimination). In certain embodiments, one atom may be substituted with more than one substituent, provided that such substitution corresponds to the allowable valency of the atom. Suitable substituents are defined herein for each substituted or optionally substituted group.

The term "polymorphs" refers to crystalline forms of the same molecule, and different polymorphs may have different physical properties such as, for example, melting point values, heat of fusion values, solubility properties, dissolution rates, and/or vibrational spectra due to location. or conformations of molecules in a crystal lattice.

The term "prodrugs" refers to a precursor compound of formula (I, II and III) which, when administered, undergoes chemical transformation via metabolic processes before being converted into active pharmacological agents. In general, such prodrugs will be functional derivatives of the compound of the present invention that are easily converted in vivo to the compound of the present invention.

The term "alkyl" refers to a saturated hydrocarbon chain containing the specified number of carbon atoms. For example, without limitation, C _1-6 alkyl refers to an alkyl group containing 1 to 6 carbon atoms or 1 to 3 carbon atoms. The alkyl groups may be straight or branched chain groups. Exemplary branched alkyl groups have one, two or three branches. Preferred alkyl groups include, without limitation, methyl, ethyl, n-propyl, isopropyl, butyl, and isobutyl.

The term "C(O)alkyl" refers to an alkyl group as defined above attached via a carbonyl group to the rest of the molecule. For example, C(O)C _1-6 alkyl refers to an alkyl group containing 1 to 6 carbon atoms or 1 to 3 carbon atoms attached via a carbonyl group to the rest of the molecule. Preferred C(O)alkyl groups include, but are not limited to, -C(O)CH ₃ , -C(O)CH ₂ CH ₃ , and the like.

The term "SO ₂ alkyl" refers to an alkyl group as defined above attached via a sulfonyl group to the rest of the molecule. For example, SO ₂ C _1-6 alkyl refers to an alkyl group containing 1 to 6 carbon atoms or 1 to 3 carbon atoms attached via a sulfonyl group to the rest of the molecule. Preferred SO ₂ alkyl groups include, without limitation -SO ₂ CH ₃ , -SO ₂ CH ₂ CH ₃ and the like.

The term "alkoxy" refers to an alkyl group attached via an oxygen atom to the rest of the molecule. For example, C _1-6 alkoxy refers to an alkyl group containing 1 to 6 carbon atoms or 1 to 3 carbon atoms attached via an oxygen atom to the rest of the molecule. Preferred alkoxy groups include, but are not limited to, -OCH ₃ (methoxy), OC ₂ H ₅ (ethoxy), and the like.

The term "alkylamino" refers to an alkyl group as defined above attached via an amino group or an alkyl group to the rest of the molecule. For example, C _1-6 alkylamino refers to an alkyl group containing 1 to 6 carbon atoms or 1 to 3 carbon atoms attached via an amino group to the rest of the molecule. Preferred alkylamino groups include, but are not limited to -NHCH ₃ , -N(CH ₃ ) ₂ and the like.

The term "C(O)NR" refers to an alkylamino group as defined above attached via a carbonyl group to the rest of the molecule. Preferred C(O)NR groups include C(O)NCH ₃ , C(O)NCH ₂ CH ₃ and the like.

The term "SO ₂ NR" refers to an alkylamino group as defined above attached via a sulfonyl group to the rest of the molecule. Preferred SO ₂ NR-rpynnbi include SO ₂ NCH ₃ , SO ₂ NCH ₂ CH ₃ and the like.

The term "C(O)alkylamino" refers to an alkylamino group as defined above attached via a carbonyl group to the rest of the molecule. For example, C(O)C _1-6 alkylamino refers to an alkylamino group containing 1 to 6 carbon atoms or 1 to 3 carbon atoms attached via a carbonyl group to the rest of the molecule. Preferred C(O)alkylamino groups include, without limitation, -C(O)NHCH ₃ , -C(O)N(CH ₃ ) ₂ and the like.

The term "SO ₂ alkylamino" refers to an alkylamino group as defined above attached via a sulfonyl bond to the rest of the molecule. For example, SO ₂ C _1-6 alkylamino refers to an alkylamino group containing 1 to 6 carbon atoms or 1 to 3 carbon atoms attached via a sulfonyl group to the rest of the molecule. Preferred SO ₂ alkylamino groups include, without limitation, -SO ₂ NHCH ₃ , -SO ₂ N(CH ₃ ) ₂ and the like.

The term "acylamino" refers to an acyl group attached via a carbonyl group to the rest of the molecule. For example, C _1-6 acylamino refers to an acyl group containing 1 to 6 carbon atoms or 1 to 3 carbon atoms attached via an amino group to the rest of the molecule. Preferred acylamino groups include, without limitation -(CO)NHCH ₃ , -(CO)N(CH ₃ ) ₂ and the like.

The term "haloalkyl" refers to an alkyl group as defined above, containing a halogen and attached via an alkyl group to the rest of the molecule. For example, C _1-6 haloalkyl refers to an alkyl group containing 1 to 6 carbon atoms or 1 to 3 carbon atoms attached via a halogen atom to the rest of the molecule. Preferred haloalkyl groups include, without limitation -CH ₂ Cl, -CHCl ₂ and the like.

The term "C(O)haloalkyl" refers to a haloalkyl group as defined above attached via a carbonyl group to the rest of the molecule. For example, C(O)C _1-6 haloalkyl refers to a haloalkyl group containing 1 to 6 carbon atoms or 1 to 3 carbon atoms attached via a carbonyl group to the rest of the molecule. Preferred C(O)haloalkyl groups include, without limitation -(CO)CH ₂ Cl, -C(O)CHCl ₂ and the like.

The term "SO ₂ haloalkyl" refers to a halo alkyl group, as defined above, attached via a sulfonyl bond to the rest of the molecule. For example, SO ₂ C _1-6 haloalkyl refers to a haloalkyl group containing 1 to 6 carbon atoms or 1 to 3 carbon atoms attached via a sulfonyl group to the rest of the molecule. Preferred SO ₂ haloalkyl groups include, without limitation -SO ₂ CH ₂ Cl, -SO ₂ CHCl ₂ and the like.

The term "haloalkoxy" refers to an alkoxy group as defined above attached via an oxygen atom to the rest of the molecule. For example, C _1-6 haloalkoxy refers to an alkoxy group containing 1 to 6 carbon atoms or 1 to 3 carbon atoms attached via a halogen atom to the rest of the molecule. Preferred haloalkoxy groups include, without limitation, -OCH ₂ Cl, -OCHCl ₂ and the like.

The term "halogen" refers to a halogen radical, such as fluorine, chlorine, bromine, or iodine. "Haloalkyl" refers to an alkyl group, as previously defined herein, in which at least one of the hydrogen atoms has been replaced by a halogen radical. "C _1-6 haloalkyl" refers to a C _1-6 alkyl group in which at least one of the hydrogen atoms has been replaced by a halogen radical. An example of "haloalkyl" is trifluoromethyl or 2,2,2-trifluoroethyl.

The term "cycloalkyl" refers to a saturated hydrocarbon ring containing the specified number of carbon atoms. For example, without limitation, C _3-6 cycloalkyl refers to a cycloalkyl group containing 3 to 6 member atoms or 3 member atoms. Preferred cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl groups, and the like.

The term "SO ₂ C _3-6 cycloalkyl" refers to a cycloalkyl group as defined above attached via a sulfonyl group to the rest of the molecule. For example, SO ₂ C _3-6 cycloalkyl refers to a cycloalkyl group containing 3 to 6 carbon atoms attached via a sulfonyl group to the rest of the molecule. Preferred SO ₂ cycloalkyl groups include, but are not limited to -SO ₂ C ₃ cycloalkyl and the like.

The term "aryl" refers to an aromatic ring containing the specified number of carbon atoms. For example, C _5-6 aryl refers to an aryl group containing 5 or 6 member atoms or 6 member atoms. Preferred aryl groups include, without limitation, phenyl and the like.

The term "C(O)aryl" refers to an aryl group as defined above attached via a carbonyl group to the rest of the molecule. For example, C(O)C _5-6 aryl refers to an alkyl group containing 5 to 6 carbon atoms attached via a carbonyl group to the rest of the molecule. Preferred C(O)aryl groups include, but are not limited to -C(O)C ₆ H ₅ , -C(O)C ₅ H ₅ , and the like.

The term "SO ₂ aryl" refers to an aryl group as defined above attached via a sulfonyl group to the rest of the molecule. For example, SO ₂ C _5-6 aryl refers to an aryl group containing 5 to 6 carbon atoms attached via a sulfonyl group to the rest of the molecule. Preferred SO ₂ aryl groups include, without limitation -SO ₂ C ₆ H ₅ , -SO ₂ C ₅ H ₅ , and the like.

The term "heteroaryl" refers to aromatic rings containing from 1 to 3 heteroatoms in the ring. "Heteroaryl" groups may be substituted with one or more substituents, as defined herein. "C _1-6 heteroaryl" rings have 1 or 6 carbon atoms as member atoms. "Heteroaryl" includes pyridinyl, tetrazolyl and pyrazolyl. "Heteroatom" refers to a nitrogen, sulfur or oxygen atom, such as a nitrogen atom or an oxygen atom.

The term "C(O)heteroaryl" refers to a heteroaryl group as defined above attached via a carbonyl group to the rest of the molecule. For example, C(O)C _1-6 heteroaryl refers to an alkyl group containing 1 to 6 carbon atoms attached via a carbonyl group to the rest of the molecule. Preferred C(O)heteroaryl groups include, but are not limited to -C(O)pyridinyl, -C(O)pyrazolyl, and the like.

The term "SO ₂ heteroaryl" refers to an aryl group as defined above attached via a sulfonyl group to the rest of the molecule. For example, SO ₂ C _1-6 heteroaryl refers to an aryl group containing 1 to 6 carbon atoms attached via a sulfonyl group to the rest of the molecule. Preferred SO ₂ heteroaryl groups include, but are not limited to, -SO ₂ pyridinyl, -SO ₂ pyrazolyl, and the like.

The terms "heterocyclic" and "heterocyclyl" refer to saturated or unsaturated monocyclic aliphatic rings containing 5, 6 or 7 ring members, including 1 or 2 heteroatoms, or to saturated or unsaturated bicyclic aliphatic rings containing 5, 6 or 7 ring members, including 1 or 2 heteroatoms. In certain embodiments, the "heterocyclyl" groups are saturated. In other embodiments, the "heterocyclyl" groups are unsaturated. 'Heterocyclyl' groups containing more than one heteroatom may contain different heteroatoms. 'Heterocyclyl' groups may be substituted with one or more substituents as defined herein. 'Heterocyclyl' includes piperidinyl, tetrahydropyranyl, azepinyl, oxazepinyl, azabicyclo[3.1.0]hexanyl.

The phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions and dosage forms which, within the scope of careful medical judgment, are suitable for use in contact with human and animal tissues without undue toxicity, irritation or other problem or complication in accordance with an acceptable ratio benefit/risk.

Used in this document, the term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the claimed compounds and exhibit minimal undesirable toxicological effects. Such pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free base form with an appropriate acid.

Salts and solvates having other than pharmaceutically acceptable counterions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of formula (I), formula (II) and formula (III), and their pharmaceutically acceptable salts. Thus, one embodiment of the present invention includes compounds of formula (I), formula (II) and formula (III) and their salts. Compounds according to formula (I), formula (II) and formula (III) contain a basic functional group and are therefore capable of forming pharmaceutically acceptable acid addition salts by treatment with an appropriate acid. Suitable acids include pharmaceutically acceptable inorganic acids and pharmaceutically acceptable organic acids. Exemplary pharmaceutically acceptable acid addition salts include hydrochloride, hydrobromide, nitrate, methyl nitrate, sulfate, bisulfate, sulfamate, phosphate, acetate, hydroxyacetate, phenylacetate, propionate, butyrate, isobutyrate, valerate, maleate, hydroxymaleate, acrylate, fumarate, malate, tartrate, citrate , salicylate, glycolate, lactate, heptanoate, phthalate, oxalate, succinate, benzoate, o-acetoxybenzoate, chlorobenzoate, methyl benzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, naphthoate, hydroxynaphthoate, mandelate, tannate, formate, stearate, ascorbate, palmitate, oleate, pyruvate , pamoate, malonate, laurate, glutarate, glutamate, estolate, methanesulfonate (mesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonate, benzenesulfonate (besylate), aminobenzenesulfonate, p-toluenesulfonate (tosylate), and naphthalene-2-sulfonate.

The term "PAD inhibitor" or "PAD inhibitor" is used to identify a compound that is capable of interacting with neutrophil extracellular traps (NETs) and, more specifically, of histone citrullination that occurs during netosis. Inhibition of PAD4 enzymatic activity means reducing the ability of the PAD4 enzyme such that the formation of citrulline is inhibited during the citrullination process. Preferably, such inhibition is specific to the PAD4 enzyme.

A term described once has the same meaning throughout the patent.

Despite the wide applicability of the PAD4 inhibitory compounds described above, the identification of a chemical moiety that contributes to PAD inhibition still remains a challenge. The identification and development of new PAD4 inhibitor compounds for the treatment of PAD4 mediated disorders is essential for the treatment of diseases such as rheumatoid arthritis, vasculitis, systemic lupus erythematosus, cutaneous lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, disseminated sclerosis and psoriasis.

In one embodiment, the present invention provides a compound of formula I, polymorphs, stereoisomers, prodrugs thereof, solvates, co-crystals, intermediates thereof, pharmaceutically acceptable salts thereof, and metabolites, wherein

X is selected from O or S; Z is N; A is selected from N or CR ₁ ;

B is selected from N or CR ₂ ; D is selected from N or CR ₃ ; R ₁ , R ₂ , R ₃ and R ₄ are independently selected from hydrogen, hydroxyl, cyano, amino, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _1-6 haloalkyl, C _{1 -6} haloalkoxy, C _1-6 acylamino, C _1-6 alkylamino, C _5-10 aryl, C _1-6 heterocyclyl, C _1-6 heteroaryl, C(O)NR ₁₅ , C(O)C _1-6 alkylamino , C(O)C _5-6 aryl, C(O)C _1-6 heteroaryl, C(O)C _1-6 alkyl, C(O)C _1-6 haloalkyl, SO ₂ C _1-6 alkyl, SO ₂ C _1-6 haloalkyl, SO ₂ C _3-6 cycloalkyl, SO ₂ NR ₁₅ , SO ₂ NC _1-6 alkylamino, SO ₂ C _5-6 aryl or SO ₂ C _1-6 heteroaryl, where C _1-6 alkyl , C _1-6 alkoxy, C _1-6 heteroaryl and C _1-6 haloalkoxy are optionally substituted with one or more groups selected from hydrogen, oxo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _5-10 aryl, C _1-6 heterocyclyl, C _1-6 heteroaryl, cyano and hydroxyl; R ₁₁ is hydrogen; R ₁₂ is selected from C _1-6 alkylamino and a 5-10 membered monocyclic or bicyclic saturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, or R ₁₁ and R ₁₂ may be taken together to form 5-10 -membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-5 heteroatoms selected from N, S or O, where the 5-10-membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring is optionally substituted with substituents selected from amino, C _1-6 alkylamino, C _1-6 acylamino, -NHC(NH)CH ₂ Cl, NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ , C _1-6 alkyl, halogen, C _1-6 alkoxy or hydroxyl ; R ₁₃ is selected from hydrogen, 5-10 membered monocyclic or bicyclic aryl and 5-10 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where 5-10 membered monocyclic or bicyclic aryl and 5-10 membered monocyclic or bicyclic heteroaryl optionally substituted with 1-5 substituents selected from hydroxyl, cyano, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _1-6 haloalkyl, C _{1 -6} haloalkoxy, C _1-6 acylamino, C _1-6 alkylamino, C _5-10 aryl, C _1-10 heterocyclyl, C _1-10 heteroaryl, C (O) C _1-6 alkyl, C (O) C _{1 -6} haloalkyl, C(O)NR ₁₅ , C(O)C _1-6 alkylamino, C(O)C _5-6 aryl, C(O)C _1-6 heteroaryl, SO ₂ C _1-6 alkyl, SO ₂ C _1-6 haloalkyl, SO ₂ C _3-6 cycloalkyl, SO ₂ NR ₁₅ , SO ₂ NC _1-6 alkylamino, SO ₂ C _5-6 aryl or SO ₂ C _1-6 heteroaryl, where C _1-6 alkyl , C _1-6 alkoxy, C _3-6 cycloalkyl, C _5-10 aryl, C _1-10 heterocyclyl and C _1-10 heteroaryl are optionally substituted with one or more groups, selected from hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _5-6 aryl, C _1-6 heteroaryl, C _1-6 heterocyclyl, oxo, halogen, hydroxyl and cyano, where C _5-6 aryl, C _1-6 heteroaryl and C _1-6 heterocyclyl are optionally substituted with one or more groups selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, oxo, halogen, hydroxyl , -CH ₂ OH and cyano; and R ₁₅ is selected from the group consisting of hydrogen, C _1-6 alkyl, and combinations thereof.

In one embodiment, the present invention provides a compound of formula I as described herein, wherein X is selected from O or S; Z is N; A is selected from N or CR ₁ ; B is selected from N or CR ₂ ; D is selected from N or CR ₃ ; R ₁ , R ₂ , R ₃ and R ₄ are independently selected from hydrogen, hydroxyl, cyano, amino, halogen, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _1-4 haloalkyl, C _{1 -4} haloalkoxy, C _1-4 acylamino, C _1-4 alkylamino, C _5-6 aryl, C _1-6 heterocyclyl, C _1-6 heteroaryl, C (O) NR ₁₅ , C (O) C _1-4 alkylamino , C(O)C _5-6 aryl, C(O)C _1-6 heteroaryl, C(O)C _1-4 alkyl, C(O)C _1-4 haloalkyl, SO ₂ C _1-4 alkyl, SO ₂ C _1-4 haloalkyl, SO ₂ C _3-6 cycloalkyl, SO ₂ NR ₁₅ , SO ₂ NC _1-4 alkylamino, SO ₂ C _5-6 aryl or SO ₂ C _1-6 heteroaryl, where C _1-4 alkyl , C _1-4 alkoxy, C _1-6 heteroaryl and C _1-4 haloalkoxy are optionally substituted with one or more groups selected from hydrogen, oxo, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _5-6 aryl, C _1-6 heterocyclyl, C _1-6 heteroaryl, cyano and hydroxyl; R ₁₁ is hydrogen; R ₁₂ is selected from C _1-6 alkylamino and a 5-10 membered monocyclic or bicyclic saturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, or R ₁₁ and R ₁₂ may be taken together to form 5-10 -membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-5 heteroatoms selected from N, S or O, where the 5-10-membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring is optionally substituted with substituents selected from amino, C _1-6 alkylamino, C _1-6 acylamino, -NHC(NH)CH ₂ Cl, NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ , C _1-6 alkyl, halogen, C _1-6 alkoxy and hydroxyl ; R ₁₃ is selected from hydrogen, 5-10 membered monocyclic or bicyclic aryl and 5-10 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where 5-10 membered monocyclic or bicyclic aryl and 5 -10-membered monocyclic or bicyclic heteroaryl is optionally substituted with 1-5 substituents selected from hydroxyl, cyano, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _1-6 haloalkyl, C _{1- 6} haloalkoxy, C _1-6 acylamino, C _1-6 alkylamino, C _5-10 aryl, C _1-10 heterocyclyl, C _1-10 heteroaryl, C (O) C _1-6 alkyl, C (O) C _{1- 6} haloalkyl, C(O)NR ₁₅ , C(O)C _1-6 alkylamino, C(O)C _5-6 aryl, C(O)C _1-6 heteroaryl, SO ₂ C _1-6 alkyl, SO ₂ C _1-6 haloalkyl, SO ₂ C _3-6 cycloalkyl, SO ₂ NR ₁₅ , SO ₂ NC _1-6 alkylamino, SO ₂ C _5-6 aryl and SO ₂ C _1-6 heteroaryl, where C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _5-10 aryl, C _1-10 heterocyclyl and C _1-10 heteroaryl are optionally substituted with one or more groups, in selected from hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _5-6 aryl, C _1-6 heteroaryl, C _1-6 heterocyclyl, oxo, halogen, hydroxyl and cyano, where C _5-6 aryl, C _1-6 heteroaryl and C _1-6 heterocyclyl are optionally substituted with one or more groups selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, oxo, halogen, hydroxyl , -CH ₂ OH and cyano; and R ₁₅ is selected from the group consisting of hydrogen, C _1-6 alkyl, and combinations thereof.

In one embodiment, the present invention provides a compound of formula I as described herein, wherein X is selected from O or S; Z is N; A is selected from N or CR ₁ ; B is selected from N or CR ₂ ; D is selected from N or CR ₃ ; R ₁ , R ₂ and R ₃ are independently selected from hydrogen, hydroxyl, cyano, amino, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _3-5 cycloalkyl, C _1-4 haloalkyl, C _1-4 haloalkoxy , C _5-6 aryl, C _1-6 heterocyclyl or C _1-6 heteroaryl; R ₄ is selected from hydrogen, hydroxyl, cyano, amino, halogen, C _1-6 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _1-4 acylamino, C _1-4 alkylamino, C _5-6 aryl, C _1-6 heterocyclyl, C _1-6 heteroaryl, C(O)NR ₁₅ , C(O)C _1-4 alkylamino, C(O)C _5-6 aryl , C (O) C _1-6 heteroaryl, C (O) C _1-4 alkyl, C (O) C _1-4 haloalkyl, SO ₂ C _1-4 alkyl, SO ₂ C _1-4 haloalkyl, SO ₂ C _3-6 cycloalkyl, SO ₂ NR ₁₅ , SO ₂ NC _1-4 alkylamino, SO ₂ C _5-6 aryl or SO ₂ C _1-6 heteroaryl, where C _1-4 alkyl, C _1-4 alkoxy, C _{1- 6} heteroaryl and C _1-4 haloalkoxy are optionally substituted with one or more groups selected from hydrogen, oxo, C _1-4 alkyl, C _1-6 alkoxy, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _5-6 aryl , C _1-6 heterocyclyl, C _1-6 heteroaryl, cyano and hydroxyl; R ₁₁ is hydrogen; R ₁₂ is selected from C _1-6 alkylamino and a 5-10 membered monocyclic or bicyclic saturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, or R ₁₁ and R ₁₂ may be taken together to form 5-10 -membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-5 heteroatoms selected from N, S or O, where the 5-10-membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring is optionally substituted with substituents selected from amino, C _1-6 alkylamino, C _1-6 acylamino, -NHC(NH)CH ₂ Cl, NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ , C _1-6 alkyl, halogen, C _1-6 alkoxy or hydroxyl ; R ₁₃ is selected from hydrogen, 5-10 membered monocyclic or bicyclic aryl and 5-10 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where 5-10 membered monocyclic or bicyclic aryl and 5 -10-membered monocyclic or bicyclic heteroaryl is optionally substituted with 1-5 substituents selected from hydroxyl, cyano, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _1-6 haloalkyl, C _{1- 6} haloalkoxy, C _1-6 acylamino, C _1-6 alkylamino, C _5-10 aryl, C _1-10 heterocyclyl, C _1-10 heteroaryl, C (O) C _1-6 alkyl, C (O) C _{1- 6} haloalkyl, C(O)NR ₁₅ , C(O)C _1-6 alkylamino, C(O)C _5-6 aryl, C(O)C _1-6 heteroaryl, SO ₂ C _1-6 alkyl, SO ₂ C _1-6 haloalkyl, SO ₂ C _3-6 cycloalkyl, SO ₂ NR ₁₅ , SO ₂ NC _1-6 alkylamino, SO ₂ C _5-6 aryl or SO ₂ C _1-6 heteroaryl, where C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _5-10 aryl, C _1-10 heterocyclyl and C _1-10 heteroaryl are optionally substituted with one or more groups, selected from hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _5-6 aryl, C _1-6 heteroaryl, C _1-6 heterocyclyl, oxo, halogen, hydroxyl and cyano, where C _5-6 aryl, C _1-6 heteroaryl and C _1-6 heterocyclyl are optionally substituted with one or more groups selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, oxo, halogen, hydroxyl , -CH ₂ OH and cyano; and R ₁₅ is selected from the group consisting of hydrogen, C _1-6 alkyl, and combinations thereof.

In one embodiment, the present invention provides a compound of formula I as described herein, wherein X is selected from O or S; Z is N; A is selected from N or CR ₁ ; B is selected from N or CR ₂ ; D is selected from N or CR ₃ ; R ₁ , R ₂ , R ₃ and R ₄ are independently selected from hydrogen, hydroxyl, cyano, amino, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _1-4 haloalkyl, C _{1 -4} haloalkoxy, C _1-4 acylamino, C _1-4 alkylamino, C _5-6 aryl, C _1-6 heterocyclyl, C _1-6 heteroaryl, C (O) NR ₁₅ , C (O) C _1-4 alkylamino , C(O)C _5-6 aryl, C(O)C _1-6 heteroaryl, C(O)C _1-4 alkyl, C(O)C _1-4 haloalkyl, SO ₂ C _1-4 alkyl, SO ₂ C _1-4 haloalkyl, SO ₂ C _3-6 cycloalkyl, SO ₂ NR ₁₅ , SO ₂ NC _1-4 alkylamino, SO ₂ C _5-6 aryl or SO ₂ C _1-6 heteroaryl, where C _1-4 alkyl , C _1-4 alkoxy, C _1-6 heteroaryl and C _1-4 haloalkoxy are optionally substituted with one or more groups selected from hydrogen, oxo, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _5-6 aryl, C _1-6 heterocyclyl, C _1-6 heteroaryl, cyano and hydroxyl; R ₁₁ is hydrogen; R ₁₂ is selected from C _1-6 alkylamino and a 5-10 membered monocyclic or bicyclic saturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, or R ₁₁ and R ₁₂ may be taken together to form 5-10 -membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-5 heteroatoms selected from N, S or O, where the 5-10-membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring is optionally substituted with substituents selected from amino, C _1-6 alkylamino, C _1-6 acylamino, -NHC(NH)CH ₂ Cl, NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ , C _1-6 alkyl, halogen, C _1-6 alkoxy and hydroxyl ; R ₁₃ is selected from hydrogen, 5-10 membered monocyclic or bicyclic aryl and 5-10 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where 5-10 membered monocyclic or bicyclic aryl and 5-10 membered monocyclic or bicyclic heteroaryl optionally substituted with 1-5 substituents selected from cyano, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _1-6 haloalkyl, C _5-10 aryl, C _1-10 heterocyclyl or C _1-10 heteroaryl, where C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _5-10 aryl, C _1-10 heterocyclyl and C _1-10 heteroaryl optionally substituted with one or more groups selected from hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _5-6 aryl, C _1-6 heteroaryl, C _{1- 6} heterocyclyl, oxo, halogen, hydroxyl and cyano, where C _5-6 aryl, C _1-6 heteroaryl and C _1-6 heterocyclyl are optionally substituted with one or more groups selected from hydrogen, C _1-6 alkyl, C _{1- 6} alkoxy, oxo, halogen, hydroxyl, -CH ₂ OH and cyano; and R ₁₅ is selected from the group consisting of hydrogen, C _1-6 alkyl, and combinations thereof.

In one embodiment, the present invention provides a compound of formula I as described herein, wherein X is selected from O or S; Z is N; A is selected from N or CR ₁ ; B is selected from N or CR ₂ ; R ₁ , R ₂ and R ₃ are independently selected from hydrogen, hydroxyl, cyano, amino, halogen, C _1-4 alkyl, C _1-4 alkoxy, C _3-5 cycloalkyl, C _1-4 haloalkyl, C _1-4 haloalkoxy , C _5-6 aryl, C _1-6 heterocyclyl or C _1-6 heteroaryl; R ₄ is selected from hydrogen, hydroxyl, cyano, amino, halogen, C _1-4 alkyl, C _1-4 alkoxy, C _3-5 cycloalkyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _5-6 aryl, C _1-4 heterocyclyl, C _1-4 heteroaryl, C (O) C _1-4 alkyl, C (O) C _1-4 haloalkyl, C (O) NR ₁₅ , C (O) C _1-4 alkylamino, C (O)C _5-6 aryl, C(O)C _1-4 heteroaryl, SO ₂ C _1-4 alkyl, SO ₂ C _1-4 haloalkyl, SO ₂ C _3-6 cycloalkyl, SO ₂ NR ₁₅ , SO ₂ NC _1-4 alkylamino, SO ₂ C _5-6 aryl, SO ₂ C _1-4 heteroaryl, C _1-4 acylamino or C _1-4 alkylamino, where C _1-4 alkyl, C _1-4 alkoxy, C _{1- 4} heteroaryl and C _1-4 haloalkoxy are optionally substituted with one or more groups selected from hydrogen, oxo, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _3-5 cycloalkyl, C _5-6 aryl , C _1-4 heterocyclyl, C _1-4 heteroaryl, cyano and hydroxyl; R ₁₁ is hydrogen; R ₁₂ is selected from C _1-4 alkylamino and a 5-10 membered monocyclic or bicyclic saturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, or R ₁₁ and R ₁₂ may be taken together to form 5-10 -membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-5 heteroatoms selected from N, S or O, where the 5-10-membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring is optionally substituted with substituents selected from amino, C _1-6 alkylamino, C _1-6 acylamino, -NHC(NH)CH ₂ Cl, NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ , C _1-6 alkyl, halogen, C _1-6 alkoxy or hydroxyl ; R ₁₃ is selected from hydrogen, 5-10 membered monocyclic or bicyclic aryl and 5-10 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where 5-10 membered monocyclic or bicyclic aryl and 5-10 membered monocyclic or bicyclic heteroaryl optionally substituted with 1-5 substituents selected from hydroxyl, cyano, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _1-6 haloalkyl, C _{1 -6} haloalkoxy, C _1-6 acylamino, C _1-6 alkylamino, C _5-10 aryl, C _1-10 heterocyclyl, C _1-10 heteroaryl, C (O) C _1-6 alkyl, C (O) C _{1 -6} haloalkyl, C(O)NR ₁₅ , C(O)C _1-6 alkylamino, C(O)C _5-6 aryl or C(O)C _1-6 heteroaryl, where C _1-6 alkyl, C _{1 -6} alkoxy, C _3-6 cycloalkyl, C _5-10 aryl, C _1-10 heterocyclyl and C _1-10 heteroaryl are optionally substituted with one or more groups selected from hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _5-6 aryl, C _1-6 heteroaryl, C _1-6 heterocyclyl, o xo, halogen, hydroxyl and cyano, where C _5-6 aryl, C _1-6 heteroaryl and C _1-6 heterocyclyl are optionally substituted with one or more groups selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, oxo , halogen, hydroxyl, -CH ₂ OH and cyano; and R ₁₅ is selected from the group consisting of hydrogen, C _1-6 alkyl, and combinations thereof.

In one embodiment, the present invention provides a compound of formula I as described herein, wherein X is selected from O or S; Z is N; A is selected from N or CR ₁ ; B is selected from N or CR ₂ ; R ₁ , R ₂ and R ₃ are independently selected from hydrogen, hydroxyl, cyano, amino, halogen, C _1-4 alkyl, C _1-4 alkoxy, C _3-5 cycloalkyl, C _1-4 haloalkyl, C _1-4 haloalkoxy , C _5-6 aryl, C _1-6 heterocyclyl and C _1-6 heteroaryl; R ₄ is selected from hydrogen, hydroxyl, cyano, amino, halogen, C _1-4 alkyl, C _1-4 alkoxy, C _3-5 cycloalkyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _5-6 aryl, C _1-4 heterocyclyl, C _1-4 heteroaryl, C (O) C _1-4 alkyl, C (O) C _1-4 haloalkyl, C (O) NR ₁₅ , C (O) C _1-4 alkylamino, C (O)C _5-6 aryl, C(O)C _1-4 heteroaryl, SO ₂ C _1-4 alkyl, SO ₂ C _1-4 haloalkyl, SO ₂ C _3-6 cycloalkyl, SO ₂ NR ₁₅ , SO ₂ NC _1-4 alkylamino, SO ₂ C _5-6 aryl, SO ₂ C _1-4 heteroaryl, C _1-4 acylamino or C _1-4 alkylamino, where C _1-4 alkyl, C _1-4 alkoxy, C _{1- 4} heteroaryl and C _1-4 haloalkoxy are optionally substituted with one or more groups selected from hydrogen, oxo, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _3-5 cycloalkyl, C _5-6 aryl , C _1-4 heterocyclyl, C _1-4 heteroaryl, cyano and hydroxyl; R ₁₁ is hydrogen; R ₁₂ is selected from C _1-4 alkylamino and a 5-10 membered monocyclic or bicyclic saturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, or R ₁₁ and R ₁₂ may be taken together to form 5-10 -membered monocyclic or bicyclic saturated heterocyclic ring with 1-5 heteroatoms selected from N, S or O, where 5-10-membered monocyclic or bicyclic saturated heterocyclic ring is optionally substituted with substituents selected from amino, C _1-4 alkylamino, C _{1 -4} acylamino, -NHC(NH)CH ₂ Cl, NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ , C _1-4 alkyl, halogen, C _1-44 alkoxy or hydroxyl; R ₁₃ is selected from hydrogen, 5-10 membered monocyclic or bicyclic aryl and 5-10 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where 5-10 membered monocyclic or bicyclic aryl and 5-10 membered monocyclic or bicyclic heteroaryl optionally substituted with 1-5 substituents selected from hydroxyl, cyano, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _1-6 haloalkyl, C _{1 -6} haloalkoxy, C _1-6 acylamino, C _1-6 alkylamino, C _5-10 aryl, C _1-10 heterocyclyl, C _1-10 heteroaryl, C (O) C _1-6 alkyl, C (O) C _{1 -6} haloalkyl, C(O)NR ₁₅ , C(O)C _1-6 alkylamino, C(O)C _5-6 aryl or C(O)C _1-6 heteroaryl, where C _1-6 alkyl, C _{1 -6} alkoxy, C _3-6 cycloalkyl, C _5-10 aryl, C _1-10 heterocyclyl and C _1-10 heteroaryl are optionally substituted with one or more groups selected from hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _5-6 aryl, C _1-6 heteroaryl, C _1-6 heterocyclyl, o xo, halogen, hydroxyl and cyano, where C _5-6 aryl, C _1-6 heteroaryl and C _1-6 heterocyclyl are optionally substituted with one or more groups selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, oxo , halogen, hydroxyl, -CH ₂ OH and cyano; and R ₁₅ is selected from the group consisting of hydrogen, C _1-6 alkyl, and combinations thereof.

In one embodiment, the present invention provides a compound of formula I as described herein, wherein X is selected from O or S; Z is N; A is selected from N or CR ₁ ; B is selected from N or CR ₂ ; R ₁ , R ₂ and R ₃ are independently selected from hydrogen, hydroxyl, cyano, amino, halogen, C _1-4 alkyl, C _1-4 alkoxy, C _3-5 cycloalkyl, C _1-4 haloalkyl, C _1-4 haloalkoxy , C _5-6 aryl, C _1-6 heterocyclyl or C _1-6 heteroaryl and combinations thereof; R ₄ is selected from hydrogen, hydroxyl, cyano, amino, halogen, C _1-4 alkyl, C _1-4 alkoxy, C _3-5 cycloalkyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _5-6 aryl, C _1-4 heterocyclyl, C _1-4 heteroaryl, C (O) C _1-4 alkyl, C (O) C _1-4 haloalkyl, C (O) NR ₁₅ , C (O) C _1-4 alkylamino, C (O)C _5-6 aryl, C(O)C _1-4 heteroaryl, SO ₂ C _1-4 alkyl, SO ₂ C _1-4 haloalkyl, SO ₂ C _3-6 cycloalkyl, SO ₂ NR ₁₅ , SO ₂ NC _1-4 alkylamino, SO ₂ C _5-6 aryl, SO ₂ C _1-4 heteroaryl, C _1-4 acylamino or C _1-4 alkylamino, where C _1-4 alkyl, C _1-4 alkoxy, C _{1- 4} heteroaryl and C _1-4 haloalkoxy are optionally substituted with one or more groups selected from hydrogen, oxo, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _3-5 cycloalkyl, C _5-6 aryl , C _1-4 heterocyclyl, C _1-4 heteroaryl, cyano and hydroxyl; R ₁₁ is hydrogen; R ₁₂ is selected from C _1-4 alkylamino and a 5-10 membered monocyclic or bicyclic saturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, or R ₁₁ and R ₁₂ may be taken together to form 5-10 -membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-5 heteroatoms selected from N, S or O, where the 5-10-membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring is optionally substituted with substituents selected from amino, C _1-6 alkylamino, C _1-6 acylamino, -NHC(NH)CH ₂ Cl, NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ , C _1-6 alkyl, halogen, C _1-6 alkoxy and hydroxyl and their combinations; R ₁₃ is selected from hydrogen, 5-10 membered monocyclic or bicyclic aryl and 5-10 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where 5-10 membered monocyclic or bicyclic aryl and 5-10 membered monocyclic or bicyclic heteroaryl optionally substituted with 1-5 substituents selected from hydroxyl, cyano, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _1-6 haloalkyl, C _{1 -6} haloalkoxy, C _1-6 acylamino, C _1-6 alkylamino, C _5-10 aryl, C _1-10 heterocyclyl, C _1-10 heteroaryl, C (O) C _1-4 alkyl, C (O) C _{1 -4} haloalkyl, C(O)NR ₁₅ , C(O)C _1-4 alkylamino, C(O)C _5-6 aryl and C(O)C _1-6 heteroaryl, where C _1-6 alkyl, C _{1 -6} alkoxy, C _3-6 cycloalkyl, C _5-10 aryl, C _1-10 heterocyclyl and C _1-10 heteroaryl are optionally substituted with one or more groups selected from hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _5-6 aryl, C _1-6 heteroaryl, C _1-6 heterocyclyl, ox o, halogen, hydroxyl and cyano, where C _5-6 aryl, C _1-6 heteroaryl and C _1-6 heterocyclyl are optionally substituted with one or more groups selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, oxo , halogen, hydroxyl, -CH ₂ OH and cyano; and R ₁₅ is independently selected from the group consisting of hydrogen, C _1-6 alkyl, and combinations thereof.

In one embodiment, the present invention provides a compound of formula I as described herein, wherein X is selected from O or S; Z is N; A is selected from N or CR ₁ ; B is selected from N or CR ₂ ; D is selected from N or CR ₃ ; R ₁ , R ₂ and R ₃ are independently selected from hydrogen, hydroxyl, cyano, amino, halogen, C _1-4 alkyl, C _1-4 alkoxy, C _5-6 cycloalkyl, C _1-4 haloalkyl, C _1-4 haloalkoxy , C _5-6 aryl, C _1-6 heterocyclyl or C _1-6 heteroaryl; R ₄ is selected from hydrogen, hydroxyl, cyano, amino, halogen, C _1-4 alkyl, C _1-4 alkoxy, C _5-6 cycloalkyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _5-6 aryl, C _1-6 heterocyclyl, C _1-6 heteroaryl, C (O) C _1-4 alkyl, C (O) C _1-4 haloalkyl, C (O) NR ₁₅ , C (O) C _1-4 alkylamino, C (O)C _5-6 aryl, C(O)C _1-6 heteroaryl, SO ₂ C _1-4 alkyl, SO ₂ C _1-4 haloalkyl, SO ₂ C _3-6 cycloalkyl, SO ₂ NR ₁₅ , SO ₂ NC _1-4 alkylamino, SO ₂ C _5-6 aryl, SO ₂ C _1-6 heteroaryl, C _1-4 acylamino or C _1-4 alkylamino, where C _1-4 alkyl, C _1-6 alkoxy, C _{1- 6} heteroaryl and C _1-4 haloalkoxy are optionally substituted with one or more groups selected from hydrogen, oxo, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _3-5 cycloalkyl, C _5-6 aryl , C _1-6 heterocyclyl, C _1-6 heteroaryl, cyano and hydroxyl; R ₁₁ and R ₁₂ are taken together to form a 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-5 heteroatoms selected from N or O, where the 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring is optionally substituted substituents selected from amino, C _1-4 alkylamino, C _1-4 acylamino, -NHC(NH)CH ₂ Cl, NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ , C _1-4 alkyl , halogen, C _1-4 alkoxy or hydroxyl; R ₁₃ is selected from hydrogen, 5-10 membered monocyclic or bicyclic aryl and 5-10 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where 5-10 membered monocyclic or bicyclic aryl and 5-10 membered monocyclic or bicyclic heteroaryl is optionally substituted with 1-5 substituents selected from halogen, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _1-4 acylamino, C _1-4 alkylamino, C _5-9 aryl, C _1-9 heterocyclyl and C _1-9 heteroaryl, where C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _5-9 aryl, C _1-9 heterocyclyl and C _1-9 heteroaryl are optionally substituted with one or more groups selected from hydrogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _3-6 cycloalkyl , C _5-6 aryl, C _1-6 heteroaryl, C _1-6 heterocyclyl, oxo, halogen, hydroxyl and cyano, where C _5-6 aryl, C _1-6 heteroaryl and C _1-6 heterocyclyl are optionally substituted with one or more groups, selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, oxo, halogen, hydroxyl, —CH ₂ OH and cyano; and R ₁₅ is selected from the group consisting of hydrogen, C _1-6 alkyl, and combinations thereof.

In one embodiment, the present invention provides a compound of formula I as described herein, wherein X is selected from O or S; Z is N; And represents CR ₁ ; B is CR ₂ ; D is CR ₃ ; R ₁ , R ₂ and R ₃ are independently selected from hydrogen, hydroxyl, cyano, amino, halogen, C _1-4 alkyl, C _1-4 alkoxy, C _3-5 cycloalkyl, C _1-4 haloalkyl, C _1-4 haloalkoxy , C _5-6 aryl, C _1-6 heterocyclyl or C _1-6 heteroaryl; R ₄ is selected from hydrogen, hydroxyl, cyano, amino, halogen, C _1-4 alkyl, C _1-4 alkoxy, C _3-5 cycloalkyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _5-6 aryl, C _1-6 heterocyclyl, C _1-6 heteroaryl, C(O)C _1-4 alkyl, C(O)C _1-4 haloalkyl, C(O)NR ₁₅ , C(O)C _1-4 alkylamino, C (O)C _5-6 aryl, C(O)C _1-6 heteroaryl, SO ₂ C _1-4 alkyl, SO ₂ C _1-4 haloalkyl, SO ₂ C _3-6 cycloalkyl, SO ₂ NR ₁₅ , SO ₂ NC _1-4 alkylamino, SO ₂ C _5-6 aryl, SO ₂ C _1-6 heteroaryl, C _1-4 acylamino or C _1-6 alkylamino, where C _1-4 alkyl, C _1-4 alkoxy, C _{1- 6} heteroaryl and C _1-4 haloalkoxy are optionally substituted with one or more groups selected from hydrogen, oxo, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _3-5 cycloalkyl, C _5-6 aryl , C _1-6 heterocyclyl, C _1-6 heteroaryl, cyano and hydroxyl; R ₁₁ and R ₁₂ are taken together to form a 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-5 heteroatoms selected from N or O, where the 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring is optionally substituted substituents selected from amino, C _1-4 alkylamino, C _1-4 acylamino, -NHC(NH)CH ₂ Cl, NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ , C _1-4 alkyl , halogen, C _1-4 alkoxy or hydroxyl; R ₁₃ is selected from hydrogen, 5-10 membered monocyclic or bicyclic aryl and 5-10 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where 5-10 membered monocyclic or bicyclic aryl and 5-10 membered monocyclic or bicyclic heteroaryl optionally substituted with 1-5 substituents selected from halogen, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _1-4 acylamino, C _1-4 alkylamino, C _5-9 aryl, C _1-9 heterocyclyl or C _1-9 heteroaryl, where C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _5-9 aryl, C _1-9 heterocyclyl and C _1-6 heteroaryl are optionally substituted with one or more groups selected from hydrogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _3-6 cycloalkyl , C _5-6 aryl, C _1-6 heteroaryl, C _1-6 heterocyclyl, oxo, halogen, hydroxyl and cyano, where C _5-6 aryl, C _1-6 heteroaryl and C _1-6 heterocyclyl are optionally substituted with one or more groups selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, oxo, halogen, hydroxyl, —CH ₂ OH, and cyano; and R ₁₅ is selected from the group consisting of hydrogen, C _1-6 alkyl, and combinations thereof.

In one embodiment, the present invention provides a compound of formula I as described herein, wherein X is selected from O or S; Z is N; A is selected from N or CR ₁ ; B is selected from N or CR ₂ ; D is selected from N or CR ₃ ; R ₁ , R ₂ and R ₃ are independently selected from hydrogen, hydroxyl, cyano, amino, halogen, C _1-4 alkyl or C _1-6 alkoxy; R ₄ is selected from hydrogen, hydroxyl, cyano, amino, halogen, C _1-4 alkyl, C _1-4 alkoxy, C _3-5 cycloalkyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _5-6 aryl, C _1-6 heterocyclyl, C _1-6 heteroaryl, C (O) C _1-4 alkyl, C (O) C _1-4 haloalkyl, C (O) NR ₁₅ , C (O) C _1-4 alkylamino, C (O)C _5-6 aryl, C(O)C _1-6 heteroaryl, SO ₂ C _1-4 alkyl, SO ₂ C _1-4 haloalkyl, SO ₂ C _3-6 cycloalkyl, SO ₂ NR ₁₅ , SO ₂ NC _1-4 alkylamino, SO ₂ C _5-6 aryl, SO ₂ C _1-6 heteroaryl, C _1-4 acylamino or C _1-4 alkylamino, where C _1-4 alkyl, C _1-4 alkoxy, C _{1- 6} heteroaryl and C _1-4 haloalkoxy are optionally substituted with one or more groups selected from hydrogen, oxo, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _3-5 cycloalkyl, C _5-6 aryl , C _1-6 heterocyclyl, C _1-6 heteroaryl, cyano and hydroxyl; R ₁₁ and R ₁₂ are taken together to form a 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-5 heteroatoms selected from N or O, where the 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring is optionally substituted substituents selected from amino, C _1-4 alkylamino, C _1-4 acylamino, -NHC(NH)CH ₂ Cl, NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ , C _1-4 alkyl , halogen, C _1-4 alkoxy or hydroxyl; R ₁₃ is selected from hydrogen, 5-10 membered monocyclic or bicyclic aryl and 5-10 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where 5-10 membered monocyclic or bicyclic aryl and 5-10 membered monocyclic or bicyclic heteroaryl is optionally substituted with 1-5 substituents selected from halogen, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _1-4 acylamino, C _1-4 alkylamino, C _5-9 aryl, C _1-9 heterocyclyl and C _1-9 heteroaryl, where C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _5-9 aryl, C _1-9 heterocyclyl and C _1-9 heteroaryl are optionally substituted with one or more groups selected from hydrogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _3-6 cycloalkyl , C _5-6 aryl, C _1-6 heteroaryl, C _1-6 heterocyclyl, oxo, halogen, hydroxyl and cyano, where C _5-6 aryl, C _1-6 heteroaryl and C _1-6 heterocyclyl are optionally substituted with one or more groups, selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, oxo, halogen, hydroxyl, —CH ₂ OH and cyano; and R ₁₅ is selected from the group consisting of hydrogen, C _1-6 alkyl, and combinations thereof.

In one embodiment, the present invention provides a compound of formula I as described herein, wherein X is selected from O or S; Z is N; A is selected from N or CR ₁ ; B is selected from N or CR ₂ ; D is selected from N or CR ₃ ; R ₁ , R ₂ and R ₃ are independently selected from hydrogen, hydroxyl, cyano, amino, halogen, C _1-4 alkyl, C _1-4 alkoxy, C _3-5 cycloalkyl, C _1-4 haloalkyl, C _1-4 haloalkoxy , C _5-6 aryl, C _1-6 heterocyclyl or C _1-6 heteroaryl; R ₄ is selected from hydrogen, hydroxyl, cyano, amino, halogen, C _1-4 alkyl, C _1-4 alkoxy, C _3-5 cycloalkyl, C _1-4 haloalkyl, C _1-4 haloalkoxy and C _5-6 aryl, where C _1-4 alkyl, C _1-4 alkoxy and C _1-4 haloalkoxy are optionally substituted with one or more groups selected from hydrogen, oxo, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _3-5 cycloalkyl, C _5-6 aryl, cyano and hydroxyl; R ₁₁ and R ₁₂ are taken together to form a 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-5 heteroatoms selected from N or O, where the 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring is optionally substituted substituents selected from amino, C _1-4 alkylamino, C _1-4 acylamino, -NHC(NH)CH ₂ Cl, NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ , C _1-4 alkyl , halogen, C _1-4 alkoxy or hydroxyl; R ₁₃ is selected from hydrogen, 5-10 membered monocyclic or bicyclic aryl and 5-10 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where 5-10 membered monocyclic or bicyclic aryl and 5-10 membered monocyclic or bicyclic heteroaryl is optionally substituted with 1-5 substituents selected from halogen, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _1-4 acylamino, C _1-4 alkylamino, C _5-9 aryl, C _1-9 heterocyclyl or C _1-9 heteroaryl, where C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _5-9 aryl, C _1-9 heterocyclyl and C _1-9 heteroaryl are optionally substituted with one or more groups selected from hydrogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _3-6 cycloalkyl , C _5-6 aryl, C _1-6 heteroaryl, C _1-6 heterocyclyl, oxo, halogen, hydroxyl and piano, where C _5-6 aryl, C _1-6 heteroaryl and C _1-6 heterocyclyl are optionally substituted with one or more groups selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, oxo, halogen, hydroxyl, —CH ₂ OH, and cyano; and R ₁₅ is selected from the group consisting of hydrogen, C _1-6 alkyl, and combinations thereof.

In one embodiment, the present invention provides a compound of formula I as described herein, wherein X is selected from O or S; Z is N; A is selected from N or CR ₁ ; B is selected from N or CR ₂ ; D is selected from N or CR ₃ ; R ₁ , R ₂ and R ₃ are independently selected from hydrogen, hydroxyl, cyano, amino, halogen, C _1-4 alkyl, C _1-4 alkoxy, C _3-5 cycloalkyl, C _1-4 haloalkyl, C _1-4 haloalkoxy , C _5-6 aryl, C _1-6 heterocyclyl or C _1-6 heteroaryl; R ₄ is selected from hydrogen, hydroxyl, cyano, amino, halogen, C _1-4 alkyl, C 1-4 alkoxy, C _3-5 cycloalkyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _5-6 aryl, C _{1 -6} heterocyclyl, C _1-6 heteroaryl, C (O) C _1-4 alkyl, C (O) C _1-4 haloalkyl, C (O) NR ₁₅ , C (O) C _1-4 alkylamino, C (O )C _5-6 aryl, C (O) C _1-6 heteroaryl, SO ₂ C _1-4 alkyl, SO ₂ C _1-4 haloalkyl, SO ₂ C _3-6 cycloalkyl, SO ₂ NR ₁₅ , SO ₂ NC _{1 -4} alkylamino, SO ₂ C _5-6 aryl, SO ₂ C _1-6 heteroaryl, C _1-4 acylamino or C _1-4 alkylamino, where C _1-4 alkyl, C _1-4 alkoxy, C _1-6 heteroaryl and C _1-4 haloalkoxy are optionally substituted with one or more groups selected from hydrogen, oxo, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _3-5 cycloalkyl, C _5-6 aryl, C _1-6 heterocyclyl, C _1-6 heteroaryl, cyano and hydroxyl; R ₁₁ and R ₁₂ are taken together to form a 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-5 heteroatoms selected from N or O, where the 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring is optionally substituted substituents selected from amino, C _1-4 alkylamino, C _1-4 acylamino, -NHC(NH)CH ₂ Cl, NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ , C _1-4 alkyl , halogen, C _1-4 alkoxy or hydroxyl; R ₁₃ is selected from hydrogen, 5-10 membered monocyclic or bicyclic aryl and 5-10 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where 5-10 membered monocyclic or bicyclic aryl and 5 -10-membered monocyclic or bicyclic heteroaryl optionally substituted with 1-5 substituents selected from halogen, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _1-4 haloalkyl, C _5-9 aryl, C _1-9 heterocyclyl or C _1-9 heteroaryl, where C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _5-9 aryl, C _1-9 heterocyclyl and C _1-9 heteroaryl are optionally substituted with one or several groups selected from hydrogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _5-6 aryl, C _1-6 heteroaryl, C _1-6 heterocyclyl, oxo, halogen, hydroxyl and cyano, where C _5-6 aryl, C _1-6 heteroaryl and C _1-6 heterocyclyl are optionally substituted with one or more groups selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, ox o, halogen, hydroxyl, -CH ₂ OH and cyano; and R ₁₅ is selected from the group consisting of hydrogen, C _1-6 alkyl, and combinations thereof.

In one embodiment, the present invention provides a compound of formula I as described herein, wherein X is selected from O or S; Z is N; And represents CR ₁ ;

B is CR ₂ ; D is CR ₃ ; R ₁ , R ₂ and R ₃ are independently selected from hydrogen or C _1-2 alkyl; R ₄ is selected from hydrogen, C _1-4 alkyl, C _1-4 alkoxy, C _3-5 cycloalkyl, or C _5-6 aryl, where C _1-4 alkyl and C _1-4 alkoxy are optionally substituted with one or more groups selected from from C _1-4 alkyl and C _1-4 alkoxy; R ₁₁ and R ₁₂ are taken together to form a 5-10 membered monocyclic or bicyclic saturated heterocyclic ring with 1-5 heteroatoms selected from N, S or O, where the 5-10 membered monocyclic or bicyclic saturated heterocyclic ring is optionally substituted with substituents selected from from amino, NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ or C _1-2 alkylamino; and R ₁₃ is selected from hydrogen, 5-9 membered monocyclic or bicyclic aryl and 5-9 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where 5-9 membered monocyclic or bicyclic aryl and 5-9 membered monocyclic or bicyclic heteroaryl are optionally substituted with 1-5 substituents selected from hydroxyl, cyano, fluorine, bromine, chlorine, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _{3- 5} cycloalkyl, C _5-9 aryl, C _1-9 heterocyclyl or C _1-9 heteroaryl, where C _1-4 alkyl, C _1-4 alkoxy, C _3-5 cycloalkyl, C _5-9 aryl, C _1-9 heterocyclyl and C _1-9 heteroaryl are optionally substituted with one or more groups selected from hydrogen, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _3-5 cycloalkyl, C _5-6 aryl, C _{1 -6} heteroaryl, C _1-6 heterocyclyl, oxo, halogen and cyano, where C _5-6 aryl, C _1-6 heteroaryl and C _1-6 heterocyclyl are optionally substituted with one or more groups selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, oxo, halogen, hydroxyl, -CH ₂ OH and cyano.

In one embodiment, the present invention provides a compound of formula I as described herein, wherein X is selected from O or S; Z is N; And represents CR ₁ ; B is CR ₂ ; D is CR ₃ ; R ₁ , R ₂ and R ₃ are independently selected from hydrogen or C _1-2 alkyl; R ₄ is selected from hydrogen, C ₁ alkyl, C ₁ alkoxy, C ₃ cycloalkyl or C ₆ aryl, where C ₁ alkyl and C ₁ alkoxy are optionally substituted with one or more groups selected from C ₁ alkyl and C ₁ alkoxy; R ₁₁ and R ₁₂ are taken together to form a 5-10 membered monocyclic or bicyclic saturated heterocyclic ring with 1-5 heteroatoms selected from N, S or O, where the 5-10 membered monocyclic or bicyclic saturated heterocyclic ring is optionally substituted with substituents, selected from amino, NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ or C _1-2 alkylamino; and R ₁₃ is selected from hydrogen, 5-9 membered monocyclic or bicyclic aryl and 5-9 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where 5-9 membered monocyclic or bicyclic aryl and 5-9 membered monocyclic or bicyclic heteroaryl are optionally substituted with 1-5 substituents selected from hydroxyl, cyano, fluorine, bromine, chlorine, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _{3- 5} cycloalkyl, C _5-9 aryl, C _1-9 heterocyclyl or C _1-9 heteroaryl, where C _1-4 alkyl, C _1-4 alkoxy, C _3-5 cycloalkyl, C _5-9 aryl, C _1-9 heterocyclyl and C _1-9 heteroaryl are optionally substituted with one or more groups selected from hydrogen, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _3-5 cycloalkyl, C _5-6 aryl, C _{1 -6} heteroaryl, C _1-6 heterocyclyl, oxo, halogen and cyano, where C _5-6 aryl, C _1-6 heteroaryl and C _1-6 heterocyclyl are optionally substituted with one or more groups selected from hydrogen, C _1-6 alkyl , WITH _1-6 alkoxy, oxo, halogen, hydroxyl, -CH ₂ OH and cyano.

In one embodiment, the present invention provides a compound of formula I as described herein, wherein X is selected from O or S; Z is N; And represents CR ₁ ; B is CR ₂ ; D is CR ₃ ; R ₁ , R ₂ and R ₃ are independently selected from hydrogen and C _1-2 halkyl; R ₄ is selected from hydrogen, C _1-4 alkyl, C _1-4 alkoxy, C _3-5 cycloalkyl and C _5-6 aryl, where C _1-4 alkyl and C _1-4 alkoxy are optionally substituted with one or more groups selected from from C _1-4 alkyl and C _1-4 alkoxy; R ₁₁ and R ₁₂ are taken together to form a 5-10 membered monocyclic or bicyclic saturated heterocyclic ring with 1-5 heteroatoms selected from N, S or O, where the 5-10 membered monocyclic or bicyclic saturated heterocyclic ring is optionally substituted with amino and NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ ; and R ₁₃ is selected from hydrogen, 5-9 membered monocyclic or bicyclic aryl, and 5-9 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where 5-9 membered monocyclic or bicyclic aryl and 5-9 membered monocyclic or bicyclic heteroaryl are optionally substituted with 1-5 substituents selected from hydroxyl, cyano, fluorine, bromine, chlorine, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _{3- 5} cycloalkyl, C _5-9 aryl, C _1-9 heterocyclyl and C _1-9 heteroaryl, where C _1-4 alkyl, C _1-4 alkoxy, C _3-5 cycloalkyl, C _5-9 aryl, C _1-9 heterocyclyl and C _1-9 heteroaryl are optionally substituted with one or more groups selected from hydrogen, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _3-5 cycloalkyl, C _5-6 aryl, C _{1 -6} heteroaryl, C _1-6 heterocyclyl, oxo, halogen and cyano, where C _5-6 aryl, C _1-6 heteroaryl and C _1-6 heterocyclyl are optionally substituted with one or more groups selected from hydrogen, C _1-6 alkyl , С _{1 -6} alkoxy, oxo, halogen, hydroxyl, -CH ₂ OH and cyano.

In one embodiment, the present invention provides a compound of formula I as described herein, wherein X is selected from O or S; Z is N; And represents CR ₁ ; B is CR ₂ ; D is CR ₃ ; R ₁ , R ₂ and R ₃ are independently selected from hydrogen and C ₁ alkyl; R ₄ is selected from hydrogen, C ₁ alkyl, C ₁ alkoxy, C ₃ cycloalkyl and C ₆ aryl, where C ₁ alkyl and C ₁ alkoxy are optionally substituted with one or more groups selected from C ₁ alkyl and C ₁ alkoxy; R ₁₁ and R ₁₂ are taken together to form a 5-10 membered monocyclic or bicyclic saturated heterocyclic ring with 1-5 heteroatoms selected from N, S or O, where the 5-10 membered monocyclic or bicyclic saturated heterocyclic ring is optionally substituted with amino and NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ ; and R ₁₃ is selected from hydrogen, 5-9 membered monocyclic or bicyclic aryl and 5-9 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where 5-9 membered monocyclic or bicyclic aryl and 5-9 membered monocyclic or bicyclic heteroaryl are optionally substituted with 1-5 substituents selected from hydroxyl, cyano, fluorine, bromine, chlorine, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _{3 -5} cycloalkyl, C _5-9 aryl, C _1-9 heterocyclyl and C _1-9 heteroaryl, where C _1-4 alkyl, C _1-4 alkoxy, C _3-5 cycloalkyl, C _5-9 aryl, C _{1- 9} heterocyclyl and C _1-9 heteroaryl are optionally substituted with one or more groups selected from hydrogen, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _3-5 cycloalkyl, C _5-6 aryl, C _1-6 heteroaryl, C _1-6 heterocyclyl, oxo, halogen and cyano, where C _5-6 aryl, C _1-6 heteroaryl and C _1-6 heterocyclyl are optionally substituted with one or more groups selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, oxo, halogen, hydroxyl, -CH ₂ OH and cyano.

In one embodiment, the present invention provides a compound of formula I as described herein, wherein X is selected from O or S; Z is N; And represents CR ₁ ; B is CR ₂ ; D is CR ₃ ; R ₁ , R ₂ and R ₃ are independently selected from hydrogen or C ₁ alkyl; R ₄ is selected from hydrogen, C ₁ alkyl, C ₁ alkoxy, C ₃ cycloalkyl or C ₆ aryl, where C ₁ alkyl and C ₁ alkoxy are optionally substituted with one or more groups selected from C ₁ alkyl and C ₁ alkoxy; R ₁₁ and R ₁₂ are taken together to form a 5-6 membered monocyclic saturated heterocyclic ring with 1-5 heteroatoms selected from N, S or O, where the 5-6 membered monocyclic saturated heterocyclic ring is optionally substituted with amino and NH(CO) CH=CH-CH ₂ -N(CH ₃ ) ₂ ; and R ₁₃ is selected from hydrogen, 5-9 membered monocyclic or bicyclic aryl, and 5-9 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where 5-9 membered monocyclic or bicyclic aryl and 5-9 membered monocyclic or bicyclic heteroaryl are optionally substituted with 1-5 substituents selected from hydroxyl, cyano, fluorine, bromine, chlorine, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _{3- 5} cycloalkyl, C _5-9 aryl, C _1-9 heterocyclyl or C _1-9 heteroaryl, where C _1-4 alkyl, C _1-4 alkoxy, C _3-5 cycloalkyl, C _5-9 aryl, C _1-9 heterocyclyl and C _1-9 heteroaryl are optionally substituted with one or more groups selected from hydrogen, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _3-5 cycloalkyl, C _5-6 aryl, C _{1 -6} heteroaryl, C _1-6 heterocyclyl, oxo, halogen and cyano, where C _5-6 aryl, C _1-6 heteroaryl and C _1-6 heterocyclyl are optionally substituted with one or more groups selected from hydrogen, C _1-6 alkyl , WITH _1-6 alkoxy, oxo, halogen, hydroxyl, -CH ₂ OH and cyano.

In one embodiment, the present invention provides a compound of formula I as described herein, wherein X is selected from O or S; Z is N; And represents CR ₁ ; B is CR ₂ ; D is CR ₃ ; R ₁ , R ₂ and R ₃ are independently selected from hydrogen or C ₁ alkyl; R ₄ is selected from hydrogen, C ₁ alkyl, C ₁ alkoxy, C ₃ cycloalkyl or C ₆ aryl, where C ₁ alkyl and C ₁ alkoxy are optionally substituted with one or more groups selected from C ₁ alkyl and C ₁ alkoxy; R ₁₁ and R ₁₂ are taken together to form a 5-10 membered bicyclic saturated heterocyclic ring with 1-5 heteroatoms selected from N, S or O; and R ₁₃ is selected from hydrogen, 5-9 membered monocyclic or bicyclic aryl and 5-9 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where 5-9 membered monocyclic or bicyclic aryl and 5-9 membered monocyclic or bicyclic heteroaryl are optionally substituted with 1-5 substituents selected from hydroxyl, cyano, fluorine, bromine, chlorine, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _{3- 5} cycloalkyl, C _5-9 aryl, C _1-9 heterocyclyl or C _1-9 heteroaryl, where C _1-4 alkyl, C _1-4 alkoxy, C _3-5 cycloalkyl, C _5-9 aryl, C _1-9 heterocyclyl and C _1-9 heteroaryl are optionally substituted with one or more groups selected from hydrogen, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _3-5 cycloalkyl, C _5-6 aryl, C _{1 -6} heteroaryl, C _1-6 heterocyclyl, oxo, halogen and cyano, where C _5-6 aryl, C _1-6 heteroaryl and C _1-6 heterocyclyl are optionally substituted with one or more groups selected from hydrogen, C _1-6 alkyl , WITH _1-6 alkoxy, oxo, halogen, hydroxyl, -CH ₂ OH and cyano.

In one embodiment, the present invention provides a compound of formula I as described herein, wherein X is selected from O or S; Z is N; And represents CR ₁ ; B is CR ₂ ; D is CR ₃ ; R ₁ , R ₂ and R ₃ are independently selected from hydrogen or C ₁ alkyl; R ₄ is selected from hydrogen, C ₁ alkyl, C ₁ alkoxy, C ₃ cycloalkyl or C ₆ aryl, where C ₁ alkyl and C ₁ alkoxy are optionally substituted with one or more groups selected from C ₁ alkyl and C ₁ alkoxy; R ₁₁ and R ₁₂ are taken together to form a 5-membered monocyclic saturated heterocyclic ring with 1-5 heteroatoms selected from N, S or O, where the 5-membered monocyclic saturated heterocyclic ring is optionally substituted with amino; and R ₁₃ is selected from hydrogen, 5-9 membered monocyclic or bicyclic aryl, and 5-9 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where 5-9 membered monocyclic or bicyclic ar yl and 5-9 membered monocyclic or bicyclic heteroaryl are optionally substituted with 1-5 substituents selected from hydroxyl, cyano, fluorine, bromine, chlorine, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _{3 -5} cycloalkyl, C _5-9 aryl, C _1-9 heterocyclyl or C _1-9 heteroaryl, where C _1-4 alkyl, C _1-4 alkoxy, C _3-5 cycloalkyl, C _5-9 aryl, C _{1- 9} heterocyclyl and C _1-9 heteroaryl are optionally substituted with one or more groups selected from hydrogen, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _3-5 cycloalkyl, C _5-6 aryl, C _1-6 heteroaryl, C _1-6 heterocyclyl, oxo, halogen and cyano, where C _5-6 aryl, C _1-6 heteroaryl and C _1-6 heterocyclyl are optionally substituted with one or more groups selected from hydrogen, C _{1- 6} alkyl, C _1-6 alkoxy, oxo, halogen, hydroxyl, -CH ₂ OH and cyano.

In one embodiment, the present invention provides a compound of formula I as described herein, wherein X is selected from O or S; Z is N; And represents CR ₁ ; B is CR ₂ ; D is CR ₃ ; R ₁ , R ₂ and R ₃ are independently selected from hydrogen or C ₁ alkyl; R ₄ is selected from hydrogen, C ₁ alkyl, C ₁ alkoxy, C ₃ cycloalkyl or C ₆ aryl, where C ₁ alkyl and C ₁ alkoxy are optionally substituted with one or more groups selected from C ₁ alkyl and C ₁ alkoxy; R ₁₁ and R ₁₂ are taken together to form a 5-10 membered monocyclic or bicyclic saturated heterocyclic ring with 1-5 heteroatoms selected from N, S or O, where the 5-10 membered monocyclic or bicyclic saturated heterocyclic ring is optionally substituted with amino and NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ ; and R ₁₃ is selected from hydrogen, 5-9 membered monocyclic aryl, where 5-9 membered monocyclic aryl is optionally substituted with 1-5 substituents selected from hydroxyl, cyano, fluorine, bromine, chlorine, C _1-4 alkyl, C _{1 -4} alkoxy, C _1-4 haloalkyl, C _3-5 cycloalkyl, C _5-6 aryl, C _1-6 heterocyclyl, or C _1-6 heteroaryl.

In one embodiment, the present invention provides a compound of formula I as described herein, wherein X is selected from O or S; Z is N; And represents CR ₁ ; B is CR ₂ ; D is CR ₃ ; R ₁ , R ₂ and R ₃ are independently selected from hydrogen or C ₁ alkyl; R ₄ is selected from hydrogen, C ₁ alkyl, C ₁ alkoxy, C ₃ cycloalkyl or C ₆ aryl, where C ₁ alkyl and C ₁ alkoxy are optionally substituted with one or more groups selected from C ₁ alkyl and C ₁ alkoxy; R ₁₁ and R ₁₂ are taken together to form a 5-6 membered monocyclic or bicyclic saturated heterocyclic ring with 1-5 heteroatoms selected from N, S or O, where the 5-6 membered monocyclic or bicyclic saturated heterocyclic ring is optionally substituted with amino; and R ₁₃ is selected from hydrogen, 5-9 membered monocyclic or bicyclic aryl and 5-9 membered monocyclic or bicyclic heteroaryl with 1 heteroatom selected from S or O, where 5-9 membered monocyclic or bicyclic aryl and 5-9 -membered monocyclic or bicyclic heteroaryl optionally substituted with 1-5 substituents selected from hydroxyl, cyano, fluorine, bromine, chlorine, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _3-5 cycloalkyl, C _5-6 aryl, C _1-6 heterocyclyl, or C _1-6 heteroaryl.

In one embodiment, the present invention provides a compound of formula I as described herein, wherein X is selected from O or S; Z is N; And represents CR ₁ ; B is CR ₂ ; D is CR ₃ ; R ₁ , R ₂ and R ₃ are independently selected from hydrogen or C ₁ alkyl; R ₄ is selected from hydrogen, C ₁ alkyl, C ₁ alkoxy, C ₃ cycloalkyl or C ₆ aryl, where C ₁ alkyl and C ₁ alkoxy are optionally substituted with one or more groups selected from C ₁ alkyl and C ₁ alkoxy; R ₁₁ and R ₁₂ are taken together to form a 5-6 membered monocyclic or bicyclic saturated heterocyclic ring with 1-5 heteroatoms selected from N, S or O, where the 5-6 membered monocyclic or bicyclic saturated heterocyclic ring is optionally substituted with amino; and R ₁₃ is indole, where the indole is optionally substituted with 1-5 substituents selected from hydroxyl, cyano, fluorine, bromine, chlorine, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _3-5 cycloalkyl, C _5-9 aryl, C _1-9 heterocyclyl or C _1-9 heteroaryl, where C _1-4 alkyl, C _1-4 alkoxy, C _3-5 cycloalkyl, C _5-9 aryl, C _1-9 heterocyclyl and C _1-9 heteroaryl are optionally substituted with one or more groups selected from hydrogen, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _3-5 cycloalkyl, C _5-6 aryl, C _{1- 6} heteroaryl, C _1-6 heterocyclyl, oxo, halogen and cyano, where C _5-6 aryl, C _1-6 heteroaryl and C _1-6 heterocyclyl are optionally substituted with one or more groups selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, oxo, halogen, hydroxyl, -CH ₂ OH and cyano.

In one embodiment, the present invention provides a compound of formula I as described herein, wherein X is O; Z is N; And represents CR ₁ ; B is CR ₂ ; D is CR ₃ ; R ₁ , R ₂ and R ₃ are independently selected from hydrogen or C _1-2 alkyl; R ₄ is selected from hydrogen, C _1-4 alkyl, C _1-4 alkoxy, C _3-5 cycloalkyl, or C _5-6 aryl, where C _1-4 alkyl and C _1-4 alkoxy are optionally substituted with one or more groups selected from from C _1-4 alkyl and C _1-4 alkoxy; R ₁₁ and R ₁₂ are taken together to form a 5-10 membered monocyclic or bicyclic saturated heterocyclic ring with 1-5 heteroatoms selected from N, S or O, where the 5-10 membered monocyclic or bicyclic saturated heterocyclic ring is optionally substituted with substituents, selected from amino, C _1-2 alkylamino and NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ ; and R ₁₃ is selected from hydrogen, 5-9 membered monocyclic or bicyclic aryl, and 5-9 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where 5-9 membered monocyclic or bicyclic aryl and 5-9 membered monocyclic or bicyclic heteroaryl are optionally substituted with 1-5 substituents selected from hydroxyl, cyano, fluorine, bromine, chlorine, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _{3- 5} cycloalkyl, C _5-9 aryl, C _1-9 heterocyclyl or C _1-9 heteroaryl, where C _1-4 alkyl, C _1-4 alkoxy, C _3-5 cycloalkyl, C _5-9 aryl, C _1-9 heterocyclyl and C _1-9 heteroaryl are optionally substituted with one or more groups selected from hydrogen, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _3-5 cycloalkyl, C _5-6 aryl, C _{1 -6} heteroaryl, C _1-6 heterocyclyl, oxo, halogen and cyano, where C _5-6 aryl, C _1-6 heteroaryl and C _1-6 heterocyclyl are optionally substituted with one or more groups selected from hydrogen, C _1-6 alkyl , WITH _1-6 alkoxy, oxo, halogen, hydroxyl, -CH ₂ OH and cyano.

In one embodiment, the present invention provides a compound of formula I as described herein, wherein X is O; Z is N; And represents CR ₁ ; B is CR ₂ ; D is CR ₃ ; R ₁ , R ₂ and R ₃ are independently selected from hydrogen or C _1-2 alkyl; R ₄ is selected from hydrogen, C _1-4 alkyl, C ₁ - ₄ alkoxy, C _3-5 cycloalkyl, or C _5-6 aryl, where C _1-4 alkyl and C _1-4 alkoxy are optionally substituted with one or more groups selected from from C _1-4 alkyl and C _1-4 alkoxy; R ₁₁ and R ₁₂ are taken together to form a 5-10 membered monocyclic or bicyclic saturated heterocyclic ring with 1-5 heteroatoms selected from N, S or O, where the 5-10 membered monocyclic or bicyclic saturated heterocyclic ring is optionally substituted with substituents selected from from amino, C _1-2 alkylamino and NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ ; and R ₁₃ is selected from hydrogen, 5-9 membered monocyclic or bicyclic aryl and 5-9 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N or O, where 5-9 membered monocyclic or bicyclic aryl and 5 -9-membered monocyclic or bicyclic heteroaryl optionally substituted with 1-5 substituents selected from hydroxyl, cyano, fluorine, bromine, chlorine, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _3-5 cycloalkyl , C _5-9 aryl, C _1-9 heterocyclyl and C _1-9 heteroaryl, where C _1-4 alkyl, C _1-4 alkoxy, C _3-5 cycloalkyl, C _5-9 aryl, C _1-9 heterocyclyl and C _1-9 heteroaryl optionally substituted with one or more groups selected from hydrogen, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _3-5 cycloalkyl, C _5-6 aryl, C _1-6 heteroaryl, C _1-6 heterocyclyl, oxo, halogen and cyano, where C _5-6 aryl, C _1-6 heteroaryl and C _1-6 heterocyclyl are optionally substituted with one or more groups selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, oxo, halogen, hydroxyl, -CH ₂ OH and cyano.

In one embodiment, the present invention provides a compound of formula I as described herein, wherein X is O; Z is N; And represents CR ₁ ; B is CR ₂ ; D is CR ₃ ; R ₁ , R ₂ and R ₃ are independently selected from hydrogen or C _1-2 alkyl; R ₄ is selected from hydrogen, C _1-4 alkyl, C _1-4 alkoxy, C _3-5 cycloalkyl and C _5-6 aryl, where C _1-4 alkyl and C _1-4 alkoxy are optionally substituted with one or more groups selected from from C _1-4 alkyl and C _1-4 alkoxy; R ₁₁ and R ₁₂ are taken together to form a 5-10 membered monocyclic or bicyclic saturated heterocyclic ring with 1-5 heteroatoms selected from N, S or O, where the 5-10 membered monocyclic or bicyclic saturated heterocyclic ring is optionally substituted with substituents, selected from amino, C _1-2 alkylamino and NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ ; and R ₁₃ is selected from hydrogen and 5-9 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where 5-9 membered monocyclic or bicyclic heteroaryl is optionally substituted with 1-5 substituents selected from hydroxyl , cyano, fluorine, bromine, chlorine, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _3-5 cycloalkyl, C _5-9 aryl, C _1-9 heterocyclyl and C _1-9 heteroaryl , where C _1-4 alkyl, C _1-4 alkoxy, C _3-5 cycloalkyl, C _5-9 aryl, C _1-9 heterocyclyl and C _1-9 heteroaryl are optionally substituted with one or more groups selected from hydrogen, C _{1 -4} alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _3-5 cycloalkyl, C _5-6 aryl, C _1-6 heteroaryl, C _1-6 heterocyclyl, oxo, halogen and cyano, where C _5-6 aryl, C _1-6 heteroaryl and C _1-6 heterocyclyl are optionally substituted with one or more groups selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, oxo, halogen, hydroxyl, —CH ₂ OH and cyano.

In one embodiment, the present invention provides a compound of formula I as described herein, wherein X is O; Z is N; And represents CR ₁ ; B is CR ₂ ; D is CR ₃ ; R ₁ , R ₂ and R ₃ are independently selected from hydrogen or C _1-2 alkyl; R ₄ is selected from hydrogen, C _1-4 alkyl, C _1-4 alkoxy, C _3-5 cycloalkyl, or C _5-6 aryl, where C _1-4 alkyl and C _1-4 alkoxy are optionally substituted with one or more groups selected from from C _1-4 alkyl and C _1-4 alkoxy; R ₁₁ and R ₁₂ are taken together to form a 5-10 membered monocyclic or bicyclic saturated heterocyclic ring with 1-5 heteroatoms selected from N, S or O, where the 5-10 membered monocyclic or bicyclic saturated heterocyclic ring is optionally substituted with substituents, selected from amino, C _1-2 alkylamino and NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ ; and R ₁₃ is selected from hydrogen, 5-9 membered monocyclic aryl and 5-9 membered bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where 5-9 membered monocyclic aryl and 5-9 membered bicyclic heteroaryl optionally substituted with 1-5 substituents selected from hydroxyl, cyano, fluorine, bromine, chlorine, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _3-5 cycloalkyl, C _5-9 aryl , C _1-9 heterocyclyl and C _1-9 heteroaryl, where C _1-4 alkyl, C _1-4 alkoxy, C _3-5 cycloalkyl, C _5-9 aryl, C _1-9 heterocyclyl and C _1-9 heteroaryl are optional substituted with one or more groups selected from hydrogen, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _3-5 cycloalkyl, C _5-6 aryl, C _1-6 heteroaryl, C _1-6 heterocyclyl, oxo, halogen and cyano, where C _5-6 aryl, C _1-6 heteroaryl and C _1-6 heterocyclyl are optionally substituted with one or more groups selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, oxo , halogen, hydroxyl, -CH ₂ OH and cyano.

In one embodiment, the present invention provides a compound of formula I as described herein, wherein X is selected from O or S; Z is N; And represents CR ₄ ; B is CR ₂ ; D is CR ₃ ; R ₁ , R ₂ and R ₃ are independently selected from hydrogen or C _1-2 alkyl; R ₄ is selected from hydrogen, C _1-4 alkyl, C _1-4 alkoxy, C _3-5 cycloalkyl, or C _5-6 aryl, where C _1-4 alkyl and C _1-4 alkoxy are optionally substituted with one or more groups selected from from C _1-4 alkyl and C _1-4 alkoxy; R ₁₁ and R ₁₂ are taken together to form a 5-10 membered monocyclic or bicyclic saturated heterocyclic ring with 1-5 heteroatoms selected from N, S or O, where the 5-10 membered monocyclic or bicyclic saturated heterocyclic ring is optionally substituted with substituents, selected from amino, C _1-2 alkylamino and NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ ; and R ₁₃ is selected from hydrogen and 5-9 membered bicyclic heteroaryl with 1-5 heteroatoms selected from N or O, where 5-9 membered bicyclic heteroaryl is optionally substituted with 1-5 substituents selected from hydroxyl, cyano, fluorine, bromine , chlorine, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _3-5 cycloalkyl, C _5-9 aryl, C _1-9 heterocyclyl or C _1-9 heteroaryl, where C _1-4 alkyl, C _1-4 alkoxy, C _3-5 cycloalkyl, C _5-9 aryl, C _1-9 heterocyclyl and C _1-9 heteroaryl are optionally substituted with one or more groups selected from hydrogen, C _1-4 alkyl, C _{1 -4} alkoxy, C _1-4 haloalkyl, C _3-5 cycloalkyl, C _5-6 aryl, C _1-6 heteroaryl, C _1-6 heterocyclyl, oxo, halogen and cyano, where C _5-6 aryl, C _{1- 6} heteroaryl and C _1-6 heterocyclyl are optionally substituted with one or more groups selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, oxo, halogen, hydroxyl, —CH ₂ OH, and cyano.

In one embodiment, the present invention provides a compound of formula I as described herein, wherein X is O; Z is N; And represents CR ₁ ; B is CR ₂ ; D is CR ₃ ; R ₁ , R ₂ and R ₃ are independently selected from hydrogen or C _1-2 alkyl; R ₄ is selected from hydrogen, C _1-4 alkyl, C _1-4 alkoxy, C _3-5 cycloalkyl, or C _5-6 aryl, where C _1-4 alkyl and C _1-4 alkoxy are optionally substituted with one or more groups selected from from C _1-4 alkyl and C _1-4 alkoxy; R ₁₁ and R ₁₂ are taken together to form a 5-10 membered monocyclic or bicyclic saturated heterocyclic ring with 1-5 heteroatoms selected from N, S or O, where the 5-10 membered monocyclic or bicyclic saturated heterocyclic ring is optionally substituted with substituents selected from from amino, C _1-2 alkylamino or NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ ; and R ₁₃ is selected from hydrogen, 5-9 membered monocyclic or bicyclic aryl, and 5-9 membered monocyclic or bicyclic heteroaryl with 1 heteroatom selected from N, S or O, where 5-9 membered monocyclic or bicyclic aryl and 5-9 membered monocyclic or bicyclic heteroaryl optionally substituted with 1-5 substituents selected from hydroxyl, cyano, fluorine, bromine, chlorine, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _3-5 cycloalkyl, C _5-9 aryl, C _1-9 heterocyclyl or C _1-9 heteroaryl, where C _1-4 alkyl, C _1-4 alkoxy, C _3-5 cycloalkyl, C _5-9 aryl, C _1-9 heterocyclyl and C _1-9 heteroaryl are optionally substituted with one or more groups selected from hydrogen, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _3-5 cycloalkyl, C _5-6 aryl, C _{1- 6} heteroaryl, C _1-6 heterocyclyl, oxo, halogen and cyano, where C _5-6 aryl, C _1-6 heteroaryl and C _1-6 heterocyclyl are optionally substituted with one or more groups selected from hydrogen, C _1-6 alkyl, From _{1- 6} alkoxy, oxo, halogen, hydroxyl, -CH ₂ OH and cyano.

In one embodiment, the present invention provides a compound of formula I as described herein, wherein X is S; Z is N; And represents CR ₁ ; B is CR ₂ ; D is CR ₃ ; R ₁ , R ₂ and R ₃ are independently selected from hydrogen or C _1-2 alkyl; R ₄ is selected from hydrogen, C _1-4 alkyl, C _1-4 alkoxy, C _3-5 cycloalkyl, or C _5-6 aryl, where C _1-4 alkyl and C _1-4 alkoxy are optionally substituted with one or more groups selected from from C _1-4 alkyl and C _1-4 alkoxy; R ₁₁ and R ₁₂ are taken together to form a 5-10 membered monocyclic or bicyclic saturated heterocyclic ring with 1-5 heteroatoms selected from N, S or O, where the 5-10 membered monocyclic or bicyclic saturated heterocyclic ring is optionally substituted with substituents, selected from amino, C _1-2 alkylamino or NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ ; and R ₁₃ is selected from hydrogen, 5-9 membered monocyclic or bicyclic aryl, and 5-9 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where 5-9 membered monocyclic or bicyclic aryl and 5-9 membered monocyclic or bicyclic heteroaryl optionally substituted with 1-5 substituents selected from hydroxyl, cyano, fluorine, bromine, chlorine, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _3-5 cycloalkyl, C _5-9 aryl, C _1-9 heterocyclyl or C _1-9 heteroaryl, where C _1-4 alkyl, C _1-4 alkoxy, C _3-5 cycloalkyl, C _5-9 aryl, C _1-9 heterocyclyl and C _1-9 heteroaryl are optionally substituted with one or more groups selected from hydrogen, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _3-5 cycloalkyl, C _5-6 aryl, C _{1- 6} heteroaryl, C _1-6 heterocyclyl, oxo, halogen and cyano, where C _5-6 aryl, C _1-6 heteroaryl and C _1-6 heterocyclyl are optionally substituted with one or more groups selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, oxo, halogen, hydroxyl, -CH ₂ OH and cyano.

In one embodiment, the present invention provides a compound of formula II, its polymorphs, stereoisomers, prodrugs thereof, solvates, co-crystals, intermediates thereof, pharmaceutically acceptable salts and metabolites thereof, wherein

X is selected from O or S; Z is N; A is selected from N or CR ₁ ; B is selected from N or CR ₂ ; D is selected from N or CR ₃ ; E is selected from N or CR ₆ ; F absent or selected from N and CR ₇ ; G is absent or selected from N and CR ₈ ; H is absent or selected from N and CR ₉ ; R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ and R ₁₀ are independently selected from hydrogen, hydroxyl, cyano, amino, halogen, C _1-6 alkyl, C _{1 -6} alkoxy, C _3-6 cycloalkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 acylamino, C _1-6 alkylamino, C _5-10 aryl, C _1-10 heterocyclyl, C _1-10 heteroaryl, C(O)C _1-6 alkyl, C(O)C _1-6 haloalkyl, C(O)NR ₁₅ , C(O)C _1-6 alkylamino, C(O)C _5-6 aryl, C (O)C _1-6 heteroaryl, SO ₂ C _1-6 alkyl, SO ₂ C _1-6 haloalkyl, SO ₂ C _3-6 cycloalkyl, SO ₂ NR ₁₅ , SO ₂ NC _1-6 alkylamino, SO ₂ C _{5 -6} aryl or SO ₂ C _1-6 heteroaryl, where C _1-6 alkyl, C _1-6 alkoxy, C _1-10 heteroaryl and C _1-6 haloalkoxy are optionally substituted with one or more groups selected from hydrogen, oxo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 alkylhydroxy, C _3-6 cycloalkyl, C _5-9 aryl, C _1-6 heterocyclyl, C _1-6 heteroaryl, cyano, halogen and hydroxyl, where C _5-9 aryl, C _1-6 heteroaryl and C _1-6 heterocyclyl are optionally substituted with one or more any groups selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, oxo, halogen, hydroxyl, —CH ₂ OH and cyano;

R ₁₁ and R ₁₂ are taken together to form a 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-5 heteroatoms selected from N, S or O, where 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring optionally substituted with substituents selected from amino, C _1-6 alkylamino, C _1-6 acylamino, -NHC(NH)CH ₂ Cl, NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ , C _{1- 6} alkyl, halogen, C _1-6 alkoxy or hydroxyl; and R ₁₅ is selected from the group consisting of hydrogen, C _1-6 alkyl, and combinations thereof.

In one embodiment, the present invention provides a compound of formula II as described herein, wherein X is selected from O or S; Z is N; A is selected from N or CR ₁ ; B is selected from N or CR ₂ ; D is selected from N or CR ₃ ; E is selected from N or CR ₆ ; F absent or selected from N and CR ₇ ; G is absent or selected from N and CR ₈ ; H is absent or selected from N and CR ₉ ; R ₁ , R ₂ , R ₃ , R ₆ , R ₇ , R ₈ , R ₉ and R ₁₀ are independently selected from hydrogen, hydroxyl, halogen, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _3-5 cycloalkyl or C _5-6 aryl; R ₄ and R ₅ are independently selected from hydrogen, hydroxyl, cyano, amino, halogen, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _{1 -4} acylamino, C _1-4 alkylamino, C _5-6 aryl, C _1-6 heterocyclyl, C _1-9 heteroaryl, C (O) C _1-4 alkyl, C (O) C _1-4 haloalkyl, C ( O)NR ₁₅ , C(O)C _1-4 alkylamino, C(O)C _5-6 aryl, C(O)C _1-6 heteroaryl, SO ₂ C _1-4 alkyl, SO ₂ C _1-4 haloalkyl , SO ₂ C _3-6 cycloalkyl, SO ₂ NR ₁₅ , SO ₂ RC _1-4 alkylamino, SO ₂ C _5-6 aryl or SO ₂ C _1-6 heteroaryl, where C _1-4 alkyl, C _1-4 alkoxy , C _1-9 heteroaryl and C _1-4 haloalkoxy are optionally substituted with one or more groups selected from hydrogen, oxo, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 alkylhydroxy, C _3-6 cycloalkyl, C _5-6 aryl, C _1-6 heterocyclyl, C _1-6 heteroaryl, cyano, halogen and hydroxyl, where C _5-6 aryl, C _1-6 heteroaryl and C _1-6 heterocyclyl are optionally substituted with one or more groups selected from hydrogen, C _1-6 alkyl , C _1-6 alkoxy, oxo, halogen, hydroxyl, -CH ₂ OH and cyano; R ₁₁ and R ₁₂ are taken together to form a 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-5 heteroatoms selected from N, S or O, where 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring optionally substituted with substituents selected from amino, C _1-6 alkylamino, C _1-6 acylamino, -NHC(NH)CH ₂ Cl, NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ , C _{1- 6} alkyl, halogen, C _1-6 alkoxy or hydroxyl; and R ₁₅ is selected from the group consisting of hydrogen, C _1-6 alkyl, and combinations thereof.

In one embodiment, the present invention provides a compound of formula II as described herein, wherein X is selected from O or S; Z is N; And represents CR ₁ ; B is CR ₂ ; D is CR ₃ ; E is selected from N or CR ₆ ; F is absent or is CR ₇ ; G is absent or is CR ₈ ; H is absent or is CR ₉ ; R ₁ , R ₂ , R ₃ , R ₆ , R ₇ , R ₈ ; R ₉ and R ₁₀ are independently selected from hydrogen, halogen, C _1-2 alkyl, C _1-2 alkoxy, or C _5-6 aryl; R ₄ and R ₅ are independently selected from hydrogen, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _5-9 aryl, C _1-9 heterocyclyl or C _1-9 heteroaryl, where C _1-4 alkyl, C _1-4 alkoxy, C _1-9 heteroaryl and C _1-4 haloalkoxy are optionally substituted with one or more groups selected from hydrogen, oxo, C _1-4 alkyl , C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 alkylhydroxy, C _3-6 cycloalkyl, C _5-6 aryl, C _1-6 heterocyclyl, C _1-6 heteroaryl, cyano, halogen and hydroxyl, where C _5-6 aryl, C _1-6 heteroaryl and C _1-6 heterocyclyl are optionally substituted with one or more groups selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, oxo, halogen, hydroxyl, —CH ₂ OH and cyano; R ₁₁ and R ₁₂ are taken together to form a 5-10 membered monocyclic or bicyclic saturated heterocyclic ring with 1-5 heteroatoms selected from N, S or O, where the 5-10 membered monocyclic or bicyclic saturated heterocyclic ring is optionally substituted with substituents, selected from amino, NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ or C _1-2 alkylamino.

In one embodiment, the present invention provides a compound of formula II as described herein, wherein X is selected from O or S; Z is N; And represents CR ₁ ; B is CR ₂ ; D is CR ₃ ; E is selected from N or CR ₆ ; F is absent or is CR ₇ ; G is absent or is CR ₈ ; H is absent or is CR ₉ ; R ₁ , R ₂ , R ₃ , R ₆ , R ₇ , R ₈ , R ₉ and R ₁₀ are independently selected from hydrogen, halogen, C ₁ alkyl or C ₁ alkoxy; R ₄ is selected from hydrogen, C ₁ alkyl, C ₁ alkoxy, C ₃ cycloalkyl or C ₆ aryl, where C ₁ alkyl and C ₁ alkoxy are optionally substituted with one or more groups selected from C ₁ alkyl and C ₁ alkoxy; R ₅ is selected from hydrogen, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _5-9 aryl, C _1-4 heterocyclyl, or C _{1 -9} heteroaryl, where C _1-4 alkyl, C _1-4 alkoxy, C _1-9 heteroaryl and C _1-4 haloalkoxy are optionally substituted with one or more groups selected from hydrogen, oxo, C _1-4 alkyl, C _{1- 4} alkoxy, C _1-4 haloalkyl, C _1-4 alkylhydroxy, C _3-6 cycloalkyl, C _5-6 aryl, C _1-6 heterocyclyl, C _1-6 heteroaryl, cyano, halogen and hydroxyl, where C _5-6 aryl, C _1-6 heteroaryl and C _1-6 heterocyclyl are optionally substituted with one or more groups selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, oxo, halogen, hydroxyl, —CH ₂ OH and cyano; and R ₁₁ and R ₁₂ are taken together to form a 5-10 membered monocyclic or bicyclic saturated heterocyclic ring with 1-5 heteroatoms selected from N, S or O, where the 5-10 membered monocyclic or bicyclic saturated heterocyclic ring is optionally substituted with substituents selected from amino and NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ .

In one embodiment, the present invention provides a compound of formula III, polymorphs, stereoisomers, prodrugs thereof, solvates, co-crystals, intermediates thereof, pharmaceutically acceptable salts and metabolites thereof, wherein

X is selected from O or S; Z is N; R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ and R ₁₀ are independently selected from hydrogen, hydroxyl, cyano, amino, halogen, C _1-6 alkyl, C _{1 -6} alkoxy, C _3-6 cycloalkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 acylamino, C _1-6 alkylamino, C _5-10 aryl, C _1-10 heterocyclyl, C _1-10 heteroaryl, C(O)C _1-6 alkyl, C(O)C _1-6 haloalkyl, C(O)NR ₁₅ , C(O)C _1-6 alkylamino, C(O)C _5-6 aryl, C (O)C _1-6 heteroaryl, SO ₂ C _1-6 alkyl, SO ₂ C _1-6 haloalkyl, SO ₂ C _3-6 cycloalkyl, SO ₂ NR ₁₅ , SO ₂ NC _1-6 alkylamino, SO ₂ C _{5 -6} aryl or SO ₂ C _1-6 heteroaryl, where C _1-6 alkyl, C _1-6 alkoxy, C _1-10 heteroaryl and C _1-6 haloalkoxy are optionally substituted with one or more groups selected from hydrogen, oxo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 alkylhydroxy, C _3-6 cycloalkyl, C _5-9 aryl, C _1-6 heterocyclyl, C _1-6 heteroaryl, cyano, halogen and hydroxyl, where C _5-9 aryl, C _1-6 heteroaryl and C _1-6 heterocyclyl are optionally substituted with one or more any groups selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, oxo, halogen, hydroxyl, —CH ₂ OH and cyano; R ₁₁ and R ₁₂ are taken together to form a 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-5 heteroatoms selected from N, S or O, where 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring optionally substituted with substituents selected from amino, C _1-6 alkylamino, C _1-6 acylamino, NHC(NH)CH ₂ Cl, NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ , C _1-6 alkyl, halogen, C _1-6 alkoxy or hydroxyl; and R ₁₅ is selected from the group consisting of hydrogen, C _1-6 alkyl, and combinations thereof.

In one embodiment, the present invention provides a compound of formula III as described herein, wherein X is selected from O or S; Z is N; R ₁ , R ₂ , R ₃ , R ₆ , R ₇ , R ₈ , R ₉ and R ₁₀ are independently selected from hydrogen, hydroxyl, cyano, amino, halogen, C _1-4 alkyl, C _1-4 alkoxy, C _{1 -4} haloalkyl, C _1-4 haloalkoxy, C _3-5 cycloalkyl, C _5-6 aryl, C _1-6 heterocyclyl, or C _1-6 heteroaryl; R ₄ and R ₅ are independently selected from hydrogen, hydroxyl, cyano, amino, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _{1 -6} acylamino, C _1-6 alkylamino, C _5-10 aryl, C _1-10 heterocyclyl, C _1-10 heteroaryl, C (O) C _1-6 alkyl, C (O) C _1-6 haloalkyl, C ( O)NR ₁₅ , C(O)C _1-6 alkylamino, C(O)C _5-6 aryl, C(O)C _1-6 heteroaryl, SO ₂ C _1-6 alkyl, SO ₂ C _1-6 haloalkyl , SO ₂ C _3-6 cycloalkyl, SO ₂ NR ₁₅ , SO ₂ NC _1-6 alkylamino, SO ₂ C _5-6 aryl or SO ₂ C _1-6 heteroaryl, where C _1-6 alkyl, C _1-6 alkoxy , C _1-10 heteroaryl and C _1-6 haloalkoxy are optionally substituted with one or more groups selected from hydrogen, oxo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 alkylhydroxy, C _3-6 cycloalkyl, C _5-9 aryl, C _1-6 heterocyclyl, C _1-6 heteroaryl, cyano, halogen and hydroxyl, where C _5-9 aryl, C _1-6 heteroaryl and C _1-6 heterocyclyl are optionally substituted with one or several groups selected from hydrogen, C _1-6 al keel, C _1-6 alkoxy, oxo, halogen, hydroxyl, —CH ₂ OH, and cyano; R ₁₁ and R ₁₂ are taken together to form a 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-5 heteroatoms selected from N, S or O, where 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring optionally substituted with substituents selected from amino, C _1-6 alkylamino, C _1-6 acylamino, NHC(NH)CH ₂ Cl, NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ , C _1-6 alkyl, halogen, C _1-6 alkoxy or hydroxyl; and R ₁₅ is selected from the group consisting of hydrogen, C _1-6 alkyl, and combinations thereof.

In one embodiment, the present invention provides a compound of formula III as described herein, wherein X is selected from O or S; Z is N; R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ and R ₁₀ are independently selected from hydrogen, hydroxyl, cyano, amino, halogen, C _1-4 alkyl, C _{1 -4} alkoxy, C _3-6 cycloalkyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _1-4 acylamino, C _1-4 alkylamino, C _5-9 aryl, C _1-9 heterocyclyl, C _1-9 heteroaryl, C(O)C _1-4 alkyl, C(O)C _1-4 haloalkyl, C(O)NR ₁₅ , C(O)C _1-4 alkylamino, C(O)C _5-6 aryl, C (O)C _1-6 heteroaryl, SO ₂ C _1-4 alkyl, SO ₂ C _1-4 haloalkyl, SO ₂ C _3-6 cycloalkyl, SO ₂ NR ₁₅ , SO ₂ NC _1-4 alkylamino, SO ₂ C _{5 -6} aryl or SO ₂ C _1-6 heteroaryl, where C _1-4 alkyl, C _1-4 alkoxy, C _1-9 heteroaryl and C _1-4 haloalkoxy are optionally substituted with one or more groups selected from hydrogen, oxo, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 alkylhydroxy, C _3-6 cycloalkyl, C _5-6 aryl, C _1-6 heterocyclyl, C _1-6 heteroaryl, cyano, halogen and hydroxyl, where C _5-6 aryl, C _1-6 heteroaryl and C _1-6 heterocyclyl are optionally substituted with one or more mi groups selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, oxo, halogen, hydroxyl, —CH ₂ OH and cyano; R ₁₁ and R ₁₂ are taken together to form a 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-5 heteroatoms selected from N, S or O, where 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring optionally substituted with substituents selected from amino, C _1-6 alkylamino, C _1-6 acylamino, -NHC(NH)CH ₂ Cl, NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ , C _{1- 6} alkyl, halogen, C _1-6 alkoxy and hydroxyl; and R ₁₅ is selected from the group consisting of hydrogen, C _1-6 alkyl, and combinations thereof.

In one embodiment, the present invention provides a compound of formula III as described herein, wherein X is selected from O or S; Z is N; R ₁ , R ₂ , R ₃ , R ₆ , R ₇ , R ₈ , R ₉ and R ₁₀ are independently selected from hydrogen, hydroxyl, halogen, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _3-5 cycloalkyl or C _5-6 aryl; R ₄ and R ₅ are independently selected from hydrogen, hydroxyl, cyano, amino, halogen, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _{1 -4} acylamino, C _1-4 alkylamino, C _5-9 aryl, C _1-9 heterocyclyl, C _1-9 eheteroaryl, C (O) C _1-4 alkyl, C (O) C _1-4 haloalkyl, C ( O)NR ₁₅ , C(O)C _1-4 alkylamino, C(O)C _5-6 aryl, C(O)C _1-6 heteroaryl, SO ₂ C _1-4 alkyl, SO ₂ C _1-4 haloalkyl , SO ₂ C _3-6 cycloalkyl, SO ₂ NR ₁₅ , SO ₂ NC _1-4 alkylamino, SO ₂ C _5-6 aryl or SO ₂ C _1-6 heteroaryl, where C _1-4 alkyl, C _1-4 alkoxy, C _1-9 heteroaryl and C _1-4 haloalkoxy are optionally substituted with one or more groups selected from hydrogen, oxo, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 alkylhydroxy, C _{3 -6} cycloalkyl, C _5-6 aryl, C _1-6 heterocyclyl, C _1-6 heteroaryl, cyano, halogen and hydroxyl, where C _5-6 aryl, C _1-6 heteroaryl and C _1-6 heterocyclyl are optionally substituted with one or several groups selected from hydrogen, C _1-6 alkyl a, C _1-6 alkoxy, oxo, halogen, hydroxyl, -CH ₂ OH and cyano; R ₁₁ and R ₁₂ are taken together to form a 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-5 heteroatoms selected from N, S or O, where 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring optionally substituted with substituents selected from amino, C _1-6 alkylamino, C _1-6 acylamino, -NHC(NH)CH ₂ Cl, NH(CO)CH=CH-CH2-N(CH ₃ ) ₂ , C _1-6 alkyl, halogen, C _1-6 alkoxy or hydroxyl; and R ₁₅ is selected from the group consisting of hydrogen, C _1-6 alkyl, and combinations thereof.

In one embodiment, the present invention provides a compound of formula III as described herein, wherein X is selected from O or S; Z is N; R ₁ , R ₂ , R ₃ , R ₆ , R ₇ , R ₈ , R ₉ and R ₁₀ are independently selected from hydrogen, halogen, C _1-4 alkyl, C _1-4 alkoxy, or C _5-6 aryl; R ₄ and R ₅ are independently selected from hydrogen, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _5-9 aryl, C _1-9 heterocyclyl or C _1-9 heteroaryl, where C _1-4 alkyl, C _1-4 alkoxy, C _1-9 heteroaryl and C _1-4 haloalkoxy are optionally substituted with one or more groups selected from hydrogen, oxo, C _1-4 alkyl , C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 alkylhydroxy, C _3-6 cycloalkyl, C _5-6 aryl, C _1-6 heterocyclyl, C _1-6 heteroaryl, cyano, halogen and hydroxyl, where C _5-6 aryl, C _1-6 heteroaryl and C _1-6 heterocyclyl are optionally substituted with one or more groups selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, oxo, halogen, hydroxyl, —CH ₂ OH and cyano; and R ₁₁ and R ₁₂ are taken together to form a 5-10 membered monocyclic or bicyclic saturated heterocyclic ring with 1-5 heteroatoms selected from N, S or O, where the 5-10 membered monocyclic or bicyclic saturated heterocyclic ring is optionally substituted with substituents selected from amino, C _1-4 alkylamino and NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ .

In one embodiment, the present invention provides a compound of formula (I), or polymorphs, stereoisomers, prodrugs thereof, solvates, co-crystals, intermediates thereof, pharmaceutically acceptable salts and metabolites thereof, which are selected from the group consisting of

1) (R)-(3-aminopiperidin-1-yl)(2-(3-bromo-1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine- 7-yl) methanone,

2) (R)-(3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl) methanone,

3) (R)-(3-aminopiperidin-1-yl)(2-(1-benzyl-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl)methanone,

4) (R)-(3-aminopiperidin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl)methanone,

5) (R)-(3-aminopiperidin-1-yl)(2-(1-ethyl-3-phenyl-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7- yl) methanone,

6) (R)-(3-aminopyrrolidin-1-yl)(2-(1-ethyl-3-phenyl-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7- yl) methanone,

7) (R)-(3-aminopyrrolidin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl)methanone,

8) (R)-(3-aminopyrrolidin-1-yl)(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl) methanone,

9) (2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl)(hexahydro-2H-pyrido[4,3-b] [1,4]oxazin-6(5H)-yl)methanone,

10) (R)-(3-aminopiperidin-1-yl)(3-methyl-2-(1-(pyridin-4-ylmethyl)-1H-indol-2-yl)imidazo[1,2-a]pyridine -7-yl) methanone,

11) (R)-(3-aminopiperidin-1-yl)(3-methyl-2-(1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indol-2-yl)imidazo[ 1,2-a]pyridin-7-yl)methanone,

12) (R)-(3-aminopiperidin-1-yl)(2-(1-(4-methoxybenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7- yl) methanone,

13) (R)-(3-aminopiperidin-1-yl)(2-(1-(4-fluorobenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7- yl) methanone,

14) (R)-4-((2-(7-(3-aminopiperidin-1-carbonyl)-3-methylimidazo[1,2-a]pyridin-2-yl)-1H-indol-1-yl) methyl)benzonitrile,

15) (R) - (3-aminopiperidin-1-yl) (3-methyl-2- (1- (pyridin-3-ylmethyl) -1H-indol-2-yl) imidazo [1,2-a] pyridine -7-yl) methanone,

16) (R) - (3-aminopiperidin-1-yl) (3-methyl-2- (1- (pyridin-2-ylmethyl) -1H-indol-2-yl) imidazo [1,2-a] pyridine -7-yl) methanone,

17) (R) - (3-aminopiperidin-1-yl) (3-methyl-2- (1- (2,2,2-trifluoroethyl) -1H-indol-2-yl) imidazo [1,2-a ]pyridin-7-yl)methanone,

18) (R)-4-((2-(7-(3-aminopiperidin-1-carbonyl)-3-methylimidazo[1,2-a]pyridin-2-yl)-1H-indol-1-yl) methyl)-1-methylpyridin-2-(1H)-one,

19) (R)-(3-aminopiperidin-1-yl)(2-(3-ethylbenzo[b]thiophen-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl)methanone,

20) (R)-(3-aminopiperidin-1-yl)(2-(1-(4-chlorobenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7- yl) methanone,

21) (R)-(3-aminopiperidin-1-yl)(2-(1-(2-fluorobenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7- yl) methanone,

22) (R) - (3-aminopiperidin-1-yl) (2- (1-ethyl-5-phenyl-1H-pyrrol-2-yl) -3-methylimidazo[1,2-a] pyridin-7- yl) methanone,

23) (R) - (3-aminopiperidin-1-yl) (2- (1- (cyclopropylmethyl) -6-methoxy-1H-indol-2-yl) -3-methylimidazo[1,2-a] pyridin- 7-yl) methanone,

24) (R)-(3-aminopiperidin-1-yl)(2-(1-ethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylimidazo[1,2-a] pyridin-7-yl) methanone,

25) (R)-(3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-3,5-dimethylimidazo[1,2-a]pyridine-7- yl) methanone,

26) (R)-(3-aminopiperidin-1-yl)(2-(1-benzyl-1H-indol-2-yl)-3,5-dimethylimidazo[1,2-a]pyridin-7-yl) methanone,

27) (R) - (3-aminopiperidin-1-yl) (3,5-dimethyl-2- (1- (pyridin-2-ylmethyl) -1H-indol-2-yl) imidazo[1,2-a ]pyridin-7-yl)methanone,

28) (R)-(3-aminopiperidin-1-yl)(2-(1-(cytopropylmethyl)-6-fluoro-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine- 7-yl) methanone,

29) (R)-(3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-5-fluoro-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine- 7-yl) methanone,

30) (R) - (3-aminopiperidin-1-yl) (2- (1- (cyclopropylmethyl) -7-methyl-1H-indol-2-yl) -3-methylimidazo[1,2-a] pyridin- 7-yl) methanone,

31) (R)-(3-aminopiperidin-1-yl)(2-(2-ethylphenyl)-3-methylimidazo[1,2-a]pyridin-7-yl)methanone,

32) (R) - (3-aminopiperidin-1-yl) (2- (1- (cyclopropylmethyl) -1H-indol-2-yl) -3-phenylimidazo[1,2-a] pyridin-7-yl) methanone,

33) (R) - (3-aminopiperidin-1-yl) (3-cyclopropyl-2- (1- (cyclopropylmethyl) -1H-indol-2-yl) imidazo [1,2-a] pyridin-7-yl ) methanone,

34) (R) - (3-aminopiperidin-1-yl) (2- (1- (cyclopropylmethyl) -1H-indol-2-yl) -3- (methoxymethyl) imidazo [1,2-a] pyridine-7 -yl) methanone,

35) (R)-(3-aminopiperidin-1-yl)(2-(1-(3-fluorobenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7- yl) methanone,

36) (R) - (3-aminopiperidin-1-yl) (3-methyl-2- (1- (thiophen-3-ylmethyl) -1H-indol-2-yl) imidazo [1,2-a] pyridine -7-yl) methanone,

37) (R) - (3-aminopiperidin-1-yl) (2- (1- (furan-3-ylmethyl) -1H-indol-2-yl) -3-methylimidazo[1,2-a] pyridin- 7-yl) methanone,

38) (R)-3-aminopiperidin-1-yl)(2-(1-(1-(4-fluorophenyl)ethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a] pyridin-7-yl) methanone,

39) (R) - (3-aminopiperidin-1-yl) (2- (1-ethyl-5-fluoro-1H-indol-2-yl) -3-methylimidazo[1,2-a] pyridin-7- yl) methanone,

40) (R)-(3-aminopiperidin-1-yl)(2-(1-(cytopropylmethyl)-4-fluoro-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine- 7-yl) methanone,

41) (R)-(3-aminopiperidin-1-yl)(3-methyl-2-(1-((4-methylthiazol-2-yl)methyl)-1H-indol-2-yl)imidazo[1, 2-a]pyridin-7-yl)methanone,

42) (R)-(3-aminopiperidin-1-yl)(2-(1-(3-methoxybenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7- yl) methanone,

43) (R)-(3-aminopiperidin-1-yl)(2-(5-bromo-1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine- 7-yl) methanone,

44) (R) - (3-aminopiperidin-1-yl) (2- (7-chloro-1- (cyclopropylmethyl) -1H-indol-2-yl) -3-methylimidazo[1,2-a] pyridin- 7-yl) methanone,

45) (R) - (3-aminopiperidin-1-yl) (2- (1- (4-fluorobenzyl) -1H-indol-2-yl) -3-methylimidazo[1,2-a] pyridin-7- yl) methathione,

46) (R) - (3-aminopiperidin-1-yl) (3-methyl-2- (1-methyl-1H-indol-2-yl) imidazo [1,2-a] pyridin-7-yl) methanone ,

47) (R) - (3-aminopiperidin-1-yl) (2- (1- (cyclopropylmethyl) -7-methoxy-1H-indol-2-yl) -3-methylimidazo[1,2-a] pyridin- 7-yl) methanone,

48) (R)-(3-aminopiperidin-1-yl)(2-(1-((2,4-dimethylthiazol-5-yl)methyl)-1H-indol-2-yl)-3-methylimidazo[1 ,2-a]pyridin-7-yl)methanone,

49) (R)-(3-aminopiperidin-1-yl)(3-methyl-2-(1-((2-methylthiazol-5-yl)methyl)-1H-indol-2-yl)imidazo[1, 2-a]pyridin-7-yl)methanone,

50) salts of (R)-(3-aminopiperidin-1-yl)(2-(1-(3-methoxybenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine-7 -yl) methanone and trifluoroacetic acid,

51) (R)-(3-aminopiperidin-1-yl)(2-(6-methoxy-1-(pyridin-3-ylmethyl)-1H-indol-2-yl)-3-methylimidazo[1,2- a]pyridin-7-yl)methanone,

52) salts R)-(3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-6-fluoro-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine- 7-yl) methanone and trifluoroacetic acid,

53) (R) - (3-aminopiperidin-1-yl) (2- (5-fluoro-1- (3-methoxybenzyl) -1H-indol-2-yl) -3-methylimidazo [1,2-a] pyridin-7-yl) methanone,

54) (R) - (3-aminopiperidin-1-yl) (2- (6-fluoro-1- (4-fluorobenzyl) -1H-indol-2-yl) -3-methylimidazo [1,2-a] pyridin-7-yl) methanone,

55) (R)-(3-aminopiperidin-1-yl)(2-(5,6-difluoro-1-(3-methoxybenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2- a]pyridin-7-yl)methanone,

56) (R,E)-4-(dimethylamino)-N-(1-(2-(1-(4-fluorobenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a] pyridine-7-carbonyl)piperidin-3-yl)but-2-enamide,

57) (R) - (3-aminopiperidin-1-yl) (3-methyl-2- (1- (pyrazin-2-ylmethyl) -1H-indol-2-yl) imidazo [1,2-a] pyridine -7-yl) methanone,

58) salts of (R)-(3-aminopiperidin-1-yl)(3-methyl-2-(1-(pyrimidin-5-ylmethyl)-1H-indol-2-yl)imidazo[1,2-a] pyridin-7-yl) methanone and trifluoroacetic acid,

59) (R) - (3-aminopiperidin-1-yl) (3-methyl-2- (1- (pyridazin-3-ylmethyl) -1H-indol-2-yl) imidazo [1,2-a] pyridine -7-yl) methanone,

60) (R)-(3-aminopiperidin-1-yl)(2-(1-isobutyl-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl)methanone,

61) (R) - (3-aminopiperidin-1-yl) (2- (1- (cyclobutylmethyl) -1H-indol-2-yl) -3-methylimidazo[1,2-a] pyridin-7-yl) methanone,

62) (R)-(3-aminopiperidin-1-yl)(2-(1-((3-fluoropyridin-2-yl)methyl)-1H-indol-2-yl)-3-methylimidazo[1,2 -a]pyridin-7-yl)methanone,

63) (R)-(3-aminopiperidin-1-yl)(2-(1-((5-methoxypyridin-2-yl)methyl)-1H-indol-2-yl)-3-methylimidazo[1,2 -a]pyridin-7-yl)methanone,

64) (R) - (3-aminopiperidin-1-yl) (2- (1- (2-methoxyethyl) -1H-indol-2-yl) -3-methylimidazo[1,2-a] pyridin-7- yl) methanone,

65) (R) - (3-aminopiperidin-1-yl) (2- (1- (2-hydroxyethyl) -1H-indol-2-yl) -3-methylimidazo[1,2-a] pyridin-7- yl) methanone,

66) (R)-(3-aminopiperidin-1-yl)(2-(6-methoxy-1-(pyridin-4-ylmethyl)-1H-indol-2-yl)-3-methylimidazo[1,2- a]pyridin-7-yl)methanone,

67) (R) - (3-aminopiperidin-1-yl) (2- (1-ethyl-6-methoxy-1H-indol-2-yl) -3-methylimidazo[1,2-a] pyridin-7- yl) methanone,

68) (R)-(3-aminopiperidin-1-yl)(2-(6-fluoro-1-(pyridin-4-ylmethyl)-1H-indol-2-yl)-3-methylimidazo[1,2- a]pyridin-7-yl)methanone,

69) (R)-(3-aminopiperidin-1-yl)(2-(6-fluoro-1-(pyridin-3-ylmethyl)-1H-indol-2-yl)-3-methylimidazo[1,2- a]pyridin-7-yl)methanone,

70) (R)-(3-aminopiperidin-1-yl)(2-(6-fluoro-1-(3-methoxybenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a] pyridin-7-yl) methanone,

71) (R) - (3-aminopiperidin-1-yl) (2- (6-fluoro-1- (4-methoxybenzyl) -1H-indol-2-yl) -3-methylimidazo [1,2-a] pyridin-7-yl) methanone,

72) (R) - (3-aminopiperidin-1-yl) (2- (1-ethyl-6-fluoro-1H-indol-2-yl) -3-methylimidazo[1,2-a] pyridin-7- yl) methanone,

73) (R) - (3-aminopiperidin-1-yl) (2- (6-fluoro-1-isobutyl-1H-indol-2-yl) -3-methylimidazo[1,2-a] pyridin-7- yl) methanone,

74) (R)-(3-aminopiperidin-1-yl)(2-(5-fluoro-1-(pyridin-4-ylmethyl)-1H-indol-2-yl)-3-methylimidazo[1,2- a]pyridin-7-yl)methanone,

75) (R)-(3-aminopiperidin-1-yl)(2-(5-fluoro-1-(4-methoxybenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a] pyridin-7-yl) methanone,

76) (R)-(3-aminopiperidin-1-yl)(2-(5-fluoro-1-(4-fluorobenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a] pyridin-7-yl) methanone,

77) (R) - (3-aminopiperidin-1-yl) (2- (7-chloro-1- (4-fluorobenzyl) -1H-indol-2-yl) -3-methylimidazo [1,2-a] pyridin-7-yl) methanone,

78) salts of (R)-(3-aminopiperidin-1-yl)(2-(1-(2,2-difluoroethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine -7-yl) methanone and trifluoroacetic acid,

79) (R)-(3-aminopiperidin-1-yl)(2-(1-((5-fluoropyridin-2-yl)methyl)-1H-indol-2-yl)-3-methylimidazo[1,2 -a]pyridin-7-yl)methanone,

80) (R) - (3-aminopiperidin-1-yl) (2- (1- (4-fluorobenzyl) -6-methoxy-1H-indol-2-yl) -3-methylimidazo [1,2-a] pyridin-7-yl) methanone,

81) (R) - (3-aminopiperidin-1-yl) (2- (1- (4- (hydroxymethyl) benzyl) -1H-indol-2-yl) -3-methylimidazo[1,2-a] pyridine -7-yl) methanone,

82) (R) - (3-aminopiperidin-1-yl) (2- (1-isobutyl-6-methoxy-1H-indol-2-yl) -3-methylimidazo[1,2-a] pyridin-7- yl) methanone,

83) (R)-(3-aminopiperidin-1-yl)(2-(1-(2,2-difluoroethyl)-6-methoxy-1H-indol-2-yl)-3-methylimidazo[1,2- a]pyridin-7-yl)methanone,

84) (R) - (3-aminopiperidin-1-yl) (2- (5-fluoro-1-isobutyl-1H-indol-2-yl) -3-methylimidazo[1,2-a] pyridin-7- yl) methanone, and

85) (R) - (3-aminopiperidin-1-yl) (2- (1- (4-fluoro-3-methoxybenzyl) -1H-indol-2-yl) -3-methylimidazo [1,2-a] pyridin-7-yl)methanone, and

86) (R) - (3-aminopiperidin-1-yl) (2- (1- (cytopropylmethyl) -6-methoxy-1H-indol-2-yl) -3- (methoxymethyl) imidazo [1,2-a ]pyridin-7-yl)methanone.

In one embodiment, the present invention relates to a process for the preparation of compounds of formula (I), formula (II) and formula (III) according to any one of paragraphs. 1-11 or their polymorphs, stereoisomers, their prodrugs, their solvates, co-crystals, their intermediates, their pharmaceutically acceptable salts and metabolites.

In one embodiment, the present invention relates to a process for the preparation of compounds of formula (I) or their polymorphs, stereoisomers, prodrugs thereof, their solvates, co-crystals, intermediates thereof, their pharmaceutically acceptable salts and metabolites, the method comprising carrying out the reaction R ₁₃ CH(O) and R ₄ CH ₂ NO ₂ with a compound selected from formula (IVA) or formula (IV),

where R ₁₃ in R ₁₃ CH(O) is selected from hydrogen, 5-10-membered monocyclic or bicyclic aryl and 5-10-membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where 5- 10-membered monocyclic or bicyclic aryl and 5-10-membered monocyclic or bicyclic heteroaryl are optionally substituted with 1-5 substituents selected from the group consisting of hydroxyl, cyano, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _{3 -6} cycloalkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 acylamino, C _1-6 alkylamino, C _5-10 aryl, C _1-6 heterocyclyl, C _1-6 heteroaryl, C (O) C _1-6 alkyl, C (O) C _1-6 haloalkyl, C (O) NR ₁₅ , C (O) C _1-6 alkylamino, C (O) C _5-6 aryl, C (O) C _{1- 6} heteroaryl, SO ₂ C _1-6 alkyl, SO ₂ C _1-6 haloalkyl, SO ₂ C _3-6 cycloalkyl, SO ₂ NR ₁₅ , SO ₂ RC _1-6 alkylamino, SO ₂ C _5-6 aryl or SO ₂ C _1-6 heteroaryl, where C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _5-10 aryl, C _1-6 heterocyclyl and C _1-6 heteroaryl are optionally substituted are one or more groups selected from hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _5-6 aryl, C _1-6 heteroaryl, C _1-6 heterocyclyl, oxo, halogen, hydroxyl and cyano, where C _5-6 aryl, C _1-6 heteroaryl and C _1-6 heterocyclyl are optionally substituted with one or more groups selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy , oxo, halogen, hydroxyl, -CH ₂ OH and cyano; And in formulas (IVA) and (IV) is selected from N or CR ₁ ; B is selected from N or CR ₂ ; D is selected from N or CR ₃ ; R ₁₁ and R ₁₂ are taken together to form a 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring, optionally with 1-5 heteroatoms selected from N, S or O, where 5-10 membered monocyclic or bicyclic saturated or unsaturated the heterocyclic ring is optionally substituted with substituents selected from amino, C _1-6 alkylamino, C _1-6 acylamino, NHC(NH)CH ₂ Cl, -NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ , C _1-6 alkyl, halogen, C _1-6 alkoxy or hydroxyl; R ₄ to R ₄ CH ₂ NO ₂ is selected from hydrogen, hydroxyl, cyano, amino, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy , C _1-6 acylamino, C _1-6 alkylamino, C _5-10 aryl, C _1-6 heterocyclyl, C _1-6 heteroaryl, C (O) C _1-6 alkyl, C (O) C _1-6 haloalkyl , C(O)NR ₁₅ , C(O)C _1-6 alkylamino, C(O)C _5-6 aryl, C(O)C _1-6 heteroaryl, SO ₂ C _1-6 alkyl, SO ₂ C _{1 -6} haloalkyl, SO ₂ C _3-6 cycloalkyl, SO ₂ NR ₁₅ , SO ₂ RC _1-6 alkylamino, SO ₂ C _5-6 aryl or SO ₂ C _1-6 heteroaryl, where C _1-6 alkyl, C _{1 -6} alkoxy, C _1-6 heteroaryl and C _1-6 haloalkoxy are optionally substituted with one or more groups selected from hydrogen, oxo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 alkylhydroxy, C _3-6 cycloalkyl, C _5-10 aryl, C _1-6 heterocyclyl, C _1-6 heteroaryl, cyano, halogen and hydroxyl, where C _5-10 aryl, C _1-6 heteroaryl and C _1-6 heterocyclyl optionally substituted with one or more groups selected from hydrogen, C _1-6 alkyl a, C _1-6 alkoxy, oxo, halogen, hydroxyl, -CH ₂ OH and cyano; X in formula (I) is selected from O or S; Z is N; A is selected from N or CR ₁ ; B is selected from N or CR ₂ ; D is selected from N or CR ₃ ; R ₁ , R ₂ , R ₃ and R ₄ are independently selected from hydrogen, hydroxyl, cyano, amino, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _1-6 haloalkyl, C _{1 -6} haloalkoxy, C _1-6 acylamino, C _1-6 alkylamino, C _5-10 aryl, C _1-6 heterocyclyl, C _1-6 heteroaryl, C (O) NR ₁₅ , C (O) C _1-6 alkylamino , C(O)C _5-6 aryl, C(O)C _1-6 heteroaryl, C(O)C _1-6 alkyl, C(O)C _1-6 haloalkyl, SO ₂ C _1-6 alkyl, SO ₂ C _1-6 haloalkyl, SO ₂ C _3-6 cycloalkyl, SO ₂ NR ₁₅ , SO ₂ NC _1-6 alkylamino, SO ₂ C _5-6 aryl or SO ₂ C _1-6 heteroaryl, where C _1-6 alkyl , C _1-6 alkoxy, C _1-6 heteroaryl and C _1-6 haloalkoxy are optionally substituted with one or more groups selected from hydrogen, oxo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _5-10 aryl, C _1-6 heterocyclyl, C _1-6 heteroaryl, cyano and hydroxyl; R ₁₁ is hydrogen; R ₁₂ is selected from C _1-6 alkylamino and a 5-10 membered monocyclic or bicyclic saturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, or R ₁₁ and R ₁₂ may be taken together to form 5-10 -membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-5 heteroatoms selected from N, S or O, where the 5-10-membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring is optionally substituted with substituents selected from amino, C _1-6 alkylamino, C _1-6 acylamino, -NHC(NH)CH ₂ Cl, -NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ , C _1-6 alkyl, halogen, C _1-6 alkoxy or hydroxyl; R ₁₃ is selected from hydrogen, 5-10 membered monocyclic or bicyclic aryl and 5-10 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where 5-10 membered monocyclic or bicyclic aryl and 5-10 membered monocyclic or bicyclic heteroaryl optionally substituted with 1-5 substituents selected from hydroxyl, cyano, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _1-6 haloalkyl, C _{1 -6} haloalkoxy, C _1-6 acylamino, C _1-6 alkylamino, C _5-10 aryl, C _1-6 heterocyclyl, C _1-6 heteroaryl, C (O) C _1-6 alkyl, C (O) C _{1 -6} haloalkyl, C(O)NR ₁₅ , C(O)C _1-6 alkylamino, C(O)C _5-6 aryl, C(O)C _1-6 heteroaryl, SO ₂ C _1-6 alkyl, SO ₂ C _1-6 haloalkyl, SO ₂ C _3-6 cycloalkyl, SO ₂ NR ₁₅ , SO ₂ NC _1-6 alkylamino, SO ₂ C _5-6 aryl or SO ₂ C _1-6 heteroaryl, where C _1-6 alkyl , C _1-6 alkoxy, C _3-6 cycloalkyl, C _5-10 aryl, C _1-6 heterocyclyl and C _1-6 heteroaryl are optionally substituted with one or more groups, early from hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _5-6 aryl, C _1-6 heteroaryl, C _1-6 heterocyclyl, oxo, halogen, hydroxyl and cyano, where C _5-6 aryl, C _1-6 heteroaryl and C _1-6 heterocyclyl are optionally substituted with one or more groups selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, oxo, halogen, hydroxyl , -CH ₂ OH and cyano; and R ₁₅ is selected from the group consisting of hydrogen, C _1-6 alkyl, and combinations thereof.

In one embodiment, the present invention relates to a process for the preparation of compounds of formula (II) or their polymorphs, stereoisomers, prodrugs thereof, their solvates, co-crystals, intermediates thereof, their pharmaceutically acceptable salts and metabolites, the method comprising carrying out the reaction formula (V) and R ₄ CH ₂ NO ₂ with a compound selected from formula (IVA) or formula (IV),

where A in formulas (IVA) and (IV) is selected from N or CR ₁ ; B is selected from N or CR ₂ ; D is selected from N or CR ₃ ; R ₁₁ and R ₁₂ are taken together to form a 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring, optionally with 1-5 heteroatoms selected from N, S or O, where 5-10 membered monocyclic or bicyclic saturated or unsaturated the heterocyclic ring is optionally substituted with substituents selected from amino, C _1-6 alkylamino, C _1-6 acylamino, -NHC(NH)CH ₂ Cl, NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ , C _1-6 alkyl, halogen, C _1-6 alkoxy or hydroxyl; R ₄ to R ₄ CH ₂ NO ₂ is selected from hydrogen, hydroxyl, cyano, amino, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy , C _1-6 acylamino, C _1-6 alkylamino, C _5-10 aryl, C _1-6 heterocyclyl, C _1-6 heteroaryl, C (O) C _1-6 alkyl, C (O) C _1-6 haloalkyl , C(O)NR ₁₅ , C(O)C _1-6 alkylamino, C(O)C _5-6 aryl, C(O)C _1-6 heteroaryl, SO ₂ C _1-6 alkyl, SO ₂ C _{1 -6} haloalkyl, SO ₂ C _3-6 cycloalkyl, SO ₂ NR ₁₅ , SO ₂ NC _1-6 alkylamino, SO ₂ C _5-6 aryl or SO ₂ C _1-6 heteroaryl, where C _1-6 alkyl, C _{1 -6} alkoxy, C _1-6 heteroaryl and C _1-6 haloalkoxy are optionally substituted with one or more groups selected from hydrogen, oxo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 alkylhydroxy, C _3-6 cycloalkyl, C _5-10 aryl, C _1-6 heterocyclyl, C _1-6 heteroaryl, cyano, halogen and hydroxyl, where C _5-10 aryl, C _1-6 heteroaryl and C _1-6 heterocyclyl optionally substituted with one or more groups selected from hydrogen, C _1-6 alkyl a, C _1-6 alkoxy, oxo, halogen, hydroxyl, -CH ₂ OH and cyano; E in formula (V) is selected from N, C _5-6 aryl or CR ₆ ; F absent or selected from N and CR ₇ ; G is absent or selected from N and CR ₈ ; H is absent or selected from N and CR ₉ ; R ₁ , R ₂ , R ₃ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ and R ₁₀ are independently selected from hydrogen, hydroxyl, cyano, amino, halogen, C _1-6 alkyl, C _1-6 alkoxy , C _3-6 cycloalkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 acylamino, C _1-6 alkylamino, C _5-10 aryl, C _1-6 heterocyclyl, C _1-6 heteroaryl, C (O)C _1-6 alkyl, C(O)C _1-6 haloalkyl, C(O)NR ₁₅ , C(O)C _1-6 alkylamino, C(O)C _5-6 aryl, C(O) C _1-6 heteroaryl, SO ₂ C _1-6 alkyl, SO ₂ C _1-6 haloalkyl, SO ₂ C _3-6 cycloalkyl, SO ₂ NR ₁₅ , SO ₂ NC _1-6 alkylamino, SO ₂ C _5-6 aryl or SO ₂ C _1-6 heteroaryl, where C _1-6 alkyl, C _1-6 alkoxy, C _1-6 heteroaryl and C _1-6 haloalkoxy are optionally substituted with one or more groups selected from hydrogen, oxo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 alkylhydroxy, C _3-6 cycloalkyl, C _5-10 aryl, C _1-6 heterocyclyl, C _1-6 heteroaryl, cyano, halogen and hydroxyl, where C _5-10 aryl, C _1-6 heteroaryl and C _1-6 heterocyclyl are optionally substituted with one or more groups selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, oxo, halogen, hydroxyl, —CH ₂ OH and cyano; X in formula (II) is selected from O or S; Z is N; A is selected from N or CR ₁ ; B is selected from N or CR ₂ ; D is selected from N or CR ₃ ; E is selected from N or CR ₆ ; F absent or selected from N and CR ₇ ; G is absent or selected from N and CR ₈ ; H is absent or selected from N and CR ₉ ; R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ and R ₁₀ are independently selected from hydrogen, hydroxyl, cyano, amino, halogen, C _1-6 alkyl, C _{1 -6} alkoxy, C _3-6 cycloalkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 acylamino, C _1-6 alkylamino, C _5-10 aryl, C _1-6 heterocyclyl, C _1-6 heteroaryl, C(O)C _1-6 alkyl, C(O)C _1-6 haloalkyl, C(O)NR ₁₅ , C(O)C _1-6 alkylamino, C(O)C _5-6 aryl, C (O)C _1-6 heteroaryl, SO ₂ C _1-6 alkyl, SO ₂ C _1-6 haloalkyl, SO ₂ C _3-6 cycloalkyl, SO ₂ NR ₁₅ , SO ₂ NC _1-6 alkylamino, SO ₂ C _{5 -6} aryl or SO ₂ C _1-6 heteroaryl, where C _1-6 alkyl, C _1-6 alkoxy, C _1-6 heteroaryl and C _1-6 haloalkoxy are optionally substituted with one or more groups selected from hydrogen, oxo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 alkylhydroxy, C _3-6 cycloalkyl, C _5-10 aryl, C _1-6 heterocyclyl, C _1-6 heteroaryl, cyano, halogen and hydroxyl, where C _5-10 aryl, C _1-6 heteroaryl and C _1-6 heterocyclyl are optionally substituted with one or more nim groups selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, oxo, halogen, hydroxyl, —CH ₂ OH and cyano; R ₁₁ and R ₁₂ are taken together to form a 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring, optionally with 1-5 heteroatoms selected from N, S or O, where 5-10 membered monocyclic or bicyclic saturated or unsaturated the heterocyclic ring is optionally substituted with substituents selected from amino, C _1-6 alkylamino, C _1-6 acylamino, -NHC(NH)CH ₂ Cl, NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ , C _1-6 alkyl, halogen, C _1-6 alkoxy or hydroxyl; and R ₁₅ is selected from the group consisting of hydrogen, C _1-6 alkyl, and combinations thereof.

In one embodiment, the present invention relates to a process for the preparation of compounds of formula (III) or their polymorphs, stereoisomers, prodrugs thereof, their solvates, co-crystals, intermediates thereof, their pharmaceutically acceptable salts and metabolites, the method comprising carrying out the reaction formula (VII), R ₄ CH ₂ NO ₂ with a compound selected from formula (VIA) or formula (VI),

where R ₁ , R ₂ and R ₃ in formula (VIA) and formula (VI) are independently selected from hydrogen, hydroxyl, cyano, amino, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 acylamino, C _1-6 alkylamino, C _5-10 aryl, C _1-6 heterocyclyl, C _1-6 heteroaryl, C (O) C _1-6 alkyl, C(O)C _1-6 haloalkyl, C(O)NR ₁₅ , C(O)C _1-6 alkylamino, C(O)C _5-6 aryl, C(O)C _1-6 heteroaryl, SO ₂ C _1-6 alkyl, SO ₂ C _1-6 haloalkyl, SO ₂ C _3-6 cycloalkyl, SO ₂ NR ₁₅ , SO ₂ NC _1-6 alkyl amino, SO ₂ C _5-6 aryl or SO ₂ C _{1- 6} heteroaryl, where C _1-6 alkyl, C _1-6 alkoxy, C _1-6 heteroaryl and C _1-6 haloalkoxy are optionally substituted with one or more groups selected from hydrogen, oxo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 alkylhydroxy, C _3-6 cycloalkyl, C _5-10 aryl, C _1-6 heterocyclyl, C _1-6 heteroaryl, cyano, halogen and hydroxyl, where C _5-10 aryl , C _1-6 heteroaryl and C _1-6 heterocyclyl are optionally substituted with one or more g groups selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, oxo, halogen, hydroxyl, —CH ₂ OH and cyano; R ₅ , R ₆ , R ₇ , R ₈ , R ₉ and R ₁₀ in formula (VII) and R ₄ in R ₄ CH ₂ NO ₂ are independently selected from hydrogen, hydroxyl, cyano, amino, halogen, C _1-6 alkyl , C _1-6 alkoxy, C _3-6 cycloalkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 acylamino, C _1-6 alkylamino, C _5-10 aryl, C _1-6 heterocyclyl, C _1-6 heteroaryl, C(O)C _1-6 alkyl, C(O)C _1-6 haloalkyl, C(O)NR ₁₅ , C(O)C _1-6 alkylamino, C(O)C _5-6 aryl, C(O)C _1-6 heteroaryl, SO ₂ C _1-6 alkyl, SO ₂ C _1-6 haloalkyl, SO ₂ C _3-6 cycloalkyl, SO ₂ NR ₁₅ , SO ₂ NC _1-6 alkylamino, SO ₂ C _5-6 aryl or SO ₂ C _1-6 heteroaryl, where C _1-6 alkyl, C _1-6 alkoxy, C _1-6 heteroaryl and C _1-6 haloalkoxy are optionally substituted with one or more groups selected from hydrogen, oxo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 alkylhydroxy, C _3-6 cycloalkyl, C _5-10 aryl, C _1-6 heterocyclyl, C _1-6 heteroaryl, cyano, halogen and hydroxyl, where C _5-10 aryl, C _1-6 heteroaryl and C _1-6 heterocyclyl are optionally substituted with one one or more groups selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, oxo, halogen, hydroxyl, —CH ₂ OH, and cyano; X in formula (III) is selected from O or S; Z is N; R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ and R ₁₀ are independently selected from hydrogen, hydroxyl, cyano, amino, halogen, C _1-6 alkyl, C _{1 -6} alkoxy, C _3-6 cycloalkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 acylamino, C _1-6 alkylamino, C _5-10 aryl, C _1-6 heterocyclyl, C _1-6 heteroaryl, C(O)C _1-6 alkyl, C(O)C _1-6 haloalkyl, C(O)NR ₁₅ , C(O)C _1-6 alkylamino, C(O)C _5-6 aryl, C (O)C _1-6 heteroaryl, SO ₂ C _1-6 alkyl, SO ₂ C _1-6 haloalkyl, SO ₂ C _3-6 cycloalkyl, SO ₂ NR ₁₅ , SO ₂ NC _1-6 alkylamino, SO ₂ C _{5 -6} aryl or SO ₂ C _1-6 heteroaryl, where C _1-6 alkyl, C _1-6 alkoxy, C _1-6 heteroaryl and C _1-6 haloalkoxy are optionally substituted with one or more groups selected from hydrogen, oxo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 alkylhydroxy, C _3-6 cycloalkyl, C _5-10 aryl, C _1-6 heterocyclyl, C _1-6 heteroaryl, cyano, halogen and hydroxyl, where C _5-10 aryl, C _1-6 heteroaryl and C _1-6 heterocyclyl are optionally substituted with one or more nim groups selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, oxo, halogen, hydroxyl, —CH ₂ OH and cyano; R ₁₁ and R ₁₂ are taken together to form a 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring, optionally with 1-5 heteroatoms selected from N, S or O, where 5-10 membered monocyclic or bicyclic saturated or unsaturated the heterocyclic ring is optionally substituted with substituents selected from amino, C _1-6 alkylamino, C _1-6 acylamino, -NHC(NH)CH ₂ Cl, -NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ , C _1-6 alkyl, halogen, C _1-6 alkoxy or hydroxyl; and R ₁₅ is selected from the group consisting of hydrogen, C _1-6 alkyl, and combinations thereof.

In another embodiment, the present invention relates to a pharmaceutical composition containing a compound of formula (I), formula (II) and formula (III) or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 1-11 together with a pharmaceutically acceptable carrier, optionally in combination with one or more other pharmaceutical compositions.

In yet another embodiment, the present invention relates to a pharmaceutical composition as described herein, wherein the composition is in a form selected from tablet, capsule, powder, syrup, solution, aerosol, and suspension.

In one embodiment, the present invention provides compounds of formula (I), formula (II), and formula (III), or a pharmaceutically acceptable salt thereof, as described herein, wherein the pharmaceutically acceptable salt is selected from a salt derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn and Mn; salts of organic bases such as salts of N,N'-diacetylethylenediamine, glucamine, triethylamine, choline, dicyclohexylamine, benzylamine, trialkylamine, thiamine, guanidine, diethanolamine, α-phenylethylamine, piperidine, morpholine, pyridine, hydroxyethylpyrrolidine, hydroxyethylpiperidine, ammonium, salts substituted ammonium, aluminum salts, and the like. Salts also include salts of amino acids such as glycine, alanine, cystine, cysteine, lysine, arginine, phenylalanine and guanidine. Where appropriate, the salts may include acid addition salts which are sulfates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulfonates, tosylates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates.

In one embodiment, the present invention provides compounds of formula (I), formula (II), and formula (III), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for inhibiting one or more PADs in a cell.

In one embodiment, the present invention relates to a method of inhibiting one or more members of the PAD family in a cell using an effective amount of compounds of formula (I), formula (II) and formula (III) or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, optionally in combinations with one or more other pharmaceutical compositions.

In one embodiment, the present invention relates to a method of treating a condition mediated by one or more PADs, the method comprising administering to a subject suffering from a condition mediated by one or more members of the PAD family a therapeutically effective amount of compounds of formula (I), formula (II) and formula (III) or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, optionally in combination with one or more other pharmaceutical compositions.

In one embodiment, the present invention provides a compound of formula (I), formula (II), and formula (III) for use in the treatment of rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, and psoriasis. .

In one embodiment, the present invention relates to the use of a compound of formula (I), formula (II) and formula (III) or a pharmaceutically acceptable salt or composition for the treatment of a condition mediated by one or more members of the PAD family; or for the treatment and/or prevention of treatment of rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus and psoriasis, together with other clinically necessary agents or biological agents.

In one embodiment, the present invention relates to the use of a compound of formula (I), formula (II) and formula (III) or a pharmaceutically acceptable salt or composition for the treatment of a condition mediated by one or more members of the PAD family; or for the treatment and/or prevention of acid-induced lung injury, respiratory failure syndrome, allergen-induced asthma, allergic bronchopulmonary disease, chronic lung disease in preterm infants, chronic obstructive pulmonary disease, colitis, cystic fibrosis, gouty arthritis, inflammatory bowel disease, inflammatory disease lung disease, inflammatory pain, juvenile rheumatoid arthritis, kidney disease, kidney injury caused by parasitic infections, prevention of kidney transplant rejection, lung injury, lupus, lupus nephritis, multiple sclerosis, muscular dystrophy, non-allergen-induced asthma, osteoarthritis, periodontitis, peritoneal endometriosis, psoriasis, pulmonary disease, pulmonary fibrosis, pyogenic sterile arthritis, kidney disease, rheumatic disease, rheumatoid arthritis, sepsis, acute pain, and ulcerative colitis, together e with other clinically necessary agents or biological agents.

In one embodiment, the present invention relates to a method of treating and/or preventing a condition mediated by a malfunction of one or more members of the PAD family, comprising administering to a subject suffering from a condition mediated by one or more members of the PAD family, a therapeutically effective amount of a compound of formula (I) , formula (II) and formula (III), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, optionally in combination with one or more other pharmaceutical compositions.

In one embodiment, the present invention relates to a method for the treatment of rheumatoid arthritis, which method comprises administering a combination of compounds of formula (I), formula (II) and formula (III) or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, optionally in combination with one or more other pharmaceutical compositions, with other clinically necessary agents or biological agents to a subject in need thereof.

In one embodiment, the present invention relates to a method of treating cancer, which method includes the introduction of a combination of compounds of formula (I), formula (II) and formula (III) or their pharmaceutically acceptable salts together with a pharmaceutically acceptable carrier, with other clinically necessary point of view means that are immunomodulators, the subject in need of it.

EXAMPLES

As used herein, the symbols and conventions used in such methods, schemes, and examples are consistent with those used in current scientific literature, such as the Journal of the American Chemical Society. Unless otherwise indicated, all starting materials were obtained from commercial suppliers and used without further purification. In the examples and throughout the description, in particular, the following abbreviations may be used.

Abbreviations:

AcOH - Acetic acid

BOC ₂ O - Di-tert-butyl dicarbonate

nBuLi - n-Butyllithium

ViON - Butanol

Bz - Benzyl

Cbz - Carboxybenzyl

cHex - Cyclohexane

Cs ₂ CO ₃ - Cesium carbonate

DCM / CH ₂ C1 ₂ - Dichloromethane

DIAD - Diisopropylazodicarboxylate

Dioxane - 1,4-Dioxane

DIPEA - N,N-diisopropylethylamine

DMSO - Dimethyl Sulfoxide

DMF - N,N-dimethylformamide

Et ₃ N - Triethylamine

Ether - Diethyl ether

EtOAc - Ethyl acetate

HATU - o-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

HPLC - High Performance Liquid Chromatography

IPA - Isopropyl Alcohol

K ₂ CO ₃ - Potassium carbonate

KOH - Potassium hydroxide

LiOH - Lithium hydroxide

LCMS or LC/MS - Liquid Chromatography with Mass Spectrometry

MeOH - Methanol

Min. - Minutes

Na ₂ SO ₄ - Sodium sulfate

NaHCO ₃ - Sodium Bicarbonate

NH ₄ Cl - Ammonium chloride

Tetrakispalladium - Tetrakis(triphenylphosphine)palladium

Pd/C - Palladium on carbon

PTSA - p-Toluenesulfonic acid

K. d. - round-bottomed (flask)

K. t. / K. t. - Room temperature

Rt - Retention time

TFA - Trifluoroacetic acid

TFAA - Trifluoroacetic anhydride

THF/thf - Tetrahydrofuran

TLC/tic - Thin Layer Chromatography

TMEDA - Tetramethylethylenediamine

HOBt - Hydroxybenzotriazole

EDC.HCl - 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride.

The following examples provide details regarding the synthesis, reactions and uses of the compounds of the present invention. It should be understood that the following examples are illustrative only and that the present invention is not limited to the details set forth in these examples.

Compounds according to the present invention can be obtained in a variety of ways, including standard methods in the field of chemistry. Any previously defined variable will still have the previously defined value unless otherwise specified. Illustrative methods of general synthesis are indicated in the following schemes and can be easily adjusted to obtain other compounds of the present invention.

Also provided is a process for the preparation of compounds of formula (I, II and III) shown in the following Scheme 1, wherein all groups are as defined above.

Example 1

General procedure for the synthesis of compounds of formula I, formula II and formula III

Scheme 1

Said process for the preparation of compounds of formula (I, II and III) comprises the following steps.

Step 1 Compound 1 was converted to compound 2 under standard conditions using N,O-dimethylhydroxylamine hydrochloride, triethylamine, HOBt and EDC.HCl (reaction condition a).

Step 2 By treating compound 2 with ethylmagnesium bromide (reaction condition b), intermediate 3 was obtained.

Step 3 Intermediate 3 was converted to compound 4 using phenyltrimethylammonium tribromide (reaction condition c).

Step 4 Treating compound 4 with methyl 2-aminoisonicotinate or ethyl 2-chloro-6-methylisonicotinate and NaHCO ₃ (reaction condition d) gave intermediate 5.

Step 5 Intermediate 5 was converted to compound 6 by reaction with substituted bromides (bromomethylcyclopropane) and Cs ₂ CO ₃ (reaction condition e).

Step 6 Compound 6 was subjected to hydrolysis to give compound 7 under reaction condition f.

Step 7 By conducting a coupling reaction between compound 7 and substituted carbamates, for example tert-butyl-(R)-piperidin-3-ylcarbamate (reaction condition g), compound 8 was obtained.

Step 8 Compound 8 was converted to final compound 9 by removing the Boc protecting group (reaction condition h).

General provisions and methods of analysis

The compounds used in the reaction processes, unless otherwise indicated, were commercially available and purchased from Combi-Blocks, India. NMR data were obtained on a 400 MHz spectrometer from Varian. All compounds were characterized by ¹ H NMR as well as mass spectrometry (MS-ESI, electrospray ionization mass spectrometry). All ¹ H chemical shifts were reported in parts per million (ppm) and measured relative to TMS or residual deuterated DMSO solvent. MS (ESI) measurements were performed on a Waters mass spectrometer. The yields of the compounds shown are those of isolated compounds.

The following examples are presented solely as an illustration and, therefore, should not be construed as limiting the scope of the present invention.

In addition, a class of compounds of formula I, formula II and formula III were obtained using the general procedure as described above.

Compound 1

Synthesis of (R)-(3-aminopiperidin-1-yl)(2-(3-bromo-1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine-7 -yl) methanone (compound-1)

Scheme 2

Stage 1. Obtaining N-Methoxy-N-methyl-1H-indole-2-carboxamide (2)

Triethylamine (107 ml, 775.6 mmol) and HOBt (36.7 g, 232.9 mmol) followed by the addition of EDC.HCl (44.4 g, 232.6 mmol) at 0°C (reaction condition a). The reaction mixture was stirred at RT for 4 hours. Water and DCM were added to the reaction mixture. The DCM layer was separated and washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Diethyl ether (200 ml) was added to the resulting crude material, stirred for 30 minutes. and filtered to give a white solid. This solid was dissolved in EtOAc, passed through a plug of celite and evaporated to give the title compound as an off-white solid (2) (27 g, 87% yield). MS (ESI): mass, calc. for C ₁₁ H ₁₂ N ₂ O ₂ , 204.23; found mass/charge value, 205.1 [M+H] ⁺ .

Stage 2. Obtaining 1-(1H-indol-2-yl)propan-1-one (3)

To a stirred solution of N-methoxy-N-methyl-1H-indole-2-carboxamide (2.10 g, 49.01 mmol) in THF (200 ml) was added 3 M ethylmagnesium bromide solution (49 ml, 147 mmol) dropwise. at 0°C (reaction condition b). The reaction mixture was stirred at RT for 16 hours. The reaction mixture was quenched with saturated NH ₄ Cl solution (100 ml) at 0° C. and extracted with EtOAc (500 ml). The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by flash column chromatography to give the title compound as an off-white solid (3) (53%, 4.5 g, 53% yield). MS (ESI): mass, calc. for C ₁₁ H ₁₁ NO, 173.22; found mass/charge value, 174.1 [M+H] ⁺ .

Step 3. Preparation of 2-bromo-1-(3-bromo-1H-indol-2-yl)propan-1-one (4)

To a stirred solution of 1-(1H-indol-2-yl)propan-1-one (3.2.5 g, 14.45 mmol) in THF (50 mL) was added phenyltrimethylammonium tribromide (16.3 g, 43.35 mmol) and stirred at reflux for 16 hours (reaction condition c). The reaction mixture was cooled to rt, water (25 ml) was added and extracted with EtOAc (100 ml). The organic layer was washed with saturated NaHCO ₃ solution (20 ml), brine (20 ml) and evaporated. The crude product was purified by column chromatography to give the title compound as a brown solid (4) (4 g, 86% yield). MS (ESI): mass, calc. for C ₁₁ H ₉ Br ₂ MO, 331.01; found mass/charge value, 333.9 [M+2H] ⁺ .

Stage 4. Preparation of methyl 2-(3-bromo-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine-7-carboxylate (5)

To a stirred solution of 2-bromo-1-(3-bromo-1H-indol-2-yl)propan-1-one (4.2 g, 5.24 mmol) and methyl 2-aminoisonicotinate (0.92 g, 5.24 mmol) in EtOH (20 ml) was added NaHCO ₃ (1.52 g, 26.2 mmol) and stirred at 90°C for 16 hours in a sealed tube (reaction condition d). The reaction mixture was cooled to rt, water (50 ml) was added and extracted with EtOAc (2×50 ml). The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated to give the crude product. The crude product was purified by flash column chromatography using 25-30% EtOAc in hexanes to give the title product as a brown solid (5) (0.45 g, 20.5% yield). MS (ESI): mass, calc. for C ₁₈ H ₁₄ BrN ₃ O ₂ , 384.23; found mass/charge value, 385.0 [M+H] ⁺ .

Step 5. Preparation of methyl 2-(3-bromo-1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine-7-carboxylate (6)

To a stirred solution of methyl 2-(3-bromo-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine-7-carboxylate (5, 0.4 g, 1.01 mmol) in DMF (8 ml) was added Cs ₂ CO ₃ (0.98 g, 3.01 mmol) followed by the addition of (bromomethyl)cyclopropane (0.24 ml, 1.51 mmol) and stirred at 80°C for 16 h. (reaction condition e). The reaction mixture was cooled to rt, water (20 ml) was added and extracted with EtOAc (50 ml). The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated to give the crude product. The crude product was purified by flash column chromatography using 25-30% EtOAc in hexanes to give the title product as a brown gum (6) (0.42 g, 90% yield). MS (ESI): mass, calc. for C ₂₂ H ₂₀ BrN ₃ O ₂ , 438.33; found mass/charge value, 440.1 [M+2H] ⁺ .

Step 6. Preparation of 2-(3-bromo-1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine-7-carboxylic acid (7)

To a stirred solution of methyl 2-(3-bromo-1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine-7-carboxylate (6, 0.42 g, 0.98 mmol) in MeOH (10 ml) was added 5N. NaOH solution (0.2 ml, 4.51 mmol) and stirred at reflux for 1 h (reaction condition f). The reaction mixture was cooled to rt, evaporated to dryness. The resulting crude material was dissolved in water (10 ml), acidified using a saturated citric acid solution, and the compound was extracted with EtOAc (2×30 ml). The organic layer was separated, washed with brine (10 ml), dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo to give the product as a brown solid (7) (0.34 g, 83% yield). MS (ESI): mass, calc. for C ₂₁ H ₁₈ BrN ₃ O ₂ , 424.30; found mass/charge value, 426.1 (M+2H) ⁺ .

Step 7. Preparation of tert-butyl-(R)-(1-(2-(3-bromo-1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine- 7-carbonyl)piperidin-3-yl)carbamate (8)

To a solution of tert-butyl-(R)-piperidin-3-yl-12-azancarboxylate (0.018 g, 0.09 mmol) and 2-(3-bromo-1-(cyclopropylmethyl)-1H-indol-2-yl) -3-methylimidazo[1,2-a]pyridine-7-carboxylic acid (7, 0.04 g, 0.09 mmol) in DCM (10 ml) mmol) and propylphosphonic anhydride (T3P, 50% in ethyl acetate solvent) (0.05 ml, 0.18 mmol). The reaction mixture was stirred at rt. within 12 hours (reaction condition g). It was diluted with DCM and washed with saturated sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure to give the crude material. The crude product was purified by flash column chromatography using 5% methanol in DCM to give the desired product (8) (0.035 g, 82.5% yield). MS (ESI): mass, calc. for C ₃₁ H ₃₆ BrN ₅ O ₃ , 605.0; the found mass/charge value is 606.3 [M+H] ⁺ .

Step 8. Preparation of (R)-(3-aminopiperidin-1-yl)(2-(3-bromo-1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a] pyridin-7 -yl)methanone (compound 1)

To a stirred solution of tert-butyl-(R)-(1-(2-(3-bromo-1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine-7 -carbonyl)piperidin-3-yl)carbamate (8, 0.035 g, 0.005 mmol) in DCM (10 ml) was added trifluoroacetic acid (0.5 ml) at 0°C, then it was stirred at rt. for 2 h (reaction condition h). After completion of the reaction, the solvent was evaporated. The crude material was dissolved in water (10 ml) and neutralized with saturated NaHCO ₃ to give the crude product. The crude material was purified by flash column chromatography using 3-5% methanol in DCM to give the desired product (compound 1) (0.012 g, 60% yield). ¹ HNMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.45 (d, J=7.2 Hz, 1H), 7.67-7.61 (m, 2H), 7.49 (d , J=8 Hz, 1H), 7.29 (t, J=7.6 Hz, 1H), 7.20 (t, J=7.6 Hz, 1H), 7.02 (d, J=6 .8 Hz, 1H), 4.49 (bs, 1H), 4.17 (d, J=7.2 Hz, 2H), 2.99 (bs, 1H), 1.97 (m, 2H), 1.69 (m, 2H), 1.50 (m, 2H), 1.31 (m, 1H), 1.26 (s, 3H), 1.00 (m, 1H), 0.87-0 .84 (m, 2H), 0.26-0.25 (m, 2H), 0.04 (m, 2H). MS (ESI): mass, calc. for C ₂₆ H ₂₈ BrN ₅ O, 506.1; mass/charge found value 508.3 [M+2H] ⁺ .

Compound 2

Synthesis of (R)-(3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl)methanone (compound-2)

Intermediate 8 was synthesized using the procedure outlined in Scheme 2 above.

Scheme 3

Step 1. Preparation of tert-butyl-(R)-(1-(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine-7-carbonyl) piperidin-3-yl) carbamate (10)

To a stirred solution of tert-butyl-(R)-(1-(2-(3-bromo-1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine-7 -carbonyl)piperidin-3-yl)carbamate (8, 0.07 g, 0.33 mmol) in MeOH (6 ml) was added zinc powder (0.1 g, 3.33 mmol) followed by ammonium hydroxide (2 ml) and stirred at 90° C. for 16 h (reaction condition i). The reaction mixture was cooled to rt, filtered through celite and the filtrate was evaporated. Water (10 ml) was added to the crude product and extracted with DCM (30 ml). The organic layer was separated, dried over sodium sulfate and evaporated to give the crude product. The crude product was purified by flash column chromatography using 2-6% MeOH in DCM to give the product as an off-white solid (10) (0.03 g, 35% yield). MS (ESI): mass, calc. for C ₃₁ H ₃₇ N ₅ O ₃ , 527.29; found mass/charge value, 528.3 (M+H) ⁺ .

Step 2: Preparation of (R)-(3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7- yl) methanone (compound 2)

To a stirred solution of tert-butyl-(R)-(1-(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-3-metalimidazo[1,2-a]pyridthm-7-carbonyl)piperidine -3-sh[)carbamate (10, 0.03 g, 0.05 mmol) in 1,4-dioxane (1 ml) was added 4 M HCl in dioxane (0.5 ml) and the reaction mixture was stirred at rt. within 2 hours (reaction condition j). The reaction mixture was evaporated, dissolved in water (5 ml) and increased basicity using a saturated solution of NaHCO ₃ . The compound was extracted with EtOAc (2×15 ml). The combined organic layer was dried over anhydrous Na ₂ SO ₄ . The crude product was purified by flash column chromatography using 2-8% MeOH in DCM to give the product as a brown solid (compound 2) (0.005 g, 20% yield).

¹ HNMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.42 (d, J=6.8 Hz, 1H), 7.57 (t, J=6.8 Hz, 2H), 7. 16-7.14 (m, 2H), 7.06-6.99 (m, 2H), 6.64 (s, 1H), 4.46 (d, J=6.8 Hz, 2H), 2 .91(s, 3H), 2.65-2.59(m, 2H), 2.00-1.95(m, 3H), 1.69-l.55(m, 2H), 1.43 -1.35(m, 2H), 1.10(m, 1H), 0.83-0.81(m, 2H), 0.27-0.25(m, 2H), 0.15-0 .13 (m, 2H). MS (ESI): mass, calc. for C ₂ 6H ₂ 9N ₅ O, 427.55; mass/charge value found, 428.3 [M+H] ⁺ .

The following compounds (compounds 3, 4, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 35, 36, 37, 38, 41, 42, 45, 46, 48 and 49) were synthesized using the same procedure as described for compound 2 above.

Compound 3

(R)-(3-aminopiperidin-1-yl)(2-(1-benzyl-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl)methanone

¹ HNMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.40 (d, J=6.8 Hz, 1H), 7.61-7.59 (m, 2H), 7.37 (d , J=7.6Hz, 1H), 7.16-7.02(m, 5H), 6.95-6.93(m, 3H), 6.75(s, 1H), 5.89( s, 2H), 2.97-2.88 (m, 2H), 2.69-2.59 (m, 3H), 2.58-2.50 (m, 3H), 1.82-1, 75 (m, 1H), 1.66-1.59 (m, 1H), 1.33-1.25 (m, 1H), 1.21-1.15 (m, 3H). MS (ESI): mass, calc. for C ₂₉ H ₂₉ N ₅ O, 463.59; mass/charge found value, 464.2 (M+H) ⁺ .

Compound 4

(R)-(3-aminopiperidin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl)methanone

¹ HNMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.42 (d, J=6.8 Hz, 1H), 7.63 (s, 1H), 7.58 (d, J=8 Hz, 1H), 7.51 (d, J=8 Hz, 1H), 7.18 (t, J=7.6 Hz, 1H), 7.06 (t, J=8 Hz, 1H), 7 .00 (d, J=7.2 Hz, 1H), 6.63 (s, 1H), 4.54 (t, J=7.2 Hz, 2H), 3.01 (bs, 1H), 2 .84 (bs, 2H), 2.65 (s, 3H), 1.99-1.97 (m, 2H), 1.88 (bs, 1H), 1.69 (bs, 1H), 1, 45 (bs, 2H), 1.33-1.31 (m, 2H), 1.32 (t, J=6.8 Hz, 3H). MS (ESI): mass, calc. for C ₂₄ H ₂₇ N ₅ O, 401.22; mass/charge value found, 402.2 [M+H] ⁺ .

Compound 5

Synthesis of (R)-(3-aminopiperidin-1-yl)(2-(1-ethyl-3-phenyl-1H-indol-2-yl)-3-methylimidazo[1,2-а]pyridin-7-yl ) methanone (compound 5)

Intermediate 1 was synthesized using the procedure described for Intermediate 6 in Scheme 2 above.

Scheme 4

Step 6. Preparation of methyl 2-(1-ethyl-3-phenyl-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine-7-carboxylate (2)

To a stirred solution of methyl 2-(3-bromo-1-ethyl-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine-7-carboxylate (1, 0.27 g, 0. 65 mmol) in dioxane:water (8:2, 10 ml) was added phenylboronic acid (0.12 g, 0.98 mmol), K ₂ CO ₃ (0.27 g, 1.96 mmol), Pd(PPh ₃ ) ₄ (0.04 g, 0.03 mmol) and stirred at 85° C. for 16 h. The reaction mixture was cooled to rt, filtered through celite and the dioxane was evaporated. Water (10 ml) was added to the obtained crude product, acidified using a saturated citric acid solution, and the compound was extracted with EtOAc (50 ml). The organic layer was washed with brine (10 ml), dried over anhydrous Na ₂ SO ₄ and evaporated under vacuum. The crude residue was purified by gradient column chromatography using 15-30% EtOAc in hexane to give the title product as a brown gum (2) (0.22 g, 78% yield). MS (ESI): mass, calc. for C ₂₆ H ₂₃ N ₃ O ₂ , 409.49; found mass/charge value, 410.2 (M+H) ⁺ .

Additional steps for compounds 5 and 6 were performed using the procedure illustrated for compound 1.

Compound 5

¹ HNMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.26 (d, J=7.2 Hz, 1H), 7.71-7.66 (m, 2H), 7.59 (d , J=8.0 Hz, 1H), 7.30-7.24 (m, 3H), 7.20-7.16 (m, 2H), 7.13-7.11 (m, 2H), 6.95-6.93-7.01 (m, 1H), 4.30-4.28 (m, 2H), 3.65-3.62 (m, 2H), 3.02-2.98 (m, 2H), 3.27-3.23 (m, 1H), 1.85 (s, 3H), 1.69-1.65 (m, 1H), 1.47-1.44 (m , 1H), 1.26-1.24 (m, 5H), 1.18-1.15 (m, 2H). MS (ESI): mass, calc. for C ₃₀ H ₃₁ N ₅ O, 477.61; mass/charge found value, 478.3 (M+H) ⁺ .

Compound 6

(R)-(3-Aminopyrrolidin-1-yl)(2-(1-ethyl-3-phenyl-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl) methanone

¹ HNMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.25 (d, J=7.2 Hz, 1H), 7.81-7.78 (m, 1H), 7.69 (d , J=8.0 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.30-7.24 (m, 3H), 7.19-7.13 (m, 4H), 7.06-7.01 (m, 1H), 4.31-4.28 (m, 2H), 3.65-3.62 (m, 2H), 3.51-3.47 ( m, 2H), 3.27-3.23(m, 1H), 1.96-1.94(m, 2H), 1.86(s, 3H), 1.65-1.62(m, 1H), 1.26-1.24(m, 3H), 1.18-1.15(m, 1H). MS (ESI): mass, calc. for C ₂₉ H ₂₉ N ₅ O, 463.59; mass/charge found value, 464.2 (M+H) ⁺ .

Compound 7

(R)-(3-aminopyrrolidin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl)methanone

¹ HNMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.41 (d, J=6.8 Hz, 1H), 7.76-7.74 (m, 1H), 7.58 (d , J=8.0Hz, 1H), 7.51(d, J=8.4Hz, 1H), 7.17(t, J=7.6Hz, 1H), 7.11-7.03 (m, 2H), 6.64 (s, 1H), 4.58-4.53 (m, 2H), 3.67-3.63 (m, 2H), 3.55-3.49 (m , 2H), 3.27 (br s, 2H), 3.10-2.99 (m, 2H), 2.88-2.81 (m, 2H), 2.63 (s, 3H), 1 .99-1.95 (m, 1H), 1.22 (t, J=6.8 Hz, 1H). MS (ESI): mass, calc. for C ₂₃ H ₂₅ N ₅ O, 387.49; mass/charge found value, 388.2 (M+H) ⁺ .

Compound 8

(R)-(3-Ads-1-rrolidin-1-yl)(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl)methanone

¹ HNMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.41 (d, J=7.2 Hz, 1H), 7.77-6.73 (m, 1H), 7.57 (t , J=7.6 Hz, 2H), 7.18-7.14 (m, 1H), 7.11-7.09 (m, 1H), 7.06-7.03 (m, 1H), 6.65 (s, 1H), 4.49 (d, J=6.8 Hz, 2H), 3.67-3.60 (m, 2H), 3.57-3.50 (m, 2H) , 3.23-3.19 (m, 1H), 2.63 (s, 3H), 1.96-1.89 (m, 1H), 1.65-1.60 (m, 1H), 1 .23-1.15(m, 2H), 1.09(m, 1H), 0.26-0.25(m, 2H), 0.15-0.13(m, 2H). MS (ESI): mass, calc. for C ₂₅ H ₂₇ N ₅ O, 413.53; mass/charge found value, 414.2 (M+H) ⁺ .

Compound 9

(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl)(hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-6(5Н)-yl)methanone

¹ HNMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.41 (d, J=7.2 Hz, 1H), 7.62 (s, 1H), 7.57 (t, J=6 .8 Hz, 2H), 7.18-7.14 (m, 1H), 7.06-6.99 (m, 2H), 6.64 (s, 1H), 4.48 (d, J= 7.2 Hz, 2H), 3.76-3.72 (m, 2H), 3.44-3.40 (m, 2H), 2.85-2.78 (m, 2H), 2.65 (s, 3H), 2.01-1.97 (m, 2H), 1.85-1.81 (m, 1H), 1.67-l.61 (m, 1H), 1.21-1 .19 (m, 3H), 1.10-1.05 (m, 1H), 0.27-0.25 (m, 2H), 0.15-0.13 (m, 2H). MS (ESI): mass, calc. for C ₂₈ H ₃₁ N ₅ O ₂ , 469.59; mass/charge found value, 470.3 (M+H) ⁺ .

Compound 10

(R)-(3-aminopiperidin-1-yl)(3-methyl-2-(1-(pyridin-4-ylmethyl)-1H-indol-2-yl)imidazo[1,2-a]pyridin-7 -yl) methanone

¹ HNMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.40 (d, J=6.8 Hz, 1H), 7.35-7.33 (m, 2H), 7.63 (d , J=7.6 Hz, 1H), 7.57 (s, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.13-7.07 (m, 2H), 6 .98-6.96(m, 1H), 6.90-6.88(m, 2H), 6.78(s, 1H), 5.95(s, 2H), 4.19-4.11 (m, 1H), 3.65-3.61 (m, 2H), 2.99-2.95 (m, 1H), 2.80-2.79 (m, 2H), 2.64 (s , 3H), 1.86-1.83 (m, 1H), 1.66-1.63 (m, 1H), 1.45-1.42 (m, 1H), 1.31-1.29 (m, 1H), 1.21-1.18 (m, 1H). MS (ESI): mass, calc. for C ₂₈ H ₂₈ N ₆ O, 464.57; mass/charge found value, 465.3 (M+H) ⁺ .

Compound 11

(R)-(3-aminopiperidin-1-yl)(3-methyl-2-(1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indol-2-yl)imidazo[1, 2-а]pyridin-7-yl)methanone

¹ HNMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.41 (d, J=6.8 Hz, 1H), 7.62 (s, 1H), 7.56 (t, J=7 .2 Hz, 2H), 7.18-7.14 (m, 1H), 7.06-7.00 (m, 1H), 6.98-6.95 (m, 1H), 6.65 ( s, 1H), 4.52 (d, J=7.2 Hz, 1H), 4.19-4.11 (m, 1H), 3.65-3.62 (m, 2H), 3.48 -3.41(m, 1H), 3.07-3.01(m, 2H), 2.78-2.75(m, 2H), 2.67-2.63(m, 2H), 2 .61 (s, 3H), 1.99-1.95 (m, 2H), 1.70-1.67 (m, 1H), 1.1.65-1.61 (m, 1H), 1.28 -1.21(m, 1H), 1.18-1.11(m, 4H), 1.03-1.00(m, 2H). MS (ESI): mass, calc. for C ₂₈ H ₃₃ N ₅ O ₂ , 471.61; mass/charge found value, 472.3 (M+H) ⁺ .

Compound 12

(R)-(3-aminopiperidin-1-yl)(2-(1-(4-methoxybenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl) methanone

¹ HNMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.40 (s, 1H), 7.60-7.57 (m, 2H), 7.41-7.39 (m, 2H) , 7.11-7.07(m, 1H), 7.05-7.01(m, 1H), 6.99-6.97(m, 1H), 6.92-6.90(m, 2H), 6.72-6.70(m, 2H), 5.80(s, 2H), 3.63(s, 3H), 2.83-2.8l(m, 2H), 2.68 -2.65 (m, 2H), 2.64 (s, 3H), 2.06-2.01 (m, 2H), 1.88-1.85 (m, 1H), 1.68-1 .65 (m, 1H), 1.44-1.41 (m, 1H), 1.21-1.18 (m, 2H). MS (ESI): mass, calc. for C ₃₀ H ₃₁ N ₅ O ₂ , 493.61; mass/charge found value, 494.3 (M+H) ⁺ .

Compound 13

(R)-(3-aminopiperidin-1-yl)(2-(1-(4-fluorobenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridn-7-yl) methanone

¹ HNMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.40 (d, J=7.2 Hz, 1H), 7.61-7.59 (m, 2H), 7.40 (d , J=7.2 Hz, 1H), 7.12-7.08 (m, 1H), 7.02-6.98 (m, 6H), 6.75 (s, 1H), 5.86 ( s, 2H), 4.05-4.01 (m, 1H), 3.57-3.51 (m, 1H), 2.97-2.94 (m, 1H), 2.78-2, 71 (m, 1H), 2.62 (s, 3H), 2.02-1.98 (m, 2H), 1.84-1.81 (m, 1H), 1.67-1.61 ( m, 1H), 1.44-1.41 (m, 1H), 1.25-1.21 (m, 2H). MS (ESI): mass, calc. for C ₂₉ H ₂₈ FN ₅ O, 481.58; mass/charge found value, 482.2 (M+H) ⁺ .

Compound 14

(R)-4-((2-(7-(3-aminopiperidin-1-carbonyl)-3-methylimidazo[1,2-a]pyridin-2-yl)-1H-indol-1-yl)methyl) benzonitrile

¹ HNMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.41 (d, J=7.2 Hz, 1H), 7.66-7.59 (m, 4H), 7.35 (d , J=8.0 Hz, 1H), 7.14-7.12 (m, 2H), 7.08-7.05 (m, 2H), 6.97 (d, J=7.2 Hz, 1H), 6.81 (s, 1H), 5.99 (s, 2H), 2.93-2.89 (m, 2H), 2.64 (s, 3H), 1.99-1.97 (m, 1H), 1.88-1.85 (m, 1H), 1.68-1.65 (m, 1H), 1.45-1.41 (m, 3H), 1.33-1 .29 (m, 1H), 1.22-1.19 (m, 2H). MS (ESI): mass, calc. for C ₃₀ H ₂₈ N ₆ O 488.60; mass/charge found value, 489.2 (M+H) ⁺ .

Compound 15

(R)-(3-aminopiperidin-1-yl)(3-methyl-2-(1-(pyridin-3-ylmethyl)-1H-indol-2-yl)imidazo[1,2-a]pyridin-7 -yl) methanone

¹ HNMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.41 (d, J=6.8 Hz, 1H), 8.32 (d, J=4.0 Hz, 1H), 8. 26 (s, 1H), 7.62-7.59 (m, 2H), 7.46-7.44 (m, 1H), 7.37-7.35 (m, 1H), 7.20- 7.18 (m, 1H), 7.13-7.07 (m, 2H), 6.99-6.97 (m, 1H), 6.78 (s, 1H), 5.93 (s, 2H), 4.19-4.11 (m, 1H), 3.65-3.61 (m, 2H), 2.98-2.95 (m, 1H), 2.70-2.67 ( m, 2H), 2.63 (s, 3H), 1.85-1.83 (m, 1H), 1.66-1.63 (m, 1H), 1.45-1.42 (m, 1H), 1.27-1.21 (m, 2H). MS (ESI): mass, calc. for C ₂ 8H ₂ 8N6O, 464.23; mass/charge found value, 465.2 (M+H) ⁺ .

Compound 16

(R)-(3-aminopiperidin-1-yl)(3-methyl-2-(1-(pyridin-2-ylmethyl)-1H-indol-2-yl)imidazo[1,2-a]pyridine-7 -yl) methanone

¹ HNMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.42-8.38 (m, 2H), 7.62 (d, J=6.8 Hz, 1H), 7.57-7 .52 (m, 2H), 7.34 (d, J=8.0 Hz, 1H), 7.15-7.05 (m, 3H), 7.04-6.95 (m, 1H), 6.78 (s, 1H), 6.64 (d, J=8.0 Hz, 1H), 5.96 (s, 2H), 4.19-4.11 (m, 1H), 3.55 -3.49 (m, 1H), 2.97-2.95 (m, 2H), 2.79-2.73 (m, 2H), 2.63 (s, 3H), 1.87-1 .82 (m, 1H), 1.66-1.63 (m, 1H), 1.45-1.42 (m, 1H), 1.28-1.22 (m, 2H). MS (ESI): mass, calc. for C ₂₈ H ₂₈ N ₆ O, 464.23; mass/charge found value, 465.2 (M+H) ⁺ .

Compound 17

(K)-(3-aminopiperidin-1-yl)(3-methyl-2-(1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)imidazo[1,2-a] pyridin-7-yl) methanone

¹ HNMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.43 (d, J=7.2 Hz, 1H), 7.66-7.61 (m, 3H), 7.24 (t , J=7.2Hz, 1H), 7.12(t, J=7.4Hz, 1H), 7.01(d, J=7.2Hz, 1H), 6.83(s, 1H ), 5.85-5.80 (m, 2H), 4.1 (bs, 1H), 3.60 (bs, 1H), 3.00 (bs, 1H), 2.66-2.63 ( m, 4H), 1.88-1.83 (m, 2H), 1.67 (bs, 2H), 1.46 (bs, 1H), 1.27-1.22 (m, 2H). MS (ESI): mass, calc. for C ₂₄ H ₂₄ F ₃ N ₅ O, 455.49; mass/charge found value, 456.2 (M+H) ⁺ .

Compound 18

(R)-4-((2-(7-(3-aminopiperidin-1-carbonyl)-3-methylimidazo[1,2-a]pyridin-2-yl)-1H-indol-1-yl)methyl) -1-methylpyridin-2(1Н)-one

¹ HNMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.41 (d, J=6.8 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 7. 57 (s, 1H), 7.47 (d, J=6.8 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.16-7.10 (m, 2H ), 6.98 (d, J=7.2 Hz, 1H), 6.80 (s, 1H), 5.87 (d, J=5.6 Hz, 1H), 5.77 (s, 2H ), 5.65 (s, 1H), 4.19-4.11 (m, 1H), 3.65-3.61 (m, 1H), 3.24 (s, 3H), 2.97- 2.93 (m, 1H), 2.65 (s, 3H), 2.64-2.61 (m, 2H), 1.86-1.83 (m, 2H), 1.66-1, 63 (m, 2H), 1.44-1.41 (m, 1H), 1.24-1.19 (m, 1H). MS (ESI): mass, calc. for C ₂₉ H ₃₀ N ₆ O ₂ , 494.24; mass/charge found value, 495.4 (M+H) ⁺ .

Compound 19

(R)-(3-aminopiperidin-1-yl)(2-(3-ethylbenzo[b]thiophen-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl)methanone

¹ HNMR (400 MHz, DMSO-ds) δ (ppm): 8.38 (d, J=6.8 Hz, 1H), 7.96 (d, J=7.2 Hz, 1H), 7.87 (d, J=7.5 Hz, 1H), 7.59 (s, 1H), 7.45-7.36 (m, 2H), 6.97 (d, J=7.2 Hz, 1H) , 4.02-3.99 (m, 1H), 3.49-3.45 (m, 1H), 3.03-2.97 (m, 3H), 2.69-2.60 (m, 2H), 2.58 (s, 3H), 2.14-2.08 (m, 1H), 1.88-1.83 (m, 1H), 1.69-1.61 (m, 1H) , 1.46-1.39(m, 1H), 1.31-1.26(m, 2H), 1.19-1.12(m, 3H). MS (ESI): mass, calc. for C ₂₄ H ₂₆ N ₄ OS, 418.56; mass/charge found value, 419.2 (M+H) ⁺ .

Compound 20

Synthesis of (R)-(3-aminopiperidin-1-yl)(2-(1-(4-chlorobenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl ) methanone (compound 20)

Step 1. Preparation of ethyl 2-(1-(4-chlorobenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine-7-carboxylate (2)

To a stirred solution of 1H-indole-2-carbaldehyde (1.0.5 g, 3.44 mmol) in DMF (10 mL) was added potassium carbonate (1.42 g, 10.3 mmol) followed by 1-(bromomethyl )-4-chlorobenzene (0.84 g, 4.13 mmol) and then the reaction mixture was stirred at rt. within 4 hours (reaction condition a). The reaction mixture was poured into crushed ice, which resulted in the formation of a precipitate. The precipitate was filtered through a sintered funnel and dried under vacuum to give the title compound as a beige solid (2) (0.86 g, 93.4% yield). MS (ESI): mass, calc. for C ₁₆ H ₁₂ ClNO, 269.73; the found mass/charge value is 270.1 (M+H) ⁺ .

Step 2. Preparation of ethyl 2-(1-(4-chlorobenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-а]pyridine-7-carboxylate (3)

To a stirred solution of 1-(4-chlorobenzyl)-1H-indole-2-carbaldehyde (2, 0.38 g, 1.44 mmol) and ethyl 2-aminoisonicotinate (0.2 g, 1.2 mmol) in DMF nitroethane (1.1 g, 14.3 mmol) was added followed by FeCl ₃ (0.04 g, 0.28 mmol) and stirred at 90° C. in air for 5 h (reaction condition b). The reaction mixture was cooled to rt, diluted with ethyl acetate and evaporated in vacuo to give the crude compound. The crude material was purified by flash column chromatography using ethyl acetate in hexane as eluent to give the product as a pale yellow resinous solid (3) (0.07 g, 10.9% yield). MS (ESI): mass, calc. for C ₂₆ H ₂₂ ClN ₃ O ₂ , 443.93; found mass/charge value, 444.1 (M+H) ⁺ .

Stage 3. Preparation of 2-(1-(4-chlorobenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine-7-carboxylic acid (4)

To a stirred solution of ethyl 2-(1-(4-chlorobenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine-7-carboxylate (3, 0.08 g, 0. 18 mmol) in ethanol (5 ml) was added 5 N. sodium hydroxide solution (0.18 ml, 9.0 mmol) and heated at 80° C. for 1 h (reaction condition c). The reaction mixture was cooled to rt. and evaporated to dryness. The resulting crude product was dissolved in water (10 ml), acidified using a saturated citric acid solution and extracted with dichloromethane (40 ml). The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo to give the product as a colorless tarry solid (4) (0.06 g, 80.3% yield). MS (ESI): mass, calc. for C ₂₄ H ₁₈ ClN ₃ O ₂ , 415.88; found mass/charge value, 416.1 (M+H) ⁺ .

Step 4. Obtaining tert-butyl-(R)-(1-(2-(1-(4-chlorobenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyrides1-7- carbonyl)piperidin-3-yl)carbamate (5)

To a stirred solution of 2-(1-ethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylimidazo[1,2-a]pyridine-7-carboxylic acid (4, 0.06 g , 0.144 mmol) in DCM (3 ml) was added tert-butyl-(R)-piperidin-3-ylcarbamate (0.043 g, 0.216 mmol), Et ₃ N (0.06 ml, 0.432 mmol), 50% solution of T3P in ethyl acetate (0.068 ml, 0.216 mmol) and the reaction mixture was stirred at rt. within 5 hours (reaction condition d). The reaction mixture was quenched with water (10 ml) and extracted with ethyl acetate (25 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated under vacuum. The crude material was purified by column chromatography using ethyl acetate in hexane to give the product as an off-white solid (5) (0.09 g, 61% yield). MS (ESI): mass, calc. for C ₃₄ H ₃₆ ClN ₅ O ₃ , 598.14; found mass/charge value, 599.2 (M+H) ⁺ .

Step 5: Preparation of (R)-(3-aminopiperidin-1-yl)(2-(1-(4-chlorobenzyl)-1H-indol-2-yl)-3-methylimidazo[1D-a]pyridin-7- yl) methanone (6, compound 20)

To a stirred solution of tert-butyl-(R)-(1-(2-(1-ethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylimidazo[1,2-a]pyridine -7-carbonyl)piperidin-3-yl)carbamate (5, 0.05 g, 0.083 mmol) in DCM (3 ml) TFA (0.5 ml) was added and the reaction mixture was stirred at rt. for 2 h (reaction condition e). The reaction mixture was made basic with saturated sodium bicarbonate solution and extracted with MeOH/DCM (2×25 ml). The combined organic layer was dried over anhydrous sodium sulfate. The crude product was purified by flash column chromatography using 7% MeOH in DCM to give the title compound as a brown solid (0.007 g, 26.8% yield) (6, compound 20) ¹ HNMR (400 MHz, DMSO -d ₆ ) δ (ppm): 8.41 (d, J=6.8 Hz, 1H), 7.62-7.59 (m, 2H), 7.37 (d, J=8.0 Hz , 1H), 7.23 (d, J=8.4 Hz, 2H), 7.12-7.00 (m, 2H), 6.99-6.98 (m, 3H), 6.76 ( s, 1H), 5.91 (s, 2H), 4.12 (bs, 1H), 3.6 (bs, 1H), 3.00 (bs, 1H), 2.79 (bs, 1H), 2.65-2.63 (m, 1H), 1.88-1.84 (m, 2H), 1.68 (bs, 2H), 1.46-1.43 (m, 2H), 1, 28-1.12 (m, 3H). MS (ESI): mass, calc. for C ₂₉ H ₂₈ ClN ₃ O, 498.03; found mass/charge value, 499.2 (M+H) ⁺ .

The following compounds (compounds 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 39, 40, 43, 44 and 47) were synthesized using the above procedure illustrated for compound 20.

Compound 21

(R)-(3-aminopiperidin-1-yl)(2-(1-(2-fluorobenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl) methanone

¹ HNMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.39 (d, J=7.2 Hz, 1H), 7.62-7.59 (m, 2H), 7.37 (d , J=8 Hz, 1H), 7.17-7.05 (m, 4H), 7.14 (d, J=6.8 Hz, 1H), 6.96-6.89 (m, 1H) , 6.78 (s, 1H), 6.52-6.48 (m, 1H), 5.97 (s, 2H), 4.10 (bs, 1H), 2.99 (bs, 1H), 2.80 (bs, 2H), 2.62 (s, 3H), 1.88 (bs, 2H), 1.68 (bs, 1H), 1.46 1.68 (bs, 1H), 1, 31-1.21 (m, 3H). MS (ESI): mass, calc. for C ₂₉ H ₂₈ FN ₅ O, 481.58; found mass/charge value, 482.4 (M+H) ⁺ .

Compound 22

(R)-(3-aminopiperidin-1-yl)(2-(1-ethyl-5-phenyl-1H-pyrrol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl) methanone

¹ HNMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.35 (d, J=7.2 Hz, 1H), 7.56 (s, 1H), 7.46-7.44 (m , 4H), 7.36-7.34 (m, 1H), 6.95 (d, J=6.8 Hz, 1H), 6.30 (d, J=3.6 Hz, 1H), 6 .21 (d, J=3.6 Hz, 1H), 4.40-4.38 (m, 2H), 3.05 (bs, 1H), 2.73 (bs, 2H), 2.57 ( s, 3H), 1.88-1.84 (m, 2H), 1.68 (bs, 2H), 1.46 (bs, 1H), 1.28-1.22 (m, 3H), 0 .90-0.83 (m, 3H). MS (ESI): mass, calc. for C ₂₆ H ₂₉ N ₅ O, 427.55; found mass/charge value, 428.3(M+H) ⁺ .

Compound 23

(R)-(3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-6-methoxy-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7- silt) methanone

¹ HNMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.41 (d, J=6.8 Hz, 1H), 7.63 (s, 1H), 7.45 (d, J=8 .8 Hz, 1H), 7.08 (s, 1H), 6.99 (d, J=6.4 Hz, 1H), 6.71 (d, J=7.6 Hz, 1H), 6, 55 (s, 1H), 5.15 (bs, 2H), 4.46 (d, J=6.8 Hz, 2H), 3.82 (s, 3H), 3.08-2.92 (m , 3H), 2.61 (s, 3H), 1.97-1.88 (m, 2H), 1.71 (bs, 1H), 1.48-1.36 (bs, 3H), 1, 09 (m, 1H), 0.26 (d, J=7.6 Hz, 2H), 0.13 (d, J=4 Hz, 2H). MS (ESI): mass, calc. for C ₂₇ H ₃₁ N ₅ O ₂ , 457.58; found mass/charge value, 458.58 (M+H).

Compound 24

(R)-(3-aminopiperidin-1-yl)(2-(1-ethyl-1H-pyrrolo[23-b]pyridin-2-yl)-3-methylimidazo[1,2-a]pyridin-7- silt) methanone

¹ HNMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.43 (d, J=6.4 Hz, 1H), 8.28-8.25 (m, 1H), 7.98 (d , J=7.2Hz, 1H), 7.63(s, 1H), 7.13-7.11(m, 1H), 7.01-6.99(m, 1H), 6.67( s, 1H), 4.71-4.65 (m, 2H), 4.24-4.21 (m, 1H), 3.55-3.49 (m, 1H), 3.00-2, 96 (m, 1H), 2.69-2.66 (m, 1H), 2.65 (s, 3H), 2.21-2.19 (m, 2H), 1.87-1.83 ( m, 2H), 1.68-1.65 (m, 1H), 1.45-1.42 (m, 1H), 1.35-1.33 (m, 1H), 1.26-1, 24 (m, 3H). MS (ESI): mass, calc. for C ₂₃ H ₂₆ N ₆ O, 402.22; found mass/charge value, 403.1(M+H) ⁺ .

Compound 25

(R)-(3-adshnopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-3,5-dimethylimidazo[1,2-a]pyridin-7-yl) methanone

¹ HNMR (400 MHz, DMSO-d ₆ ) δ (ppm): 7.57 (t, J=7.2 Hz, 2H), 7.40 (s, 1H), 7.16 (t, J=7 .6 Hz, 1H), 7.04 (t, J=7.6 Hz, 1H), 6.66 (s, 1H), 6.53 (s, 1H), 4.33 (d, J=6 .8 Hz, 2H), 4.09-4.04 (m, 1H), 2.95 (s, 3H), 2.88 (s, 3H), 2.65-2.61 (m, 2H) , 1.88-1.85(m, 2H), 1.67-1.64(m, 1H), 1.43-1.39(m, 1H), 1.27-1.24(m, 2H), 1.21-1.19 (m, 2H), 1.06-1.02 (m, 1H), 0.27-0.25 (m, 2H), 0.11-0.09 ( m, 2H). MS (ESI): mass, calc. for C ₂₇ H ₃₁ N ₅ O, 441.25; found mass/charge value, 442.3 (M+H) ⁺ .

Compound 26

(R)-(3-aminopiperidin-1-yl)(2-(1-benzyl-1H-indol-2-yl)-3,5-dimethylimidazo[1,2-a]pyridin-7-yl)methanone

¹ HNMR (400 MHz, DMSO-d ₆ ) δ (ppm): 7.62 (d, J=8.0 Hz, 1H), 7.40-7.37 (m, 2H), 7.19-7 .09 (m, 5H), 6.94 (d, J=6.8 Hz, 2H), 6.66 (s, 2H), 5.75 (s, 2H), 4.19-4.14 ( m, 1H), 3.75-3.71 (m, 1H), 2.94 (s, 3H), 2.89 (s, 3H), 1.89-1.87 (m, 2H), 1 .86-1.85 (m, 2H), 1.67-1.64 (m, 1H), 1.43-1.39 (m, 2H), 1.27-1.24 (m, 2H) . MS (ESI): mass, calc. for C ₃₀ H ₃₁ N ₅ 0, 477.25; found mass/charge value, 478.5 (M+H) ⁺ .

Compound 27

(R)-(3-adshnopiperidin-1-yl)(3,5-dimethyl-2-(1-(pyridin-2-ylmethyl)-1H-indol-2-yl)imidazo[1,2-a]pyridine -7-yl) methanone

¹ HNMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.40 (d, J=6.8 Hz, 1H), 7.63-7.61 (m, 1H), 7.55-7 .51 (m, 1H), 7.37-7.35 (m, 2H), 7.15-7.10 (m, 4H), 6.67-6.64 (m, 2H), 5.80 (s, 2H), 3.75-3.71 (m, 1H), 2.92 (s, 3H), 2.88 (s, 3H), 2.65-2.61 (m, 1H), 2.01-1.98(m, 1H), 1.97-1.94(m, 2H), 1.88-1.85(m, 2H), 1.43-1.39(m, 2H ), 1.27-1.24 (m, 2H). MS (ESI): mass, calc. for C ₂₉ H ₃₀ N ₆ O, 478.25; found mass/charge value, 479.2 (M+H) ⁺ .

Compound 28

(R)-(3-adshnopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-6-fluoro-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7- silt) methanone

¹ HNMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.41 (d, J=6.4 Hz, 1H), 7.60-7.55 (m, 2H), 7.44 (d , J=9.6 Hz, 1H), 6.9 (d, J=7.2 Hz, 1H), 6.92-6.88 (m, 1H), 6.54 (s, 1H), 4 .46 (d, J=6.8 Hz, 2H), 4.25 (m, 1H), 3.28 (m, 2H), 2.83 (m, 1H), 2.62 (s, 3H) , 1.99-1.95(m, 1H), 1.82(m, 2H), 1.68(m, 2H), 1.46(m, 2H), 1.07(m, 1H), 0.27-0.25 (m, 2H), 0.14-013 (m, 2H). MS (ESI): mass, calc. for C ₂₆ H ₂₈ FN ₅ O, 445.23; found mass/charge value, 446.2 (M+H) ⁺ .

Compound 29

(R)-(3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-5-fluoro-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7- silt) methanone

¹ HNMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.41 (d, J=7.2 Hz, 1H), 7.61-7.57 (m, 2H), 7.35-7 .32 (m, 1H), 7.03-6.98 (m, 2H), 6.64 (s, 1H), 4.48 (d, J=6.8 Hz, 2H), 4.21- 4.11 (m, 2H), 3.63-3.60 (m, 1H), 2.99-2.95 (m, 1H), 2.78-2.74 (m, 1H), 2. 65 (s, 3H), 1.86-1.83 (m, 1H), 1.71-1.68 (m, 3H), 1.46-1.43 (m, 1H), 1.28- 1.25 (m, 1H), 1.09-1.03 (m, 1H), 0.27-0.25 (m, 2H), 0.14-0.11 (m, 2H). MS (ESI): mass, calc. for C ₂₆ H ₂₈ FN ₅ O, 445.23; found mass/charge value, 446.2 (M+H) ⁺ .

Compound 30

(R)-(3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-methyl-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7- silt) methanone

¹ HNMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.41 (d, J=7.2 Hz, 1H), 7.60 (s, 1H), 7.42 (d, J=6 .4 Hz, 1H), 7.00-6.98 (m, 1H), 6.96-6.93 (m, 2H), 6.60 (s, 1H), 4.65 (d, J= 6.0 Hz, 2H), 4.21-4.11 (m, 2H), 3.01-2.98 (m, 1H), 2.79-2.77 (m, 2H), 2.76 (s, 3H), 2.65 (s, 3H), 1.89-1.85 (m, 2H), 1.69-1.66 (m, 1H), 1.46-1.43 (m , 1H), 1.32-1.27 (m, 2H), 0.89-0.85 (m, 1H), 0.15-0.14 (m, 2H), 0.24-0.25 (m, 2H). MS (ESI): mass, calc. for C ₂₇ H ₃₁ N ₅ O, 441.25; found mass/charge value, 442.4 (M+H) ⁺ .

Compound 31

Synthesis of (R)-(3-aminopiperidin-1-yl)(2-(2-ethylphenyl)-3-methylimidazo[1,2-а]pyridin-7-yl)methanone (compound 31)

Scheme 6

Stage 1. Ethyl-2-(2-bromopropanamido)isonicotinate

To a stirred solution of ethyl 2-aminoisonicotinate (1.2 g, 12.0 mmol) in DCM (20 ml) was added 2-bromopropanoic acid (2.2 g, 14.4 mmol), Et ₃ N (3.3 ml , 24.1 mmol), 50% solution of T3P in ethyl acetate (12.1 ml, 18.1 mmol) and the reaction mixture was stirred at rt. over 16 hours. Water (50 ml) was added to the reaction mixture and the compound was extracted with DCM (100 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated under vacuum. The crude product was purified by column chromatography using 20-30% EtOAc in hexane to give the product as a yellow solid (2.3 g, 64% yield). MS (ESI): mass, calc. for C ₁₁ H ₁₃ BrN ₂ O ₃ , 301.14; found mass/charge value, 303.0 (M+2H) ⁺ .

Stage 2. Ethyl 2-hydroxy-3-methylimidazo[1,2-a]pyridine-7-carboxylate

To a stirred solution of ethyl 2-(2-bromopropanamido)isonicotinate (2.1 g, 3.33 mmol) in EtOH (20 ml) was added K ₂ CO ₃ (1.37 g, 9.99 mmol) and stirred at 80 °C for 5 hours. The reaction mixture was evaporated to dryness, triturated with diethyl ether and dried to give the crude product as a brown tarry solid (1.0 g, 80% yield). MS (ESI): mass, calc. for C ₁₁ H ₁₂ N ₂ O ₃ , 220.08; found mass/charge value, 221.1 (M+H) ⁺ .

Stage 3. Ethyl 2-bromo-3-methylimidazo[1,2-a]pyridine-7-carboxylate

POBr ₃ (4.6 g, 16.3 mmol) and stirred at 90° C. for 16 h. The reaction mixture was cooled to rt, quenched with saturated Na ₂ CO ₃ solution (50 ml) and extracted with EtOAc (100 ml ). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated under vacuum. The crude product was purified by column chromatography using 30-40% EtOAc in hexane to give the product as a brown solid (0.2 g, 21% yield). MS (ESI): mass, calc. for C ₁₁ H ₁₁ BrN ₂ O ₂ , 283.13; found mass/charge value, 285.0 (M+2H) ⁺ .

Step 4 Ethyl 2-(2-ethylphenyl)-3-methylimidazo[1,2-a]pyridine-7-carboxylate

To a stirred solution of ethyl 2-bromo-3-methylimidazo[1,2-a]pyridine-7-carboxylate (5, 0.2 g, 0.70 mmol) in dioxane (5 ml) was added acid (0.16 g, 1.06 mmol), K ₂ CO ₃ (0.3 g, 2.12 mmol), Pd (dppf) Cl ₂ .DCM (0.03 g, 0.03 mmol) and reaction the mixture was stirred at 85° C. for 16 hours. The reaction mixture was filtered through celite and the solvent was evaporated. Water (10 ml) was added to the resulting crude product and the compound was extracted with EtOAc (25 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated under vacuum. The crude product was purified by column chromatography using 25-30% EtOAc in hexane to give the product as a brown solid (0.15 g, 71% yield). MS (ESI): mass, calc. for C ₁₉ H ₂₀ N ₂ O ₂ , 308.15; found mass/charge value, 309.1 (M+H) ⁺ .

The remaining steps for compound 31 were carried out using the procedure illustrated for compound 20.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.34 (d, J=6.8 Hz, 1H), 7.57 (s, 1H), 7.35-7.31 (m, 2H), 7.27-7.24 (m, 2H), 6.96 (d, J=6.4 Hz, 1H), 4.01-3.98 (m, 2H), 3, 66-3.61 (m, 1H), 3.49-3.41 (m, 1H), 3.02-2.97 (m, 1H), 2.83-2.79 (m, 2H), 2.67-2.61(m, 1H), 2.38(s, 3H), 1.88-1.82(m, 1H), 1.69-1.62(m, 1H), 1, 48-1.42(m, 1H), 1.33-1.29(m, 1H), 1.21-1.19(m, 1H), 1.02-0.98(m, 3H). MS (ESI): mass, calc. for C ₂₂ H ₂₆ N ₄ O, 362.21; found mass/charge value, 363.2 (M+H) ⁺ .

Compound 32

Synthesis of (R)-(3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-3-phenylimidazo[1,2-a]pyridin-7-yl)methanone (compound 32)

Scheme 7

Step 1. Methyl 2-iodo-3-phenylimidazo[1,2-a]pyridine-7-carboxylate

To a stirred solution of methyl 2-aminoisonicotinate (1.1 g, 6.5 mmol) and phenylacetylene (0.79 ml, 7.8 mmol) in 1,2-dichlorobenzene (20 ml) 6.5 mol) and copper(II) acetate (0.1 g, 0.65 mmol). The reaction mixture was filled with 5 kg/cm oxygen in a steel vessel and stirred at 120° C. for 12 hours. The reaction mixture was then filtered and evaporated to give a residue which was dissolved in water (50 ml). It was extracted with ethyl acetate (2×20 ml) and the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to obtain the crude product. The crude product was purified by gradient column chromatography using 20% EtOAc/hexane as eluent to give the desired product as a pale yellow solid (0.3 g, 12.2% yield). MS (ESI): mass, calc. for C ₁₅ H ₁₁ IN ₂ O ₂ , 377.99; found mass/charge value, 380.0 [M+H] ⁺ .

Step 2. Methyl 2-(1-(tert-butoxycarbonyl)-1H-indol-2-yl)-3-phenylimidazo[1,2-a]pyridine-7-carboxylate

To a solution of methyl 2-iodine-3-phenylimidazo[1,2-a]pyridine-7-carboxylate (2, 0.17 g, 0.44 mmol) and (1-(tert-butoxycarbonyl)-1H-indol- 2-yl)boronic acid (0.17 g, 0.66 mmol) in 1,4-dioxane (10 mL) and water (2 mL) sodium carbonate (0.13 g, 1.3 mmol) was added and the mixture was purged gaseous argon for 20 min. Then Pd(PPh ₃ ) ₄ (0.015 g, 0.002 mmol) was added and the purge was continued for 5 minutes. The reaction mixture was then stirred for 12 hours at 90° C. in a sealed tube. Water (10 ml) was added to the reaction mixture and it was extracted with EtOAc (2×20 ml). The organic layer was washed with saturated NH ₄ Cl solution and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by gradient column chromatography using 20% EtOAc/hexane as eluent to give the desired product as a pale yellow solid (0.1 g, 53.5% yield). MS (ESI): mass, calc. for C ₂₈ H ₂₅ N ₃ O ₄ , 467.18; found mass/charge value, 468.3 [M+H] ⁺ .

Step 3. Methyl 2-(1H-indol-2-yl)-3-phenylimidazo[1,2-a]pyridine-7-carboxylate

To a solution of methyl 2-(1-(tert-butoxycarbonyl)-1H-indol-2-yl)-3-phenylimidazo[1,2-a]pyridine-7-carboxylate (3, 0.08 g, 0.1 mmol) in DCM (2 ml) was added trifluoroacetic acid (0.04 ml, 0.5 mmol) at 0°C. The mixture was stirred for 2 h at rt. in N ₂ atmosphere. The reaction mixture was concentrated in vacuo and neutralized using aqueous sodium bicarbonate solution. The aqueous phase was then extracted with DCM (2×20 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated to give the desired product as a pale yellow solid (4; 0.06 g, 99% yield). MS (ESI): mass, calc. for C ₂₃ H ₁₇ N ₃ O ₂ , 367.13; found mass/charge value, 368.3 [M+H] ⁺ .

Step 4. Methyl 2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-3-fenshtimidazo[1,2-a]pyridine-7-carboxylate

To a solution of methyl 2-(1H-indol-2-yl)-3-phenylimidazo[1,2-a]pyridine-7-carboxylate (4, 0.06 g, 0.16 mmol) in DMF (10 ml) cesium carbonate (0.025 g, 0.19 mmol) was added followed by (bromomethyl)cyclopropane (0.025 g, 0.19 mmol). The mixture was stirred for 12 h at rt. Water (20 ml) was added to the reaction mixture and it was extracted with EtOAc (2×20 ml). The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a pale yellow solid (5; 0.06 g, 88.9% yield). MS (ESI): mass, calc. for C ₂₇ H ₂₃ N ₃ O ₂ , 421.8; found mass/charge value, 422.3 [M+H] ⁺ .

Step 5. 2-(1-(Cyclopropylmethyl)-1H-indol-2-yl)-3-phenylimidazo[1,2-a]pyridine-7-carboxylic acid

To a solution of methyl 2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-3-phenylimidazo[1,2-a]pyridine-7-carboxylate (5, 0.06 g, 0.14 mmol) in ethanol (20 ml) was added 5 M sodium hydroxide solution (0.14 ml, 0.72 mmol). The reaction mixture was stirred at 80°C for 45 min. After completion of the reaction, the reaction mixture was evaporated to dryness. The crude product was then dissolved in water, neutralized with citric acid until the product precipitated. The mixture was filtered to give the desired product as an off-white solid (6; 0.04 g, 70.2% yield). MS (ESI): mass, calc. for C ₂₆ H ₂₁ N ₃ O ₂ , 407.16; found mass/charge value, 408.3 [M+H] ⁺ .

Step 6. tert-Butyl-(R)-(1-(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-3-phenylimidazo[1,2-a]pyridine-7-carbonyl)piperidine -3-yl)carbamate

To a solution of tert-butyl-(R)-piperidin-3-yl-12-azancarboxylate (0.02 g, 0.1 mmol) and 2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-3 -phenylimidazo[1,2-a]pyridine-7-carboxylic acid (6, 0.04 g, 0.09 mmol) in DCM (10 mL) at RT triethylamine (0.04 ml, 0.2 mmol) and propylphosphonic anhydride (T ₃ R, 50% in ethyl acetate) (0.67 ml, 0.2 mmol) were added. The reaction mixture was stirred at rt. for 12 hours. It was diluted with DCM and washed with saturated sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure to give the crude material. The crude residue was purified by gradient column chromatography using 5% methanol in DCM to give the desired product (7; 0.04 g, 69.2% yield). MS (ESI): mass, calc. for C ₃₆ H ₃₉ N ₅ O ₃ , 589.3; found mass/charge value, 590.3 [M+H] ⁺ .

Step 7: (R)-(3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-3-phenylimidazo[1,2-a]pyridin-7-yl ) methanone (compound 32)

To a stirred solution of tert-butyl-(R)-(1-(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-3-phenylimidazo[1,2-a]pyridine-7-carbonyl)piperidine -3-yl)carbamate (7, 0.04 g, 0.06 mmol) in DCM (10 ml) TFA (0.02 ml, 0.3 mmol) was added at 0°C, then it was stirred at r.t. . within 2 hours. After completion of the reaction, the solvent was evaporated. The crude material was dissolved in water (10 ml) and neutralized with saturated NaHCO ₃ solution to give the crude material. The crude product was purified by gradient column chromatography using 5% methanol in DCM followed by a preparative HPLC column: Inertsil ODS 3V (250 mm X 4.6 mm X 5 microns), mobile phase (A): 0.1% ammonia in water, mobile phase (B): acetonitrile, flow rate: 1.0 ml/min to give the desired product as an off-white solid (0.02 g, 68.9% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.21 (d, J=7.2 Hz, 1H), 7.21 (s, 1H), 7.52 (m, 6H) , 7.39 (d, J=8 Hz, 1H), 7.13 (d, J=7.2 Hz, 1H), 6.98-6.94 (m, 2H), 6.19 (s, 1H), 4.46 (d, J=8 Hz, 2H), 2.78 (m, 2H), 1.86 (m, 2H), 1.72 (m, 2H), 1.45 (m, 2H), 1.30 (m, 2H), 1.12 (m, 2H), 0.30 (d, J=7.6 Hz, 2H), 0.16 (d, J=3.6 Hz, 2H). MS (ESI): mass, calc. for C ₃₁ H ₃₁ N ₅ O, 489.25; found mass/charge value, 490.3 [M+H] ⁺ .

The following compounds (compounds 33 and 34) were synthesized using the procedure described above for compound 32.

Compound 33

(R)-(3-aminopiperidin-1-yl)(3-cyclopropyl-2-(1-(cyclopropylmethyl)-1H-indol-2-yl)imidazo[1,2-a]pyridin-7-yl)methanone

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.55 (d, J=7.2 Hz, 1H), 7.63 (s, 1H), 7.58 (t, J= 7.6Hz, 2H), 7.17(t, J=7.2Hz, 1H), 7.05(t, J=8Hz, 2H), 6.73(s, 1H), 4.47 (d, J=7.2 Hz, 2H), 3.9 (bs, 2H), 3.03 (bs, 1H), 2.85 (m, 2H), 2.12-2.08 (m, 1H), 2.01-1.95 (m, 2H), 1.88 (m, 1H), 1.73-1.69 (m, 1H), 1.45-1.44 (m, 2H) , 1.08-1.06 (m, 2H), 0.85-0.81 (m, 1H), 0.39 (d, J=4.4 Hz, 2H), 0.21 (d, J =8 Hz, 2H), 0.01 (d, J=4.4 Hz, 2H). MS (ESI): mass, calc. for C ₂₈ H ₃₁ N ₅ O, 453.25; found mass/charge value, 454.3 [M+H] ⁺ .

Compound 34

(R)-(3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-3-(methoxymethyl)imidazo[1,2-a]pyridin-7-yl ) methanone

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.52 (d, J=7.2 Hz, 1H), 7.66 (s, 1H), 7.59 (t, J= 8.8 Hz, 2H), 7.19 (t, J=7.6 Hz, 1H), 7.07-7.02 (m, 2H), 6.47 (s, 1H), 4.87 ( s, 2H), 4.47 (d, J=6.8 Hz, 2H), 3.8 (m, 3H), 3.04 (bs, 1H), 2.96-2.92 (m, 3H ), 2.81 (s, 1H), 2.01-1.95 (m, 2H), 1.88 (m, 1H), 1.73-1.69 (m, 2H), 1.45- 1.44 (m, 2H), 0.21 (d, J=8 Hz, 2H), 0.01 (d, J=4.4 Hz, 2H). MS (ESI): mass, calc. for C ₂₇ H ₃₁ N ₅ O ₂ , 457.25; found mass/charge value, 458.2 [M+H] ⁺ .

Compound 35

(R)-(3-aminopiperidin-1-yl)(2-(1-(3-fluorobenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl) methanone

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.41 (d, J=6.8 Hz, 1H), 7.61-7.59 (m, 2H), 7.39 ( d, J=8.0 Hz, 1H), 7.23-7.18 (m, 1H), 7.13-7.04 (m, 2H), 6.99-6.97 (m, 1H) , 6.93-6.91(m, 1H), 6.80-6.76(m, 3H), 5.91(s, 2H), 4.05-4.01(m, 1H), 3 .49-3.45 (m, 1H), 2.99-2.95 (m, 1H), 2.73-2.71 (m, 2H), 2.63 (s, 3H), 1.86 -1.83(m, 2H), 1.67-1.61(m, 1H), 1.44-1.41(m, 1H), 1.26-1.21(m, 2H). MS (ESI): mass, calc. for C ₂₉ H ₂₈ FN ₅ O, 481.23; found mass/charge value, 482.2 (M+H) ⁺ .

Compound 36

(R)-(3-aminopiperidin-1-yl)(3-methyl-2-(1-(thiophen-3-ylmethyl)-1H-indol-2-yl)imidazo[1,2-a]pyridine-7 -yl) methanone

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.43 (d, J=7.2 Hz, 1H), 7.63 (s, 1H), 7.58 (d, J= 8.0 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.31-7.29 (m, 1H), 7.13-7.11 (m, 2H), 7.06-7.00 (m, 2H), 6.76 (d, J=4.4 Hz, 1H), 6.71 (s, 1H), 5.85 (s, 2H), 4.22 -4.16(m, 1H), 3.66-3.61(m, 1H), 2.97-2.95(m, 1H), 2.64-2.61(m, 5H), 1 .84-1.81(m, 2H), 1.66-1.59(m, 2H), 1.44-1.42(m, 2H). MS (ESI): mass, calc. for C ₂₇ H ₂₇ N ₅ OS, 469.19; found mass/charge value, 470.2 (M+H) ⁺ .

Compound 37

(R)-(3-aminopiperidin-1-yl)(2-(1-(furan-3-ylmethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7- silt) methanone

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.43 (d, J=7.2 Hz, 1H), 7.65 (s, 1H), 7.58 (d, J= 8.0Hz, 2H), 7.48(s, 1H), 7.40(s, 1H), 7.16-7.12(m, 1H), 7.06-7.00(m, 2H ), 6.69 (s, 1H), 6.15 (s, 1H), 5.67 (s, 2H), 4.22-4.16 (m, 1H), 3.57-3.55 ( m, 1H), 3.02-2.99 (m, 1H), 2.76-2.73 (m, 2H), 2.64 (s, 3H), 1.84-1.81 (m, 2H), 1.69-1.65(m, 2H), 1.30-1.28(m, 1H), 1.21-1.18(m, 1H). MS (ESI): mass, calc. for C ₂₇ H ₂₇ N ₅ O ₂ , 453.22; found mass/charge value, 454.2 (M+H) ⁺ .

Compound 38

(R)-3-aminopiperidin-1-yl)(2-(1-(1-(4-fluorophenyl)ethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine- 7-yl) methanone

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.42 (d, J=6.4 Hz, 1H), 7.61-7.57 (m, 2H), 7.32- 7.30 (m, 2H), 7.11-7.08 (m, 2H), 6.98-6.95 (m, 4H), 6.74 (s, 1H), 6.48-6, 45 (m, 1H), 4.22-4.18 (m, 1H), 3.59-3.55 (m, 1H), 2.97-2.94 (m, 1H), 2.72- 2.70 (m, 2H), 2.63 (s, 3H), 1.88-1.86 (m, 4H), 1.68-1.65 (m, 2H), 1.44-1, 41 (m, 1H), 1.27-1.25 (m, 2H). MS (ESI): mass, calc. for C ₃₀ H ₃₀ FN ₅ O, 495.24; found mass/charge value, 496.2 (M+H) ⁺ .

Compound 39

(R)-(3-aminopiperidin-1-yl)(2-(1-ethyl-5-fluoro-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl) methanone

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.36 (d, J=7.2 Hz, 1H), 7.60 (s, 1H), 7.5-7.750 (m, 1H), 7.33 (d, J=9.6 Hz, 1H), 7.02-6.97 (m, 2H), 6.62 (s, 1H), 4.7-4.46 (m , 2H), 4.20 (m, 2H), 2.65 (s, 4H), 1.84 (m, 2H), 1.69 (m, 1H), 1.41 (m, 1H), 1 .29-1.13 (m, 7H). MS (ESI): mass, calc. for C ₂₄ H ₂₆ FN ₅ O, 419.2; the found mass/charge value is 420.2 (M+H) ⁺ .

Compound 40

(R)-(3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-4-fluoro-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7- silt) methanone

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.43 (d, J=6.8 Hz, 1H), 7.63 (s, 1H), 7.44 (d, J= 8.4 Hz, 1H), 7.17-7.11 (m, 1H), 7.01 (d, J=6.4 Hz, 1H), 6.82 (t, J=8.4 Hz, 1H), 6.69 (s, 1H), 4.50 (d, J=6.4 Hz, 2H), 4.20 (m, 1H), 3.49 (m, 1H), 3.02 ( m, 1H), 2.79 (m, 2H), 2.63 (s, 3H), 1.88 (m, 2H), 1.70 (m, 2H), 1.48-1.45 (m , 1H), 1.31-1.28 (m, 1H), 1.10 (m, 1H), 0.27 (m, 2H), 0.15 (m, 2H). MS (ESI): mass, calc. for C ₂₆ H ₂₈ FN ₅ O, 445.2; the found mass/charge value, 446 (M+H) ⁺ .

Compound 41

(R)-(3-aminopiperidin-1-yl)(3-methyl-2-(1-((4-methylthiazol-2-yl)methyl)-1H-indol-2-yl)imidazo[1,2- a]pyridin-7-yl)methanone

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.43 (d, J=4.4 Hz, 1H), 7.61 (d, J=8 Hz, 2H), 7.52 (d, J=8.4 Hz, 1H), 7.17 (t, J=7.6 Hz, 1H), 7.09 (t, J=7.6 Hz, 1H), 7.0 (d , J=7.2Hz, 1H), 7.44(d, J=8.4Hz, 1H), 7.17-7.11(m, 1H), 7.01(d, J=6, 4Hz, 1H), 6.80(s, 1H), 3.02(m, 2H), 2.80(m, 2H), 2.65(s, 3H), 2.23(s, 3H) , 1.68 (m, 2H), 1.47-1.45 (m, 2H), 1.1-1.22 (m, 3H). MS (ESI): mass, calc. for C ₂₇ H ₂₈ N ₆ OS, 484.2; found mass/charge value, 485.2 (M+H) ⁺ .

Compound 42

(R)-(3-aminopiperidin-1-yl)(2-(1-(3-methoxybenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl) methanone

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.41 (d, J=6.8 Hz, 1H), 7.61 (t, J=8.8 Hz, 2H), 7 .39 (d, J=8.0 Hz, 1H), 7.12-7.03 (m, 3H), 6.69 (d, J=5.2 Hz, 1H), 6.75 (s, 1H), 6.67-6.64 (m, 1H), 6.51 (s, 2H), 5.86 (s, 2H), 4.71-4.67 (m, 1H), 4.22 -4.19(m, 1H), 3.55(s, 3H), 3.09-2.99(m, 1H), 2.91-2.88(m, 2H), 2.63(s , 3H), 1.89-1.86 (m, 1H), 1.68-1.65 (m, 1H), 1.48-1.41 (m, 2H), 1.21-1.18 (m, 2H). MS (ESI): mass, calc. for C ₃₀ H ₃₁ N ₅ O ₂ , 493.25; found mass/charge value, 494.2 (M+H) ⁺ .

Compound 43

(R)-(3-aminopiperidin-1-yl)(2-(5-bromo-1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7- silt) methanone

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.45 (d, J=7.2 Hz, 1H), 7.77 (s, 1H), 7.70 (s, 1H) , 7.57 (d, J=8.4 Hz, 1H), 7.28 (bs, 1H), 6.71 (bs, 1H), 6.65 (s, 1H), 4.49 (bs, 2H), 3.16 (bs, 3H), 2.06-1.89 (m, 2H), 1.53 (bs, 2H), 1.31-1.28 (m, 5H), 1.09 (bs, 1H), 0.83 (bs, 2H), 0.28 (bs, 2H), 0.15 (bs, 2H). MS (ESI): mass, calc. for C ₂₆ H ₂₈ BrN ₅ O, 506.45; found mass/charge value, 508.1 [M+H] ²⁺ .

Compound 44

(R)-(3-aminopiperidin-1-yl)(2-(7-chloro-1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7- silt) methanone

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.41 (d, J=7.2 Hz, 1H), 7.67 (s, 1H), 7.58 (d, J= 8 Hz, 1H), 7.22 (d, J=7.6 Hz, 1H), 7.08-7.02 (m, 2H), 6.74 (s, 1H), 4.80 (d, J=6.8Hz, 2H), 4.0(bs, 2H), 2.98(m, 3H), 2.61(s, 3H), 1.89(m, 2H), 1.71( m, 1H), 1.48-1.46 (m, 2H), 1.22 (m, 1H), 1.02 (m, 1H), 0.20-0.18 (m, 2H), - 0.08(m, 2H). MS (ESI): mass, calc. for C ₂₆ H ₂₈ ClN ₅ O, 461.20; found mass/charge value, 462.1 (M+H) ⁺ .

Compound 45

Synthesis of (R)-(3-aminopiperidin-1-yl)(2-(1-(4-fluorobenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl )methanthione

Compound 45 was obtained from compound 13 according to the step below.

To a stirred solution of (R)-(3-aminopiperidin-1-yl)(2-(1-(4-fluorobenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine-7 -yl)methanone (compound 13, 0.05 g, 0.11 mmol) in toluene (2 ml) was added Lawesson's reagent (0.06 g, OD 5 mmol) and stirred at 100° C. for 16 h (reaction condition a). The reaction mixture was cooled to rt, saturated NaHCO ₃ (10 ml) was added and the compound was extracted with EtOAc (30 ml). The organic extract was washed with brine (10 ml), dried over sodium sulfate and evaporated. The crude product was purified by column chromatography using 2-6% MeOH in DCM followed by prep. HPLC (analytical conditions: column: Inertsil ODS 3V (250 mm X 4.6 mm X 5 microns), mobile phase (A): 0.1% ammonium acetate in water, mobile phase (B): ACN, flow rate: 1 0 ml/min, Rt: 14.43) to give the product as a yellow solid (compound 45) (0.015 g, 29% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.36 (d, J=5.2 Hz, 1H), 7.61-7.59 (m, 1H), 7.42- 7.38 (m, 2H), 7.12-7.00 (m, 6H), 6.92-6.90 (m, 1H), 6.74 (s, 1H), 5.86 (s, 2H), 5.08-4.90(m, 2H), 3.84-3.76(m, 1H), 3.45-3.42(m, 1H), 3.10-3.05( m, 1H), 2.84-2.81(m, 1H), 2.62(s, 3H), 1.85-1.81(m, 2H), 1.67-1.59(m, 2H), 1.32-1.29 (m, 1H). MS (ESI): mass, calc. for C ₂₉ H ₂₈ FN ₅ S, 497.20; found mass/charge value, 498.1 (M+H) ⁺ .

Compound 46

(R)-(3-aminopiperidin-1-yl)(3-methyl-2-(1-methyl-1H-indol-2-yl)imidazo[1,2-a]pyridin-7-yl)methanone

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.42 (d, J=7.2 Hz, 1H), 7.64 (s, 1H), 7.59 (d, J= 8 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.20 (t, J=6.4 Hz, 1H), 7.07 (t, J=7.6 Hz , 1H), 6.99 (d, J=6.8 Hz, 1H), 6.66 (s, 1H), 4.12 (m, 1H), 3.96 (s, 3H), 2.65 (s, 3H), 1.87 (m, 1H), 1.68 (m, 2H), 1.47 (m, 1H), 1.26-1.22 (m, 4H), 0.88- 0.84 (m, 2H). MS (ESI): mass, calc. for C ₂₃ H ₂₅ N ₅ O, 387.20; the found mass/charge value is 388.2 (M+H) ⁺ .

Compound 47

(R)-(3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-methoxy-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7- silt) methanone

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.41 (d, J=7.2 Hz, 1H), 7.67 (s, 1H), 7.58 (d, J= 8 Hz, 1H), 7.22 (d, J=7.6 Hz, 1H), 7.08-7.02 (m, 2H), 6.74 (s, 1H), 4.80 (d, J=6.8Hz, 2H), 4.0(bs, 2H), 3.95(s, 3H), 2.98(m, 3H), 2.61(s, 3H), 1.89( m, 2H), 1.71 (m, 1H), 1.48-1.46 (m, 2H), 1.22 (m, 1H), 1.02 (m, 1H), 0.20-0 .18 (m, 2H), -0.08 (m, 2H). MS (ESI): mass, calc. for C ₂₇ H ₃₁ N ₅ O ₂ , 457.2; found mass/charge value, 458.1 (M+H) ⁺ .

Compound 48

(R)-(3-aminopiperidin-1-yl)(2-(1-((2,4-dimethylthiazol-5-yl)methyl)-1H-indol-2-yl)-3-methylimidazo[1,2 -a]pyridin-7-yl)methanone

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.43 (d, J=6.8 Hz, 1H), 7.62-7.58 (m, 2H), 7.49 ( d, J=8.0 Hz, 1H), 7.18 (t, J=6.8 Hz, 1H), 7.07 (t, J=6.8 Hz, 1H), 7.00 (d, J=7.2Hz, 1H), 6.72(s, 1H), 6.00(s, 2H), 4.22-4.16(m, 1H), 3.66-3.61(m , 1H), 2.99-2.95 (m, 1H), 2.64-2.63 (m, 1H), 2.62 (s, 3H), 2.56 (s, 3H), 2, 17 (s, 3H), 2.01-1.95 (m, 1H), 1.84-1.81 (m, 2H), 1.66-1.59 (m, 2H), 1.44- 1.42(m, 1H), 1.22-1.20(m, 1H). MS (ESI): mass, calc. for C ₂₈ H ₃₀ N ₆ OS, 498.22; found mass/charge value, 499.2 (M+H) ⁺ .

Compound 49

(R)-(3-aminopiperidin-1-yl)(3-methyl-2-(1-((2-methylthiazol-5-yl)methyl)-1H-indol-2-yl)imidazo[1,2- a]pyridin-7-yl)methanone

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.46 (d, J=7.2 Hz, 1H), 7.67-7.64 (m, 2H), 7.58 ( d, J=7.6 Hz, 1H), 7.51 (s, 1H), 7.17 (t, J=7.2 Hz, 1H), 7.08-7.02 (m, 2H), 6.74 (s, 1H), 6.07 (s, 2H), 4.66-4.61 (m, 1H), 4.12-4.08 (m, 1H), 3.05-3, 01 (m, 1H), 2.94-2.91 (m, 2H), 2.66 (s, 3H), 2.41 (s, 3H), 1.90-1.87 (m, 1H) , 1.70-1.67(m, 1H), 1.49-1.45(m, 1H), 1.37-1.33(m, 1H), 1.26-1.21(m, 2H). MS (ESI): mass, calc. for C ₂₇ H ₂₈ N ₆ OS, 484.20; the found mass/charge value is 485.1 (M+H) ⁺ .

Compound 50

Synthesis of Salt yl) methanone and trifluoroacetic acid (compound 50)

Step 1. Synthesis of ethyl 3-methyl-2-(1-(phenylsulfonyl)-1H-indol-2-yl)imidazo[1,2-а]pyridine-7-carboxylate (2)

To a stirred solution of ethyl 2-aminoisonicotinate (1.6.0 g, 36.11 mmol) and 1-(phenylsulfonyl)-1H-indole-2-carbaldehyde (11.3 g, 40.44 mmol) in nitroethane (60 ml) ferric chloride (0.55 g, 3.37 mmol) was added and then the reaction mixture was heated under reflux at 90° C. for 5 hours. After completion of the reaction, ice water was added and the reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude material. The crude material was purified by CombiFlash using a 12.0 g RediSep column and 0-30% ethyl acetate in hexane as eluent. The desired fractions were concentrated under reduced pressure to give ethyl 3-methyl-2-(1-(phenylsulfonyl)-1H-indol-2-yl)imidazo[1,2a]pyridine-7-carboxylate (2) as a yellow solid . Yield: 3.4 g (35%). MS (ESI): 459.22; found mass/charge value: 460.39 [M+H] ⁺¹ .

Stage 2. Synthesis of ethyl 2-(1Н-indol-2-yl)-3-methylimidazo[1,2-а]pyridine-7-carboxylate (3)

To a stirred solution of ethyl 3-methyl-2-(1-(phenylsulfonyl)-1H-indol-2-yl)imidazo[1,2a]pyridine-7-carboxylate (2, 3.40 g 7.40 mmol) in tetrahydrofuran (10 ml) was slowly added 1 M tetrabutylammonium fluoride in tetrahydrofuran (30 ml) at 0°C. The reaction mixture was heated under reflux at 60° C. for approximately 12 hours. After completion of the reaction, ice water was added and the reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude material. The crude material was purified by CombiFlash using a 12.0 g RediSep column and 30% ethyl acetate in hexane as eluent to give ethyl 2-(1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine- 7-carboxylate (3) as a yellow solid. Yield: 2.2 g (93%), MS (ESI): 319.11; found mass/charge value, 320.34 [M+H] ⁺ .

Step 3. Synthesis of ethyl 2-(1-(3-methoxybenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-а]pyridine-7-carboxylate (4)

To a stirred solution of ethyl 2-(1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine-7-carboxylate (3, 2.20 g, 6.89 mmol) in N,N- dimethylformamide (20 ml) was added cesium carbonate (6.72 g, 20.68 mmol) at rt. 1-(Chloromethyl)-3-methoxybenzene (1.20 g, 20.68 mmol) was added and stirred for approximately 10 minutes. at rt, and then the resulting mixture was heated to 90°C for 3 hours. After completion of the reaction, the reaction mixture was cooled to rt. and diluted with ethyl acetate (50 ml x 3). The organic phase was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude compound. The crude material was purified by CombiFlash using a 12.0 g RediSep column and 30-50% ethyl acetate in hexane as eluent to give ethyl 2-(1-(3-methoxybenzyl)-1H-indol-2-yl)-3- methylimidazo[1,2-a]pyridine-7-carboxylate (4) as a yellow solid. Yield: 1.2 g (40%). MS (ESI): 439.50; found mass/charge value, 440.04 [M+H] ⁺¹ .

Stage 4. Synthesis of 2-(1-(3-methoxybenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-а]pyridine-7-carboxylic acid (5)

To a stirred solution of ethyl 2-(1-(3-methoxybenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine-7-carboxylate (1.20 g, 2.73 mmol ) in tetrahydrofuran (10 ml) was added methanol (4 ml) and 5 N. sodium hydroxide solution (4 ml) and the resulting mixture was heated to 60°C for 3 hours. After completion of the reaction, the reaction mixture was evaporated under reduced pressure and acidified to pH 2-3 with citric acid at 0°C. The crude material was extracted with dichloromethane (30 mL×2), washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to 2-(1-(3-methoxybenzyl)-1H-indol-2-yl)- 3-methylimidazo[1,2-a]pyridine-7-carboxylic acid (5) as a pale yellow solid. Yield: 0.850 g (78%). MS (ESI): 412; the found mass/charge value, 413 [M+H] ⁺ .

Step 5. Synthesis of tert-butyl-(R)-(1-(2-(1-(3-methoxybenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine-7- carbonyl)piperidin-3-yl)carbamate (6)

To a stirred solution of 2-(1-(3-methoxybenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine-7-carboxylic acid (5, 0.85 g, 2.06 mmol) in dichloromethane (20 ml) was added tert-butyl-(11)-piperidin-3-ylcarbamate (0.49 g, 2.47 mmol), triethylamine (0.8 ml, 6.18 mmol) and propyl phosphoric anhydride in 50% ethyl acetate (2.1 ml, 6.80 mmol) at 0°C. The reaction mixture was stirred at rt. within 1 h. After completion of the reaction, the reaction mixture was quenched with a solution of sodium bicarbonate (20 ml) and was extracted with dichloromethane (20 ml × 2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude material was purified by CombiFlash using a RediSep 40.0 g column and 30-50% ethyl acetate in hexane as eluent to give t-butyl-(R)-(1-(2-(1-(3-methoxybenzyl)-1H -indol-2-yl)-3-methylimidazo[1,2-a]pyridine-7-carbonyl)piperidin-3-yl)carbamate (6) as a brown solid. Yield: 0.640 g (86%). MS (ESI): 594.30; found mass/charge value, 595.41 [M+H] ⁺ 1.

Step 6. Synthesis of (R)-(3-aminopiperidin-1-yl)(2-(1-(3-methoxybenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine salt -7-yl)methanone and trifluoroacetic acid (compound 50)

To a stirred solution of a mixture of tert-butyl-(R)-(1-(2-(1-(3-methoxybenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7- carbonyl)piperidin-3-yl)carbamate (0.64 g, 1.08 mmol) in dichloromethane (60 ml) trifluoroacetic acid (10 ml) was added at 0°C. The reaction mixture was stirred at rt. for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove trifluoroacetic acid. The crude material was dissolved in a minimum volume of water and made basic with saturated sodium bicarbonate solution (20 ml) and extracted with dichloromethane (50 ml×2). The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated to give the crude product. The crude material was purified by prep. Reverse phase HPLC to give (R)-(3-aminopiperidin-1-yl)(2-(1-(3-methoxybenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a] pyridin-7-yl)methanone trifluoroacetate as an off-yellow solid. Yield: 0.49 g (93%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.49 (d, J=7.0 Hz, 1H), 7.76 (s, 1H), 7.63 (d, J= 7.6 Hz, 1H), 7.42 (d, J=8.04 Hz, 1H)), 7.15-7.07 (m, 4H), 6.80 (s, 1H), 6.69 (dJ=8.2Hz, 1H), 6.53(s, 2H), 5.83(s, 2H), 4.ll(bs, 2H), 3.57(s, 3H), 3.27 (bs, 3H), 2.65 (s, 3H), 1.98 (m, 1H), 1.73 (m, 1H), 1.58 (m, 2H). MS (ESI): mass, calc. for C ₃₀ H ₃₁ N ₅ O ₂ , 494.11; found mass/charge value, 495.07 [M+H] ⁺¹ .

The following compounds were synthesized using the above procedure illustrated for compound 50.

Compound 51

(R)-(3-aminopiperidin-1-yl)(2-(6-methoxy-1-(pyridin-3-ylmethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a] pyridin-7-yl) methanone

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.41 (d, J=7.08 Hz, 1H), 8.33 (d, J=4.52 Hz, 1H), 8 .26 (s, 1H), 7.59 (s, 1H), 7.50 (d, J=8.6 Hz, 1H), 7.36 (dJ=7.81 Hz, 1H), 7.22 -7.19 (m, 1H), 7.03 (s, 1H), 6.98 (d, J=7.08 Hz, 1H), 6.74 (d, J=8.01 Hz, 1H) , 6.70 (s, 1H), 5.92 (bs, 2H), 4.27-4.10 (m, 1H), 3.75 (s, 3H), 3.56 (bs, 1H), 2.98-2.95(m, 2H), 2.66(m, 1H), 2.62(s, 3H), 1.85-1.82(m, 1H), 1.71-1, 67 (m, 3H), 1.44-1.42 (m, 1H), 1.27-1.23 (m, 1H). MS (ESI): mass, calc. for C ₂₉ H ₃₀ N ₆ O ₂ , 494.43; found mass/charge value, 495.07 [M+H] ⁺ .

Compound 52

Salt (R)-(3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-6-fluoro-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7 -yl) methanone and trifluoroacetic acid

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.51 (d, J=7.08 Hz, 1H), 7.95 (s, 1H), 7.76 (s, 1H) , 7.62-7.58 (m, 1H), 7.49 (d, J=10.3 Hz, 1H), 7.10 (d, J=6.56 Hz, 1H), 6.94 ( t, J=8.04Hz, 1H), 6.70(s, 1H), 4.45(d, J=6.64Hz, 2H), 3.29(s, 4H), 2.64( s, 3H), 2.01(s, 1H), 1.75(s, 1H), 1.60(s, 2H), 1.06(s, 1H), 0.28(d, J=7 .48 Hz, 2H), 0.15 (d, J=3.88 Hz, 2H). MS (ESI): mass, calc. for C ₂₆ H ₂₈ FN ₅ O, 445; found mass/charge value, 446.45 [M+H] ⁺ .

Compound 53

(R)-(3-aminopiperidin-1-yl)(2-(5-fluoro-1-(3-methoxybenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine- 7-yl) methanone

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.42 (d, J=6.9 Hz, 1H), 7.62 (s, 1H), 7.43-7.36 ( m, 2H), 7.08 (t, J=7.3 Hz, 1H), 7.01-6.94 (m, 2H), 6.76 (s, 1H), 6.67 (d, J = 6.9 Hz, 1H), 6.53-6.51 (m, 2H), 5.87 (s, 2H), 4.30-4.08 (m, 1H), 3.57 (s, 4H), 2.98 (s, 1H), 2.80 (s, 1H), 2.64 (s, 5H), 2.01 (bs, 1H), 1.85-1.83 (m, 1H ), 1.68 (m, 1H), 1.45-1.42 (m, 1H), 1.26-1.23 (s, 1H). MS (ESI): mass, calc. for C ₃₀ H ₃₀ FN ₅ O ₂ , 511.51; the found mass/charge value is 512.67 [M+1] ⁺¹ .

Compound 54

(R)-(3-aminopiperidin-1-yl)(2-(6-fluoro-1-(4-fluorobenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine- 7-yl) methanone

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.42 (d, J=6.96 Hz, 1H), 7.63-7.60 (m, 2H), 7.31 ( d, J=10.04 Hz, 1H), 7.03-6.99 (m, 5H), 6.93 (t, J=8.6 Hz, 1H), 6.78 (s, 1H), 5.86 (s, 2H), 4.25-4.10 (m, 1H), 3.56 (m, 1H), 2.98 (bs, 1H), 2.82 (m, 1H), 2 .62 (m, 5H), 1.85-1.82 (m, 1H), 1.69 (bs, 2H), 1.45-1.42 (m, 1H), 1.24-1.22 (m, 1H). MS (ESI): mass, calc. for C ₂₉ H ₂₇ F ₂ N ₅ O, 499.22; found mass/charge value, 500.37 [M+H] ⁺ .

Compound 55

(R)-(3-aminopiperidin-1-yl)(2-(5,6-difluoro-1-(3-methoxybenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a] pyridin-7-yl) methanone

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.42 (d, J=6.84 Hz, 1H), 7.63-7.54 (m, 2H), 7.08 ( t, J=7.8 Hz, 1H), 6.99 (d, J=6.76 1H), 6.77 (s, 1H), 6.69 (d, J=7.56 2H), 6 .50 (m, 2H), 5.86 (s, 2H), 4.24-4.01 (bs, 2H), 3.56 (s, 3H), 2.97 (bs, 2H), 2, 62 (m, 4H), 1.82 (m, 1H), 1.69 (m, 2H), 1.43 (d, J=9.08, 1H), 1.23-1.09 (m, 2H). MS (ESI): mass, calc. for C ₃₀ H ₂₉ F ₂ N ₅ O ₂ .529.59; found mass/charge value, 530.29 [M+H] ⁺¹ .

Compound 56

Synthesis of (R,E)-4-(dimethylamino)-N-(1-(2-(1-(4-fluorobenzyl)-1Н-indol-2-yl)-3-methylimidazo[1,2-а]pyridine -7-carbonyl)piperidin-3-yl)but-2-enamide

(R)-(3-Aminopiperidin-1-yl)(2-(1 -(4-fluorobenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl)methanone (0.200 g, 0.415 mmol), triethylamine (0.18 ml, 1, 28 mmol), propylphosphonic anhydride in 50% ethyl acetate (0.85 ml, 1.33 mmol) at 0°C. The reaction mixture was stirred at rt. within 2 hours After completion of the reaction, the reaction mixture was quenched with sodium bicarbonate solution (20 ml) and was extracted with dichloromethane (50 ml × 2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by prep. HPLC to give (R,E)-4-(dimethylamino)-N-(1-(2-(1-(4-fluorobenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a ]pyridine-7-carbonyl)piperidin-3-yl)but-2-enamide as an off-white solid. Yield: 0.12 g (49%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.40 (s, 1H), 8.01 (s, 1H), 7.62 (d, J=7.6 Hz, 2H) , 7.44 (d, J=7.6 Hz, 1H), 7.14-7.11 (m, 1H), 7.06-6.99 (m, 6H), 6.76 (s, 1H ), 6.55-6.43 (m, 1H), 6.06 (d, J=14.2 Hz, 1H), 5.88 (s, 2H), 4.13-3.68 (m, 3H), 3.11-2.94 (m, 4H), 2.63 (s, 3H), 2.11 (s, 6H), 1.87 (d, J=9.2 Hz, 1H), 1.79 (m, 1H), 1.53-1.51 (m, 2H). MS (ESI): mass, calc. for C ₃₅ H ₃₇ FN ₆ O ₂ , 592.30; the found mass/charge value is 593.4 [M+H] ⁺¹ .

Compound 57

Synthesis of (R)-(3-aminopiperidin-1-yl)(3-methyl-2-(1-(pyrazin-2-ylmethyl)-1H-indol-2-yl)imidazo[1,2-а]pyridin- 7-yl)methanone (compound 57)

Step 1. Ethyl 3-methyl-2-(1-(pyrazin-2-ylmethyl)-1H-indol-2-yl)imidazo[1,2-а]pyridine-7-carboxylate (2)

To a stirred solution of ethyl 2-(1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine-7-carboxylate (1, 0.3 g, 0.94 mmol) in N,N- dimethylformamide (10 ml) was added cesium carbonate (1.5 g, 4.7 mmol) and 2-(chloromethyl)pyrazine (0.15 g, 1.13 mmol) and stirred at 60° C. for 3 h. reaction, the reaction mixture was cooled to rt. and diluted with ethyl acetate (10 ml x 3). The organic phase was washed with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude compound. The crude material was purified using CombiFlash, RediSep 12 g and 50-70% ethyl acetate in hexane as eluent to give ethyl 3-methyl-2-(1-(pyrazin-2-ylmethyl)-1H-indol-2-yl) imidazo[1,2-a]pyridine-7-carboxylate (2) as a light brown solid. Yield: 0.108 g (28%). MS (ESI): 411.17; found mass/charge value, 412.21.

Step 2. Synthesis of 3-methyl-2-(1-(pyrazin-2-ylmethyl)-1H-indol-2-yl)imidazo[1,2-a]pyridine-7-carboxylic acid (3)

To a stirred solution of ethyl 3-methyl-2-(1-(pyrazin-2-ylmethyl)-1H-indol-2-yl)imidazo[1,2-a]pyridine-7-carboxylate (2, 0.108 g, 0.267 mmol) in tetrahydrofuran (4 ml) was added methanol (2 ml) and 5 N. a solution of sodium hydroxide in water (2 ml) and the resulting mixture was heated to 60°C for 1 hour. After completion of the reaction, the reaction mixture was evaporated under reduced pressure and acidified to pH 2-3 with citric acid at 0°C. The crude material was extracted with dichloromethane (50 mL×2), washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 3-methyl-2-(1-(pyrazin-2-ylmethyl)-1H- indol-2-yl)imidazo[1,2-a]pyridine-7-carboxylic acid (3) as an off-white solid. Yield: 0.10 g, 99%. MS (ESI): 383.14; found mass/charge value, 382.11 [M-N] ^-1 .

Stage 3. Synthesis of tert-butyl-(R)-(1-(3-methyl-2-(1-(pyrazin-2-ylmethyl)-1H-indol-2-yl)imidazo[1,2-a]pyridine -7-carbonyl)piperidin-3-yl)carbamate (4)

To a stirred solution of 3-methyl-2-(1-(pyrazin-2-ylmethyl)-1H-indol-2-yl)imidazo[1,2-a]pyridine-7-carboxylic acid (3, 0.10 g, 0.261 mmol) in dichloromethane (10 ml) was added tert-butyl-(11)-piperidin-3-ylcarbamate (0.06 g, 0.313 mmol), triethylamine (0.11 ml, 0.80 mmol), propylphosphonic anhydride in 50 % ethyl acetate (0.50 ml, 0.83 mmol) at 0°C. The reaction mixture was stirred at rt. within 3 hours After completion of the reaction, the reaction mixture was quenched with sodium bicarbonate solution (20 ml) and was extracted with dichloromethane (5 ml × 2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude material was purified using CombiFlash, RediSep 4.0 g and 1-5% methanol in dichloromethane as eluent to give t-butyl-(R)-(1-(3-methyl-2-(1-(pyrazine-2 -ylmethyl)-1H-indol-2-yl)imidazo[1,2-a]pyridine-7-carbonyl)piperidin-3-yl)carbamate (4) as an off-white solid. Yield: 0.07 g, 47%. MS (ESI): 565.28; found mass/charge value, 566.18 [M+H] ⁺¹ .

Step 4. Synthesis of (R)-(3-aminopiperidin-1-yl)(3-methyl-2-(1-(pyrazin-2-ylmethyl)-1H-indol-2-yl)imidazo[1,2-a ]pyridin-7-yl)methanone (compound 57)

To a stirred solution of a mixture of tert-butyl-(R)-(1-(3-methyl-2-(1-(pyrazin-2-ylmethyl)-1H-indol-2-yl)imidazo[1,2-a]pyridine -7-carbonyl)piperidin-3-yl)carbamate (4, 0.07 g, 0.123 mmol) in dichloromethane (2.0 ml) was added trifluoroacetic acid (0.5 ml) at 0°C. The reaction mixture was stirred at rt. within 3 hours After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove triperoxonane acid. The crude material was dissolved in a minimum volume of water and made basic with saturated sodium bicarbonate solution (20 ml) and extracted with dichloromethane (10 ml x 2). The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated to give (R)-(3-aminopiperidin-1-yl)(3-methyl-2-(1-(pyrazin-2-ylmethyl)-1H-indol- 2-yl)imidazo[1,2-a]pyridin-7-yl)methanone as a white solid. Yield: 0.05 g (87%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.49 (s, 1H), 8.43-8.40 (m, 2H), 8.15 (s, 1H), 7, 64 (d, J=7.56 Hz, 1H), 7.57 (s, 1H), 7.47 (d, J=8.12 Hz, 1H), 7.16-7.07 (m, 2H ), 6.99 (d, J=7.04 Hz, 1H), 6.82 (s, 1H), 6.05 (s, 2H), 4.26-4.09 (m, 2H), 3 .59-3.51 (m, 2H), 3.00 (bs, 2H), 2.64 (s, 3H), 1.85 (bs, 1H), 1.68 (bs, 1H), 1, 46-1.43(m, 1H), 1.35-1.23(m, 2H). MS (ESI): mass, calc. for C ₂₇ H ₂₇ N ₇ O, 465.23; found mass/charge value, 466.17 [M+H] ⁺¹ .

The following compounds were synthesized using the above procedure illustrated for compound 57.

Compound 58

Salt (R)-(3-aminopiperidin-1-yl)(3-methyl-2-(1-(pyrimidin-5-ylmethyl)-1H-indol-2-yl)imidazo[1,2-a]pyridin- 7-yl) methanone and trifluoroacetic acid

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.99 (s, 1H), 8.54 (s, 2H), 8.48 (d, J=6.5 Hz, 1H) , 7.70 (s, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.20-7.16 ( m, 1H), 7.13-7.09 (m, 1H), 7.05 (d, J=11.4 Hz, 1H), 6.84 (s, 1H), 5.93 (s, 2H ), 4.09 (s, 2H), 3.29 (m, 3H), 2.67 (s, 3H), 1.99 (s, 2H), 1.74 (s, 1H), 1.58 (m, 2H), 1.23 (s, 1H). MS (ESI): mass, calc. for C ₂₇ H ₂₇ N ₇ O, 465.11; found mass/charge value, 466.07 [M+H] ⁺¹ .

Compound 59

(R)-(3-aminopiperidin-1-yl)(3-methyl-2-(1-(pyridazin-3-ylmethyl)-1H-indol-2-yl)imidazo[1,2-a]pyridin-7 -yl) methanone

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 9.06 (d, J=4.76 Hz, 1H), 8.43 (d, J=7.0 Hz, 1H), 7 .64 (d, J=7.25 Hz, 1H), 7.57 (s, 1H), 7.55-7.51 (m, 1H), 7.43 (d, J=7.68 Hz, 1H), 7.18 (d, J=7.31 Hz, 1H), 7.13-7.07 (m, 2H), 7.00 (d, J=6.96 Hz, 1H), 6, 83 (s, 1H), 6.17 (s, 2H), 4.25-4.08 (s, 1H), 3.54 (bs, 1H), 2.96 (bs, 1H), 2.66 (s, 3H), 1.88-1.83 (m, 4H), 1.70 (m, 2H), 1.44-1.41 (m, 1H), 1.28-1.23 (m , 1H). MS (ESI): mass, calc. for C ₂₇ H ₂₇ N ₇ O, 465.34; found mass/charge value, 466.67 [M+H] ⁺¹ .

Compound 60

(R)-(3-aminopiperidin-1-yl)(2-(1-isobutyl-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl)methanone

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.45 (d, J=2.9 Hz, 1H), 7.71 (s, 1H), 7.59 (d, J= 7.8 Hz, 1H), 7.54 (d, J=8.2 Hz, 1H), 7.17 (t, J=7.2 Hz, 1H), 7.07-7.02 (m, 2H), 6.65 (s, 1H), 4.45 (d, J=7.0 Hz, 2H), 4.18 (m, 2H), 3.12 (bs, 2H), 2.63 ( s, 3H), 1.98-1.95(m, 2H), 1.73(m, 1H), 1.53(m, 2H), 1.23(s, 2H), 0.84(m , 1H), 0.64 (d, J=6.4 Hz, 6H). MS (ESI): mass, calc. for C ₂₆ H ₃₁ N ₅ O, 429.31; the mass/charge value found, 430.24 [M+H] ⁺ .

Compound 61

(R)-(3-aminopiperidin-1-yl)(2-(1-(cyclobutylmethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl)methanone

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.43 (d, J=6.92 Hz, 1H), 7.65 (s, 1H), 7.57 (t, J= 7.56Hz, 2H), 7.17(t, J=7.20Hz, 1H), 7.07-7.00(m, 2H), 6.63(s, 1H), 4.67( d, J=6.76Hz, 2H), 4.30-4.14(m, 1H), 3.63(bs, 1H), 3.01(bs, 2H), 2.72(m, 1H ), 2.63 (s, 3H), 2.59-2.55 (m, 1H), 1.87 (d, J=9.8 Hz, 1H), 1.70-1.62 (m, 6H), 1.53-1.48(m, 4H), 1.35-1.23(m, 1H). MS (ESI): mass, calc. for C ₂₇ H ₃₁ N ₅ O, 441.25; the found mass/charge value, 442.27 [M+H] ⁺¹ .

Compound 62

(R)-(3-aminopiperidin-1-yl)(2-(1-((3-fluoropyridin-2-yl)methyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a ]pyridin-7-yl) methanone

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.39 (d, J=6.92 Hz, 1H), 8.14 (d, J=4.44 Hz, 1H), 7 .61-7.54 (m, 3H), 7.44 (d, J=8.08 Hz, 1H), 7.27-7.23 (m, 1H), 7.13-7.09 (m , 1H), 7.07-7.03 (m, 1H), 6.97 (d, J=6.04 Hz, 1H), 6.73 (s, 1H), 6.09 (s, 2H) , 4.25-4.07 (m, 1H), 3.57 (bs, 1H), 2.98 (m, 2H), 2.66 (m, 1H), 2.61 (s, 3H), 1.85 (d, J=9.68 Hz, 1H), 1.69-1.58 (m, 2H), 1.45-1.42 (m, 1H), 1.23 (m, 2H) . MS (ESI): mass, calc. for C ₂₇ H ₃₁ N ₅ O, 482.22; found mass/charge value, 483.30 [M+H] ⁺¹ .

Compound 63

(R)-(3-aminopiperidin-1-yl)(2-(1-((5-methoxypyridin-2-yl)methyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a ]pyridin-7-yl) methanone

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.42 (d, J=6.96 Hz, 1H), 8.13 (d, J=2.72 Hz, 1H), 7 .63-7.60 (m, 1H), 7.38 (d, J=7.96 Hz, 1H), 7.19-7.16 (dd, J=2.8 Hz, 8.6 Hz, 1H), 7.13-7.04 (m, 2H), 7.00 (d, J=6.24 Hz, 1H), 6.77 (s, 1H), 6.70 (d, J=8 .64Hz, 2H), 5.90(s, 2H), 4.26-4.01(s, 2H), 3.71(s, 3H), 3.58(m, 1H), 2.96 (bs, 2H), 2.65 (s, 3H), 1.85-1.69 (m, 4H), 1.45-1.42 (m, 1H), 1.26-1.23 (m , 1H). MS (ESI): mass, calc. for C ₂₉ H ₃₀ N ₆ O ₂ , 494.23; found mass/charge value, 495.29 [M+H] ⁺¹ .

Compound 64

(R)-(3-aminopiperidin-1-yl)(2-(1-(2-methoxyethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl) methanone

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.43 (d, J=7.0 Hz, 1H), 7.62 (s, 1H), 7.60-7.54 ( m, 2H), 7.18 (t, J=1.6 Hz, 1H), 7.06 (t, J=7.4 Hz, 1H), 7.00 (d, J=6.8 Hz, 1H), 6.67 (s, 1H), 4.72 (t, J=5.6 Hz, 2H), 4.28-4.12 (m, 1H), 3.58 (t, J=5 .8 Hz, 2H), 3.07 (s, 3H), 2.98-2.74 (m, 2H), 2.64 (s, 5H), 1.86-1.84 (m, 1H) , 1.72(m, 2H), 1.47-1.44(m, 1H), 1.29-1.24(m, 1H). MS (ESI): mass, calc. for C ₂₅ H ₂₉ N ₅ O ₂ , 431.23; the found mass/charge value, 432.27 [M+H] ⁺¹ .

Compound 65

Synthesis of (R)-(3-aminopiperidin-1-yl)(2-(1-(2-hydroxyethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-а]pyridin-7-yl ) methanone

To a stirred solution of tert-butyl-(R)-(1-(2-(1-(2-methoxyethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine-7-carbonyl )pipfidin-3-yl)carbamate (4, 0.20 g, 0.30 mmol) in dichloromethane (4 ml) was added boron tribromide (1 M solution in dichloromethane) (5 ml) at 0°C. The reaction mixture was stirred at rt. within 3 hours After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove boron tribromide. The crude product was dissolved in a minimum volume of water and made basic with saturated sodium bicarbonate solution (20 ml) and extracted with dichloromethane (20 ml×2). The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated to give the crude product. The crude product was purified by prep. HPLC to give (R)-(3-aminopiperidin-1-yl)(2-(1-(2-hydroxyethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine-7 -yl)methanone as an off-white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.45 (d, J=6.8 Hz, 1H), 7.64 (s, 1H), 7.60 (d, J= 7.2 Hz, 1H), 7.55 (d, J=6.9 Hz, 1H), 7.18 (t, J=7.4 Hz, 1H), 7.08 (d, J=7, 44 Hz, 1H), 7.05-7.02 (m, 1H), 6.66 (s, 1H), 5.24 (bs, 1H), 4.56 (t, J=5.80 Hz, 2H), 4.25-4.06 (m, 1H), 3.69 (t, J=5.8 Hz, 2H), 3.07 (bs, 1H), 2.80 (bs, 2H), 2.64 (s, 3H), 1.87 (s, 4H), 1.75-1.72 (m, 1H), 1.49 (m, 1H), 1.32 (m, 1H). MS (ESI): mass, calc. for C ₂₄ H ₂₇ N ₅ O ₂ , 417.22; found mass/charge value, 418.39 [M+H] ⁺¹ .

Compound 66

(R)-(3-aminopiperidin-1-yl)(2-(6-methoxy-1-(pyridin-4-ylmethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a] pyridin-7-yl) methanone

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.35 (s, 2H), 7.55 (s, 2H), 6.90 (s, 4H), 6.74 (s, 3H), 5.94 (s, 2H), 4.21-4.05 (m, 1H), 3.72 (s, 3H), 2.97 (bs, 2H), 2.63-2.49 (m, 4H), 1.84 (m, 2H), 1.69 (m, 2H), 1.44 (bs, 1H), 1.24 (m, 2H). MS (ESI): mass, calc. for C ₂₉ H ₃₀ N ₆ O ₂ , 494.22; the mass/charge value found, 495.07 [M+H] ⁺¹ .

Compound 67

(R)-(3-aminopiperidin-1-yl)(2-(1-ethyl-6-methoxy-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl) methanone

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.41 (d, J=6.96 Hz, 1H), 7.61 (s, 1H), 7.46 (d, J= 8.56Hz, 1H), 7.04(s, 1H), 6.99(d, J=6.56Hz, 1H), 6.72(d, J=8.56Hz, 1H), 6 .56 (s, 1H), 4.54 (d, J=7.0 Hz, 2H), 4.28-4.08 (m, 2H), 3.83 (s, 3H), 3.63 ( m, 1H), 3.00 (bs, 2H), 2.67 (m, 1H), 2.62 (s, 3H), 1.85 (d, J=9.80 Hz, 1H), 1, 71 (bs, 2H), 1.45 (d, J=10.08 Hz, 2H), 1.23-1.20 (t, J=6.8 Hz, 3H). MS (ESI): mass, calc. for C ₂₅ H ₂₉ N ₅ O ₂ , 431.23; the found mass/charge value, 432.32 [M+H] ⁺ .

Compound 68

(R)-(3-aminopiperidin-1-yl)(2-(6-fluoro-1-(pyridin-4-ylmethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a] pyridin-7-yl) methanone

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.36 (s, 3H), 7.65 (s, 1H), 7.56 (s, 1H), 7.28 (d, J=8.4 Hz, 1H), 6.97-6.84(m, 5H), 5.95(s, 2H), 4.21-4.10(m, 2H), 3.50(m , 1H), 2.97 (bs, 2H), 2.64 (s, 3H), 1.83 (m, 2H), 1.67 (m, 2H), 1.23 (s, 2H). MS (ESI): mass, calc. for C ₂₈ H ₂₇ FN ₆ O, 482; the found mass/charge value, 483.33 [M+H] ⁺ .

Compound 69

(R)-(3-aminopiperidin-1-yl)(2-(6-fluoro-1-(pyridin-3-ylmethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a] pyridin-7-yl) methanone

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.43 (d, J=7.0 Hz, 1H), 8.34 (d, J=3.8 Hz, 1H), 8 .27 (s, 1H), 7.63 (t, J=6.2 Hz, 2H), 7.39-7.36 (m, 2H), 7.23-7.19 (m, 1H), 7.02 (d, J=7.0 Hz, 1H), 6.94 (t, J=6.3 Hz, 1H), 6.81 (s, 1H), 5.92 (s, 2H), 4.08 (bs, 2H), 3.5 (bs, 1H), 3.02 (bs, 1H), 2.85 (bs, 2H), 2.63 (s, 3H), 1.88-1 .87 (m, 1H), 1.69 (bs, 1H), 1.48-1.45 (m, 1H), 1.35-1.33 (m, 1H), 1.22 (s, 1H ). MS (ESI): mass, calc. for C ₂₈ H ₂₇ FN ₆ O, 482.22; the mass/charge value found, 483.14 [M+H] ⁺¹ .

Compound 70

(R)-(3-aminopiperidin-1-yl)(2-(6-fluoro-1-(3-methoxybenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine- 7-yl) methanone

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.42 (d, J=7.96 Hz, 1H), 7.63-7.60 (m, 2H), 7.29 ( d, J=9.36 Hz, 1H), 7.08 (t, J=8.12 Hz, 1H), 6.99 (d, J=6.4 Hz, 1H), 6.92 (t, J=8.3Hz, 1H), 6.78(s, 1H), 6.69(d, J=7.04Hz, 1H), 6.53(s, 2H), 5.85(s, 2H), 4.26-4.08(m, 1H), 3.56(s, 4H), 2.98(m, 1H), 2.62(s, 3H), 1.84-1.83 (m, 2H), 1.71-1.70 (m, 2H), 1.46-1.42(m, 1H), 1.23 (s, 3H). MS (ESI): mass, calc. for C ₃₀ H ₃₀ FN ₅ O ₂ , 511.24; found mass/charge value, 512.38 [M+H] ⁺¹ .

Compound 71

(R)-(3-aminopiperidin-1-yl)(2-(6-fluoro-1-(4-methoxybenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine- 7-yl) methanone

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.43 (d, J=6.96 Hz, 1H), 7.62-7.58 (m, 2H), 7.29 ( d, J=10.24Hz, 1H), 7.00(d, J=6.72Hz, 1H), 6.94-6.88(m, 3H), 6.75-6.72(m , 3H), 5.79 (s, 2H), 4.27-4.08 (m, 1H), 3.62 (s, 3H), 2.98 (bs, 2H), 2.63 (m, 5H), 1.85-1.73(m, 4H), 1.45-1.42(m, 1H), 1.25-1.22(m, 1H). MS (ESI): mass, calc. for C ₃₀ H ₃₀ FN ₅ O ₂ , 511.24; found mass/charge value, 512.25 [M+H] ⁺¹ .

Compound 72

(R)-(3-aminopiperidin-1-yl)(2-(1-ethyl-6-fluoro-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl) methanone

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.43 (d, J=6.96 Hz, 1H), 7.62-7.57 (m, 2H), 7.42 ( d, J=9.2 Hz, 1H), 7.00 (d, J=6.52 Hz, 1H), 6.92 (t, J=8.24 Hz, 1H), 6.66 (s, 1H), 4.54 (d, J=7.04 Hz, 2H), 4.28-4.03 (m, 2H), 3.60 (bs, 1H), 3.00 (bs, 2H), 2.80 (m, 1H), 2.63 (s, 3H), 1.86-1.83 (m, 1H), 1.68-1.56 (m, 2H), 1.46-1, 44 (m, 1H), 1.23-1.19 (s, 4H). MS (ESI): mass, calc. for C ₂₄ H ₂₆ FN ₅ O, 419.21; found mass/charge value, 420.31 [M+H] ⁺¹ .

Compound 73

(R)-(3-aminopiperidin-1-yl)(2-(6-fluoro-1-isobutyl-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl) methanone

¹ H NMR (400 MHz, DMSO-d6) (ppm): 8.42 (d, J=7.0 Hz, 1H), 7.63 (s, 1H), 7.60-7.56 (m, 1H), 7.43 (d, J=9.44Hz, 1H), 7.00 (d, J=6.16Hz, 1H), 6.91 (t, J=7.6Hz, 1H) , 6.66 (s, 1H), 4.41 (d, J=7.28 Hz, 2H), 4.27-4.11 (m, 1H), 3.00 (bs, 2H), 2, 83-2.66(m, 2H), 2.62(s, 3H), 1.93-1.92(m, 1H), 1.88(s, 2H), 1.75-1.72( m, 2H), 1.47-1.45(m, 1H), 1.28-1.25(m, 1H), 0.64(d, J=6.64Hz, 6H). MS (ESI): mass, calc. for C ₂₆ H ₃₀ FN ₅ O, 447.24; the mass/charge value found, 448.45 [M+H] ⁺¹ .

Compound 74

(R)-(3-aminopiperidin-1-yl)(2-(5-fluoro-1-(pyridin-4-ylmethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a] pyridin-7-yl) methanone

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.42 (d, J=6.9 Hz, 1H), 8.37 (d, J=4.8 Hz, 2H), 7 .57 (s, 1H), 7.36-7.42 (m, 2H), 6.99-6.96 (m, 2H), 6.91 (d, J=4.7 Hz, 2H), 6.82 (s, 1H), 5.97 (s, 2H), 4.24-4.08 (m, 1H), 3.50 (m, 1H), 3.38 (m, 1H), 2 .96 (bs, 1H), 2.65 (s, 3H), 1.82 (m, 2H), l.71(m, 1H), 1.60 (m, 1H), 1.41 (m, 1H), 1.23(m, 2H). MS (ESI): mass, calc. for C ₂₈ H ₂₇ FN ₆ O, 482.21; the mass/charge value found, 483.21 [M+H] ⁺¹ .

Compound 75

(R)-(3-aminopiperidin-1-yl)(2-(5-fluoro-1-(4-methoxybenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine- 7-yl) methanone

¹ H NMR (400 MHz, DMSO-d6) δ (ppm): 8.44 (d, J=6.96 Hz, 1H), 7.63 (s, 1H), 7.44-7.41 (m , 1H), 7.36 (d, J=7.6 Hz, 1H), 7.01-6.91(m, 4H), 6.74-6.72 (m, 3H), 5.82 ( s, 2H), 4.27-4.10 (m, 1H), 3.62 (s, 3H), 2.97 (bs, 2H), 2.79 (m, 2H), 2.64 (s , 3H), 1.83 (m, 1H), 1.70 (m, 2H), 1.45-1.43 (m, 1H), 1.27-1.24 (m, 1H). MS (ESI): mass, calc. for C ₃₀ H ₃₀ FN ₅ O ₂ , 511.32; found mass/charge value, 512.32 [M+H] ⁺¹ .

Compound 76

(R)-(3-aminopiperidin-1-yl)(2-(5-fluoro-1-(4-fluorobenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine- 7-yl) methanone

¹ H NMR (400 MHz, DMSO-d6) δ (ppm): 8.43 (d, J=6.92 Hz, 1H), 7.61 (s, 1H), 7.44-7.37 (m , 2H), 7.03-7.37 (m, 6H), 6.77 (s, 1H), 5.88 (s, 2H), 4.27-4.09 (m, 1H), 3, 60 (bs, 1H), 2.98 (bs, 1H), 2.83 (bs, 1H), 2.64 (s, 3H), 1.85-1.83 (m, 1H), 1.69 (bs, 3H), 1.45-1.42 (m, 1H), 1.31-1.20 (m, 2H). MS (ESI): mass, calc. for C ₂₉ H ₂₇ F ₂ N ₅ O, 499.22; the mass/charge value found, 500.38 [M+H] ⁺¹ .

Compound 77

(R)-(3-aminopiperidin-1-yl)(2-(7-chloro-1-(4-fluorobenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine- 7-yl) methanone

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.41 (d, J=6.96 Hz, 1H), 7.63 (d, J=7.72 Hz, 1H), 7 .61 (s, 1H), 7.16 (d, J=7.44 Hz, 1H), 7.08 (t, J=7.68 Hz, 1H), 6.99-6.97 (m, 3H), 6.89 (s, 1H), 6.73-6.70 (m, 2H), 6.15 (s, 2H), 4.26-4.09 (m, 2H), 2.98 (bs, 2H), 2.66 (m, 1H), 2.59 (s, 3H), 1.88 (s, 2H), 1.83 (m, 1H), 1.75-1.65 ( m, 1H), 1.45-1.42(m, 1H), 1.28-1.23(m,

1H). MS (ESI): mass, calc. for C ₂₉ H ₂₇ ClFN ₅ O, 515.19; found mass/charge value, 516.18 [M+H] ⁺¹ .

Compound 78

Synthesis of salt 7-yl) methanone and trifluoroacetic acid

Step 1. Synthesis of tert-butyl-(R)-(1-(2-(1-(2,2-difgorethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine- 7-carbonyl)piperidin-3-yl)carbamate (2)

To a stirred solution of tert-butyl-(R)-(1-(2-(1H-indol-2-yl)-3-metalimidazo[1,2-a]pyridine-7-carbonyl)piperidin-3-yl)carbamate (1, 0.50 g, 1.05 mmol) in N,N-dimethylformamide (5.0 mL) was added cesium carbonate (1.7 g, 5.28 mmol) and 2-bromo-1,1-difluoroethane ( 0.22 ml, 2.64 mmol) at RT The reaction mixture was stirred at 60° C. for 4 hours. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (200 ml × 2). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by CombiFlash using a 12.0 g RediSep column and 70% ethyl acetate in hexane as eluent to give t-butyl-(R)-(1-(2-(1-(2,2-difluoroethyl)-1H -indol-2-yl)-3-methylimidazo[1,2-a]pyridine-7-carbonyl)piperidin-3-yl)carbamate as a brown solid (2). Yield: 0.13 g (26%), MS (ESI): 537; the found mass/charge value is 538.32 [M+l] ⁺¹ .

Stage 2. Synthesis of salt (R)-(3-aminopiperidin-1-yl)(2-(1-(2,2-difluoroethyl)-1H-indol-2-yl)-3-methylimidazo ]pyridin-7-yl)methanone and trifluoroacetic acid (compound 78)

To a stirred solution of tert-butyl-(R)-(1-(2-(1-(2,2-difluoroethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine-7 -carbonyl)piperidin-3-yl)carbamate (2, 0.13 g, 0.24 mmol) in dichloromethane (2.0 ml) trifluoroacetic acid (1.0 ml) was added at 0°C. The reaction mixture was stirred at rt. for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove trifluoroacetic acid. The crude material was dissolved in a minimum volume of water and made basic with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated to give the crude material. The crude material was purified by prep. HPLC to give (R)-(3-aminopiperidin-1-yl)(2-(1-(2,2-difluoroethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a] salt pyridin-7-yl)methanone and trifluoroacetic acid as a white solid. Yield: 0.007 g (7%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.50 (d, J=6.9 Hz, 1H), 7.75 (s, 1H), 7.64-7.60 ( m, 2H), 7.23 (t, J=7.3 Hz, 1H), 7.14 -7.07 (m, 2H), 6.81 (s, 1H), 6.47 (t, J =55.6Hz, 1H), 5.05(t, J=14.4Hz, 2H), 3.29(m, 4H), 2.68(s, 3H), 2.58(s, 1H ), 2.00 (m, 2H), 1.76 (m, 2H), 1.60-1.59 (m, 2H). MS (ESI): mass, calc. for C ₂₄ H ₂₅ F ₂ N ₅ O, 437.23; found mass/charge value, 438.27 [M+l] ⁺¹ .

The following compounds 79-82 were synthesized using the above procedure illustrated for compound 78.

Compound 79

(R)-(3-aminopiperidin-1-yl)(2-(1-((5-fluoropyridin-2-yl)methyl)-1H-indol-2-yl)-3-methylimidazo[1,2- a]pyridin-7-yl)methanone

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.44 (s, 1H), 8.42 (s, 1H), 7.62 (t, J=7.96 Hz, 2H) , 7.53 (t, J=9.00 Hz, 1H), 7.38 (d, J=7.92 Hz, 1H), 7.14-7.06 (m, 2H), 7.00 ( d, J=6.96Hz, 1H), 6.84-6.80(m, 2H), 5.97(s, 2H), 4.14(s, 2H), 3.65(bs, 1H ), 3.12 (bs, 2H), 2.96 (m, 2H), 2.65 (s, 3H), 1.90-1.87 (m, 1H), 1.69 (bs, 1H) , 1.48-1.46(m, 1H), 1.36-1.23(m, 1H). MS (ESI): mass, calc. for C ₂₈ H ₂₇ FN ₆ O, 482; found mass/charge value, 483.30 [M+l] ⁺¹ .

Compound 80

(R)-(3-aminopiperidin-1-yl)(2-(1-(4-fluorobenzyl)-6-methoxy-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine- 7-yl) methanone

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.41 (d, J=6.96 Hz, 1H), 7.60 (s, 1H), 7.49 (d, J= 8.6 Hz, 1H), 7.03-6.96 (m, 6H), 6.73 (d, J=8.56 Hz, 1H), 6.68 (s, 1H), 5.85 ( s, 2H), 4.29-4.08 (m, 2H), 3.73 (s, 3H), 3.00 (bs, 2H), 2.71 (m, 1H), 2.61 (s , 3H), 1.8-1.84 (m, 2H), 1.68 (bs, 2H), 1.45-1.43 (m, 1H), 1.27-1.23 (m, 1H ). MS (ESI): mass, calc. for C ₃₀ H ₃₀ FN ₅ O ₂ , 511; the found mass/charge value is 512.35 [M+1] ⁺ .

Compound 81

(R)-(3-aminopiperidin-1-yl)(2-(1-(4-(hydroxymethyl)benzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine-7 -yl) methanone

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.42 (d, J=6.96 Hz, 1H), 7.61 (s, 2H), 7.38 (d, J= 8.0 Hz, 1H), 7.11-7.03 (m, 4H), 6.99 (d, J=6.72 Hz, 1H), 6.91 (d, J=7.88 Hz, 2H), 6.76 (s, 1H), 5.89 (s, 2H), 5.02 (t, J=5.44 Hz, 1H), 4.33 (s, 2H), 4.09 ( bs, 1H), 3.59 (bs, 1H), 3.00-2.95 (m, 2H), 2.65 (s, 3H), 2.17-1.99 (m, 2H), 1 .83 (m, 1H), 1.69 (m, 1H), 1.45 (m, 1H), 1.26-1.24 (m, 1H). MS (ESI): mass, calc. for C ₃₀ H ₃₁ N ₅ O ₂ , 493.25; the mass/charge value found, 494.39 [M+H] ⁺¹ .

Compound 82

(R)-(3-aminopiperidin-1-yl)(2-(1-isobutyl-6-methoxy-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl) methanone

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.40 (d, J=7.0 Hz, 1H), 7.61 (s, 1H), 7.46 (d, J= 8.5 Hz, 1H), 7.04 (s, 1H), 6.98 (d, J=6.9 Hz, 1H), 6.72 (dd, J=8.7, 1.5 Hz, 1H), 6.55 (s, 1H), 4.41 (d, J=7.1 Hz, 2H), 4.11 (bs, 1H), 3.82 (s, 3H), 3.61 ( bs, 1H), 2.98 (bs, 1H), 2.66 (m, 1H), 2.61 (s, 3H), 1.98-1.91 (m, 1H), 1.88 (m , 3H), 1.75-1.70 (m, 1H), 1.47-1.44 (m, 1H), 1.29-1.24 (m, 1H), 0.64 (d, J =6.6Hz, 6H). MS (ESI): mass, calc. for C ₂₇ H ₃₃ N ₅ O ₂ , 459.59; the found mass/charge value, 460.41 [M+H] ⁺¹ .

Compound 83

(R)-(3-aminopiperidin-1-yl)(2-(1-(2,2-difluoroethyl)-6-methoxy-1H-indol-2-yl)-3-methylimidazo[1,2-a] pyridin-7-yl) methanone

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.44 (d, J=7.0 Hz, 1H), 7.63 (s, 1H), 7.49 (d, J= 8.5 Hz, 1H), 7.16 (s, 1H), 7.02 (d, J=6.8 Hz, 1H), 6.78-6.75 (m, 1H), 6.70 ( s, 1H), 6.45 (t, J=56.0 Hz, 1H), 5.03 (t, J=14.5 Hz, 2H), 4.17 (bs, 1H), 3.83 ( s, 3H), 3.04 (bs, 1H), 2.81 (m, 2H), 2.65 (s, 3H), 1.90 (m, 4H), 1.75-1.70 (m , 1H), 1.48-1.46(m, 1H), 1.32-1.01(m, 1H). MS (ESI): mass, calc. for C ₂₅ H ₂₇ F ₂ N ₅ O ₂ , 467.52; found mass/charge value, 468.17 [M+H] ⁺¹ .

Compound 84

(R)-(3-aminopiperidin-1-yl)(2-(5-fluoro-1-isobutyl-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl) methanone

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.42 (d, J=7.0 Hz, 1H), 7.63 (s, 1H), 7.58-7.55 ( m, 1H), 7.36-7.33 (dd, J=2.3 Hz, 7.0 Hz, 1H), 7.03-6.99 (m, 2H), 6.64 (s, 1H ), 4.44 (d, J=7.2 Hz, 2H), 4.28-4.11 (m, 1H), 3.60 (bs, 1H), 2.99-2.78 (m, 2H), 2.66 (m, 1H), 2.62 (s, 3H), 1.98-1.91 (m, 1H), 1.87-1.73 (m, 4H), 1.47 -1.44 (m, 1H), 1.29-1.23 (m, 1H), 0.63 (d, J=6.6 Hz, 6H). MS (ESI): mass, calc. for C ₂₆ H ₃₀ FN ₅ O, 447.24; found mass/charge value, 448.39 [M+H] ⁺¹ .

Compound 85

(R)-(3-aminopiperidin-1-yl)(2-(1-(4-fluoro-3-methoxybenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine- 7-yl) methanone

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.43 (d, J=7.0 Hz, 1H), 7.62 (d, J=7.9 Hz, 2H), 7 .47 (d, J=8.0 Hz, 1H), 7.13 (t, Y=7.84 Hz, 1H), 7.06 (t, /=7.32 Hz, 1H), 7.01 -6.96 (t, 3H), 6.76 (s, 1H), 6.49 (bs, 1H), 5.83 (s, 2H), 4.29-4.10 (m, 1H), 3.62 (s, 3H), 2.98 (bs, 2H), 2.63 (s, 3H), 1.82 (m, 1H), 1.66 (m, 3H), 1.45 (m , 1H), 1.23 (m, 3H). MS (ESI): mass, calc. for C ₂₆ H ₃₀ FN ₅ O, 511.24; found mass/charge value, 512.48 [M+H] ⁺¹ .

Compound 86

(R)-(3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-6-methoxy-1H-indol-2-yl)-3-(methoxymethyl)imidazo[1,2-a]pyridine -7-yl) methanone

Step 1. Synthesis of ethyl 2-iodo-3-(methoxymethyl)imidazo[1,2-а]pyridine-7-carboxylate(2)

To a stirred solution of methyl 2-aminoisonicotinate (1.5.0 g, 30.0 mmol) and 3-methoxyprop-1-yne (2.53 g, 36.1 mmol) in 1,2-dichlorobenzene (100 ml) iodine (7.63 g, 30.0 mol) and copper(II) acetate (0.54 g, 3.0 mmol) were added. The reaction mixture was purged with 5 kg/cm ² oxygen in a steel vessel and stirred at 120° C. for 12 h. eluting with 20% ethyl acetate in hexane as eluent to give ethyl 2-iodo-3-(methoxymethyl)imidazo[1,2-a]pyridine-7-carboxylate (2) as a white solid. Yield 7.40 g (68.1%). MS (ESI): weight 360.15; found mass/charge value, 361.01 [M+H] ⁺¹ .

Step 2. Synthesis of ethyl 2-(1-(tert-butoxycarbonyl)-6-methoxy-1H-indol-2-yl)-3-(methoxymethyl)imidazo[1,2-а]pyridine-7-carboxylate (3 )

To a solution of ethyl 2-iodo-3-(methoxymethyl)imidazo[1,2-a]pyridine-7-carboxylate (2, 0.8 g, 2.22 mmol) and (1-(tert-butoxycarbonyl)-6 -methoxy-1H-indol-2-yl)boronic acid (0.97 g, 3.33 mmol) in 1,4-dioxane (40 ml) and water (8 ml) was added potassium phosphate (1.4 g, 6 .66 mmol) and the mixture was purged with argon gas for 20 min. Tetrakis(triphenylphosphine)palladium(0) (0.12 g, 0.11 mmol) was then added and the purge continued for 5 minutes. The reaction mixture was stirred for 4 h at 90°C in a sealed tube. After completion of the reaction, water (100 ml) was added and extracted with ethyl acetate (200 ml×2). The organic layer was washed with saturated ammonium chloride solution, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by CombiFlash using a RediSep 40.0 g column and 30-40% ethyl acetate in hexane as eluent to give ethyl 2-(1-(tert-butoxycarbonyl)-6-methoxy-1H-indol-2-yl )-3-(methoxymethyl)imidazo[1,2-a]pyridine-7-carboxylate (3) in the form of an oily liquid. Yield 0.8 g (80%). MS (ESI): mass 479.21; found mass/charge value, 480.19 [M+H] ⁺¹ .

Step 3. Synthesis of ethyl 2-(6-methoxy-1H-indol-2-yl)-3-(methoxymethyl)imidazo[1,2-а]pyridine-7-carboxylate (4)

To a solution of ethyl 2-(1-(tert-butoxycarbonyl)-6-methoxy-1H-indol-2-yl)-3-(methoxymethyl)imidazo[1,2-а]pyridine-7-carboxylate (3, 0 .8 g, 1.64 mmol) in dichloromethane (50 ml) was added trifluoroacetic acid (8.0 ml) at 0°C. The reaction mixture was stirred for 5 hours at room temperature. After completion of the reaction, the mixture was concentrated in vacuo and neutralized using aqueous sodium bicarbonate solution. The aqueous phase was then extracted with dichloromethane (2×20 ml). The organic layer was dried over sodium sulfate and concentrated to give ethyl 2-(6-methoxy-1H-indol-2-yl)-3-(methoxymethyl)imidazo[1,2-a]pyridine-7-carboxylate (4) in as a pale yellow solid. Yield 0.55 g. MS (ESI): wt 379.15; the found mass/charge value, 380.24 [M+H] ⁺¹ .

Step 4. Synthesis of ethyl 2-(1-(cyclopropylmethyl)-6-methoxy-1H-indol-2-yl)-3-(methoxymethyl)imidazo[1,2-а]pyridine-7-carboxylate (5)

To a stirred solution of ethyl 2-(6-methoxy-1H-indol-2-yl)-3-(methoxymethyl)imidazo[1,2-a]pyridine-7-carboxylate (4, 0.5 g, 1.32 mmol) in N,N-dimethylformamide (10 ml) were added cesium carbonate (1.23 g, 3.95 mmol) and (bromomethyl)cyclopropane (0.21 g, 1.58 mmol). The reaction mixture was stirred at 60° C. for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and diluted with ethyl acetate (100 ml × 3). The organic phase was washed with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude compound. The crude material was purified by CombiFlash using a RediSep 40.0 g column and 10-15% ethyl acetate in hexane as eluent to give ethyl 2-(1-(cyclopropylmethyl)-6-methoxy-1H-indol-2-yl)- 3-(methoxymethyl)imidazo[1,2-a]pyridine-7-carboxylate (5) as a yellow solid. Yield: 0.30 g (52%). MS (ESI): 433.20; the found mass/charge value, 434.14 [M+H] ⁺¹ .

Step 5. Synthesis of 2-(1-(cyclopropylmethyl)-6-methoxy-1H-indol-2-yl)-3-(methoxymethyl)imidazo[1,2-а]pyridine-7-carboxylic acid (6)

To a stirred solution of ethyl 2-(1-(cyclopropylmethyl)-6-methoxy-1H-indol-2-yl)-3-(methoxymethyl)imidazo[1,2-a]pyridine-7-carboxylate (5, 0, 30 g, 0.629 mmol) in tetrahydrofuran (10 ml) was added methanol (5 ml) and 5N. a solution of sodium hydroxide in water (5 ml) and the resulting mixture was heated to 60°C for 3 hours. After completion of the reaction, the reaction mixture was evaporated under reduced pressure and acidified to pH 2-3 with citric acid at 0°C. The crude material was extracted with dichloromethane (10 mL×2), washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-(1-(cyclopropylmethyl)-6-methoxy-1H-indole-2- yl)-3-(methoxymethyl)imidazo[1,2-a]pyridine-7-carboxylic acid (6) as a yellow solid. Yield: 0.20 g (71%). MS (ESI): 405.17; found mass/charge value, 404.12 [M-N] ^-1 .

Stage 6. Synthesis of tert-butyl-(R)-(1-(2-(1-(cyclopropylmethyl)-6-methoxy-1H-indole-2-u l)-3-(methoxymethyl)imidazo[1,2- a]pyridine-7-carbonyl)piperidin-3-yl)carbamate (7)

To a stirred solution of 2-(1-(cyclopropylmethyl)-6-methoxy-1H-indol-2-yl)-3-(methoxymethyl)imidazo[1,2-a]pyridine-7-carboxylic acid (6, 0.20 g, 0.508 mmol) in dichloromethane (10 ml) was added tert-butyl-(11)-piperidin-3-ylcarbamate (0.122 g, 0.61 mmol), triethylamine (0.22 ml, 1.57 mmol) and propylphosphonic anhydride in 50% ethyl acetate (1.2 ml, 1.62 mmol) at 0°C. The reaction mixture was allowed to stir at room temperature for 1 hour. After completion of the reaction, the reaction mixture was quenched with sodium bicarbonate solution (20 ml) and extracted with dichloromethane (20 ml × 2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude material was purified by CombiFlash using a 12.0 g RediSep column and 2-5% methanol in dichloromethane as eluent to give t-butyl-(R)-(1-(2-(1-(cyclopropylmethyl)-6-methoxy -1H-indol-2-yl)-3-(methoxymethyl)imidazo[1,2-a]pyridine-7-carbonyl)piperidin-3-yl)carbamate (7) as an off-white solid. Yield: 0.14 g (48%). MS (ESI): 587.31; found mass/charge value, 588.27 [M+H] ⁺¹ .

Step 7 Synthesis of (R)-(3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-6-methoxy-1H-indol-2-yl)-3-(methoxymethyl)imidazo[1,2 -a]pyridin-7-yl)methanone (Example 86)

To a stirred solution of a mixture of tert-butyl-(R)-(l-(2-(l-(cyclopropylmethyl)-6-methoxy-1H-indol-2-yl)-3-(methoxymethyl)imidazo[1,2-a ]pyridine-7-carbonyl)piperidin-3-yl)carbamate (7, 0.14 g, 0.24 mmol) in dichloromethane (5 ml) trifluoroacetic acid (1.0 ml) was added at 0°C. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove trifluoroacetic acid. The crude material was dissolved in a minimum volume of water and made basic with saturated sodium bicarbonate solution (20 ml) and extracted with dichloromethane (20 ml x 2). The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated and purified by reverse phase preparative chromatography to give (R)-(3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-6-methoxy- 1H-indol-2-yl)-3-(methoxymethyl)imidazo[1,2-a]pyridin-7-yl)methanone as a yellow solid. Yield: 0.03 g (30%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.54 (d, J=7.0 Hz, 1H), 7.66 (s, 1H), 7.48 (d, J= 8.56Hz, 1H), 7.1(s, 1H), 7.03(d, J=7.21Hz, 1H), 6.72(d, J=8.56Hz, 1H), 6 .58 (s, 1H), 4.88 (s, 2H), 4.49 (d, J=6.64 Hz, 2H), 4.28-4.09 (m, 1H), 3.83 ( s, 3H), 3.76-3.53 (m, 1H), 3.34-3.32 (m, 4H), 3.00-2.85 (m, 2H), 2.65 (s, 1H), 1.83(m, 1H), 1.72(bs, 2H), 1.47-1.44(m, 1H), 1.26-1.23(m, 1H), 1.09 (m, 1H), 0.27 (d, J=7.64 Hz, 2H), 0.15 (d, J=3.96 Hz, 2H). MS (ESI): mass calculated for C ₂₈ H ₃₃ N ₅ O ₃ , 487.26; the found mass/charge value, 488.41 [M+H] ⁺¹ .

SYNTHESIS OF INTERMEDIATES

Synthesis of 2-bromo-1-(3-ethylbenzo[b]thiophen-2-yl)propan-1-one (intermediate for compound 19)

Stage 1. Obtaining methyl-3-ethylbenzo[b]thiophene-2-carboxylate (2)

To a suspension of NaH (60% in oil, 1.7 g, 42.7 mmol) in THF (50 mL) was added methyl 2-mercaptoacetate (4.1 g, 39.4 mmol) at rt. and stirred for 30 min. A solution of 1-(2-fluorophenyl)propan-1-one (1.5.0 g, 32.8 mmol) in THF was added to the reaction mixture and refluxed for 16 h (reaction condition a). The completion of the reaction was monitored by LCMS, since the starting material and product are very similar in TLC (2:8 EtOAc:hexane). The reaction mixture was cooled to rt, diluted with EtOAc (100 ml) and washed with 1N. NaOH (20 ml) and water (20 ml). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude material was purified by column chromatography to give the product as a brown oil (2) (4.0 g, 57.14% yield). MS (ESI): mass, calc. for C ₁₂ H ₁₂ O ₂ S, 220.06; found mass/charge value, 221.1 (M+H) ⁺ .

Stage 2. Obtaining 3-ethylbenzo[b]thiophene-2-carboxylic acid (3)

_LiOH ( 1.7 g, 72.7 mmol) at 0° C. and stirred at rt. for 3 hours (reaction condition b). The reaction mixture was evaporated, dissolved in water (20 ml) and acidified using a saturated citric acid solution. The white precipitate formed was collected by filtration and dried to give product (3) (2.7 g, 73% yield). MS (ESI): mass, calc. for C ₁₁ H ₁₀ O ₂ S, 206.04; found mass/charge value, 207.1 (M+H) ⁺ .

Stage 3. Obtaining 3-ethyl-N-methoxy-N-methylbenzo[b]thiophene-2-carboxamide (4)

To a stirred solution of 3-ethylbenzo[b]thiophene-2-carboxylic acid (3.2.5 g, 12.1 mmol) and N,O-dimethylhydroxylamine hydrochloride (1.8 g, 18.2 mmol) in DCM (30 ml) was added triethylamine (8.4 ml, 60.6 mmol), HOBt (2.4 g, 18.2 mmol) followed by the addition of EDC.HC1 (2.8 g, 18.2 mmol) at 0°C and the reaction mixture was stirred at room temperature. for 4 hours (reaction condition c). Water (50 ml) was added to the reaction mixture and the DCM layer was separated. The organic layer was washed with brine (20 ml), dried and evaporated to give the crude product. The crude material was purified by gradient column chromatography using 20-25% ethyl acetate in hexane to give the product as an off-white solid (4) (2.15 g, 72% yield). MS (ESI): mass, calc. for C ₁₃ H ₁₅ NO ₂ S, 249.08; found mass/charge value, 250.2 [M+H] ⁺ .

Stage 4. Obtaining 1-(3-ethylbenzo[b]thiophen-2-yl)propan-1-one (5)

A 3 M ethylmagnesium bromide solution ( 8.4 ml, 25.3 mmol) at 0° C. and the reaction mixture was stirred at rt. within 16 hours (reaction condition d). The reaction mixture was quenched with a saturated solution of NH ₄ Cl (10 ml) at 0°C and was extracted with EtOAc (50 ml). The organic layer was evaporated, purified by flash column chromatography to give the title compound as a brown oil (5) (1.7 g, 92% yield). MS (ESI): mass, calc. for C ₁₃ H ₁₄ OS, 218.08; found mass/charge value, 219.1 [M+H] ⁺ .

Step 5. Preparation of 2-bromo-1-(3-ethylbenzo[b]thiophen-2-yl)propan-1-one (6)

Trimethylphenylammonium tribromide (0.95 g , 2.52 mmol) and stirred at 80° C. for 3 hours (reaction condition e). The reaction mixture was cooled to rt, water (20 ml) was added and the compound was extracted with EtOAc (50 ml). The organic extract was washed with saturated NaHCO ₃ solution (20 ml), dried over sodium sulfate and evaporated. The crude material was purified by column chromatography using 0-25% EtOAc in hexane to give the product as a pale yellow resinous solid (6) (0.6 g, 88% yield). MS (ESI): mass, calc. for C ₁₃ H ₁₃ BrOS, 295.99; found mass/charge value, 297.0 (M+H) ⁺ .

The remaining stages are similar to those indicated for compound-1 (starting from stage 4).

Synthesis of 1-(4-chlorobenzyl)-1H-indole-2-carbaldehyde (intermediate for compound 20)

To a stirred solution of 1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde (1.0.5 g, 3.44 mmol) in DMF (10 ml) was added potassium carbonate (1.42 g, 10.3 mmol ) followed by the addition of 1-(bromomethyl)-4-chlorobenzene (0.84 g, 4.13 mmol) and the reaction mixture was stirred at the same temperature for 4 h (reaction condition a). The reaction mixture was quenched with water and extracted with ethyl acetate (30 ml x 2). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated to give the crude product. The crude residue was purified by gradient column chromatography using 10-15% ethyl acetate in hexane to give the product as an off-white solid (2) (0.86 g, 93.4% yield). ¹ H NMR (400 MHz, DM SO) δ (ppm): 9.9 (s, 1H), 7.79 (d, J=8 Hz, 1H), 7.60-7.56 (m, 2H) , 7.39-7.36(m, 1H), 7.31(d, J=8Hz, 2H), 7.18-7.14(m, 1H), 7.06(d, J=8 Hz, 2H), 5.8(s, 2H). MS (ESI): mass, calc. for C ₁₆ H ₁₂ ClNO, 269.73; found mass/charge value, 270.1 (M+H) ⁺ .

The following compound below was synthesized using the above procedure illustrated for 1-(4-chlorobenzyl)-1H-indole-2-carbaldehyde (intermediate for compound 20).

Synthesis of 1-(2-fluorobenzyl)-1H-indole-2-carbaldehyde (intermediate for compound 21)

To a stirred solution of 1H-indole-2-carbaldehyde (1.1 g, 6.89 mmol) in DMF (15 mL) was added potassium carbonate (2.85 g, 20.6 mmol) followed by 1-(chloromethyl)- 2-fluorobenzene (1.19 g, 8.26 mmol) and the reaction mixture was stirred at the same temperature for 4 hours (reaction condition a). The reaction mixture was poured into crushed ice, diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, evaporated in vacuo to give the crude material. The crude material was purified by flash column chromatography using ethyl acetate and hexane to give 1-(2-fluorobenzyl)-1H-indole-2-carbaldehyde as a gray solid (2) (yield: 1.8 g, 96.5 %). ¹ H NMR (400 MHz, DMSO) δ (ppm): 9.90 (s, 1H), 7.81 (d, J=8 Hz, 1H), 7.58-7.54 (m, 2H), 7.40-7.36(m, 1H), 7.28-7.15(m, 3H), 7.01-6.97(m, 1H), 6.55-6.51(m, 1H ), 5.88 (s, 2H). MS (ESI): mass, calc. for C ₁₆ H ₁₂ FNO, 253.09; found mass/charge value, 254.0 (M+H) ⁺ .

Synthesis of 1-ethyl-5-phenyl-1H-pyrrole-2-carbaldehyde (intermediate for compound 22)

Stage 1. Obtaining 5-bromo-1-ethyl-1H-pyrrole-2-carbaldehyde (2)

To a stirred solution of 5-bromo-1H-pyrrole-2-carbaldehyde (1.1 g, 5.7 mmol) in DMF (15 ml) was added potassium carbonate (3.14 g, 22 mmol) followed by the addition of ethyl iodide (1. 33 g, 8.6 mmol) and the reaction mixture was stirred at the same temperature for 16 hours (reaction condition a). The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo to give the crude material. The crude material was purified by flash column chromatography using ethyl acetate in hexane as eluent to give the title compound as an orange liquid (0.9 g, 77.58% yield) (2) MS (ESI): wt, calcd . for C ₇ H ₈ BrNO, 202.05; the found mass/charge value is 204.0 (M+2H) ⁺ .

Stage 2. Obtaining 1-ethyl-5-phenyl-1H-pyrrole-2-carbaldehyde (3)

Phenylboronic acid (0.8 g, 6 .67 mmol), potassium carbonate (1.84 g, 13.3 mmol), then the reaction mixture was purged with nitrogen. After purging for several minutes, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.18 g, 0.22 mmol) was added and then heated to 80° C. for 12 h (condition reactions b). After completion of the reaction, the reaction mixture was filtered through a pad of celite, the filtrates were evaporated to dryness to obtain a crude product. The crude material was purified by gradient column chromatography using 12% ethyl acetate in hexane to give the title compound as a pale yellow solid (3) (0.52 g, 59.09% yield). MS (ESI): mass, calc. for C ₁₃ H ₁₃ NO, 199.25; the found mass/charge value is 200.0 (M+H) ⁺ .

Synthesis of 1-(cyclopropylmethyl)-6-methoxy-1H-indole-2-carbaldehyde (intermediate for compound 23)

Stage 1. Obtaining N,6-dimethoxy-N-methyl-1H-indole-2-carboxamide (3)

To a stirred solution of 6-methoxy-1H-indole-2-carboxylic acid (1.3 g, 15.69 mmol) in DCM (20 mL) was added N,O-dimethylhydroxylamine hydrochloride (2.3 g, 31.38 mmol) followed by the addition of hydroxybenzotriazole (3.6 g, 23.5 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (4.5 g, 23.5 mmol) and TEA (11.3 ml, 120, 7 mmol) and the reaction mixture was stirred at the same temperature for 5 hours (reaction condition a). The reaction mixture was quenched with water, extracted with ethyl acetate (50 ml x 2). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated to give the crude product. The crude residue was purified by gradient column chromatography using 25-30% ethyl acetate in hexane to give the product as a beige solid (3) (Yield: 75%, 0.86 g). MS (ESI): mass, calc. for C ₁₂ H ₁₄ N ₂ O ₃ , 234.10, found mass/charge value, 235 (M+H) ⁺ .

Stage 2. Preparation of 6-methoxy-1H-indole-2-carbaldehyde (4)

To a stirred solution of N,6-dimethoxy-N-methyl-1H-indole-2-carboxamide (3.2 g, 8.54 mmol) in THF (20 ml) was slowly added a 1 M solution of LAH in THF (12.8 ml , 12.75 mmol) under cooling conditions and then the reaction mixture was stirred at rt. for 1 h (reaction condition b). The reaction mixture was quenched with ammonium chloride, extracted with ethyl acetate (50 ml x 2). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated to give the crude product. The crude residue was purified by gradient column chromatography using 5-10% ethyl acetate in hexane to give the product as a white solid (4) (Yield: 60%, 0.9 g). MS (ESI): mass, calc. for C ₁₀ H ₉ NO ₂ , 175.06; found mass/charge value, 176.1 (M+H) ⁺ .

Stage 3. Obtaining 1-(cyclopropylmethyl)-6-methoxy-1H-indole-2-carbaldehyde (6)

To a stirred solution of 6-methoxy-1H-indole-2-carbaldehyde (4, 0.28 g, 1.6 mmol) in DMF (5 ml) was added potassium carbonate (1.1 g, 8 mmol) followed by (bromomethyl )cyclopropane (5, 0.23 ml, 1.72 mmol) and the reaction mixture was stirred at the same temperature for 4 hours (reaction condition c). The reaction mixture was quenched with water, extracted with ethyl acetate (20 ml x 2). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated to give the crude product. The crude residue was purified by gradient column chromatography using 5-10% ethyl acetate in hexane to give the product as a brown liquid (6) (yield: 63%, 0.23 g). ¹ H NMR (400 MHz, DMSO) δ (ppm): 9.72 (s, 1H), 7.62 (d, J=8 Hz, 1H), 7.3 (s, 1H), 7.07 ( s, 1H), 6.78 (d, J=8 Hz, 1H), 4.43 (d, J=8 Hz, 2H), 3.84 (s, 3H), 1.26-1.21 ( m, 1H), 0.40-0.38 (m, 4H). MS (ESI): mass, calc. for C ₁₄ H ₁₅ NO ₂ , 229.1; found mass/charge value, 230.2 (M+H) ⁺ .

Synthesis of 1-ethyl-1Н-pyrrolo[2,3-b]pyridine-2-carbaldehyde (intermediate for compound 24)

Step 1. Preparation of ethyl 1H-pyrrolo[2,3-b]pyridine-2-carboxylate (3)

To a stirred solution of 2-bromonicotinaldehyde (1, 10.0 g, 53.7 mmol) in DMSO (100 ml) was added CS ₂ CO ₃ (35.0 g, 107 mmol), CuI (1.05 g, 5.37 mmol) followed by the addition of ethyl 2-isocyanoacetate (2, 7.9 ml, 69.8 mmol) and stirred at 80° C. for 16 h (reaction condition a). The reaction mixture was cooled to rt. and filtered through celite. To this was added water (100 ml) and the compound was extracted with EtOAc (200 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated under vacuum. The crude material was purified by column chromatography using 30-50% EtOAc in hexanes to give the product as a brown resinous solid (3) (4.5 g, 45% yield). MS (ESI): mass, calc. for C ₁₀ H ₁₀ N ₂ O ₂ , 190.20; the found mass/charge value is 191.0 (M+H) ⁺ .

Stage 2. Obtaining 1-(tert-butyl)-2-ethyl-1H-pyrrolo[2,3-b]pyridine-1,2-dicarboxylate (4)

Triethylamine (6.5 ml, 47.3 mmol) followed by the addition of Boc anhydride (3.6 g, 35.5 mmol) and stirred at rt. within 16 hours (reaction condition b). Water (100 ml) was added to the reaction mixture and extracted with EtOAc (200 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated under vacuum. The crude material was purified by column chromatography using 20-30% EtOAc in hexane to give the product as a brown gum (4) (5.5 g, 81% yield). MS (ESI): mass, calc. for C ₁₅ H ₁₈ N ₂ O ₄ , 290.32; found mass/charge value, 291.1 (M+H) ⁺ .

Stage 3. Obtaining 1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (5)

To a stirred solution of 1-(tert-butyl)-2-ethyl-1H-pyrrolo[2,3-b]pyridine-1,2-dicarboxylate (4.5.5 g, 18.9 mmol) in THF (40 ml ) was added LiOH (3.9 g, 94.8 mmol) in water (10 ml) and stirred at rt. for 4 hours (reaction condition c). The reaction mixture was evaporated, dissolved in a minimum amount of water. A saturated citric acid solution was added thereto until acidic conditions were reached, and the precipitate formed was collected by filtration and dried to give the product as a white solid (5) (2.5 g, 81% yield). MS (ESI): mass, calc. for C ₈ H ₆ N ₂ O ₂ , 162.04; found mass/charge value, 163.1 (M+H) ⁺ .

Stage 4. Preparation of N-methoxy-N-methyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (7)

To a stirred solution of 1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (5.2.5 g, 15.4 mmol) and N,O-dimethylhydroxylamine hydrochloride (6.1.8 g, 18.5 mmol) in DCM (50 ml) was added triethylamine (10.6 ml, 77.1 mmol), HOBt (3.54 g, 23.14 mmol) followed by the addition of EDC. HCl (4.42 g, 23.18 mmol ) at 0°C and the reaction mixture was stirred at room temperature. within 16 hours (reaction condition d). The reaction mixture was cooled to rt, filtered through celite and the filtrate was evaporated. Water (10 ml) was added to the crude material and the compound was extracted with DCM (30 ml). The organic layer was dried over sodium sulfate and evaporated to give the crude product. The crude residue was purified by gradient column chromatography using 2-4% MeOH in DCM to give the product as an off-white solid (7) (2.6 g, 82% yield). MS (ESI): mass, calc. for C ₁₀ H ₁₁ N ₃ O ₂ , 205.09; the found mass/charge value is 206.1 (M+H) ⁺ .

Stage 5. Preparation of 1Н-pyrrolo[2,3-b]pyridine-2-carbaldehyde (8)

To a stirred solution of N-methoxy-N-methyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (7, 0.5 g, 2.43 mmol) in THF (10 ml) was added 1 M THF (3.6 ml, 3.65 mmol) at -78°C and the reaction mixture was stirred at the same temperature for 3 hours (reaction condition e). The reaction mixture was made basic with saturated Na ₂ CO ₃ solution and extracted with DCM (2 x 25 ml). The reaction mixture was quenched with saturated NH ₄ Cl solution (10 ml) and the compound was extracted with EtOAc (50 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to give the crude product. The crude material was purified by flash column chromatography using 25-30% EtOAc in hexanes to give the compound as a white solid (8) (0.3 g, 85% yield). MS (ESI): mass, calc. for C ₈ H ₆ N ₂ O, 146.15; found mass/charge value, 147.1 (M+H) ⁺ .

Stage 6. Obtaining 1-ethyl-1Н-pyrrolo[2,3-b]pyridine-2-carbaldehyde (9)

To a stirred solution of 1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde (8.0.3 g, 2.19 mmol) in DMF (10 ml) was added K ₂ CO ₃ (0.91 g, 6. 57 mmol) followed by the addition of ethyl iodide (0.5 g, 3.28 mmol) and the reaction mixture was stirred at the same temperature for 16 h (reaction condition f). Water (15 ml) was added to the reaction mixture and extracted with EtOAc (50 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to give the crude product. The crude material was purified by flash column chromatography using 15-20% EtOAc in hexane to give the compound as a colorless oil (9) (0.34 g, 95% yield). MS (ESI): mass, calc. for C ₁₀ H ₁₀ N ₂ O, 174.08; found mass/charge value, 175.2 (M+H) ⁺ .

Synthesis of 1-(cyclopropylmethyl)-1H-indole-2-carbaldehyde (intermediate for compound 25)

To a stirred solution of 1H-indole-2-carbaldehyde (1.1 g, 6.89 mmol) in DMF (20 mL) were added potassium carbonate (2.8 g, 20.67 mmol) and (bromomethyl)cyclopropane (0.678 mL, 7.58 mmol) at r.t. The reaction mixture was stirred at rt. within 12 h (reaction condition a). The reaction mixture was diluted with water and extracted with ethyl acetate (50 ml x 2). The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated to give the crude product. The crude residue was purified by gradient column chromatography using 3-7% ethyl acetate in hexane to give 1-(cyclopropylmethyl)-1H-indole-2-carbaldehyde as a yellow solid (2) (1 g, 76 yield). ¹ H NMR (400 MHz, DMSO) δ (ppm): 9.88 (s, 1H), 7.75 (d, J=8 Hz, 1H), 7.64 (d, J=8 Hz, 1H) , 7.46 (s, 1H), 7.41-7.37 (m, 1H), 7.16-7.12 (m, 1H), 4.45 (d, J=8 Hz, 2H), 1.24-1.14 (m, 1H), 0.39-0.35 (m, 4H). MS (ESI): mass, calc. for C ₁₃ H ₁₃ NO, 199.1; found mass/charge value, 200.1 (M+H) ⁺ .

Synthesis of 1-benzyl-1H-indole-2-carbaldehyde (intermediate for compound 26)

To a stirred solution of 1H-indole-2-carbaldehyde (1.1 g, 6.89 mmol) in DMF (20 mL) were added potassium carbonate (2.8 g, 20.68 mmol) and (bromomethyl)benzene (1.2 g, 7.58 mmol) at r.t. (reaction condition a). The reaction mixture was stirred at rt. within 12 hours the Reaction mixture was diluted with water and was extracted with ethyl acetate (50 ml × 2). The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated to give the crude product. The crude residue was purified by gradient column chromatography using 3-7% ethyl acetate in hexane to give 1-benzyl-1H-indole-2-carbaldehyde as a viscous liquid (2) (0.5 g, 33% yield). ¹ H NMR (400 MHz, DMSO) δ (ppm): 9.92 (s, 1H), 7.78 (d, J=8 Hz, 1H), 7.58 (d, J=8 Hz, 1H) , 7.54 (s, 1H), 7.38-7.35 (m, 1H), 7.26-7.20 (m, 2H), 7.18-7.13 (m, 2H), 7 .05 (d, J=4 Hz, 2H), 5.82 (s, 2H). MS (ESI): mass, calc. for C ₁₆ H ₁₃ NO, 235.10; found mass/charge value, 236.1 (M+H) ⁺ .

Synthesis of 1-(pyridin-2-ylmethyl)-1H-indole-2-carbaldehyde (intermediate for compound 27)

Cesium carbonate (6.7 g, 20.68 mmol) and 2-(bromomethyl)pyridine (1 .1 g, 6.89 mmol) at r.t. (reaction condition a). The reaction mixture was heated under reflux at 80° C. for 12 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (50 ml x 2). The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated to give the crude product. The crude residue was purified by gradient column chromatography using 3-7% ethyl acetate in hexane to give 1-(pyridin-2-ylmethyl)-1H-indole-2-carbaldehyde as a yellow solid (2) (0.8 g, yield fifty%). ¹ H NMR (400 MHz, DMSO) δ (ppm): 9.92 (s, 1H), 8.45 (d, J=4 Hz, 1H), 7.79 (d, J=8 Hz, 1H) , 7.66 (m, 1H), 7.56 (d, J=12 Hz, 2H), 7.37-7.33 (m, 1H), 7.22-7.19 (m, 1H), 7.17-7.13 (m, 1H), 6.88 (d, J=8 Hz, 1H), 5.89 (s, 2H). MS (ESI): mass, calc. for C ₁₆ H ₁₂ ClNO, 269.73; found mass/charge value, 270.1 (M+H) ⁺ .

Synthesis of 1-(cyclopropylmethyl)-6-fluoro-1H-indole-2-carbaldehyde (intermediate for compound 28)

Stage 1. Obtaining 6-fluoro-1-(phenylsulfonyl)-1H-indole (2)

To a solution of sodium hydride (0.88 g, 22.2 mmol) in DMF (50 ml) was added a solution of 6-fluoro-1H-indole (1, 3.0 g, 22.2 mmol) in DMF at 0°C according to drops for 15 minutes. Benzenesulfonyl chloride in DMF (2.86 mL, 22.2 mmol) was added at 0° C. and stirred for 2 h at rt. in an atmosphere of N ₂ (reaction condition a). Ice water (50 ml) was added to the reaction mixture, then the precipitate was filtered off and washed with ice water to give a white solid (2) (6.0 g, 98.19%).

Stage 2. Preparation of 6-fluoro-1-(phenylsulfonyl)-1H-indole-2-carbaldehyde (3) (intermediate for compounds 52, 54, 68, 69, 70, 71, 72 and 73)

To a solution of 6-fluoro-1-(phenylsulfonyl)-1H-indole (2.6.0 g, 22.0 mmol) in dry THF (60 ml) was added a 2 M solution of lithium diisopropylamide in THF (10.9 ml g, 22.0 mmol) at -78°C and stirred for 5-8 min followed by the addition of dry DMF (2.5 ml, 33.0 mmol) at -78°C and stirred for 10 min at -78°C in an N ₂ atmosphere (reaction condition b). An aqueous ammonium chloride solution (20 ml) was added to the reaction mixture, followed by extraction with EtOAc. The organic layer was washed with saturated NH ₄ Cl and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a yellow solid (3) (6.0 g, 90.90%). MS (ESI): mass/charge 304.2 (M+H) ⁺ .

Stage 3. Obtaining 6-fluoro-1-(phenylsulfonyl)-1H-indole-2-carbaldehyde (4)

To a stirred solution of 6-difluoro-1-(phenylsulfonyl)-1H-indole-2-carbaldehyde (3.1 g, 3.3 mmol) in THF (50 ml) was added TBAF (1 M in THF) (9.15 ml , 16.5 mmol) at r.t. The reaction mixture was stirred at rt. within 12 hours (reaction condition c). The reaction mixture was diluted with water and extracted with ethyl acetate (50 ml x 2). The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated to give the crude product. The crude residue was purified by gradient column chromatography using 15-25% ethyl acetate in hexane to give 6-fluoro-1-(phenylsulfonyl)-1H-indole-2-carbaldehyde as a sticky solid (4) (0.45 g, yield 90%) MS (ESI): mass, calc. for C ₉ H ₆ FNO, mass/charge 163; found value, 164 (M+H) ⁺ .

Stage 4. Obtaining 1-(cyclopropylmethyl)-6-fluoro-1H-indole-2-carbaldehyde (5)

To a stirred solution of 6-fluoro-1H-indole-2-carbaldehyde (4, 0.5 g, 3.44 mmol) in DMF (10 mL) was added potassium carbonate (1.42 g, 10.3 mmol) followed by (bromomethyl)cyclopropane (0.84 g, 4.13 mmol) and the reaction mixture was stirred at the same temperature for 4 hours (reaction condition d). The reaction mixture was quenched with water, extracted with ethyl acetate (30 ml x 2). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated to give the crude product. The crude residue was purified by gradient column chromatography using 10-15% ethyl acetate in hexane to give the product as a half white solid (5) (yield: 93.4%, 0.86 g). ¹ H NMR (400 MHz, DMSO) δ (ppm): 9.81 (s, 1H), 7.69-7.66 (m, 1H), 7.25 (d, J=6.8 Hz, 1H ), 7.07 (d, J=8 Hz, 1H), 6.97-6.91 (m, 1H), 4.43 (d, J=8 Hz, 2H), 1.32-1.25 (m, 1H), 0.5-0.45 (m, 2H), 0.42-0.38 (m, 2H). MS (ESI): mass, calc. for C ₁₃ H ₁₂ FNO, 217.09; found mass/charge value, 218.0 (M+H) ⁺ .

Synthesis of 1-(cyclopropylmethyl)-5-fluoro-1H-indole-2-carbaldehyde (intermediate for compound 29)

Stage 1. Obtaining 5-fluoro-1-(phenylsulfonyl)-1H-indole (3)

To a solution of sodium hydride (0.06 g, 15 mmol) in DMF (10 ml) was added dropwise a solution of 5-fluoro-1H-indole (1, 0.2 g, 15 mmol) in DMF at 0°C for 15 min followed by the addition of a solution of benzenesulfonyl chloride (2, 0.26 g, 15 mmol) in DMF at 0° C. and the reaction mixture was stirred for 2 h at rt. in an atmosphere of N ₂ (reaction condition a). Ice water (50 ml) was added to the reaction mixture, then the precipitate was filtered off and washed with ice water to give a brown solid (3) (0.25 g, 62.50% yield). MS (ESI) mass/charge 275.0 (M+H) ⁺ .

Stage 2. Preparation of 5-fluoro-1-(phenylsulfonyl)-1H-indole-2-carbaldehyde (4) (intermediate for compounds 53, 74, 75, 76 and 84)

To a solution of 5-fluoro-1-(phenylsulfonyl)-1H-indole (3, 0.250 g, 1.0 mmol) in dry THF (50 ml) was added a 1 M solution of lithium diisopropylamide in THF (0.5 ml g, 1.0 mmol). 0 mmol) at -78°C followed by the addition of dry DMF (0.11 ml, 1.5 mmol) at -78°C and stirring for 10 min at -78°C under N ₂ atmosphere (reaction condition b). Aqueous ammonium chloride solution (20 ml) was added to the reaction mixture and extracted with EtOAc. The organic layer was washed with saturated NH ₄ Cl and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a brown solid (4) (0.150 g, 54.54% yield). MS (ESI) mass/charge 304.1 (M+H) ⁺ .

Stage 3. Obtaining 5-fluoro-1H-indole-2-carbaldehyde (5)

TBAF (1 M in THF) (9.15 ml , 9.158 mmol) at r.t. (reaction condition c). The reaction mixture was stirred at rt. within 12 hours the Reaction mixture was diluted with water and was extracted with ethyl acetate (50 ml × 2). The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated to give the crude product. The crude residue was purified by gradient column chromatography using 15-25% ethyl acetate in hexanes to give 5-fluoro-1H-indole-2-carbaldehyde as a sticky solid (5) (0.65 g, 65% yield) MS (ESI ): mass, calc. for C ₉ H ₆ FNO, 163.15; found mass/charge value, 162.0 [M-N] ^- .

Stage 4. Obtaining 1-(cyclopropylmethyl)-5-fluoro-1H-indole-2-carbaldehyde (7)

To a stirred solution of 5-fluoro-1H-indole-2-carbaldehyde (5.0.65 g, 3.98 mmol) in DMF (50 ml) was added potassium carbonate (1.64 g, 11.94 mmol) )cyclopropane (6, 0.58 ml, 5.98 mmol) at RT The reaction mixture was stirred at rt. within 12 hours (reaction condition d). The reaction mixture was diluted with water and extracted with ethyl acetate (50 ml x 2). The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated to give the crude product. The crude residue was purified by gradient column chromatography using 3-7% ethyl acetate in hexane to give 1-(cyclopropylmethyl)-5-fluoro-1H-indole-2-carbaldehyde as a sticky solid (7) (0.76 g, yield 88%). ¹ H NMR (400 MHz, DMSO-d6) δ (ppm): 9.90 (s, 1H), 7.73-7.69 (m, 1H), 7.55-7.52 (m, 1H) , 7.44 (s, 1H), 7.29-7.24 (m, 1H), 4.50 (d, J=7.2 Hz, 2H), 1.23-1.16 (m, 1H ), 0.41-0.32 (m, 4H). MS (ESI): mass, calc. for C ₁₃ H ₁₂ FNO, 217.24: found mass/charge value, 218.1 [M+H] ⁺ .

Synthesis of 1-(cyclopropylmethyl)-7-methyl-1H-indole-2-carbaldehyde (intermediate for compound 30)

Stage 1. Obtaining 7-methyl-1-(phenylsulfonyl)-1H-indole (2)

To a solution of sodium hydride (0.92 g, 23 mmol) in DMF (10 ml) was added dropwise a solution of 7-methyl-1H-indole (1.3.0 g, 23 mmol) in DMF at 0°C for 15 min. Benzenesulfonyl chloride in DMF (2.96 ml, 23 mmol) was added at 0° C. and stirred for 2 h at rt. in an atmosphere of N ₂ (reaction condition a). Ice water (50 ml) was added to the reaction mixture, then the precipitate was filtered off and washed with ice water to give a brown solid (2) (5.30 g, 85.50%). MS (ESI) mass/charge 272.1 (M+H) ⁺ .

Stage 2. Obtaining 7-methyl-1-(phenylsulfonyl)-1H-indole-2-carbaldehyde (3)

To a solution of 7-methyl-1-(phenylsulfonyl)-1H-indole (2.5.3 g, 20.0 mmol) in dry THF (50 ml) was added a 1.5 M solution of lithium diisopropylamide in THF (13.0 ml , 20.0 mmol) at -78°C and stirred for 5-8 min followed by the addition of dry DMF (2.33 ml, 30.0 mmol) at -78°C and stirred for 10 min at -78° C in an N ₂ atmosphere (reaction condition b). An aqueous ammonium chloride solution (20 ml) was added to the reaction mixture, followed by extraction with EtOAc. The organic layer was washed with saturated NH ₄ Cl solution and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a red viscous liquid (3) (5.0 g, 85.47%). MS (ESI) mass/charge 300.2 (M+H) ⁺ .

Stage 3. Obtaining 7-methyl-1H-indole-2-carbaldehyde (4)

To a stirred solution of 7-methyl-1-(phenylsulfonyl)-1H-indole-2-carbaldehyde (3.2 g, 6.68 mmol) in THF (20 ml) was added a 1 M solution of tetrabutylammonium fluoride in THF (10 ml, 10 .2 mmol) and stirred at 80° C. for 1 h (reaction condition c). The reaction mixture was cooled to rt, water (20 ml) was added and extracted with EtOAc (100 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated under vacuum. The crude material was purified by column chromatography using 15-20% EtOAc in hexane to give the product as a brown solid (4) (0.8 g, 58% yield). MS (ESI): mass, calc. for C ₁₀ H ₉ NO, 159.07; the found mass/charge value is 160.1 (M+H) ⁺ .

Stage 4. Obtaining 1-(cyclopropylmethyl)-7-methyl-1H-indole-2-carbaldehyde (5)

To a stirred solution of 7-methyl-1H-indole-2-carbaldehyde (4, 0.85 g, 5.345 mmol) in DMF (20 mL) were added potassium carbonate (2.21 g, 16.035 mmol) and (bromomethyl)cyclopropane (4a , 0.78 ml, 8.018 mmol) at r.t. The reaction mixture was stirred at rt. within 12 hours (reaction condition d). The reaction mixture was diluted with water and extracted with ethyl acetate (50 ml x 2). The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated to give the crude product. The crude residue was purified by gradient column chromatography using 3-7% ethyl acetate in hexane to give 1-(cyclopropylmethyl)-7-methyl-1H-indole-2-carbaldehyde as a sticky solid (5) (0.52 g, yield 45%). ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.82 (s, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.26 (s, 1H), 7 .13 (d, J=6.8 Hz, 1H), 6.26 (m, 1H), 4.83 (d, J=6.8 Hz, 2H), 2.77 (s, 3H), 1 .15-1.10 (m, 1H), 0.41-0.33 (m, 4H). MS (ESI): mass, calc. for C ₁₄ H ₁₅ NO, 213.28; found mass/charge value, 214.1 [M+H] ⁺ .

Synthesis of 3-(chloromethyl)thiophene (intermediate for compound 36)

Stage 1. Obtaining thiophen-3-ylmethanol (2)

To a stirred solution of thiophene-3-carbaldehyde (1.1 g, 8.92 mmol) in MeOH (10 ml) was added NaBH ₄ (0.5 g, 13.3 mmol) in portions at 0°C and stirred at r.t. . for 1 h (reaction condition a). The reaction mixture was quenched with ice and the MeOH was evaporated. Water (5 ml) was added to the resulting crude material and extracted with EtOAc (2 X 20 ml). The organic layer was washed with brine (5 ml), dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo to give the product as a brown oil (2) (0.9 g, 90% yield). ¹ H NMR (400 MHz, DMSO-d6) δ (ppm): 7.45-7.43 (m, 1H), 7.26 (s, 1H), 7.03 (d, J=4.4 Hz , 1H), 5.05 (t, J=6.0 Hz, 1H), 4.45 (d, J=5.6 Hz, 2H).

Stage 2. Obtaining 3-(chloromethyl)thiophene (3)

To a stirred solution of thiophen-3-ylmethanol (2, 0.5 g, 4.38 mmol) in DCM (5 ml) was added SOCl ₂ (0.6 ml, 8.77 mmol) dropwise at 0°C and the reaction mixture stirred at rt. for 1 h (reaction condition b). The reaction mixture was evaporated in vacuo and dried to give the product as a brown oil (3) (0.5 g, 80% yield). ¹ H NMR (400 MHz, DMSO-d6): δ 7.45-7.43 (m, 1H), 7.26 (s, 1H), 7.03 (d, J=4.4 Hz, 1H) , 4.78 (s, 2H).

Synthesis of 3-(chloromethyl)furan (intermediate for compound 37)

Stage 1. Obtaining furan-3-ylmethanol (2)

To a stirred solution of furan-3-carbaldehyde (1.1 g, 10.4 mmol) in MeOH (10 ml) was added NaBH ₄ (0.6 g, 15.6 mmol) in portions at 0°C and stirred at r.t. . for 1 h (reaction condition a). The reaction mixture was quenched with ice and the MeOH was evaporated. Water (5 ml) was added to the resulting crude material and extracted with EtOAc (2 X 20 ml). The organic layer was washed with brine (5 ml), dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo to give the product as a brown oil (2) (0.6 g, 60% yield). ¹ H NMR (400 MHz, DMSO-d6) δ (ppm): 7.56-7.50 (m, 2H), 6.41 (s, 1H), 4.90 (t, J=5.2 Hz , 1H), 4.31 (d, J=6.0 Hz, 2H).

Stage 2. Obtaining 3-(chloromethyl)furan (3)

To a stirred solution of furan-3-ylmethanol (2, 0.5 g, 5.10 mmol) in DCM (5 ml) was added SOCl ₂ (0.7 ml, 10.2 mmol) dropwise at 0°C and the reaction mixture stirred at rt. for 1 h (reaction condition b). The reaction mixture was evaporated in vacuo and dried to give the product as a brown oil (3) (0.5 g, 84% yield). ¹ H NMR (400 MHz, DMSO-d6) δ (ppm): 7.75-7.65 (m, 2H), 6.53 (s, 1H), 4.68 (s, 2H).

Synthesis of 1-(1-chloroethyl)-4-fluorobenzene (intermediate for compound 38)

Stage 1. Obtaining 1-(4-fluorophenyl)ethan-1-ol (2)

To a stirred solution of 1-(4-fluorophenyl)ethan-1-one (1.2.0 g, 17.6 mmol) in MeOH (20 ml) was added NaBH ₄ (1.0 g, 26.5 mmol) in portions at 0°C and stirred at rt. for 1 h (reaction condition a). The reaction mixture was quenched with ice and the MeOH was evaporated. Water (10 ml) was added to the resulting crude material and extracted with EtOAc (2 X 25 ml). The organic layer was washed with brine (10 ml), dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo to give the product as a colorless oil (2) (1.9 g, 95% yield). ¹ H NMR (400 MHz, DMSO-d6) δ (ppm): 7.36-7.33 (m, 2H), 7.14-7.07 (m, 2H), 5.12 (d, J= 4.0 Hz, 1H), 4.72-4.67 (m, 1H), 1.28 (d, J=6.8 Hz, 3H).

Stage 2. Obtaining 1-(1-chloroethyl)-4-fluorobenzene (3)

To a stirred solution of 1-(4-fluorophenyl)ethan-1-ol (2, 0.5 g, 3.57 mmol) in DCM (5 ml) was added SOCl ₂ (0.7 ml, 7.10 mmol) dropwise at 0°C and the reaction mixture was stirred at room temperature. for 1 h (reaction condition b). The reaction mixture was evaporated in vacuo and dried to give the product as a brown oil (3) (0.5 g, 89% yield). ¹ H NMR (400 MHz, DMSO-d6) δ (ppm): 7.53-7.51 (m, 2H), 7.21-7.16 (m, 2H), 5.36-5.33 ( m, 1H), 1.76 (d, J=6.8 Hz, 3H).

Synthesis of 1-ethyl-5-fluoro-1H-indole-2-carbaldehyde (intermediate for compound 39)

Stage 1. Obtaining 5-fluoro-1-(phenylsulfonyl)-1H-indole (3)

To a solution of sodium hydride (0.06 g, 15 mmol) in DMF (10 ml) was added dropwise a solution of 5-fluoro-1H-indopa (1, 0.2 g, 15 mmol) in DMF at 0°C for 15 min followed by the addition of a solution of benzenesulfonyl chloride (2, 0.26 g, 15 mmol) in DMF at 0°C and the reaction mixture was stirred for 2 h at rt. in an atmosphere of N ₂ (reaction condition a). Ice water (50 ml) was added to the reaction mixture, then the precipitate was filtered off and washed with ice water to give a brown solid (3) (0.25 g, 62.50% yield). MS (ESI) mass/charge 275.0 (M+H) ⁺ .

Stage 2. Obtaining 5-fluoro-1-(phenylsulfonyl)-1H-indole-2-carbaldehyde (4)

To a solution of 5-fluoro-1-(phenylsulfonyl)-1H-indole (3, 0.250 g, 1.0 mmol) in dry THF (50 ml) was added a 1 M solution of lithium diisopropylamide in THF (0.5 ml, 1.0 mmol) at -78°C followed by the addition of dry DMF (0.11 ml, 1.5 mmol) at -78°C and stirring for 10 min at -78°C under N ₂ (reaction condition b). Aqueous ammonium chloride solution (20 ml) was added to the reaction mixture and extracted with EtOAc. The organic layer was washed with NH ₄ Cl sat., brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a brown solid (4) (0.150 g, 54.54% yield). MS (ESI) mass/charge 304.1 (M+H) ⁺ .

Stage 3. Obtaining 5-fluoro-1H-indole-2-carbaldehyde (5)

TBAF (1 M in THF) (9.15 ml , 9.158 mmol) at r.t. (reaction condition c). The reaction mixture was stirred at rt. within 12 hours the Reaction mixture was diluted with water and was extracted with ethyl acetate (50 ml × 2). The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated to give the crude product. The crude residue was purified by gradient column chromatography using 15-25% ethyl acetate in hexanes to give 5-fluoro-1H-indole-2-carbaldehyde as a sticky solid (5) (0.65 g, 65% yield) MS (ESI ): mass, calc. for C ₉ H ₆ FNO, 163.15; found mass/charge value, 164.0 (M+H) ⁺ .

Stage 4. Obtaining 1-ethyl-5-fluoro-1H-indole-2-carbaldehyde (7)

To a stirred solution of 5-fluoro-1H-indole-2-carbaldehyde (5.0.6 g, 3.98 mmol) in DMF (50 ml) was added potassium carbonate (1.64 g, 11.94 mmol) and ethyl iodide ( 6, 0.43 ml, 5.4 mmol) at r.t. (reaction condition d). The reaction mixture was stirred at rt. within 12 hours the Reaction mixture was diluted with water and was extracted with ethyl acetate (50 ml × 2). The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated to give the crude product. The crude residue was purified by gradient column chromatography using 3-7% ethyl acetate in hexane to give 1-(cyclopropylmethyl)-5-fluoro-1H-indole-2-carbaldehyde as a sticky solid (7) (0.3 g, yield 43.6%). MS (ESI): mass, calc. for C ₁₁ H ₁₀ FNO, 191.07: found mass/charge value, 192.1 [M+H] ⁺ .

Synthesis of 1-(cyclopropylmethyl)-4-fluoro-1H-indole-2-carbaldehyde (intermediate for compound 40)

Stage 1. Obtaining 4-fluoro-1-(phenylsulfonyl)-1H-indole (2)

To a solution of sodium hydride (0.88 g, 22.2 mmol) in DMF (50 ml) was added dropwise a solution of 4-fluoro-1H-indole (1.3.0 g, 22.2 mmol) in DMF at 0° C for 15 min. Benzenesulfonyl chloride in DMF (2.86 mL, 22.2 mmol) was added at 0° C. and stirred for 2 h at rt. in an atmosphere of N ₂ (reaction condition a). Ice water (50 ml) was added to the reaction mixture, then the precipitate was filtered off and washed with ice water to give a white solid (2). (7.0 g crude).

Stage 2. Obtaining 4-fluoro-1-(phenylsulfonyl)-1H-indole-2-carbaldehyde (3)

To a solution of 4-fluoro-1-(phenylsulfonyl)-1H-indole (2.7.0 g, 22.0 mmol) in dry THF (60 mL) was added a 2 M solution of lithium diisopropylamide in THF (10.9 mL, 22.0 mmol). .0 mmol) at -78°C and stirred for 5-8 min followed by the addition of dry DMF (2.5 ml, 33.0 mmol) at -78°C and stirring for 10 min at -78°C in N ₂ atmosphere (reaction condition b). An aqueous ammonium chloride solution (20 ml) was added to the reaction mixture, followed by extraction with EtOAc. The organic layer was washed with saturated NH ₄ Cl solution and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a red liquid (3) (6.80 g, 88.31%).

Stage 3. Obtaining 4-fluoro-1H-indole-2-carbaldehyde (4)

To a solution of 4-fluoro-1-(phenylsulfonyl)-1H-indole-2-carbaldehyde (4.3.0 g, 9.9 mmol) in dry THF (20 ml) was added a 1 M solution of tetrabutylammonium fluoride in THF (14. 8 ml) and the reaction mixture was stirred for approximately 12 hours at room temperature. (reaction condition c). The reaction mixture was quenched with water and then extracted with ethyl acetate (50 ml x 3). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated to give the crude product. The crude residue was purified by gradient column chromatography using 5-10% ethyl acetate in hexane to give the product as a yellow solid (4) (yield: 99%, 1.6 g). MS (ESI): mass, calc. for C ₉ H ₆ FNO, 163.04; the found mass/charge value is 164 (M+H) ⁺ .

Stage 4. Obtaining 1-(cyclopropylmethyl)-4-fluoro-1H-indole-2-carbaldehyde (5)

To a stirred solution of 4-fluoro-1H-indole-2-carbaldehyde (4, 1.6 g, 9.877 mmol) in DMF (10 mL) was added potassium carbonate (6.8 g, 49.38 mmol) followed by (bromomethyl )cyclopropane (6, 1.4 ml, 10.65 mmol) and the reaction mixture was stirred at rt. within 12 hours (reaction condition d). The reaction mixture was quenched with water, extracted with ethyl acetate (30 ml x 2). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated to give the crude product. The crude residue was purified by gradient column chromatography using 5-10% ethyl acetate in hexane to give the product as a brown liquid (5) (yield: 47.6%, 1 g). ¹ H NMR (400 MHz, DMSO) δ (ppm): 9.90 (s, 1H), 7.55-7.50 (m, 2H), 7.40-7.35 (m, 1H), 6 .95-6.90(m, 1H), 4.46(d, J=8Hz, 2H), 1.22-1.21(m, 1H), 0.42-0.36(m, 4H ). MS (ESI): mass, calc. for C ₁₃ H ₁₂ FNO, 217.24; the mass/charge value found, 218 [M+H] ⁺ .

Synthesis of 2-(chloromethyl)-4-methylthiazole (intermediate for compound 41)

Stage 1. Obtaining (4-methylthiazol-2-yl)methanol (2)

To a stirred solution of 4-methylthiazole-2-carbaldehyde (1.1 g, 7.8 mmol) in MeOH (10 ml) was added NaBH ₄ (0.5 g, 15.6 mmol) in portions at 0°C and stirred at .t. for 1 h (reaction condition a). The reaction mixture was quenched with ice and the MeOH was evaporated. Water (5 ml) was added to the resulting crude material and extracted with EtOAc (2 X 20 ml). The organic layer was washed with brine (5 ml), dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo to give the product as a brown oil (2) (1 g, 79.5% yield). MS (ESI): mass, calc. for C ₅ H ₇ NOS 129.02; the found mass/charge value is 130.1 (M+H) ⁺ .

Stage 2. Obtaining 2-(chloromethyl)-4-methylthiazole (3)

To a stirred solution of (4-methylthiazol-2-yl)methanol (2.1 g, 7.7 mmol) in DCM (20 mL) was added SOCl ₂ (0.89 mL, 11.55 mmol) dropwise at 0°C and the reaction mixture was stirred at rt. for 1 h (reaction condition b). The reaction mixture was evaporated in vacuo and dried to give the product as a brown oil (3) (1 g, 88.3% yield). ¹ HNMR (400 MHz, CDCl3) δ (ppm): 6.91 (s, 1H), 4.82 (s, 2H), 2.45 (s, 3H).

Synthesis of 5-bromo-1-(cyclopropylmethyl)-1Н-indole-2-carbaldehyde (intermediate for compound 43)

Stage 1. Obtaining (5-bromo-1H-indol-2-yl)methanol (2)

To a solution of ethyl 5-bromo-1H-indole-2-carboxylate (1.5.0 g, 18.6 mmol) in THF (35 ml) was added dropwise a 1 M solution of lithium aluminum hydride in THF (37.2 ml, 37.2 mmol) at 0°C for 20 min. The reaction mixture was stirred for 2 h at rt. in an atmosphere of N ₂ (reaction condition a). Ice-cold aq. was added dropwise to the reaction mixture. NH ₄ Cl solution (20 ml) at 0°C, diluted with water and extracted with ethyl acetate (2 X 200 ml). The organic layer was dried using Na ₂ SO ₄ and evaporated. The crude material was purified by gradient column chromatography using 20% ethyl acetate in hexane to give a pink solid (2) (4.1 g, 97% yield). MS (ESI): mass, calc. for C ₉ H ₈ BrNO, mass/charge 226.07 found value 228.0 [M+H] ²⁺ .

Stage 2. Obtaining 5-bromo-1H-indole-2-carbaldehyde (3)

To a solution of (5-bromo-1H-indol-2-yl)methanol (3, 4.1 g, 18.1 mmol) in chloroform (50 ml) was added MnO ₂ (15.7 g, 181 mmol) and heated at 90° C. for 2 hours under N ₂ atmosphere (reaction condition b). The reaction mixture was filtered and the filtrate was evaporated to give the crude material. The crude material was purified by gradient column chromatography using 20% ethyl acetate in hexanes to give a pink solid (3) (4.1 g, 97% yield). MS (ESI): mass, calc. for C ₉ H ₆ BrNO, mass/charge 224.06, found value 226.0 [M+H] ²⁺ .

Step 3. 5-Bromo-1-(cyclopropylmethyl)-1H-indole-2-carbaldehyde (4)

Potassium carbonate (1.4 g, 10.44 mmol) and (bromomethyl )cyclopropane (0.78 ml, 7.8 mmol) at RT The reaction mixture was stirred at rt. within 12 hours (reaction condition c). The reaction mixture was diluted with water and extracted with ethyl acetate (50 ml x 2). The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated to give the crude product. The crude material was purified by gradient column chromatography using 20% ethyl acetate in hexanes to give 5-bromo-1-(cyclopropylmethyl)-1H-indole-2-carbaldehyde as a sticky solid (4) (0.9 g, 62% yield ). MS (ESI): mass, calc. for C ₁₃ H ₁₂ BrNO, 278.15; found mass/charge value, 280.0 [M+H] ²⁺ .

Synthesis of 7-chloro-1-(cyclopropylmethyl)-1Н-indole-2-carbaldehyde (intermediate for compound 44)

Stage 1. Obtaining 7-chloro-1-(phenylsulfonyl)-1H-indole (2)

To a solution of sodium hydride (1.68 g, 42 mmol) in DMF (10 ml) was added dropwise a solution of 7-chloro-1H-indole (1.3.2 g, 21 mmol) in DMF at 0°C for 15 min. Benzenesulfonyl chloride in DMF (2.8 ml, 23 mmol) was added at 0° C. and stirred for 2 h at rt. in an atmosphere of N ₂ (reaction condition a). Ice water (50 ml) was added to the reaction mixture, and the precipitate was filtered off. The precipitate was washed with ice water and purified by gradient column chromatography using 30% ethyl acetate in hexane to give the title compound as a pale brown solid (2) (5 g, 81.8%). MS (ESI): mass, calc. for C ₁₄ H ₁₀ ClNO ₂ S, 219.01; found mass/charge value, 220.1 [M+H] ⁺ .

Step 2. Preparation of 7-chloro-1-(phenylsulfonyl)-1H-indole-2-carbaldehyde (3)

To a solution of 7-chloro-1-(phenylsulfonyl)-1H-indole (2.5 g, 17 mmol) in dry THF (50 ml) was added a 1.5 M solution of lithium diisopropylamide in THF (17.0 ml, 34 mmol) at -78°C and stirred for 30 min followed by the addition of dry DMF (1.65 ml, 20 mmol) at -78°C. It was stirred for 10 min at -78° C. under N ₂ (reaction condition b). Aqueous ammonium chloride solution (20 ml) was added to the reaction mixture and extracted with EtOAc. The organic layer was washed with saturated NH ₄ Cl solution and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by gradient column chromatography using 30% ethyl acetate in hexane to give the title compound as a pale brown viscous liquid (3) (3.0 g, 55.3%). MS (ESI): mass, calc. for C ₁₅ H ₁₀ ClNO ₃ S, 319.01; found mass/charge value, 320.1 [M+H] ⁺ .

Stage 3. Obtaining 7-chloro-1H-indole-2-carbaldehyde (4)

To a stirred solution of 7-chloro-1-(phenylsulfonyl)-1H-indole-2-carbaldehyde (3.3 g, 9.40 mmol) in THF (20 ml) was added a 1 M solution of tetrabutylammonium fluoride in THF (18.8 ml , 18.8 mmol) and stirred at 80° C. for 1 h (reaction condition c). The reaction mixture was cooled to rt, water (20 ml) was added and extracted with EtOAc (100 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated under vacuum. The crude material was purified by column chromatography using 15-20% EtOAc in hexane to give the product as a brown solid (4) (1.6 g, 95% yield). MS (ESI): mass, calc. for C ₉ H ₆ ClNO, 179.01; the found mass/charge value is 180.1 (M+H) ⁺ .

Stage 4. Obtaining 1-(cyclopropylmethyl)-7-chloro-1H-indole-2-carbaldehyde (5)

To a stirred solution of 7-chloro-1H-indole-2-carbaldehyde (4.1 g, 5.5 mmol) in DMF (20 ml) were added cesium carbonate (3.5 g, 11 mmol) and (bromomethyl)cyclopropane , 0.65 ml, 6.7 mmol) at r.t. (reaction condition d). The reaction mixture was stirred at rt. within 12 hours the Reaction mixture was diluted with water and was extracted with ethyl acetate (50 ml × 2). The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated to give the crude product. The crude material was purified by gradient column chromatography using 20% ethyl acetate in hexane to give 1-(cyclopropylmethyl)-7-chloro-1H-indole-2-carbaldehyde as a sticky solid (5) (0.7 g, 54% yield ). ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.87 (s, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.37 (d, J=7, 6 Hz, 1H) 7.29 (s, 1H), 7.08 (t, J=7.6 Hz, 1H), 5.00-4.92 (m, 2H), 1.36-1.32 (m, 2H), 1.25 (m, 1H), 0.43-0.41 (m, 2H). MS (ESI): mass, calc. for C ₁₃ H ₁₂ ClNO, 233.06; found mass/charge value, 234.1 [M+H] ⁺ .

Synthesis of 1-(cyclopropylmethyl)-7-methoxy-1H-indole-2-carbaldehyde (intermediate for compound 47)

Stage 1. Obtaining 7-methoxy-1-(phenylsulfonyl)-1H-indole

To a solution of sodium hydride (1.6 g, 40 mmol) in DMF (10 ml) was added dropwise a solution of 7-methoxy-1H-indole (1.3 g, 20 mmol) in DMF at 0°C over 15 min s followed by the addition of a solution of benzenesulfonyl chloride (2, 2.86 ml, 22 mmol) in DMF at 0° C. and the reaction mixture was stirred for 2 h at rt. in N ₂ atmosphere. Ice water (50 ml) was added to the reaction mixture, then the precipitate was filtered off and washed with ice water to give a brown solid (3) (5.6 g, 97.5% yield). MS (ESI) mass/charge 288.1 (M+H) ⁺ .

Stage 2. Obtaining 7-methoxy-1-(phenylsulfonyl)-1H-indole-2-carbaldehyde

To a solution of 7-methoxy-1-(phenylsulfonyl)-1H-indole (3.3 g, 10.4 mmol) in dry THF (50 ml) was added a 1 M solution of lithium diisopropylamide in THF (5.2 ml, 20 mmol) at -78°C and stirred for 45 min at the same temperature. Dry DMF (1 ml, 12 mmol) was added at -78°C and stirred for 10 min. Aqueous ammonium chloride solution (20 ml) was added to the reaction mixture and extracted with EtOAc. The organic layer was washed with saturated NH ₄ Cl and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a brown solid (4) (1.2 g, 37.5% yield). MS (ESI) mass/charge 304.1 (M+H) ⁺ .

Stage 3. Obtaining 7-methoxy-1H-indole-2-carbaldehyde

To a stirred solution of 7-methoxy-1-(phenylsulfonyl)-1H-indole-2-carbaldehyde (4, 1.1 g, 3.4 mmol) in THF (50 mL) was added TBAF (1 M in THF) (6, 9 ml, 6.9 mmol) at RT The reaction mixture was stirred at rt. within 12 hours the Reaction mixture was diluted with water and was extracted with ethyl acetate (50 ml × 2). The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated to give the crude product. The crude residue was purified by gradient column chromatography using 15-25% ethyl acetate in hexane to give 5-fluoro-1H-indole-2-carbaldehyde as a sticky solid (5) (0.47 g, 79.6% yield). MS (ESI): mass, calc. for C ₁₀ H ₉ NO ₂ , 175.06; found mass/charge value, 176.1 [M+H] ⁺ .

Stage 4. Obtaining 1-(cyclopropylmethyl)-7-methoxy-1H-indole-2-carbaldehyde

Potassium carbonate (0.55 g, 5.2 mmol) and (bromomethyl )cyclopropane (6, 0.41 ml, 4.02 mmol) at RT The reaction mixture was stirred at rt. within 12 hours the Reaction mixture was diluted with water and was extracted with ethyl acetate (50 ml × 2). The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated to give the crude product. The crude residue was purified by gradient column chromatography using 3-7% ethyl acetate in hexane to give the title compound as a sticky solid (6) (0.41 g, 68% yield). MS (ESI): mass, calc. for C ₁₄ H ₁₅ NO ₂ , 229.1: found mass/charge value, 230.1 [M+H] ⁺ .

Synthesis of 5-(chloromethyl)-2,4-dimethylthiazole (intermediate for compound 48)

Stage 1. (2,4-Dimethylthiazol-5-yl)methanol

To a stirred solution of ethyl 2,4-dimethylthiazole-5-carboxylate (1.0.5 g, 2.70 mmol) in THF (10 ml) was added 1 M LAH in THF (4 ml, 4.05 mmol) dropwise at 0°C and stirred at room temperature. within 1 h. The reaction mixture was extinguished with a saturated solution of NH ₄ Cl, filtered through celite and was extracted with EtOAc (2 X 25 ml). The organic layer was washed with brine (5 ml), dried over anhydrous Na ₂ SO ₄ and evaporated. The crude material was purified by gradient column chromatography using 50-60% EtOAc in hexane to give the product as a colorless oil (0.3 g, 79% yield). MS (ESI): mass, calc. for C ₆ H ₉ NOS, 143.04; the found mass/charge value is 144.1 (M+H) ⁺ .

Stage 2. 5-(Chloromethyl)-2,4-dimethylthiazole

To a stirred solution of (2,4-dimethylthiazol-5-yl)methanol (2, 0.3 g, 2.09 mmol) in DCM (5 ml) was added SOCl ₂ (0.3 ml, 4.19 mmol) dropwise at 0°C and the reaction mixture was stirred at room temperature. for 1 h. The reaction mixture was evaporated in vacuo and dried to give the product as a brown oil (0.25 g, 75% yield) (3). ¹ H NMR (400 MHz, DMSO-d6) δ (ppm): 4.99 (s, 2H), 2.59 (s, 3H), 2.30 (s, 3H).

Synthesis of 2-bromo-1-(3-ethylbenzo[b]thiophen-2-yl)propan-1-one (intermediate for compound 49)

Stage 1. (2-Methylthiazol-5-yl)methanol

To a stirred solution of 2-methylthiazole-5-carboxylic acid (1.1.0 g, 6.99 mmol) in THF (10 ml) at -10°C was added triethylamine (1.02 ml, 7.34 mmol) followed by by adding ethyl chloroformate (0.66 ml, 6.99 mmol) in THF (2 ml) dropwise at -10°C and stirred at the same temperature for 1 h. The reaction mixture was filtered through celite and the filtrate was cooled to -10°C . A suspension of NaBH ₄ (0.68 g, 17.4 mmol) in water (2 ml) was added to the filtrate and rt was reached. and stirred for 2 hours. The reaction mixture was diluted with 2N. NaOH solution (5 ml) and extracted with EtOAc (2 X 25 ml). The organic layer was washed with brine (5 ml), dried over anhydrous Na ₂ SO ₄ and evaporated. The crude residue was purified by gradient column chromatography using 40-60% EtOAc in hexane to give the product as a yellow oil (2) (0.2 g, 25% yield). MS (ESI): mass, calc. for C ₅ H ₇ NOS, 129.02; the found mass/charge value is 130.1 (M+H) ⁺ .

Stage 2. 5-(Chloromethyl)-2-methylthiazole

To a stirred solution of (2-methylthiazol-5-yl)methanol (2, 0.2 g, 1.55 mmol) in DCM (5 ml) was added SOCl ₂ (0.23 ml, 3.10 mmol) dropwise at 0 °C and the reaction mixture was stirred at room temperature. within 1 hour the Reaction mixture was neutralized using cold solution of NaHCO ₃ (5 ml) and was extracted with DCM (2 X 25 ml). The organic layer was washed with brine (5 ml), dried over anhydrous Na ₂ SO ₄ and evaporated to give the product as a yellow oil. (0.2 g, 90% yield). MS (ESI): mass, calc. for C ₅ H ₆ ClNS, 146.99; the found mass/charge value is 148.1 (M+H) ⁺ .

Synthesis of ethyl 2-amino-6-methylisonicotinate (intermediate for compounds 25, 26 and 27)

Stage 1. Preparation of ethyl 2-((tert-butoxycarbonyl)amino)-6-methylisonicotinate (2)

To a stirred solution of ethyl 2-chloro-6-methylisonicotinate (1.5.2 g, 26.1 mmol) in 1,4-dioxane (50 mL) was added tert-butyl carbamate (4.6 g, 39.1 mmol) , Cs ₂ CO ₃ (21.3 g, 65.3 mmol), XPhos (1.24 g, 2.61 mmol) followed by the addition of bis(dibenzylideneacetone)palladium(0) (0.75 g, 1.31 mmol ) and stirred at 85°C for 16 h (reaction condition a). The reaction mixture was cooled to rt, filtered through celite. To this was added water (100 ml) and the compound was extracted with EtOAc (200 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated under vacuum. The crude material was purified by column chromatography using 15-20% EtOAc in hexane to give the product as a brown tarry solid (2) (3.5 g, 58% yield). MS (ESI): mass, calc. for C ₁₄ H ₂₀ N ₂ O ₄ , 280.14; the found mass/charge value is 281.2 (M+H) ⁺ .

Stage 2. Preparation of ethyl 2-amino-6-methylisonicotinate (3)

To a stirred solution of ethyl 2-((tert-butoxycarbonyl)amino)-6-methylisonicotinate (2, 3.5 g, 12.5 mmol) in DCM (30 ml) was added TFA (10 ml) and stirred at RT . within 16 hours (reaction condition b). The reaction mixture was evaporated, water (20 ml) was added and its basicity increased using a saturated solution of Na ₂ CO ₃ . The precipitate formed was collected by filtration and dried to give the product (3) as an off-white solid. (1.6 g, 72% yield). MS (ESI): mass, calc. for C ₉ H ₁₂ N ₂ O ₂ , 180.09; the found mass/charge value is 181.1 (M+H) ⁺ .

Synthesis of 1-(phenylsulfonyl)-1H-indole-2-carbaldehyde (3) (intermediate for compounds 50, 57, 58, 59, 60, 61, 62, 63, 78, 79, 81 and 85)

Stage a. Synthesis of 1-(phenylsulfonyl)-1H-indole (2)

To a stirred solution of 1H-indole (1, 10.0 g, 85.36 mmol) in N,N-dimethylformamide (100 ml) was added sodium hydride (4.08 g, 170.94 mmol) slowly at 0°C, the reaction the mixture was stirred at 0°C for 40 min. Benzenesulfonyl chloride (22.6 g, 128.20 mmol) was added dropwise, then the reaction mixture was stirred at rt. for 1 hour. After completion of the reaction, the reaction mixture was quenched with ice, the resulting solid was filtered and dried. The crude material was purified by column chromatography (100-200 silica gel) using 20% ethyl acetate in hexane as eluent. The desired fractions were concentrated under reduced pressure to give 1-(phenylsulfonyl)-1H-indole (2) as a white solid. Yield: 16.2 g (76%). MS (ESI): 257.12; the mass/charge value found, 258.23 [M+H] ⁺ .

Stage b. Synthesis of 1-(phenylsulfonyl)-1Н-indole-2-carbaldehyde (3)

To a stirred solution of 1-(phenylsulfonyl)-1H-indole (2, 16.2 g, 62.97 mmol) in tetrahydrofuran (150 ml) was added 2.5 M n-butyllithium in hexane (35.5 ml, 89.07 mmol) dropwise at -78°C. The reaction mixture was stirred at -78°C for 1 h. N,N-dimethylformamide (6.57 ml, 83.50 mmol) was added at -78°C and the reaction mixture was further stirred at -78°C for 1 h. the reaction was completed, the reaction mixture was quenched with ammonium chloride, extracted with ethyl acetate (100 ml × 2). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to give the crude product. The crude material was purified by CombiFlash using a 40.0 g RediSep column and 20% ethyl acetate in hexane as eluent. The desired fractions were concentrated under reduced pressure to give 1-(phenylsulfonyl)-1H-indole-2-carbaldehyde (3) as a yellow solid. Yield: 12.6 g (73%). MS (ESI): 285.11; the mass/charge value found, 256.39 [M+H] ⁺ .

Synthesis of 6-methoxy-1-(phenylsulfonyl)-1Н-indole-2-carbaldehyde (3) (intermediate for compounds 51, 67, 80, 82 and 83)

Stage a. Synthesis of 6-methoxy-1-(phenylsulfonyl)-1Н-indole (2)

Sodium hydride (5.44 g, 136.05 mmol) was added slowly at 0 °C, the reaction mixture was stirred at room temperature. at 0°C for 40 min. Benzenesulfonyl chloride (17.8 g, 102.03 mmol) was added dropwise, then the reaction mixture was stirred at rt. for 1 hour. After completion of the reaction, the reaction mixture was quenched with ice, the resulting solid was filtered and dried. The crude material was purified by column chromatography (100-200 silica gel) using 20% ethyl acetate in hexane as eluent. The desired fractions were concentrated under reduced pressure to give 6-methoxy-1-(phenylsulfonyl)-1H-indole (2) as a white solid. Yield: 16.5 g (84%). MS (ESI): 286.11; mass/charge found value, 287.52 [M+H] ⁺ .

Stage b. 6-Methoxy-1-(phenylsulfonyl)-1Н-indole-2-carbaldehyde (3)

To a stirred solution of 6-methoxy-1-(phenylsulfonyl)-1H-indole (2, 6.0 g, 20.9 mmol) in tetrahydrofuran (60 ml) was added 2.5 M n-butyllithium in hexane (13.37 ml , 33.44 mmol) dropwise at -78°C and the reaction mixture was stirred at -78°C for 1 h. N,N-dimethylformamide (2.3 ml, 31.3 mmol) was added at -78°C and the reaction mixture was stirred at -78° for 1 h. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate (50 ml × 2). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to give the crude product. The crude material was purified by CombiFlash using a 40.0 g RediSep column and 20% ethyl acetate in hexane as eluent. The desired fractions were concentrated under reduced pressure to give 6-methoxy-1-(phenylsulfonyl)-1H-indole-2-carbaldehyde (3) as a yellow solid. Yield: 5.1 g (78%). MS (ESI): 314.21; the found mass/charge value, 315.22 [M+H] ⁺ .

Synthesis of 5,6-difluoro-1-(phenylsulfonyl)-1H-indole-2-carbaldehyde (intermediate for compound 55)

Stage 1. Synthesis of 5,6-difluoro-1-(phenylsulfonyl)-1H-indole (2)

Sodium hydride (60%, 3.1 g, 81.61 mmol) for 15 min at 0°C. After 15 min, benzenesulfonyl chloride (6.4 mL, 49.0 mmol) was added at 0° C. and stirred for 2 h at rt. in N ₂ atmosphere. After completion of the reaction, ice water (150 ml) was added to the reaction mixture. The solid precipitated was filtered off and washed with ice water. The crude material was purified by CombiFlash using RediSep 40 g and 20% ethyl acetate in hexane as eluent to give 5,6-difluoro-1-(phenylsulfonyl)-1H-indole (2) as an off-white solid. Yield: 8.8 g (92.63%). MS (ESI): 293; found mass/charge value, 294.01 [M+H] ⁺¹ .

Stage 2. Synthesis of 5,6-difluoro-1-(phenylsulfonyl)-1Н-indole-2-carbaldehyde (3)

To a solution of 5,6-difluoro-1-(phenylsulfonyl)-1H-indole (2.8.8 g, 30.12 mmol) in dry tetrahydrofuran (80 ml) was added a 2.5 M solution of n-butyllithium in hexane (20 0 ml, 45.37 mmol) at -78°C and stirred for 45 min followed by the addition of anhydrous N,N-dimethylformamide (2.5 ml, 45.37 mmol) at -78°C. The reaction mass was stirred for 30 min at -78°C in an atmosphere of N ₂ . After completion of the reaction, the reaction mixture was quenched with an aqueous ammonium chloride solution (30 ml) and extracted with ethyl acetate (100 ml×2). The organic layer was washed with saturated ammonium chloride solution and brine (100 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by CombiFlash using RediSep 40 g and 30% ethyl acetate in hexane as eluent to give 5,6-difluoro-1-(phenylsulfonyl)-1H-indole-2-carbaldehyde (3) as a yellow liquid. Yield: 7.0 g, (72.9%). MS (ESI): 321.30; found mass/charge value, 322.1 [M+H] ⁺¹ .

Synthesis of (1-(tert-butoxycarbonyl)-6-methoxy-1H-indol-2-yl)boronic acid (intermediate for compound 86)

Stage 1. Synthesis of tert-butyl-6-methoxy-1H-indole-1-carboxylate (2)

To a stirred solution of 6-methoxy-1H-indole (1.2.0 g, 13.64 mmol) in dichloromethane (20 mL) was added triethylamine (5.60 mL, 40.8 mmol), N,N-dimethylaminopyridine (0 08 g, 0.68 mmol) and boc anhydride (3.9 ml, 16.3 mmol) at 0°C and then the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was diluted with dichloromethane (100 ml × 3). The organic phase was washed with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude compound. The crude material was purified by CombiFlash using a RediSep 40.0 g column and 1-5% ethyl acetate in hexane as eluent to give t-butyl-6-methoxy-1H-indole-1-carboxylate (2) as an oily liquid. Yield: 3.0 g (89%). MS (ESI): 247.12; found mass/charge value, 246.01 [M-N] ^-1 .

Stage 2. Synthesis of (1-(tert-butoxycarbonyl)-6-methoxy-1H-indol-2-yl)boronic acid (3)

To a stirred solution of tert-butyl 6-methoxy-1H-indole-1-carboxylate (2.2.5 g, 10.12 mmol), triisopropyl borate (2.2.7 ml, 20.24 mmol) in tetrahydrofuran (25 ml) was added 1 M lithium diisopropylamide in tetrahydrofuran (10 ml, 20.24 mmol) dropwise at 0°C and the reaction mixture was stirred at 0°C for 3 h. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution, extracted with with ethyl acetate (50 ml × 2). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to give the crude product. The crude material was purified by CombiFlash using a 40.0 g RediSep column and 10-20% ethyl acetate in hexane as eluent. The desired fractions were concentrated under reduced pressure to give (1-(tert-butoxycarbonyl)-6-methoxy-1H-indol-2-yl)boronic acid (3) as an off-white solid. Yield: 1.3 g (44%).

¹ H NMR (400 MHz, DMSO-d6) δ (ppm): 8.11 (s, 2H), 7.65 (s, 1H), 7.43 (d, J=8.56 Hz, 1H), 6.82 (d, J=8.56 Hz, 1H), 6.55 (s, 1H), 3.79 (s, 3H), 1.59 (s, 9H). MS (ESI): mass calculated for C ₁₄ H ₁₈ BNO ₅ , 291.13; the found mass/charge value is 191.01 [M+H-100] ⁺¹ .

Example 2

General Procedure for Biological Evaluation

Binding assay with fluorescence polarization determination

The binding of compounds to PAD4 was determined by fluorescence polarization (FP) analysis. PAD4 was diluted to 1 μM in assay buffer (100 mM HEPES, 50 mM NaCl, 1 mM DTT, 5% glycerol, and 1 mM CHAPS) and added to wells containing various concentrations of compounds or DMSO (1%) carrier medium, in 384 well black plate. 10 nM fluorescein labeled probe (JPAD-00085) was added to the plate. The assay plate was incubated for 60 minutes at rt. before measuring the FP value by reading in the FP module (λex 485/λem 535 nm) on the Pherastar instrument. IC ₅₀ was calculated using XL-fit model 205 software (Lewis et. al, Nat Chem Biol. 2015, 11(3), 189-91).

Biochemical analysis with the determination of ammonia release

Citrullination analysis was performed by determining ammonia release. PAD4 was diluted to 120 nM in assay buffer (100 mM HEPES, 50 mM NaCl, 2 mM DDT, 0.6 mg/mL BSA, pH 7.4), added to wells containing various concentrations of compound or DMSO vehicle ( end value 1%), in a black 384-well plate. After a preliminary incubation of 60 minutes at rt. the reaction was initiated by adding a substrate (1.5 mM BAEE in 200 mM HEPES, 50 mM NaCl, 350 μM CaCl2, 2 mM, pH 7.4). The reaction was stopped after 60 minutes by adding stop buffer/detection buffer containing 50 mM EDTA, 2.6 mM o-phthalaldehyde and 2.6 mM DTT. The assay plate was incubated at rt. within 90 min before measuring the fluorescence values (λex 405/λem 460 nm) on the Tesal reader. IC ₅₀ was calculated using XL-fit model 205 software (Lewis et. al Nat Chem Biol. 2015, 11(3), 189-91).

PAD4 activity

Table 1 below shows the activity of selected compounds of the present invention in the PAD4 assays described above. Compounds with activity indicated as "A" were characterized by IC ₅₀ ≤1 μm; compounds with activity indicated as "B" were characterized by IC ₅₀ 1-10 μm; and compounds with activity indicated as "C" were characterized by IC ₅₀ ≥10 μm.

Table 1 shows that most of the test compounds were active against the PAD4 enzyme when assessed by biochemical analysis with determination of release of ammonia and analysis of binding with the determination of fluorescence polarization. IC ₅₀ values reflect the effectiveness of compounds in inhibiting PAD4 enzymatic activity. The IC ₅₀ value indicates how much a particular drug or compound will be required to inhibit a given biological process or process component such as an enzyme. A low IC ₅₀ value indicates a high inhibition efficiency of the test compound (compounds 1-48 described herein). However, in Table 1 above, high efficiency is referred to as "A", "B" and "C", where "A" corresponds to the lowest IC ₅₀ value and therefore the highest efficiency.

Biochemical analysis with the determination of release of ammonia showed that 55 compounds out of 86 are characterized by an IC ₅₀ value of ≤1 μm, designated as "A". These 55 compounds were compounds 3, 4, 10, 12, 13, 15-17, 21, 23-26, 28-30, 34-37, 39, 41, 42, 44, 45, 47, 49, 51- 55, 58, 60-64, 67-80, 82, 83 & 85.

On the other hand, the fluorescence polarization binding assay showed that 9 compounds actively inhibited PAD4 enzymatic activity. The individual compounds are compounds 13, 16, 23, 28-30, 33, 36, and 39, respectively.

Therefore, it can be assumed that compounds-3, 4, 10, 12, 13, 15-17, 21, 23-26, 28-30, 34-37, 39, 41, 42, 44, 45, 47, 49 , 51-55, 58, 60-64, 67-80, 82, 83 & 85 may contribute to the treatment of PAV4 mediated disorders.

Claims (246)

1. Compound of formula (I)

its stereoisomers and its pharmaceutically acceptable salts, where X is selected from O or S; Z is N; And represents CR ₁ ; B is CR ₂ ; D is CR ₃ ; R ₁ , R ₂ , R ₃ and R ₄ are independently selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl or C ₆ aryl, where C _1-6 alkyl is optionally substituted with C _1-6 alkoxy; R ₁₁ and R ₁₂ can be taken together to form a 5-10 membered monocyclic or bicyclic saturated heterocyclic ring, optionally with 1-3 heteroatoms selected from N, S or O, where The 5-10 membered monocyclic or bicyclic saturated heterocyclic ring is optionally substituted with substituents selected from amino or -NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ ; and R ₁₃ is selected from 6-membered monocyclic aryl and 5-10-membered monocyclic or bicyclic heteroaryl with 1-3 heteroatoms selected from N, S or O, where 6-membered monocyclic aryl and 5-10-membered monocyclic or bicyclic heteroaryl are optionally substituted with 1-5 substituents selected from halogen, C _1-6 alkyl, C _1-6 alkoxy or C ₆ aryl, where C _1-6 alkyl and C ₆ aryl is optionally substituted with one or more groups selected from C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C ₆ aryl, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S and O, 5-6 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, S and O, oxo, halogen and hydroxyl, where C ₆ aryl, heteroaryl and heterocyclyl are optionally substituted with one or more groups selected from C _1-6 alkyl, C _1-6 alkoxy, oxo, halogen, -CH ₂ OH and cyano. 2. The compound of formula (I) according to claim 1, its stereoisomers and its pharmaceutically acceptable salts, where X is selected from O or S; Z is N; And represents CR ₁ ; B is CR ₂ ; D is CR ₃ ; R ₁ , R ₂ and R ₃ are independently selected from hydrogen or C _1-4 alkyl; R ₄ is selected from C _1-4 alkyl, C _3-5 cycloalkyl or C ₆ aryl, where C _1-4 alkyl is optionally substituted with C _1-4 alkoxy; R ₁₁ and R ₁₂ can be taken together to form a 5-10 membered monocyclic or bicyclic saturated heterocyclic ring, optionally with 1-3 heteroatoms selected from N, S or O, where The 5-10 membered monocyclic or bicyclic saturated heterocyclic ring is optionally substituted with substituents selected from amino or -NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ ; and R ₁₃ is selected from 6-membered monocyclic aryl and 5-10-membered monocyclic or bicyclic heteroaryl with 1-3 heteroatoms selected from N, S or O, where 6-membered monocyclic aryl and 5-10-membered monocyclic or bicyclic heteroaryl are optionally substituted with 1-5 substituents selected from halogen, C _1-6 alkyl, C _1-6 alkoxy or C ₆ aryl, where C _1-6 alkyl and C ₆ aryl is optionally substituted with one or more groups selected from C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C ₆ aryl, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S and O, 5-6 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, S and O, oxo, halogen and hydroxyl, where C ₆ aryl, heteroaryl and heterocyclyl are optionally substituted with one or more groups selected from C _1-6 alkyl, C _1-6 alkoxy, oxo, halogen, -CH ₂ OH and cyano. 3. The compound of formula (I) according to claim 1, its stereoisomers and its pharmaceutically acceptable salts, where X is selected from O or S; Z is N; And represents CR ₁ ; B is CR ₂ ; D is CR ₃ ; R ₁ , R ₂ and R ₃ are independently selected from hydrogen or C _1-4 alkyl; R ₄ is selected from C _1-4 alkyl, C _3-5 cycloalkyl or C ₆ aryl, where C _1-4 alkyl is optionally substituted with C _1-4 alkoxy; R ₁₁ and R ₁₂ are taken together to form a 5-10 membered monocyclic or bicyclic saturated heterocyclic ring, optionally with 1-3 heteroatoms selected from N or O, where The 5-10 membered monocyclic or bicyclic saturated heterocyclic ring is optionally substituted with substituents selected from amino or -NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ ; R ₁₃ is selected from 6-membered monocyclic aryl and 5-10-membered monocyclic or bicyclic heteroaryl with 1-3 heteroatoms selected from N, S or O, where 6-membered monocyclic aryl and 5-10-membered monocyclic or bicyclic heteroaryl are optionally substituted with 1-5 substituents selected from halogen, C _1-4 alkyl, C _1-4 alkoxy or C ₆ aryl, where C _1-4 alkyl and C ₆ aryl is optionally substituted with one or more groups selected from C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C ₆ aryl, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S and O, 5-6 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, S and O, oxo, halogen and hydroxyl, where C ₆ aryl, heteroaryl and heterocyclyl are optionally substituted with one or more groups selected from C _1-6 alkyl, C _1-6 alkoxy, oxo, halogen, —CH ₂ OH and cyano. 4. The compound of formula (I) according to claim 1, its stereoisomers and its pharmaceutically acceptable salts, where X is selected from O or S; Z is N; And represents CR ₁ ; B is CR ₂ ; D is CR ₃ ; R ₁ , R ₂ and R ₃ are independently selected from hydrogen or C _1-2 alkyl; R ₄ is selected from hydrogen, C _1-4 alkyl, C _3-5 cycloalkyl or C ₆ aryl, where C _1-4 alkyl is optionally substituted with C _1-4 alkoxy; R ₁₁ and R ₁₂ are taken together to form a 5-10 membered monocyclic or bicyclic saturated heterocyclic ring, optionally with 1-3 heteroatoms selected from N, S or O, where The 5-10 membered monocyclic or bicyclic saturated heterocyclic ring is optionally substituted with substituents selected from amino or -NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ ; and R ₁₃ is selected from 6-membered monocyclic aryl and 5-9-membered monocyclic or bicyclic heteroaryl with 1-3 heteroatoms selected from N, S or O, where 6-membered monocyclic aryl and 5-9-membered monocyclic or bicyclic heteroaryl are optionally substituted with 1-5 substituents selected from fluorine, bromine, chlorine, C _1-4 alkyl, C _1-4 alkoxy or C ₆ aryl, where C _{1- 4} alkyl and C ₆ aryl are optionally substituted with one or more groups selected from hydroxyl, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _3-5 cycloalkyl, C ₆ aryl, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S and O, 5-6-membered heterocyclyl containing 1 or 2 heteroatoms selected from N, S and O, oxo and halogen, where C ₆ is aryl, heteroaryl and heterocyclyl is optional substituted with one or more groups selected from C _1-6 alkyl, C _1-6 alkoxy, oxo, halo, —CH ₂ OH, and cyano. 5. Compound of formula (II)

its stereoisomers and its pharmaceutically acceptable salts, where X is selected from O or S; Z is N; And represents CR ₁ ; B is CR ₂ ; D is CR ₃ ; E is selected from N or CR ₆ ; F is CR ₇ ; G is CR ₈ ; H is CR ₉ ; R ₁ , R ₂ , R ₃ and R ₄ are independently selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl or C ₆ aryl, where C _1-6 alkyl is optionally substituted with C _1-6 alkoxy; R ₅ , R ₆ , R ₇ , R ₈ , R ₉ and R ₁₀ are independently selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 alkoxy or C ₆ aryl, where C _1-6 alkyl is optionally substituted with one or more groups selected from oxo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _3-6 cycloalkyl, C ₆ aryl, 5-6 membered heterocyclyl , containing 1 or 2 heteroatoms selected from N, S and O, 5-6-membered heteroaryl containing 1-3 heteroatoms selected from N, S and O, halogen and hydroxyl, where C ₆ aryl, heteroaryl and heterocyclyl are optionally substituted one or more groups selected from C _1-6 alkyl, C _1-6 alkoxy, oxo, halogen, hydroxyl, —CH ₂ OH and cyano; and R ₁₁ and R ₁₂ are taken together to form a 5-10 membered monocyclic or bicyclic saturated heterocyclic ring, optionally with 1-3 heteroatoms selected from N, S or O, where The 5-10 membered monocyclic or bicyclic saturated heterocyclic ring is optionally substituted with substituents selected from amino or -NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ . 6. The compound of formula (II) according to claim 5, its stereoisomers and its pharmaceutically acceptable salts, where X is selected from O or S; Z is N; And represents CR ₁ ; B is CR ₂ ; D is CR ₃ ; E is selected from N or CR ₆ ; F is CR ₇ ; G is CR ₈ ; H is CR ₉ ; R ₁ , R ₂ and R ₃ are independently selected from hydrogen or C _1-4 alkyl; R ₆ , R ₇ , R ₈ , R ₉ and R ₁₀ are independently selected from hydrogen, halogen, C _1-4 alkyl, C _1-4 alkoxy, or C ₆ aryl; R ₄ is selected from hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl or C ₆ aryl, where C _1-4 alkyl is optionally substituted with C _1-4 alkoxy; R ₅ is selected from C _1-4 alkyl, C _1-4 alkoxy or C ₆ aryl, where C _1-4 alkyl is optionally substituted with one or more groups selected from oxo, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _3-6 cycloalkyl, C ₆ aryl, 5-6 membered heterocyclyl , containing 1 or 2 heteroatoms selected from N, S and O, 5-6-membered heteroaryl containing 1-3 heteroatoms selected from N, S and O, halogen and hydroxyl, where C ₆ aryl, heteroaryl and heterocyclyl are optionally substituted one or more groups selected from C _1-6 alkyl, C _1-6 alkoxy, oxo, halo, —CH ₂ OH and cyano; and R ₁₁ and R ₁₂ are taken together to form a 5-10 membered monocyclic or bicyclic saturated heterocyclic ring, optionally with 1-3 heteroatoms selected from N, S or O, where The 5-10 membered monocyclic or bicyclic saturated heterocyclic ring is optionally substituted with substituents selected from amino or -NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ . 7. The compound of formula (II) according to claim 5, its stereoisomers and its pharmaceutically acceptable salts, where X is selected from O or S; Z is N; And represents CR ₁ ; B is CR ₂ ; D is CR ₃ ; E is selected from N or CR ₆ ; F is CR ₇ ; G is CR ₈ ; H is CR ₉ ; R ₁ , R ₂ and R ₃ are independently selected from hydrogen or C _1-2 alkyl; R ₆ , R ₇ , R ₈ , R ₉ and R ₁₀ are independently selected from hydrogen, halogen, C _1-2 alkyl, C _1-2 alkoxy, or C ₆ aryl; R ₄ is selected from hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl or C ₆ aryl, where C _1-4 alkyl is optionally substituted with C _1-4 alkoxy; R ₅ is selected from C _1-4 alkyl, C _1-4 alkoxy or C ₆ aryl, where C _1-4 alkyl is optionally substituted with one or more groups selected from oxo, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _3-6 cycloalkyl, C ₆ aryl, 5-6 membered heterocyclyl , containing 1 or 2 heteroatoms selected from N, S and O, 5-6-membered heteroaryl containing 1-3 heteroatoms selected from N, S and O, halogen and hydroxyl, where C ₆ aryl, heteroaryl and heterocyclyl are optionally substituted one or more groups selected from C _1-6 alkyl, C _1-6 alkoxy, oxo, halogen, -CH ₂ OH and cyano; and R ₁₁ and R ₁₂ are taken together to form a 5-10 membered monocyclic or bicyclic saturated heterocyclic ring, optionally with 1-3 heteroatoms selected from N, S or O, where The 5-10 membered monocyclic or bicyclic saturated heterocyclic ring is optionally substituted with substituents selected from amino or -NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ . 8. Compound of formula (III)

its stereoisomers and its pharmaceutically acceptable salts, where X is selected from O or S; Z is N; R ₁ , R ₂ , R ₃ and R ₄ are independently selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl or C ₆ aryl, where C _1-6 alkyl is optionally substituted with C _1-6 alkoxy; R ₅ , R ₆ , R ₇ , R ₈ , R ₉ and R ₁₀ are independently selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 alkoxy or C ₆ aryl, where C _1-6 alkyl is optionally substituted with one or more groups selected from oxo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _3-6 cycloalkyl, C ₆ aryl, 5-6 membered heterocyclyl , containing 1 or 2 heteroatoms selected from N, S and O, 5-6-membered heteroaryl containing 1-3 heteroatoms selected from N, S and O, halogen and hydroxyl, where C ₆ aryl, heteroaryl and heterocyclyl are optionally substituted one or more groups selected from C _1-6 alkyl, C _1-6 alkoxy, oxo, halo, —CH ₂ OH and cyano; and R ₁₁ and R ₁₂ are taken together to form a 5-10 membered monocyclic or bicyclic saturated heterocyclic ring, optionally with 1-3 heteroatoms selected from N, S or O, where The 5-10 membered monocyclic or bicyclic saturated heterocyclic ring is optionally substituted with substituents selected from amino or -NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ . 9. The compound of formula (III) according to claim 8, its stereoisomers and its pharmaceutically acceptable salts, where X is selected from O or S; Z is N; R ₁ , R ₂ and R ₃ are independently selected from hydrogen or C _1-4 alkyl; R ₆ , R ₇ , R ₈ , R ₉ and R ₁₀ are independently selected from hydrogen, halogen, C _1-4 alkyl, C _1-4 alkoxy, or C ₆ aryl; R ₄ is selected from hydrogen, C ₄ alkyl, C _3-6 cycloalkyl or C ₆ aryl, where C _1-4 alkyl is optionally substituted with C _1-4 alkoxy; R ₅ is selected from C _1-4 alkyl, C _1-4 alkoxy or C ₆ aryl, where C _1-4 alkyl is optionally substituted with one or more groups selected from oxo, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _3-6 cycloalkyl, C ₆ aryl, 5-6 membered heterocyclyl , containing 1 or 2 heteroatoms selected from N, S and O, 5-6-membered heteroaryl containing 1-3 heteroatoms selected from N, S and O, halogen and hydroxyl, where C ₆ aryl, heteroaryl and heterocyclyl are optionally substituted one or more groups selected from C _1-6 alkyl, C _1-6 alkoxy, oxo, halo, —CH ₂ OH, and cyano; and R ₁₁ and R ₁₂ are taken together to form a 5-10 membered monocyclic or bicyclic saturated heterocyclic ring, optionally with 1-3 heteroatoms selected from N, S or O, where The 5-10 membered monocyclic or bicyclic saturated heterocyclic ring is optionally substituted with substituents selected from amino or -NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ . 10. The compound of formula (III) according to claim 8, its stereoisomers and its pharmaceutically acceptable salts, where X is selected from O or S; Z is N; R ₁ , R ₂ and R ₃ are independently selected from hydrogen or C _1-4 alkyl; R ₆ , R ₇ , R ₈ , R ₉ and R ₁₀ are independently selected from hydrogen, halogen, C _1-4 alkyl, C _1-4 alkoxy, or C ₆ aryl; R ₄ is selected from hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl or C ₆ aryl, where C _1-4 alkyl is optionally substituted with C _1-4 alkoxy; R ₅ is selected from C ₄ alkyl, C _1-4 alkoxy or C ₆ aryl, where C _1-4 alkyl is optionally substituted with one or more groups selected from oxo, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _3-6 cycloalkyl, C ₆ aryl, 5-6 membered heterocyclyl , containing 1 or 2 heteroatoms selected from N, S and O, 5-6-membered heteroaryl containing 1-3 heteroatoms selected from N, S and O, halogen and hydroxyl, where C ₆ aryl, heteroaryl and heterocyclyl are optionally substituted one or more groups selected from C _1-6 alkyl, C _1-6 alkoxy, oxo, halogen, -CH ₂ OH and cyano; and R ₁₁ and R ₁₂ are taken together to form a 5-10 membered monocyclic or bicyclic saturated heterocyclic ring, optionally with 1-3 heteroatoms selected from N, S or O, where The 5-10 membered monocyclic or bicyclic saturated heterocyclic ring is optionally substituted with substituents selected from amino or -NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ . 11. The compound or its stereoisomers and its pharmaceutically acceptable salts, selected from the group consisting of: (R)-(3-aminopiperidin-1-yl)(2-(3-bromo-1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7- yl) methanone (1), (R)-(3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl)methanone ( 2), (R)-(3-aminopiperidin-1-yl)(2-(1-benzyl-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl)methanone (3) , (R)-(3-aminopiperidin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-3-methylimidazo[1,2-а]pyridin-7-yl)methanone (4) , (R)-(3-aminopiperidin-1-yl)(2-(1-ethyl-3-phenyl-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl) methanone (5), (R)-(3-Aminopyrrolidin-1-yl)(2-(1-ethyl-3-phenyl-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl) methanone (6), (R)-(3-aminopyrrolidin-1-yl)(2-(1-ethyl-lH-indol-2-yl)-3-methylimidazo[l,2-a]pyridin-7-yl)methanone (7) , (R)-(3-Aminopyrrolidin-1-yl)(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl)methanone ( eight), (2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl)(hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-6(5Н)-yl)methanone (9), (R)-(3-aminopiperidin-1-yl)(3-methyl-2-(1-(pyridin-4-ylmethyl)-1H-indol-2-yl)imidazo[1,2-a]pyridin-7 -yl) methanone (10), (R)-(3-aminopiperidin-1-yl)(3-methyl-2-(1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indol-2-yl)imidazo [1, 2-а]pyridin-7-yl)methanone (11), (R)-(3-aminopiperidin-1-yl)(2-(1-(4-methoxybenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl) methanone (12), (R)-(3-aminopiperidin-1-yl)(2-(1-(4-fluorobenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl) methanone (13), (R)-4-((2-(7-(3-aminopiperidin-1-carbonyl)-3-methylimidazo[1,2-a]pyridin-2-yl)-1H-indol-1-yl)methyl) benzonitrile (14), (R)-(3-aminopiperidin-1-yl)(3-methyl-2-(1-(pyridin-3-ylmethyl)-1H-indol-2-yl)imidazo[1,2-a]pyridin-7 -yl) methanone (15), (R)-(3-aminopiperidin-1-yl)(3-methyl-2-(1-(pyridin-2-ylmethyl)-1H-indol-2-yl)imidazo[1,2-a]pyridin-7 -yl) methanone (16), (R)-(3-aminopiperidin-1-yl)(3-methyl-2-(1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)imidazo[1,2-a]pyridine -7-yl) methanone (17), (R)-4-((2-(7-(3-aminopiperidin-1-carbonyl)-3-methylimidazo[1,2-a]pyridin-2-yl)-1H-indol-1-yl)methyl) -1-methylpyridin-2(1Н)-one (18), (R)-(3-aminopiperidin-1-yl)(2-(3-ethylbenzo[b]thiophen-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl)methanone (19) , (R)-(3-aminopiperidin-1-yl)(2-(1-(4-chlorobenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl) methanone (20), (R)-(3-aminopiperidin-1-yl)(2-(1-(2-fluorobenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl) methanone (21), (R)-(3-aminopiperidin-1-yl)(2-(1-ethyl-5-phenyl-1H-pyrrol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl) methanone (22), (R)-(3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-6-methoxy-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7- yl) methanone (23), (R)-(3-aminopiperidin-1-yl)(2-(1-ethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylimidazo[1,2-a]pyridine- 7-yl) methanone (24), (R)-(3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-3,5-dimethylimidazo[1,2-a]pyridin-7-yl) methanone (25), (R)-(3-aminopiperidin-1-yl)(2-(1-benzyl-1H-indol-2-yl)-3,5-dimethylimidazo[1,2-a]pyridin-7-yl)methanone ( 26), (R)-(3-aminopiperidin-1-yl)(3,5-dimethyl-2-(1-(pyridin-2-ylmethyl)-1H-indol-2-yl)imidazo[1,2-a]pyridine -7-yl) methanone (27), (R)-(3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-6-fluoro-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7- yl) methanone (28), (R)-(3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-5-fluoro-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7- yl) methanone (29), (R)-(3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-methyl-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7- yl) methanone (30), (R)-(3-aminopiperidin-1-yl)(2-(2-ethylphenyl)-3-methylimidazo[1,2-a]pyridin-7-yl)methanone (31), (R)-(3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-3-phenylimidazo[1,2-a]pyridin-7-yl)methanone ( 32), (R)-(3-aminopiperidin-1-yl)(3-cyclopropyl-2-(1-(cyclopropylmethyl)-1H-indol-2-yl)imidazo[1,2-a]pyridin-7-yl)methanone (33), (R)-(3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-3-(methoxymethyl)imidazo[1,2-a]pyridin-7-yl ) methanone (34), (R)-(3-aminopiperidin-1-yl)(2-(1-(3-fluorobenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl) methanone (35), (R)-(3-aminopiperidin-1-yl)(3-methyl-2-(1-(thiophen-3-ylmethyl)-1H-indol-2-yl)imidazo[1,2-a]pyridin-7 -yl) methanone (36), (R)-(3-aminopiperidin-1-yl)(2-(1-(furan-3-ylmethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7- yl) methanone (37), (R)-3-aminopiperidin-1-yl)(2-(1-(1-(4-fluorophenyl)ethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine- 7-yl) methanone (38), (R)-(3-aminopiperidin-1-yl)(2-(1-ethyl-5-fluoro-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl) methanone (39), (R)-(3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-4-fluoro-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7- yl) methanone (40), (R)-(3-aminopiperidin-1-yl)(3-methyl-2-(1-((4-methylthiazol-2-yl)methyl)-1H-indol-2-yl)imidazo [1,2- a]pyridin-7-yl)methanone (41), (R)-(3-aminopiperidin-1-yl)(2-(1-(3-methoxybenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl) methanone (42), (R)-(3-aminopiperidin-1-yl)(2-(5-bromo-1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7- yl) methanone (43), (R)-(3-aminopiperidin-1-yl)(2-(7-chloro-1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7- yl) methanone (44), (R)-(3-aminopiperidin-1-yl)(2-(1-(4-fluorobenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl) methathione (45), (R)-(3-aminopiperidin-1-yl)(3-methyl-2-(1-methyl-1H-indol-2-yl)imidazo[1,2-а]pyridin-7-yl)methanone (46 ), (R)-(3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-methoxy-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7- yl) methanone (47), (R)-(3-aminopiperidin-1-yl)(2-(1-((2,4-dimethylthiazol-5-yl)methyl)-1H-indol-2-yl)-3-methylimidazo[1,2 -a]pyridin-7-yl)methanone (48), (R)-(3-aminopiperidin-1-yl)(3-methyl-2-(1-((2-methylthiazol-5-yl)methyl)-1H-indol-2-yl)imidazo [1,2- a]pyridin-7-yl)methanone (49), (R)-(3-aminopiperidin-1-yl)(2-(1-(3-methoxybenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl salts ) methanone and trifluoroacetic acid (50), (R)-(3-aminopiperidin-1-yl)(2-(6-methoxy-1-(pyridin-3-ylmethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a] pyridin-7-yl)methanone (51), (R)-(3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-6-fluoro-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7 salts -yl) methanone and trifluoroacetic acid (52), (R)-(3-aminopiperidin-1-yl)(2-(5-fluoro-1-(3-methoxybenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine- 7-yl) methanone (53), (R)-(3-aminopiperidin-1-yl)(2-(6-fluoro-1-(4-fluorobenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine- 7-yl) methanone (54), (R)-(3-aminopiperidin-1-yl)(2-(5,6-difluoro-1-(3-methoxybenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a] pyridin-7-yl) methanone (55), (R,E)-4-(dimethylamino)-N-(1-(2-(1-(4-fluorobenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine- 7-carbonyl)piperidin-3-yl)but-2-enamide (56), (R)-(3-aminopiperidin-1-yl)(3-methyl-2-(1-(pyrazin-2-ylmethyl)-1H-indol-2-yl)imidazo[1,2-a]pyridin-7 -yl) methanone (57), salts of (R)-(3-aminopiperidin-1-yl)(3-methyl-2-(1-(pyrimidin-5-ylmethyl)-1H-indol-2-yl)imidazo[1,2-a]pyridin- 7-yl) methanone and trifluoroacetic acid (58), (R)-(3-aminopiperidin-1-yl)(3-methyl-2-(1-(pyridazin-3-ylmethyl)-1H-indol-2-yl)imidazo[1,2-a]pyridin-7 -yl) methanone (59), (R)-(3-aminopiperidin-1-yl)(2-(1-isobutyl-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl)methanone (60) , (R)-(3-aminopiperidin-1-yl)(2-(1-(cyclobutylmethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl)methanone ( 61), (R)-(3-aminopiperidin-1-yl)(2-(1-((3-fluoropyridin-2-yl)methyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a ]pyridin-7-yl)methanone (62), (R)-(3-aminopiperidin-1-yl)(2-(1-((5-methoxypyridin-2-yl)methyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a ]pyridin-7-yl)methanone (63), (R)-(3-aminopiperidin-1-yl)(2-(1-(2-methoxyethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl) methanone (64), (R)-(3-aminopiperidin-1-yl)(2-(1-(2-hydroxyethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl) methanone (65), (R)-(3-aminopiperidin-1-yl)(2-(6-methoxy-1-(pyridin-4-ylmethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a] pyridin-7-yl)methanone (66), (R)-(3-aminopiperidin-1-yl)(2-(1-ethyl-6-methoxy-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl) methanone (67), (R)-(3-aminopiperidin-1-yl)(2-(6-fluoro-1-(pyridin-4-ylmethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a] pyridin-7-yl)methanone (68), (R)-(3-aminopiperidin-1-yl)(2-(6-fluoro-1-(pyridin-3-ylmethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a] pyridin-7-yl)methanone (69), (R)-(3-aminopiperidin-1-yl)(2-(6-fluoro-1-(3-methoxybenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine- 7-yl) methanone (70), (R)-(3-aminopiperidin-1-yl)(2-(6-fluoro-1-(4-methoxybenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine- 7-yl) methanone (71), (R)-(3-aminopiperidin-1-yl)(2-(1-ethyl-6-fluoro-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl) methanone (72), (R)-(3-aminopiperidin-1-yl)(2-(6-fluoro-1-isobutyl-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl) methanone (73), (R)-(3-aminopiperidin-1-yl)(2-(5-fluoro-1-(pyridin-4-ylmethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a] pyridin-7-yl)methanone (74), (R)-(3-aminopiperidin-1-yl)(2-(5-fluoro-1-(4-methoxybenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine- 7-yl) methanone (75), (R)-(3-aminopiperidin-1-yl)(2-(5-fluoro-1-(4-fluorobenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine- 7-yl) methanone (76), (R)-(3-aminopiperidin-1-yl)(2-(7-chloro-1-(4-fluorobenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine- 7-yl) methanone (77), (R)-(3-aminopiperidin-1-yl)(2-(1-(2,2-difluoroethyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine-7 salts -yl) methanone and trifluoroacetic acid (78), (R)-(3-aminopiperidin-1-yl)(2-(1-((5-fluoropyridin-2-yl)methyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a ]pyridin-7-yl)methanone (79), (R)-(3-aminopiperidin-1-yl)(2-(1-(4-fluorobenzyl)-6-methoxy-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine- 7-yl) methanone (80), (R)-(3-aminopiperidin-1-yl)(2-(1-(4-(hydroxymethyl)benzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine-7 -yl)methanone (81), (R)-(3-aminopiperidin-1-yl)(2-(1-isobutyl-6-methoxy-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl) methanone (82), (R)-(3-aminopiperidin-1-yl)(2-(1-(2,2-difluoroethyl)-6-methoxy-1H-indol-2-yl)-3-methylimidazo[1,2-a] pyridin-7-yl)methanone (83), (R)-(3-aminopiperidin-1-yl)(2-(5-fluoro-1-isobutyl-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridin-7-yl) methanone (84) and (R)-(3-aminopiperidin-1-yl)(2-(1-(4-fluoro-3-methoxybenzyl)-1H-indol-2-yl)-3-methylimidazo[1,2-a]pyridine- 7-yl)methanone (85). 12. The method of obtaining compounds of formula (I) according to any one of paragraphs. 1-4 or their stereoisomers and their pharmaceutically acceptable salts, the method comprising reacting R ₁₃ CH(O) and R ₄ CH ₂ NO ₂ with a compound selected from formula (IVA) or formula (IV),

where R ₁₃ in R ₁₃ CH(O) is selected from 6-membered monocyclic aryl and 5-10-membered monocyclic or bicyclic heteroaryl with 1-3 heteroatoms selected from N, S or O, where 6-membered monocyclic aryl and 5- 10-membered monocyclic or bicyclic heteroaryl is optionally substituted with 1-5 substituents selected from the group consisting of halogen, C _1-6 alkyl, C _1-6 alkoxy or C ₆ aryl, where C _1-6 alkyl and C ₆ aryl are optionally substituted one or more groups selected from C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C ₆ aryl, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S and O, 5-6 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, S and O, oxo, halogen and hydroxyl, where C ₆ aryl, heteroaryl and heterocyclyl are optionally substituted with one or more groups selected from C _1-6 alkyl, C _1-6 alkoxy, oxo, halogen, -CH ₂ OH and cyano; And in formulas (IVA) and (IV) is CR ₁ ; B is CR ₂ ; D is CR ₃ ; R ₁₁ and R ₁₂ are taken together to form a 5-10 membered monocyclic or bicyclic saturated heterocyclic ring, optionally with 1-3 heteroatoms selected from N, S or O, where the 5-10 membered monocyclic or bicyclic saturated heterocyclic ring is optionally substituted substituents selected from amino or -NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ ; R ₄ in R ₄ CH ₂ NO ₂ is selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl or C ₆ aryl, where C _1-6 alkyl is optionally substituted with C _1-6 alkoxy; X in formula (I) is selected from O or S; Z is N; And represents CR ₁ ; B represents

D is CR ₃ ; R ₁ , R ₂ , R ₃ and R ₄ are independently selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl or C ₆ aryl, where C _1-6 alkyl is optionally substituted with C _1-6 alkoxy; R ₁₁ and R ₁₂ may be taken together to form a 5-10 membered monocyclic or bicyclic saturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, where the 5-10 membered monocyclic or bicyclic saturated heterocyclic ring is optionally substituted substituents selected from amino or -NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ ; and R ₁₃ is selected from 6-membered monocyclic aryl and 5-10-membered monocyclic or bicyclic heteroaryl with 1-3 heteroatoms selected from N, S or O, where 6-membered monocyclic aryl and 5-10-membered monocyclic or bicyclic heteroaryl optionally substituted with 1-5 substituents selected from halogen, C _1-6 alkyl, C _1-6 alkoxy or C ₆ aryl, where C _1-6 alkyl and C ₆ aryl are optionally substituted with one or more groups selected from C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C ₆ aryl, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S and O, 5-6 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, S and O, oxo, halogen and hydroxyl, where C ₆ aryl, heteroaryl and heterocyclyl are optionally substituted with one or more groups selected from C _1-6 alkyl, C _1-6 alkoxy , oxo, halogen, -CH ₂ OH and cyano. 13. The method of obtaining compounds of formula (II) according to any one of paragraphs. 5-7 or their stereoisomers and their pharmaceutically acceptable salts, the method comprising reacting formula (V) and R ₄ CH ₂ NO ₂ with a compound selected from formula (IVA) or formula (IV),

where And in the formulas (IVA) and (IV) represents CR ₁ ; B is CR ₂ ; D is CR ₃ ; R ₁₁ and R ₁₂ are taken together to form a 5-10 membered monocyclic or bicyclic saturated heterocyclic ring, optionally with 1-3 heteroatoms selected from N, S or O, where the 5-10 membered monocyclic or bicyclic saturated heterocyclic ring is optionally substituted substituents selected from amino or -NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ ; R ₄ in R ₄ CH ₂ NO ₂ is selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl or C ₆ aryl, where C _1-6 alkyl is optionally substituted with C _1-6 alkoxy; E in formula (V) is selected from N or CR ₆ ; F is CR ₇ ; G is CR ₈ ; H is CR ₉ ; R ₁ , R ₂ and R ₃ are independently selected from hydrogen or C _1-6 alkyl; R ₅ , R ₆ , R ₇ , R ₈ , R ₉ and R ₁₀ are independently selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 alkoxy or C ₆ aryl, where C _1-6 alkyl is optionally substituted with one or several groups selected from oxo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _3-6 cycloalkyl, C ₆ aryl, 5-6 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, S and O, 5-6 membered heteroaryl containing 1-3 heteroatoms, selected H ₃ N, S and O, halogen and hydroxyl, where C ₆ aryl, heteroaryl and heterocyclyl are optionally substituted with one or more groups selected from C _1-6 alkyl, C _1-6 alkoxy, oxo, halogen, —CH ₂ OH and cyano; X in formula (II) is selected from O or S; Z is N; And represents CR ₁ ; B is CR ₂ ; D is CR ₃ ; E is selected from N or CR ₆ ; F is CR ₇ ; G is CR ₈ ; H is CR ₉ ; R ₁ , R ₂ , R ₃ and R ₄ are independently selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl or C ₆ aryl, where C _1-6 alkyl is optionally substituted with C _1-6 alkoxy; R ₅ , R ₆ , R ₇ , R ₈ , R ₉ and R ₁₀ are independently selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 alkoxy or C ₆ aryl, where C _1-6 alkyl is optionally substituted with one or several groups selected from oxo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _3-6 cycloalkyl, C ₆ aryl, 5-6 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, S and O, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S and O, halogen and hydroxyl, where C ₆ aryl, heteroaryl and heterocyclyl are optionally substituted with one or more groups selected from C _{1 -6} alkyl, C _1-6 alkoxy, oxo, halogen, -CH ₂ OH and cyano; and R ₁₁ and R ₁₂ are taken together to form a 5-10 membered monocyclic or bicyclic saturated heterocyclic ring, optionally with 1-3 heteroatoms selected from N, S or O, where a 5-10 membered monocyclic or bicyclic saturated heterocyclic ring is optional substituted with substituents selected from amino or -NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ . 14. The method of obtaining compounds of formula (III) according to any one of paragraphs. 8-10 or their stereoisomers and their pharmaceutically acceptable salts, the method comprising the reaction of formula (VII), R ₄ CH ₂ NO ₂ with a compound selected from formula (VIA) or formula (VI),

where R ₁ , R ₂ and R ₃ in formula (VIA) and formula (VI) and R ₄ in R ₄ CH ₂ NO ₂ are independently selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl or C ₆ aryl, where C _1-6 alkyl is optionally substituted with C _1-6 alkoxy; R ₅ , R ₆ , R ₇ , R ₈ , R ₉ and R ₁₀ in formula (VII) are independently selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 alkoxy or C ₆ aryl, where C _1-6 alkyl is optionally substituted with one or more groups selected from oxo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _3-6 cycloalkyl, C ₆ aryl, 5-6 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, S and O, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S and O, halogen and hydroxyl, where C ₆ aryl, heteroaryl and heterocyclyl are optionally substituted with one or more groups selected from C _1-6 alkyl, C _1-6 alkoxy, oxo, halogen, —CH ₂ OH and cyano; X in formula (III) is selected from O or S; Z is N; R ₁ , R ₂ , R ₃ and R ₄ are independently selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl or C ₆ aryl, where C _1-6 alkyl is optionally substituted with C _1-6 alkoxy; R ₅ , R ₆ , R ₇ , R ₈ , R ₉ and R ₁₀ are independently selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 alkoxy or C ₆ aryl, where C _1-6 alkyl is optionally substituted with one or several groups selected from oxo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _3-6 cycloalkyl, C ₆ aryl, 5-6 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, S and O, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S and O, halogen and hydroxyl, where C ₆ aryl, heteroaryl and heterocyclyl are optionally substituted with one or more groups selected from C _{1 -6} alkyl, C _1-6 alkoxy, oxo, halogen, -CH ₂ OH and cyano; and R ₁₁ and R ₁₂ are taken together to form a 5-10 membered monocyclic or bicyclic saturated heterocyclic ring, optionally with 1-3 heteroatoms selected from N, S or O, where a 5-10 membered monocyclic or bicyclic saturated heterocyclic ring is optional substituted with substituents selected from amino or -NH(CO)CH=CH-CH ₂ -N(CH ₃ ) ₂ . 15. A pharmaceutical composition having PAD4 inhibitory activity, which contains an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 1-11 together with a pharmaceutically acceptable carrier. 16. The pharmaceutical composition of claim 15, wherein the composition is in a form selected from a tablet, capsule, powder, syrup, solution, aerosol, and suspension. 17. Connections according to any one of paragraphs. 1-11 or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for inhibiting PAD4 in a cell. 18. A method of inhibiting PAD4 in a cell using an effective amount of a compound according to any one of paragraphs. 1-11. 19. A method of treating a condition mediated by PAD4, the method comprising administering to a subject suffering from a condition mediated by PAD4 a therapeutically effective amount of a compound according to any one of paragraphs. 1-11 or a pharmaceutical composition according to claim 15 or 16. 20. The compound of formula (I), formula (II) and formula (III) according to any one of paragraphs. 1-11 used to treat a PAD4 mediated condition selected from rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus and psoriasis. 21. The use of a compound according to any one of paragraphs. 1-11 or a pharmaceutical composition according to claim 15 or 16 for treating a PAD4 mediated condition selected from rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus and psoriasis. 22. The use of a compound according to any one of paragraphs. 1-11 or a pharmaceutical composition according to claim 15 or 16 for the treatment of a PAD4 mediated condition selected from acid-induced lung injury, respiratory failure syndrome, allergen-induced asthma, allergic bronchopulmonary disease, chronic lung disease in preterm infants, chronic obstructive pulmonary disease, colitis, cystic fibrosis, gouty arthritis, inflammatory bowel disease, inflammatory lung disease, inflammatory pain, juvenile rheumatoid arthritis, kidney disease, kidney injury caused by parasitic infections, prevention of kidney transplant rejection, lung injury, lupus, lupus nephritis, multiple sclerosis, muscle dystrophy, non-allergen-induced asthma, osteoarthritis, periodontitis, peritoneal endometriosis, psoriasis, pulmonary disease, pulmonary fibrosis, pyogenic sterile arthritis, renal disease, rheumatic disease anemia, rheumatoid arthritis, sepsis, acute pain and ulcerative colitis. 23. A method of treating and/or preventing a condition mediated by impaired functioning of PAD4, comprising administering to a subject suffering from a condition mediated by PAD4, a therapeutically effective amount of a compound according to any one of paragraphs. 1-11 or a pharmaceutical composition according to claim 15 or 16. 24. A method of treating PAD4-mediated rheumatoid arthritis, said method comprising administering a combination of compounds according to any one of paragraphs. 1-11 or a pharmaceutical composition according to claim 15 or 16 to a subject in need thereof. 25. A method of treating PAD4-mediated cancer, said method comprising administering a combination of compounds according to any one of paragraphs. 1-11 or a pharmaceutical composition according to claim 15 or 16 to a subject in need thereof.