Compounds as calcium activated chloride channel positive modulators

Abstract

Compounds of general formula (I): wherein R1, R2, R3, R4, R5a, R5b, X1, X2, Z, and Y are as defined herein, which are calcium activated chloride channel (CaCC) positive modulators, TMEM16A, as well as their use in the preparation of compounds of general formula (I): wherein R1, R2, R3, R4, R5a, R5b, X1, X2, Z, and Y are as defined herein. The compounds are useful in the treatment of diseases and conditions affected by TMEM16A modulation, in particular respiratory diseases and conditions. # imgabs0 #

Description

[0001] This application is a divisional application of the international application with application number PCT / GB2019 / 050209 and invention name “Compound” filed on January 25, 2019. The international application entered the Chinese national phase on July 27, 2020 with application number 201980010318.9. Technical Field

[0002] The present invention relates to novel compounds having activity as positive modulators of the calcium-activated chloride channel (CaCC) (TMEM16A). The present invention also relates to methods for preparing the compounds and pharmaceutical compositions containing the compounds, as well as the use of these compounds in treating diseases and conditions modulated by TMEM16A, particularly respiratory diseases and conditions. Background Art

[0003] Humans breathe in up to 12,000 liters of air daily, potentially carrying pathogens (bacteria, viruses, and fungal spores) into their respiratory tracts. To protect against these airborne pathogens, the lungs have developed innate defense mechanisms to minimize the likelihood of respiratory infection and colonization. One such mechanism is the mucus clearance system, which uses the coordinated beating of cilia and the clearing force of coughing to push secreted mucus upward and out of the respiratory tract. This continuous "clearance action" of the lungs continuously removes inhaled particles and microorganisms, thereby reducing the risk of infection.

[0004] In recent years, it has been recognized that the hydration of the mucus gel is crucial for achieving mucus clearance (Boucher 2007; Matsui et al., 1998). In the normal healthy airway, the mucus gel is typically 97% w / v water and 3% w / v solids, under which conditions mucus clearance is achieved by mucociliary action. Hydration of the respiratory mucosa is regulated by the coordinated activity of many ion channels and transporters. Anion transport (Cl) is mediated by the cystic fibrosis transmembrane conductance regulator (CFTR) and calcium-activated chloride conductance (CaCC; TMEM16A). - / HCO3 - ) secretion balance and through epithelial Na + Na channel (ENaC) + Absorption determines the hydration state of the respiratory mucosa. As ions are transported across the epithelium, water is forced to follow due to osmotic pressure, so fluid is either secreted or absorbed.

[0005] In respiratory diseases such as chronic bronchitis and cystic fibrosis, when hydration decreases and mucus clearance decreases, the % solids in the mucus gel increases (Boucher, 2007). In cystic fibrosis, when loss-of-function mutations in CFTR occur, which reduce the ability of the airways to secrete fluid, the % solids can increase to 15%, which is thought to cause small airway obstruction and loss of mucus clearance. Strategies to increase airway mucus hydration include stimulating anions, thereby stimulating fluid secretion, or inhibiting Na + To this end, stimulation of TMEM16A channel activity would increase anion secretion and, therefore, fluid accumulation in the respiratory mucosa, hydrating mucus and enhancing mucus clearance mechanisms.

[0006] TMEM16A, also known as calcium-activated chloride channel protein 1 (Anoctamin-1, Ano1), is a molecular marker for calcium-activated chloride channels (Caputo et al., 2008; Yang et al., 2008). TMEM16A channels open in response to elevated intracellular calcium levels and allow the bidirectional flow of chloride ions, bicarbonate, and other anions across the cell membrane. Functionally, TMEM16A channels have been proposed to regulate transepithelial ion transport, gastrointestinal motility, nociception, and cell migration / proliferation (Pedemonte & Galietta, 2014).

[0007] The TMEM16A channel is expressed by epithelial cells of different organs, including the lungs, liver, kidneys, pancreas, and salivary glands. In the respiratory epithelium, TMEM16A is expressed at high levels in goblet cells, ciliated cells, and submucosal glands that produce mucus. Physiologically, TMEM16A is activated by stimulants that mobilize intracellular calcium, particularly purinergic agonists (ATP, UTP), which are released by the respiratory epithelium in response to periodic shear stress caused by breathing and other mechanical stimuli such as coughing. In addition to increasing anion secretion and enhancing hydration of the respiratory tract, the activation of TMEM16A plays an important role in bicarbonate secretion. It is reported that bicarbonate secretion is an important regulator of mucus properties and control of the pH value of the respiratory tract chamber, thereby controlling the activity of natural antimicrobial agents such as defensins (Pezzulo et al., 2012).

[0008] Indirect regulation of TMEM16A through elevation of intracellular calcium has been explored clinically, for example with denufosol (Kunzelmann & Mall, 2003). While encouraging preliminary results have been observed in small patient cohorts, this approach has not provided clinical benefit in larger cohorts (Accurso et al., 2011; Kellerman et al., 2008). This lack of clinical effect has been attributed to only a transient increase in anion secretion (a consequence of denufosol's short half-life on epithelial surfaces and receptor / pathway desensitization), as well as adverse effects of elevated intracellular calcium, such as increased mucus release from goblet cells (Moss, 2013). Compounds that act directly on TMEM16A to enhance channel opening in the presence of low-level calcium elevations are expected to provide sustained enhancement of anion secretion and mucociliary clearance in patients and improve innate defenses. Because TMEM16A activity is independent of CFTR function, TMEM16A positive modulators have the potential to provide clinical benefit to all patients with CF and non-CF respiratory diseases characterized by mucus congestion, including chronic bronchitis and severe asthma.

[0009] TMEM16A modulation has been suggested for the treatment of dry mouth (xerostomia), dry eyes, cholestasis, and gastrointestinal dysmotility caused by salivary gland dysfunction and radiation therapy in Sjögren's syndrome.

[0010] The present inventors have developed novel compounds that are positive modulators of TMEM16A and are therefore useful in the treatment of diseases and disorders in which modulation of TMEM16A plays a role, particularly respiratory diseases and disorders. Summary of the Invention

[0011] In a first aspect of the present invention, there is provided a compound of formula (I), including all tautomeric forms, all enantiomers and isotopic variants thereof, and salts and solvates thereof:

[0012]

[0013] in:

[0014] R 1 is H, CN, C(O)OR 12 、C 1-3 Alkyl, C 2-3 Alkenyl or C 2-3 Alkynyl, any of the alkyl, alkenyl or alkynyl groups is optionally substituted by one or more substituents, suitably one substituent, selected from fluorine, OR 12 、N(R 12 )2、C(O)OR 12 、C(O)N(R 12)2、C(O)R 12 and N(R 13 )C(O)R 12 ;

[0015] where R 12 and R 13 Each independently selected from H, C 1-6 Alkyl and C 1-6 Fluoroalkyl

[0016] R 2 Is H or C 1-6 Alkyl, which is optionally substituted with OR 12 replace;

[0017] R 3 yes:

[0018] C 1-10 Alkyl, C 2-10 Alkenyl or C 2-10 Alkynyl, any of which is optionally substituted by one or more substituents, suitably by one substituent, selected from fluorine, CN, R 14 OR 14 , OR 15 、N(R 15 )2、C(O)OR 15 、C(O)N(R 15 )2、N(R 16 )C(O)R 15 、N(R 15 )S(O)2R 14 、N(R 15 )S(O)2R 16 and N(R 15 )C(O)OR 16 ;or

[0019] 3- to 7-membered carbocyclic or heterocyclic ring systems or 6- to 10-membered aryl or 5- to 10-membered heteroaryl ring systems, each of which is optionally substituted with one or more substituents selected from the group consisting of halo, CN, C 1-4 Alkyl, C 1-4 Halogenated alkyl, OR 17 and N(R 17 )2;

[0020] where R 14 is a 6- to 10-membered aryl or 5- to 10-membered heteroaryl ring system or a 3- to 7-membered carbocyclic or heterocyclic ring system, any of which is optionally substituted with one or more substituents selected from the group consisting of halo, C 1-4 Alkyl, C 1-4 Halogenated alkyl, OR 17 and N(R 17)2; where R 17 Each independently is H, C 1-4 Alkyl or C 1-4 alkyl halide;

[0021] R 15 and R 16 Each independently is H, C 1-6 Alkyl or C 1-6 haloalkyl; or

[0022] R 2 and R 3 Together with the carbon atoms to which they are attached, they form a 3- to 10-membered carbocyclic or heterocyclic ring system, which is optionally substituted by one or more substituents selected from the group consisting of halo, CN, OR 9 、N(R 9 )2、C(O)OR 9 、C(O)N(R 9 )2、C(O)R 9 、N(R 9 )C(O)R 9 and optionally halogenated, OR 9 or N(R 9 )2 substituted C 1-4 alkyl; or

[0023] R 1 、R 2 and R 3 Together with the carbon atoms to which they are attached, they form a bridged 5- to 10-membered carbocyclic or heterocyclic ring system or phenyl, any of which is optionally substituted with one or more substituents selected from the group consisting of halo, CN, OR 9 、N(R 9 )2、C(O)OR 9 、C(O)N(R 9 )2、C(O)R 9 、N(R 9 )C(O)R 9 and optionally halogenated, OR 9 or N(R 9 )2 substituted C 1-4 alkyl;

[0024] R 9 Each independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0025] X 1 and X 2 Each of which is independently N or CR 8 ;

[0026] R8 H, halide, OH, O(C 1-4 alkyl), CN or NH2;

[0027] Y is a bond or a linear C 1-6 Alkylene chain, which is optionally substituted by one or more substituents R 18 Substitution, where two substituents R 18 can be attached to the same or different carbon atoms;

[0028] where R 18 Each is independently C 1-3 Alkyl or C 1-3 Haloalkyl, wherein -CH2- is optionally replaced by -NH- or -O-, and wherein both R 18 The groups may be combined with the atom or atoms to which they are attached to form a 3- to 6-membered carbocyclic or heterocyclic ring system;

[0029] Z is -C(O)- or -C(O)NH-;

[0030] R 4 is a 6- to 14-membered aryl, a 5- to 14-membered heteroaryl, or a 5- to 10-membered carbocyclic ring system, any of which is optionally substituted with one or more substituents selected from:

[0031] Halo, CN, nitro, R 19 , OR 19 , OR 6 SR 6 NR 6 R 7 、C(O)R 6 、C(O)R 19 、C(O)OR 6 、C(O)N(R 6 )(R 7 )、N(R 7 )C(O)R 6 ;

[0032] C 1-6 Alkyl or O(C 1-6 alkyl), any of which is optionally substituted by one or more substituents selected from the group consisting of halo, CN, nitro, R 19 , OR 6 SR 6 NR 6 R 7 、C(O)R 6 C(O)OR 6 、C(O)N(R 6 )(R 7 ) and N(R 7 )C(O)R6 ;and

[0033] Oxo, when R 4 This is true when not completely aromatic in nature;

[0034] where R 19 is a 5- or 6-membered aryl or heteroaryl ring system or a 3- to 7-membered carbocyclic or heterocyclic ring system, any of which is optionally substituted with one or more substituents selected from the group consisting of halo, C 1-4 Alkyl, C 1-4 Haloalkyl, OH, O(C 1-4 alkyl), O(C 1-4 haloalkyl);

[0035] R 6 It is H, C 1-6 Alkyl, C 1-6 haloalkyl, benzyl, 3- to 7-membered carbocyclyl, or 3- to 7-membered heterocyclyl;

[0036] R 7 It is H, C 1-6 Alkyl or C 1-6 haloalkyl; or

[0037] R 6 and R 7 Together with the nitrogen atom to which they are attached, they may form a 4- to 7-membered heterocyclic ring, which optionally contains one or more additional heteroatoms and is optionally substituted with one or more substituents selected from oxo and halo; and

[0038] R 5a and R 5b Each of them is independently H, C 1-4 an alkyl group or a halo group;

[0039] It is used in medical applications.

[0040] In this specification, unless the context requires otherwise due to express language or necessary implication, the word "comprise" or variations such as "comprises" or "comprising" are used in an inclusive sense, that is, to specify the presence of stated features but not to preclude the presence or addition of other features in various embodiments of the invention.

[0041] As used herein, "medical use" refers to administration to humans or animals, particularly humans or mammals, such as domestic or livestock mammals, for the treatment or prevention of a disease or medical condition. The term "pharmaceutical composition" refers to a composition suitable for medical use, and "pharmaceutically acceptable" applies to the active agent of a pharmaceutical composition. Other similar terms should be interpreted accordingly.

[0042] In this specification, the term "C1-6 "Alkyl" refers to a straight or branched fully saturated hydrocarbon group having 1 to 6 carbon atoms. The term includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. Other alkyl groups, such as C 1-10 Alkyl groups are as defined above but contain different numbers of carbon atoms.

[0043] The term "C 2-6 "Alkenyl" refers to a straight or branched hydrocarbon group having 1 to 6 carbon atoms and at least one carbon-carbon double bond, and includes ethenyl, propen-1-yl, propen-2-yl, buten-1-yl and buten-2-yl. Other alkenyl groups, such as C 2-10 Alkenyl groups are as defined above but contain a different number of carbon atoms.

[0044] The term "C 2-6 "Alkynyl" refers to a straight or branched chain hydrocarbon group having 1 to 6 carbon atoms and at least one carbon-carbon triple bond, and the term includes ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl and butyn-2-yl. Other alkynyl groups, such as C 2-10 Alkynyl groups are as defined above but contain different numbers of carbon atoms.

[0045] The term "C 1-6 "Alkylene" refers to a straight or branched fully saturated hydrocarbon chain having 1 to 6 carbon atoms. Examples of alkylene include -CH2-, -CH2CH2-, CH(CH3)-CH2-, CH2CH(CH3)-, -CH2CH2CH2-, -CH2CH(CH2CH3)-, and -CH2CH(CH2CH3)CH2-. Other alkylene groups, such as C 1-3 Alkylene is as defined above, except containing the specified number of carbon atoms (eg, 1 to 3).

[0046] Unless otherwise indicated, the terms "carbocycle" and "carbocyclyl" refer to non-aromatic hydrocarbon ring systems containing from 3 to 10 ring carbon atoms, and optionally containing one or more double bonds. A carbocyclic group can be a monocyclic ring or can contain two or three rings, which can be fused or bridged, wherein the carbon atoms in the bridge are included in the number of ring carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, and cyclohexenyl, as well as bridged systems such as bicyclo[1.1.1]pentyl, bicyclo-[2.2.1]heptyl, bicyclo-[2.2.2]octyl, and adamantyl.

[0047] As used herein, the terms "heterocycle" and "heterocyclyl" refer to non-aromatic ring systems containing 3 to 10 ring atoms, including at least one heteroatom selected from N, O, and S. The heterocyclic group may be monocyclic or may comprise two or three rings, which may be fused or bridged, with the bridging atoms included in the number of ring atoms. Examples include tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, and thiomorpholinyl, as well as fused systems such as cyclopropyl-fused pyrrolidine.

[0048] In the context of this specification, the terms "aryl" and "aromatic" refer to ring systems having 5 to 14 ring carbon atoms and containing up to three rings with aromatic character. When an aryl group contains more than one ring, not all rings must be fully aromatic. Examples of aromatic groups are benzene, naphthalene, fluorene, tetrahydronaphthalene, indane, and indene.

[0049] As used herein, the terms "heteroaryl" and "heteroaromatic" refer to ring systems having aromatic character containing 5 to 14 ring atoms, wherein at least one ring atom is a heteroatom selected from N, O, and S, and containing up to three rings. When a heteroaryl group contains more than one ring, not all rings must be aromatic. Examples of heteroaryl groups include pyridine, pyrimidine, indole, indazole, thiophene, benzothiophene, benzoxazole, benzofuran, dihydrobenzofuran, tetrahydrobenzofuran, benzimidazole, benzimidazolinone, quinoline, and indoline.

[0050] The term "oxo" refers to a C=O substituent wherein the carbon atom is a ring atom of a carbocyclyl, heterocyclyl, or an aryl or heteroaryl ring that does not have aromatic character.

[0051] The term "halogen" refers to fluorine, chlorine, bromine or iodine, and the term "halo" refers to a fluorine, chlorine, bromine or iodine group. Similarly, "halide" refers to fluoride, chloride, bromide or iodide.

[0052] The term "C 1-6 "Haloalkyl" as used herein refers to a C 1-6 An alkyl group in which one or more hydrogen atoms are replaced by a halo group. Any number of hydrogen atoms may be replaced, up to perhalogenation. Examples include trifluoromethyl, chloroethyl, and 1,1-difluoroethyl. A fluoroalkyl group is a haloalkyl group in which the halo is fluorine.

[0053] The term "isotopic variant" refers to an isotopically labeled compound that is identical to those described in Formula (I), but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature, or in which the proportion of atoms having an atomic mass or mass number less common in nature is increased (the latter concept is referred to as "isotopic enrichment"). Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, iodine, and chlorine, such as 2H (deuterium), 3H, 11C, 13C, 14C, 18F, 123I, or 125I (e.g., 3H, 11C, 14C, 18F, 123I, or 125I), which may be naturally occurring or non-naturally occurring isotopes.

[0054] The compounds of formula (I) are modulators of TMEM16A. Therefore, in another aspect of the present invention, there is provided a compound of formula (I) as defined above for use in the treatment or prevention of diseases and disorders affected by TMEM16A modulation.

[0055] Also provided herein is the use of a compound of formula (I) in the preparation of a medicament for treating or preventing diseases and disorders affected by TMEM16A modulation.

[0056] Also provided herein are methods of treating or preventing diseases and conditions affected by TMEM16A modulation, comprising administering to a patient in need of such treatment an effective amount of a compound of formula (I).

[0057] Such diseases and conditions affected by TMEM16A regulation include respiratory diseases and conditions, dry mouth (xerostomia), overactive bowel, cholestasis, and ocular symptoms.

[0058] Also provided:

[0059] - Compounds of general formula (I) for use in the treatment or prevention of diseases and disorders of the respiratory system.

[0060] - A compound of formula (I) for use in the treatment or prevention of dry mouth (xerostomia).

[0061] - A compound of formula (I) for use in the treatment or prevention of intestinal hyperactivity.

[0062] - A compound of formula (I) for use in the treatment or prevention of cholestasis.

[0063] - A compound of formula (I) for use in the treatment or prevention of ocular symptoms.

[0064] Also provided:

[0065] Use of a compound of formula (I) in the preparation of a medicament for treating or preventing respiratory diseases and disorders.

[0066] Use of a compound of formula (I) in the preparation of a medicament for treating or preventing dry mouth (xerostomia).

[0067] Use of a compound of formula (I) in the preparation of a medicament for treating or preventing intestinal hyperactivity.

[0068] Use of a compound of general formula (I) in the preparation of a medicament for treating or preventing cholestasis.

[0069] Use of a compound of general formula (I) in the preparation of a medicament for treating or preventing eye symptoms.

[0070] Further provided:

[0071] A method for treating or preventing diseases and disorders of the respiratory system, which method comprises administering to a patient in need of such treatment an effective amount of a compound of general formula (I).

[0072] - A method for the treatment or prevention of dry mouth (xerostomia), which method comprises administering to a patient in need of such treatment an effective amount of a compound of general formula (I).

[0073] A method for treating or preventing intestinal hyperactivity, which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I).

[0074] A method for treating or preventing cholestasis, which comprises administering an effective amount of a compound of formula (I) to a patient in need of such treatment.

[0075] A method for treating or preventing ocular symptoms, which comprises administering an effective amount of a compound of formula (I) to a patient in need of such treatment.

[0076] Respiratory diseases and conditions that can be treated or prevented using compounds of formula (I) include cystic fibrosis, chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema, bronchiectasis, including non-cystic fibrosis bronchiectasis, asthma and primary ciliary dyskinesia.

[0077] Dry mouth (xerostomia) that can be treated or prevented by the compounds of formula (I) is caused by Sjögren's syndrome, radiation therapy, or xerogenic drugs.

[0078] Intestinal hyperactivity that can be treated or prevented by the compounds of general formula (I) may be associated with gastric dyspepsia, gastroparesis, chronic constipation or irritable bowel syndrome.

[0079] Ocular conditions that can be treated or prevented using compounds of formula (I) include dry eye.

[0080] In some cases, in the compounds of formula (I), Z is -C(O)-, and R 5b is H, such that the compound has the formula (Iz):

[0081]

[0082] where R 1 、R 2 、R 3 、R 4 、R 5a and Y is as defined in the general formula (I).

[0083] In some cases, in the compound of formula (I), Z is -C(O)NH-, and R 5b is H, so that the compound has the general formula (Iy):

[0084]

[0085] where R 1 、R 2 、R 3 、R 4 、R 5a and Y is as defined in the general formula (I).

[0086] In some compounds of Formula (Iz), Y is not a bond.

[0087] In some cases, the compound of formula (I) is a compound of formula (Ix), including all tautomeric forms, all enantiomers and isotopic variations, and salts and solvates thereof:

[0088]

[0089] in:

[0090] R 1 is H, CN or C 1-3 Alkyl, which is optionally substituted by one or more substituents selected from the group consisting of halo, OR 12 、N(R 12 )2、C(O)OR 12 、C(O)N(R 12 )2、C(O)R 12 and N(R 13 )C(O)R 12 ;

[0091] where R 12 and R 13 Each independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0092] R2 It is C 1-6 alkyl;

[0093] R 3 It is C 1-6 Alkyl, which is optionally substituted by one or more substituents selected from the group consisting of halo, OH, O(C 1-6 alkyl), C(O)O-(C 1-6 alkyl) and N(H)C(O)O-(C 1-6 alkyl); or

[0094] R 2 and R 3 Together with the carbon atoms to which they are attached, they form a 3- to 10-membered carbocyclic or heterocyclic ring system, which is optionally substituted by one or more substituents selected from the group consisting of halo, OR 9 、N(R 9 )2、C(O)OR 9 、C(O)N(R 9 )2、C(O)R 9 and N(R 9 )C(O)R 9 ;or

[0095] R 1 、R 2 and R 3 Together with the carbon atoms to which they are attached, they form a bridged 5- to 10-membered carbocyclic or heterocyclic ring system, which is optionally substituted with one or more substituents selected from the group consisting of halo, OR 9 、N(R 9 )2、C(O)OR 9 、C(O)N(R 9 )2、C(O)R 9 、N(R 9 )C(O)R 9 ;

[0096] R 9 Each independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0097] X 1 and X 2 Each of which is independently N or CR 8

[0098] R 8 is H, halo, OH, CN or NH2;

[0099] Y is a bond or C 1-6 alkylene;

[0100] R4 is a 6- to 10-membered aryl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered carbocyclic or heterocyclic ring system, any of which is optionally substituted with one or more substituents selected from:

[0101] Halo, CN, nitro;

[0102] OR 6 SR 6 NR 6 R 7 、C(O)R 6 C(O)OR 6 、C(O)N(R 6 )(R 7 )、N(R 7 )C(O)R 6 ;

[0103] C 1-6 Alkyl, which is optionally substituted with one or more substituents selected from the group consisting of halo, CN, nitro, OR 6 SR 6 NR 6 R 7 、C(O)R 6 C(O)OR 6 、C(O)N(R 6 )(R 7 ) and N(R 7 )C(O)R 6 ;and

[0104] Oxo, when R 4 This is true when not completely aromatic in nature;

[0105] where R 6 It is H, C 1-6 Alkyl, C 1-6 a haloalkyl group, a 3-7 membered carbocyclyl group, or a 3-7 membered heterocyclyl group;

[0106] R 7 It is H, C 1-6 Alkyl or C 1-6 haloalkyl; or

[0107] R 6 and R 7 Together with the nitrogen atom to which they are attached, they may form a 4- to 7-membered heterocyclic ring, which optionally contains one or more additional heteroatoms and is optionally substituted with one or more oxo substituents;

[0108] R 5 It is H, C 1-4 Alkyl or halo.

[0109] In some suitable compounds of the present invention, R 1 is H, CN, C(O)OR 12 or methyl, ethyl or ethynyl, which is optionally substituted by one or more substituents selected from the group consisting of fluorine, OR 12 、N(R 12 )2、C(O)OR 12 、C(O)N(R 12 )2、C(O)R 12 and N(R 13 )C(O)R 12 ;

[0110] where R 12 and R 13 are each independently as defined above, but more suitably are H or C 1-4 alkyl.

[0111] More appropriately, R 1 is H, CN, C(O)OH, C(O)OMe or methyl, ethyl or ethynyl, any of which may be unsubstituted or substituted by one or more substituents selected from the group consisting of fluorine, OH, methoxy, C(O)OC 1-4 Alkyl, NHC(O)C 1-4 Alkyl, C(O)NHC 1-4 Alkyl, NHC 1-4 Alkyl and NHC 1-4 Fluoroalkyl.

[0112] In some more suitable compounds, R 1 is H, CN, ethynyl or methyl, either of which may be unsubstituted or substituted by OH; in particular H, CN or methyl.

[0113] Among some suitable compounds of the present invention:

[0114] R 2 is methyl or ethyl, in particular methyl; and

[0115] R 3 It is C 1-4 Alkyl, or more suitably C 1-3 Alkyl, such as methyl, ethyl or isopropyl; any of which is optionally substituted by one or more substituents selected from the group consisting of hydroxy, methoxy, ethoxy, -C(O)O-(C 1-4 alkyl) and -N(H)C(O)O-(C 1-4 alkyl).

[0116] In this case, more preferably, R 3 Unsubstituted or substituted with a single substituent selected from methoxy, ethoxy and -N(H)C(O)O-(C1-4 alkyl), in particular methoxy or / and -N(H)C(O)O-(C 1-4 alkyl).

[0117] In these compounds, R 1 Suitably it is methyl.

[0118] In other suitable compounds of the present invention, R 2 Is H or C 1-4 Alkyl is more suitably H, methyl or ethyl, especially H or methyl.

[0119] In some suitable compounds of the present invention, R 3 It is C 1-10 Alkyl, more preferably C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl groups, any of which may be optionally substituted as described above.

[0120] More appropriately, R 3 It is C 1-10 Alkyl, more preferably C 1-6 Alkyl or C 2-3 Alkynyl.

[0121] More appropriately, when R 3 When alkyl, alkenyl or alkynyl, it is unsubstituted or substituted with a single substituent selected from the group consisting of fluorine, R 14 OR 14 , OR 15 、C(O)OR 15 、N(R 16 )S(O)2R 15 and N(R 16 )C(O)OR 15 ; where R 14 、R 15 and R 16 As described above.

[0122] Among these compounds, R 14 is selected from phenyl, pyridyl and a 5- or 6-membered heterocyclic ring, especially a nitrogen-containing ring, and more particularly a 6-membered nitrogen-containing ring such as morpholine, piperidine or piperazine. More suitably, R 15 Selected from H or C 1-4 Alkyl. R 16 Suitably H.

[0123] The R 3 Examples of groups include:

[0124] Methyl or ethyl, optionally substituted with OH, F, phenyl, O-phenyl, morpholine, NHS(O)2C1-4 Alkyl or NHC(O)C 1-4 Alkyl substitution;

[0125] Propynyl, for example prop-1-ynyl and ethynyl.

[0126] In other suitable compounds, R 3 is a 3- to 7-membered carbocyclic or heterocyclic ring system, especially C 3-7 Cycloalkyl groups, such as cyclopropyl, may be substituted as defined above, but are preferably unsubstituted.

[0127] In other suitable compounds of formula (I), R 3 is a 6- to 10-membered aryl or 5- to 10-membered heteroaryl ring system, any of which is optionally substituted as described above.

[0128] In this case, more preferably, R 3 is optionally substituted phenyl or 5- or 6-membered heteroaryl as defined above, in particular phenyl or pyridinyl.

[0129] The R 3 The group may be unsubstituted or substituted as defined above, in particular selected from OR 17 and N(R 17 )2 is substituted with a suitable substituent, wherein R 17 Each is independently as defined above, but is more suitably H or methyl.

[0130] In some particularly suitable compounds of the present invention, R 1 is methyl or CN, and R 2 and R 3 All are methyl groups.

[0131] In some suitable compounds of the present invention, R 2 and R 3 Combined with the carbon atom to which they are attached, they form a carbocyclic or heterocyclic ring system.

[0132] By R 2 and R 3 Suitable carbocycles formed include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; and bridged systems such as bicyclo[1.1.1]pentyl, bicyclo-[2.2.1]heptyl, bicyclo-[2.2.2]octyl and adamantyl, (provided that R 2 and R 3 The atoms connected are not bridge atoms).

[0133] By R 2 and R 3 More suitable carbocyclic rings formed include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0134] By R 2 and R 3 Suitable heterocycles formed include tetrahydropyran-yl, such as tetrahydropyran-4-yl; tetrahydrofuran-yl, such as tetrahydrofuran-3-yl; oxetanyl, such as oxetan-3-yl; piperidinyl, such as piperidin-2-yl and piperidin-4-yl; morpholinyl, piperazinyl and cyclopropyl-fused pyrrolidine.

[0135] By R 2 and R 3 More suitable heterocycles formed include: tetrahydropyran-yl, such as tetrahydropyran-4-yl; tetrahydrofuran-yl, such as tetrahydrofuran-3-yl; oxetanyl, such as oxetan-3-yl; piperidinyl, such as piperidin-2-yl and piperidin-4-yl; and cyclopropyl-fused pyrrolidines.

[0136] By R 2 and R 3 Any ring system formed may be substituted as described above. In some cases, the ring system is unsubstituted or is selected from OR 9 and C(O)OR 9 A single substituent is substituted, wherein R 9 As defined above, but suitably C 1-4 Alkyl, such as tert-butyl.

[0137] In other suitable compounds, R 2 and R 3 The resulting carbocyclic or heterocyclic ring system may be unsubstituted or substituted by one or more substituents, for example 1 or 2 substituents selected from halogen, OR 9 、C(O)OR 9 , unsubstituted C 1-4 Alkyl and halogen or OR 9 Substituted C 1-4 The alkyl substituent is more suitably substituted by 1 or 2 groups selected from fluorine, OR 9 、C(O)OR 9 , unsubstituted C 1-4 Alkyl and fluorinated or OR 9 Substituted C 1-4 The alkyl group is substituted with a substituent.

[0138] In particular, by R 2 and R 3 The resulting carbocyclic or heterocyclic ring system may be unsubstituted or substituted by one or more substituents, for example 1 or 2 substituents selected from fluorine, OH, C(O)O(C 1-4 Alkyl), unsubstituted C 1-4 Alkyl or C substituted by OH 1-4 alkyl.

[0139] In some compounds, where R 2 and R 3 To form a carbocyclic or heterocyclic ring system, R 1 It’s H.

[0140] In other compounds of this type, R 1 It is a methyl group.

[0141] In other compounds of this type, R 1 It is a methyl group substituted by OH.

[0142] In other such compounds, R 1 For CN.

[0143] In other such compounds, R 1 For ethynyl.

[0144] In other such compounds, R 1 C(O)OR 12 , for example C(O)OCH3.

[0145] Among particularly suitable compounds, R 2 and R 3 To form a carbocyclic or heterocyclic ring system:

[0146] R 1 is H or cyano, R 2 and R 3 Forming a 5- or 6-membered carbocyclic or heterocyclic ring system, in particular a 6-membered ring system, for example cyclohexyl or tetrahydropyranyl, such as tetrahydropyran-4-yl.

[0147] In other suitable compounds of the present invention, R 1 、R 2 and R 3 In combination with the carbon atom to which it is attached it forms a bridged carbocyclic or heterocyclic ring system, in particular a carbocyclic ring system, for example bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo-[2.2.1]heptyl, bicyclo-[2.2.2]octyl or adamantyl.

[0148] In some cases, the carbocyclic ring system can be selected from 3-bicyclo[1.1.1]pentyl, bicyclo-[2.2.1]heptyl, bicyclo-[2.2.2]octyl, and 1-adamantyl.

[0149] In other cases, the carbocyclic ring system may be selected from bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl and adamantyl, in particular 3-bicyclo[1.1.1]pentyl, 1-bicyclo[2.1.1]hexyl and 1-adamantyl.

[0150] Suitably, the ring system is unsubstituted or is selected from OR 9 and C(O)OR 9 A single substituent is substituted, wherein R 9 As defined above, but suitably is H, methyl or ethyl, especially H or methyl, and more especially methyl. More suitably, the ring system is unsubstituted.

[0151] Alternatively, the ring system may be unsubstituted or substituted with one or more substituents, suitably one or two substituents and more suitably a single substituent, selected from fluoro, cyano, C 1-4 Alkyl, OR 9 and C(O)OR 9 , where R 9 As defined above, but suitably is H, methyl or ethyl, especially H or methyl, and more especially methyl.

[0152] In other suitable compounds of the present invention, R 1 、R 2 and R 3 Combined with the carbon atom to which it is attached it forms a phenyl group which may be substituted as defined above but is more suitably unsubstituted.

[0153] In some suitable compounds of formula (I), X 1 is N, and X 2 CR 8 , where R 8 As defined above. In particular, X 1 N and X 2 For CH.

[0154] Suitably in such compounds, when -Z is C(O)-, and Y is a bond, R 4 Other than a 5- to 10-membered heteroaryl ring system, the ring system is attached to the linker Y via a ring nitrogen atom.

[0155] In other suitable compounds of general formula (I), X 1 and X 2 All CR 8 , where R 8 Each is independently as defined above.

[0156] In this type of compound, R 4 Suitably this is a phenyl group having an OH substituent in the 2- or 3-position, and optionally having one or more further substituents as defined above.

[0157] More appropriately, R 4 is phenyl having an OH substituent in the 2-position, and optionally having one or more further substituents as defined above.

[0158] In other suitable compounds of general formula (I), X 1 CR 8 , where R 8 As defined above, and X 2 is N.

[0159] In some suitable compounds of this type, Z is -C(O)- and Y is not a bond. Thus, Y may be optionally substituted with one or more substituents R as defined above. 18 Substituted straight chain C 1-6 Alkylene chain.

[0160] In other compounds, where X 1 CR 8 , X 2 is N, Z is -C(O)NH-, and Y is a bond, R 4 Suitably it is not a 12-membered heteroaryl ring system.

[0161] In other suitable compounds of general formula (I), wherein X 1 CR 8 , where R 8 As defined above, and X 2 For N:

[0162] When R 1 and R 2 When both are H, R 3 is not an optionally substituted 5- or 6-membered aryl or heteroaryl ring system as described above; and wherein when R 1 When it is H, R 2 and R 3 They do not combine to form a cyclohexyl ring.

[0163] In other suitable compounds of formula (I), X 1 and X 2 All are N.

[0164] In these compounds, suitably when R 1 and R 2 One of them is H, and R 1 and R 2 When the other is H or methyl, R 3 It is not substituted or unsubstituted phenyl.

[0165] In the compounds of the present invention, when X 1 and / or X 2 CR 8 , R 8 Suitably is H or halogen, for example H or fluorine. In other suitable compounds, R 8is H, halogen, OH, methoxy or ethoxy, especially H, fluorine, chlorine, OH or methoxy.

[0166] As mentioned above, in more suitable compounds of the present invention, Z is -C(O)- or C(O)NH, and the compound has the general formula (Iz), (Iy) or (Ix).

[0167] In some more suitable compounds of the present invention, Y is C 1-3 Alkylene is more suitably -CH2-, -CH(CH3)CH2- or -CH2CH2-. More suitably, Y is -CH2- or -CH2CH2-, and in particularly suitable compounds, Y is -CH2-.

[0168] In other suitable compounds of the invention, Y is a bond.

[0169] In other suitable compounds of the present invention, Y is optionally substituted by one or more substituents R 18 Substituted straight chain C 1-3 Alkylene, where R 18 As defined above, and wherein the two substituents R 18 They can be attached to the same or different carbon atoms.

[0170] Suitably, in such compounds, each R 18 are independently methyl or ethyl, or two R 18 The groups are attached to the same carbon atom to combine to form a cyclopropyl, cyclobutyl or cyclopentyl ring.

[0171] More suitably, Y is a bond or -C 1-3 Alkylene-.

[0172] Examples of the linking group Y include a bond, -CH2-, -CH(CH3)-, -CH2CH2- and

[0173] In other suitable compounds of general formula (I), Y is -CH2-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)- or -CH2CH2CH2-, especially -CH2- or -CH2CH2-, more especially -CH2-.

[0174] In some suitable compounds of formula (I), R 5b is H or a halogen, such as fluorine.

[0175] More generally, R 5b is H, so that the compound is a compound of the above-mentioned general formula (Iz), (Iy) or (Ix).

[0176] In some suitable compounds of formula (I), (Iz) and (Iy), R5a It is H, C 1-4 Alkyl or halogen, such as fluorine.

[0177] In some suitable compounds of formula (I), (Iz) and (Iy), R 5a is methyl or ethyl, especially methyl.

[0178] In other suitable compounds of formula (I), (Iz) and (Iy), R 5a is a halogen, especially fluorine.

[0179] More generally, in the compounds of formula (I), (Iz) and (Iy), R 5a It’s H.

[0180] In some suitable compounds of formula (Ix), R 5 It’s H.

[0181] In other suitable compounds of formula (Ix), R 5 It is C 1-4 Alkyl, more typically methyl or ethyl, and especially methyl.

[0182] In other suitable compounds of the present invention, R 5 is a halogen, especially fluorine.

[0183] In typical compounds of formula (I), R 5a and R 5b Both are H.

[0184] In the compounds of the present invention, R 4 is a 6-14-membered aryl, a 5-14-membered heteroaryl or a 5- to 10-membered carbocyclic ring system, any of which is optionally substituted as defined above. More suitably, R 4 is a 6- to 10-membered aryl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered carbocyclic or heterocyclic ring system, any of which is optionally substituted with one or more substituents as described above.

[0185] In some more suitable compounds of formula (I), R 4 is a 6- to 11-membered aryl group, for example a group selected from phenyl, naphthyl, indanyl, 1,2,3,4-tetrahydronaphthyl and benzocycloheptyl, any of which is optionally substituted as described above.

[0186] In other more suitable compounds of general formula (I), R 4 is a 5- to 10-membered heteroaryl group, for example a group selected from pyridyl, quinolinyl, quinoxalinyl, indazolyl, indolyl, benzoxazolyl, dihydrobenzofuranyl, furanyl and thienyl, any of which is optionally substituted as described above.

[0187] In some other more suitable compounds of general formula (I), R 4 is a carbocyclic group, for example a group selected from cyclohexyl and adamantyl, either of which is unsubstituted or substituted as described above.

[0188] In some suitable compounds of the present invention, R 4 is phenyl optionally substituted by one or more substituents as described above.

[0189] Or, R 4 is a 5-10-membered heteroaryl group optionally substituted by one or more substituents as described above, in which case R 4 is pyridyl, pyrrolyl, thienyl, furyl, benzoxazolyl, imidazolyl, indolyl or indazolyl.

[0190] In some suitable compounds, R 4 Substituted by one or more substituents selected from the following:

[0191] Halogen, CN;

[0192] OR 6 NR 6 R 7 、C(O)OR 6 、C(O)N(R 6 )(R 7 );

[0193] C optionally substituted by one or more substituents selected from the following 1-6 Alkyl: halogen, CN, OR 6 NR 6 R 7 、C(O)OR 6 and C(O)N(R 6 )(R 7 );

[0194] where R 6 It is H, C 1-6 Alkyl, C 1-6 a haloalkyl group, a 3-7 membered carbocyclyl group, or a 3-7 membered heterocyclyl group;

[0195] R 7 It is H, C 1-6 Alkyl or C 1-6 haloalkyl; or

[0196] R 6 and R 7 Together with the nitrogen atom to which they are attached they may form a 5- or 6-membered heterocyclic ring, which optionally contains one or more further heteroatoms and is optionally substituted by one or more oxo substituents.

[0197] In other suitable compounds, wherein R 4 is an aryl group, which is more suitably unsubstituted or substituted by one or more substituents selected from the following:

[0198] Halogen, CN, R 19 , OR 19 ;

[0199] OR 6 、C(O)OR 6 ;

[0200] C 1-4 Alkyl or O(C 1-4 alkyl), which is optionally substituted by one or more substituents selected from the group consisting of halogen, CN, R 19 , OR 19 , OR 6 and NR 6 R 7 ;

[0201] where R 6 、R 7 and R 19 As defined above.

[0202] However, more appropriately, R 6 It is H, C 1-4 Alkyl or C 1-4 Halogenated alkyl, or for NR 6 R 7 , R 6 With R 7 Combined with the nitrogen atom to which it is attached, it forms a 5- or 6-membered heterocyclic ring, which optionally contains one or more additional heteroatoms and is optionally substituted with one or more halo substituents.

[0203] R 19 More suitably, it is a 3- to 6-membered carbocyclyl or phenyl, any of which is optionally substituted by one or more substituents selected from halogen, methyl and methoxy.

[0204] In particularly suitable compounds, R 4 is a phenyl group substituted at the 2- or 3-position by an OH group, and optionally substituted by one or more further substituents as defined for general formula (I), more suitably substituted by one or more further substituents, for example one selected from the other substituents as defined immediately above.

[0205] When R 4 When it is a bicyclic aryl group, it is more preferably unsubstituted or substituted by one or two substituents selected from OH and halogen.

[0206] When R 4When it is a heteroaryl group, it is more preferably unsubstituted or substituted by one or more substituents selected from OH and halogen.

[0207] When R 4 When it is a carbocyclic group, it is more suitably unsubstituted or substituted by one or more substituents selected from OH and halogen. More suitably, it is unsubstituted.

[0208] In particularly suitable compounds of the present invention, Y is -CH2-, R 4 is phenyl and the compound is a compound of formula (Ia):

[0209]

[0210] in

[0211] R 1 、R 2 、R 3 、R 5a 、X 1 and X 2 As defined in formula (I);

[0212] R 10 It is H, OH, halide, C 1-6 Alkyl, -O(C 1-6 alkyl);

[0213] R 11 are independently H, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -O(C 1-6 alkyl) or C(O)O-(C 1-6 alkyl); and

[0214] n is 1 or 2.

[0215] More suitably, the compound is a compound of formula (Ib) or (Ic):

[0216]

[0217] in

[0218] R 1 、R 2 、R 3 、R 5a 、X 1 and X 2 As defined in formula (I);

[0219] R 11a It is H, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl or C(O)O(C1-4 alkyl);

[0220] R 11b It is H, halogen, C 1-4 Alkyl or C 1-4 haloalkyl; and

[0221] R 11c H, halogen, CN, C 1-4 Alkyl or C 1-4 Halogenated alkyl.

[0222] Among particularly suitable compounds of formula (Ib), R 11a and R 11b One or both of them are H.

[0223] In some such compounds of formula (Ib), R 11a It is H, halogen, C 1-4 Alkyl or C(O)O(C 1-4 alkyl), and R 11b It’s H.

[0224] More appropriately, R 11a It is H, chlorine, C 1-4 Alkyl or C(O)OCH3, and R 11b It’s H.

[0225] In some compounds of formula (Ib), R 11a is chlorine and R 11b It’s H.

[0226] In other such compounds of formula (Ib), R 11a is H, and R 11b is H, halo or C 1-6 Halogenated alkyl.

[0227] More appropriately, R 11a is H, and R 11b is H, chloro, bromo or trifluoromethyl.

[0228] Alternatively, in other particularly suitable compounds of formula (Ib), R 11a and R 11b Both are halo, in particular chloro or bromo.

[0229] In some particularly suitable compounds of formula (Ic), R 11a It’s H.

[0230] More preferably, in the compound of formula (Ic), R 11b C 1-4 Alkyl or C 1-4 Haloalkyl, such as tert-butyl.

[0231] In the compounds of general formula (Ia) and (Ib), suitable R 1 、R 2 、R 3 、R 5 、X 1 and X 2 The groups are as described above for compounds of formula (I). However, more suitably, X 1 N, X 2 is CH, and R 5b is H, so that the compound is of the general formula (Id) or (Ie):

[0232]

[0233] where R 1 、R 2 、R 3 、R 11a 、R 11b and R 11c are as defined above for the compounds of formula (Ib) and (Ic).

[0234] Particularly suitable groups R in the general formula (Id) are 11a and R 11b As defined above in general formula (Ib), particularly suitable radicals R in general formula (Ie) are 11a and R 11b As defined in the above general formula (Ic).

[0235] Suitable compounds of general formula (I) include:

[0236] Specific examples of the compounds of general formula (I) include the following:

[0237] N-tert-Butyl-4-[[2-(2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (Compound 1);

[0238] N-(1,1-dimethylpropyl)-3-[[2-(2-hydroxyphenyl)acetyl]amino]benzamide (Compound 1.1);

[0239] N-(1-adamantyl)-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 1.2);

[0240] N-(1-adamantyl)-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 1.3);

[0241] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3-methoxy-1,1-dimethyl-propyl)pyridine-2-carboxamide (Compound 1.4);

[0242] 3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylpropyl)benzamide (Compound 1.5);

[0243] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclobutyl)pyridine-2-carboxamide (Compound 1.6);

[0244] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclohexyl)pyridine-2-carboxamide (Compound 1.7);

[0245] N-[3-[[4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carbonyl]amino]-3-methyl-butyl]carbamic acid tert-butyl ester (Compound 1.8);

[0246] 3-[[2-(2-Hydroxyphenyl)acetyl]amino]-N-(2-methoxy-1,1-dimethyl-ethyl)benzamide (Compound 1.9);

[0247] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-cyclohexyl-pyridine-2-carboxamide (Compound 1.10);

[0248] N-tert-Butyl-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 2);

[0249] N-tert-Butyl-3-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 2.1);

[0250] N-tert-Butyl-3-[[2-(3-fluoro-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 2.2);

[0251] N-tert-Butyl-3-[[2-(4-fluoro-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 2.3);

[0252] N-tert-butyl-3-[[2-(2,6-dihydroxyphenyl)acetyl]amino]benzamide (Compound 2.4);

[0253] N-tert-butyl-3-[3-(2-hydroxyphenyl)propionylamino]benzamide (Compound 2.5);

[0254] N-tert-Butyl-3-[[2-(2-hydroxy-6-methoxy-phenyl)acetyl]amino]benzamide (Compound 2.6);

[0255] N-tert-butyl-3-[2-(2-hydroxyphenyl)propionylamino]benzamide (Compound 2.7);

[0256] N-tert-butyl-3-[[2-(2-hydroxy-3-methoxy-phenyl)acetyl]amino]benzamide (Compound 2.8);

[0257] N-tert-butyl-3-[[2-(3,5-difluoro-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 2.9);

[0258] 3-[[2-(5-Bromo-2-hydroxy-phenyl)acetyl]amino]-N-tert-butyl-benzamide (Compound 2.10);

[0259] N-tert-butyl-3-[[2-(2,3-difluoro-6-hydroxy-phenyl)acetyl]amino]benzamide (Compound 2.11);

[0260] N-tert-butyl-3-[[2-(4,5-difluoro-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 2.12);

[0261] N-(1,1-dimethylpropyl)-3-[[2-(4-fluoro-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 2.13);

[0262] N-tert-butyl-3-[[2-(2-hydroxy-4-methoxy-phenyl)acetyl]amino]benzamide (Compound 2.14);

[0263] N-tert-butyl-3-[[2-(2-fluoro-6-hydroxy-phenyl)acetyl]amino]benzamide (Compound 2.15);

[0264] N-tert-butyl-3-[[2-(2,3-dihydroxyphenyl)acetyl]amino]benzamide (Compound 2.16);

[0265] N-tert-butyl-3-[[2-[2-hydroxy-5-(trifluoromethyl)phenyl]acetyl]amino]benzamide (Compound 2.17);

[0266] 3-[2-[3-(tert-Butylcarbamoyl)anilino]-2-oxo-ethyl]-4-hydroxy-benzoic acid methyl ester (Compound 2.18);

[0267] N-tert-butyl-3-[[2-[2-hydroxy-4-(trifluoromethyl)phenyl]acetyl]amino]benzamide (Compound 2.19);

[0268] N-tert-Butyl-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3);

[0269] N-(1,1-dimethylpropyl)-4-[[2-(4-fluoro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.1a);

[0270] N-tert-Butyl-4-[[2-(4-fluoro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.2a);

[0271] N-tert-Butyl-4-[[2-(2-chloro-6-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.3a);

[0272] 4-[[2-(4-Bromo-5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (Compound 3.4a);

[0273] 4-[[2-(5-tert-Butyl-2-hydroxy-phenyl)acetyl]amino]-N-(1-cyanocyclobutyl)pyridine-2-carboxamide (Compound 3.5a);

[0274] 4-[[2-(5-tert-Butyl-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclobutyl)pyridine-2-carboxamide (Compound 3.6a);

[0275] N-tert-butyl-4-[2-(2,5-dibromo-3-fluoro-6-hydroxyphenyl)acetylamino]pyridine-2-carboxamide (Compound 3.7a);

[0276] N-tert-Butyl-4-[[2-[2-hydroxy-5-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 3.5b);

[0277] N-tert-Butyl-4-[[2-(4-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.6b);

[0278] N-tert-Butyl-4-[[2-[2-hydroxy-4-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 3.7b);

[0279] N-tert-Butyl-4-[[2-(2-hydroxy-5-methoxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.8b);

[0280] N-tert-butyl-4-[(6-hydroxyindane-1-carbonyl)amino]pyridine-2-carboxamide (Compound 3.9b);

[0281] N-tert-butyl-4-[(7-hydroxyindane-1-carbonyl)amino]pyridine-2-carboxamide (Compound 3.10b);

[0282] N-tert-Butyl-4-[[2-(2,5-dibromo-3-chloro-6-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.11b);

[0283] N-tert-Butyl-4-[[2-(3-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.12b);

[0284] N-tert-Butyl-4-[[2-(2-fluoro-5-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.13b);

[0285] N-tert-butyl-4-[[2-(4-chloro-3-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.14b);

[0286] N-tert-butyl-4-[[2-(2-chloro-3-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.15b);

[0287] N-tert-butyl-4-[[2-(2-chloro-5-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.16b);

[0288] N-tert-butyl-4-[[2-(3-chloro-5-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.17b);

[0289] N-tert-Butyl-3-[[2-(3-hydroxyphenyl)acetyl]amino]benzamide (Compound 4);

[0290] N-tert-butyl-3-[[2-(1H-indazol-3-yl)acetyl]amino]benzamide (Compound 4.1);

[0291] N-tert-butyl-3-[[2-(5-fluoro-1H-indol-3-yl)acetyl]amino]benzamide (Compound 4.2);

[0292] N-tert-Butyl-3-[[2-(2-hydroxyphenyl)acetyl]amino]benzamide (Compound 4.3);

[0293] N-tert-butyl-3-[[2-(7-fluoro-2-methyl-1H-indol-3-yl)acetyl]amino]benzamide (Compound 4.4);

[0294] N-tert-Butyl-3-[[2-(1H-indol-3-yl)acetyl]amino]benzamide (Compound 4.5);

[0295] N-tert-butyl-3-[(2-phenylacetyl)amino]benzamide (Compound 4.6);

[0296] N-tert-butyl-3-[[2-(2-fluoro-6-methoxy-phenyl)acetyl]amino]benzamide (Compound 4.7);

[0297] N-tert-butyl-3-[[2-(2,3-difluoro-6-methoxy-phenyl)acetyl]amino]benzamide (Compound 4.8);

[0298] N-tert-butyl-3-[[2-[2-methoxy-4-(trifluoromethyl)phenyl]acetyl]amino]benzamide (Compound 4.9);

[0299] N-tert-Butyl-4-[[2-(2-thienyl)acetyl]amino]pyridine-2-carboxamide (Compound 5);

[0300] 4-[[2-(2-adamantyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (Compound 5.1);

[0301] N-tert-Butyl-4-[[2-(4-fluoro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.2);

[0302] N-tert-Butyl-4-[[2-(5-chloro-2-fluoro-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.3);

[0303] N-tert-Butyl-4-[[2-(2-furyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.4);

[0304] N-tert-Butyl-4-[[2-(3-chlorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.5);

[0305] N-tert-Butyl-4-[[2-(1H-indol-3-yl)acetyl]amino]pyridine-2-carboxamide (Compound 5.6);

[0306] N-tert-Butyl-4-[[2-(o-tolyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.7);

[0307] N-tert-Butyl-4-[[2-(3,4-dichlorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.8);

[0308] N-tert-Butyl-4-[[2-(3-fluorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.9);

[0309] N-tert-Butyl-4-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.10);

[0310] N-tert-butyl-4-[[2-(p-tolyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.11);

[0311] N-tert-Butyl-4-[[2-(2-fluorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.12);

[0312] N-tert-Butyl-4-[[2-(4-fluorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.13);

[0313] N-tert-butyl-4-[[2-(m-tolyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.14);

[0314] 4-[[2-(1,3-Benzoxazol-6-yl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (Compound 5.15);

[0315] N-tert-butyl-4-[[2-(2-chloro-3-pyridinyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.16);

[0316] N-tert-Butyl-4-[[2-(2,6-dichlorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.17);

[0317] N-tert-butyl-4-[[2-(4-chloro-3-fluoro-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.18);

[0318] N-tert-butyl-4-[[2-(3,5-dichlorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.19);

[0319] N-tert-Butyl-4-[[2-(2-chlorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.20);

[0320] N-tert-Butyl-4-[[2-(3-chloro-4-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.21);

[0321] N-tert-Butyl-4-(indane-1-carbonylamino)pyridine-2-carboxamide (Compound 5.22);

[0322] N-tert-Butyl-4-[(2-quinoxalin-6-ylacetyl)amino]pyridine-2-carboxamide (Compound 5.23);

[0323] N-tert-Butyl-4-[[2-(2-naphthyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.24);

[0324] N-tert-butyl-4-(2,3-dihydrobenzofuran-3-carbonylamino)pyridine-2-carboxamide (Compound 5.25);

[0325] N-tert-butyl-4-(6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-carbonylamino)pyridine-2-carboxamide (Compound 5.26);

[0326] N-tert-butyl-4-(1,2,3,4-tetrahydronaphthalene-1-carbonylamino)pyridine-2-carboxamide (Compound 5.27);

[0327] N-tert-Butyl-4-[[2-(6-quinolinyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.29);

[0328] N-tert-butyl-4-[[1-(3-chlorophenyl)cyclopropanecarbonyl]amino]pyridine-2-carboxamide (Compound 5.31);

[0329] N-tert-butyl-4-[[2-(2,3-dihydro-1,4-benzodioxin-6-yl)acetyl]amino]pyridine-2-carboxamide (Compound 5.32);

[0330] N-(1,1-dimethylprop-2-ynyl)-4-[(2-isochroman-1-ylacetyl)amino]pyridine-2-carboxamide (Compound 5.33);

[0331] 4-[[2-(4,4-difluorocyclohexyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 5.34);

[0332] N-(1,1-dimethylprop-2-ynyl)-4-[[2-[4-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 5.35);

[0333] N-(1,1-dimethylprop-2-ynyl)-4-[[2-[3-(trifluoromethyl)-1H-pyrazol-4-yl]acetyl]amino]pyridine-2-carboxamide (Compound 5.36);

[0334] N-(1,1-dimethylprop-2-ynyl)-4-[[2-[3-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 5.37);

[0335] N-(1,1-dimethylprop-2-ynyl)-4-[[2-[2-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 5.38);

[0336] 4-[[2-(2,3-dihydro-1,4-benzoxazin-4-yl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 5.39);

[0337] N-tert-Butyl-4-[[2-(5-cyano-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 6);

[0338] 3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1,2,2-tetramethylpropyl)benzamide (Compound 7);

[0339] 3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylbutyl)benzamide (Compound 7.1);

[0340] 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylbutyl)pyridine-2-carboxamide (Compound 7.2);

[0341] 3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-cyclohexyl-benzamide (Compound 7.3);

[0342] 3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-tetrahydropyran-4-yl-benzamide (Compound 7.4);

[0343] 3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1,2-trimethylpropyl)benzamide (Compound 7.5);

[0344] 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1,2-trimethylpropyl)pyridine-2-carboxamide (Compound 7.6);

[0345] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-isopropyl-pyridine-2-carboxamide (Compound 7.7);

[0346] 3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4-methyltetrahydropyran-4-yl)benzamide (Compound 7.8);

[0347] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4-methyltetrahydropyran-4-yl)pyridine-2-carboxamide (Compound 7.9);

[0348] 3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclobutyl)benzamide (Compound 7.10);

[0349] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-tetrahydropyran-4-yl-pyridine-2-carboxamide (Compound 7.11);

[0350] 4-[2-(5-chloro-2-hydroxyphenyl)acetylamino]-N-[(1s,4s)-4-hydroxycyclohexyl]pyridine-2-carboxamide (Compound 7.12);

[0351] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-sec-butyl-pyridine-2-carboxamide (Compound 7.13);

[0352] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(2-hydroxy-1,1,2-trimethyl-propyl)pyridine-2-carboxamide (Compound 7.14);

[0353] N-(3-Bicyclo[1.1.1]pentyl)-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 7.15);

[0354] 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-cyanocyclobutyl)pyridine-2-carboxamide (Compound 7.16);

[0355] tert-Butyl 3-[[3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]benzoyl]amino]piperidine-1-carboxylate (Compound 8);

[0356] tert-Butyl 3-[[4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carbonyl]amino]piperidine-1-carboxylate (Compound 8.1);

[0357] 4-[[3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]benzoyl]amino]-4-methyl-piperidine-1-carboxylic acid tert-butyl ester (Compound 8.2);

[0358] (1r,5s,6s)-tert-butyl 6-{4-[2-(5-chloro-2-hydroxyphenyl)acetylamino]pyridine-2-amido}-3-azabicyclo[3.1.0]hexane-3-carboxylate (Compound 8.3);

[0359] N-tert-Butyl-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-4-fluoro-benzamide (Compound 9);

[0360] N-tert-Butyl-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-5-methyl-benzamide (Compound 9.1);

[0361] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylpropyl)pyridine-2-carboxamide (Compound 9.2);

[0362] N-tert-Butyl-4-[[2-(5-tert-butyl-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 10);

[0363] N-tert-Butyl-5-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-2-hydroxy-benzamide (Compound 11);

[0364] N-tert-Butyl-3-[[2-(5-cyano-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 12);

[0365] 3-[2-[[2-(tert-Butylcarbamoyl)-4-pyridinyl]amino]-2-oxo-ethyl]-4-hydroxy-benzoic acid methyl ester (Compound 13);

[0366] N-tert-Butyl-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-4-hydroxy-benzamide (Compound 14);

[0367] N-tert-Butyl-4-[[2-(2-hydroxy-5-methyl-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 15);

[0368] N-tert-Butyl-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-4-methoxy-benzamide (Compound 16);

[0369] N-tert-Butyl-5-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-2-fluoro-benzamide (Compound 17);

[0370] N-tert-Butyl-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-5-fluoro-benzamide (Compound 18);

[0371] N-tert-Butyl-4-[[2-(3-hydroxy-2-pyridinyl)acetyl]amino]pyridine-2-carboxamide (Compound 19);

[0372] N-tert-Butyl-4-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 20);

[0373] N-tert-butyl-4-[[(1R)-or (1S)-indane-1-carbonyl]amino]pyridine-2-carboxamide (Compound 21a);

[0374] N-tert-Butyl-4-[[(1R)-or (1S)-indane-1-carbonyl]amino]pyridine-2-carboxamide (Compound 21b);

[0375] N-tert-Butyl-4-[(2-phenylacetyl)amino]pyridine-2-carboxamide (Compound 22);

[0376] 4-(3,3-dimethylbutyrylamino)-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 22.1);

[0377] 4-[(2-cyclopentylacetyl)amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 22.2);

[0378] 4-[[2-(3-chloro-4-pyridinyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 22.3);

[0379] 4-[[2-(4-Chlorophenyl)acetyl]amino]-N-(1-cyanocyclopropyl)pyridine-2-carboxamide (Compound 23);

[0380] 4-[[2-(3-chlorophenyl)acetyl]amino]-N-(1-cyanocyclopropyl)pyridine-2-carboxamide (Compound 23.1);

[0381] 4-[[2-(2-Chloro-5-fluoro-phenyl)acetyl]amino]-N-(1-cyanocyclopropyl)pyridine-2-carboxamide (Compound 23.2);

[0382] N-tert-Butyl-4-(indane-2-carbonylamino)pyridine-2-carboxamide (Compound 23.3);

[0383] N-tert-Butyl-4-[[2-[2-(difluoromethoxy)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 23.4);

[0384] N-tert-Butyl-4-[[2-[2-(difluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 23.5);

[0385] N-tert-Butyl-4-[[2-(3,4-difluorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 23.6);

[0386] N-tert-Butyl-4-[[2-(3,5-difluorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 23.7);

[0387] N-tert-Butyl-4-[[2-(2,3-difluorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 23.8);

[0388] 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-tetrahydropyran-4-yl-pyridine-2-carboxamide (Compound 23.9);

[0389] N-(1-cyanocyclobutyl)-4-[[2-(6-quinolinyl)acetyl]amino]pyridine-2-carboxamide (Compound 23.11);

[0390] N-tert-Butyl-4-[[2-[2-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 23.12);

[0391] 4-[[2-(2-Bromophenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (Compound 23.13);

[0392] N-tert-Butyl-4-[[2-(2-cyanophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 23.14);

[0393] 4-[[2-(2-chlorophenyl)acetyl]amino]-N-(4-cyanotetrahydropyran-4-yl)pyridine-2-carboxamide (Compound 23.15);

[0394] N-(4-cyanotetrahydropyran-4-yl)-4-[[2-(6-quinolinyl)acetyl]amino]pyridine-2-carboxamide (Compound 23.16);

[0395] 4-[[2-(2-Chloro-5-methoxy-phenyl)acetyl]amino]-N-(1-cyanocyclopropyl)pyridine-2-carboxamide (Compound 24);

[0396] N-(3-Bicyclo[1.1.1]pentyl)-4-[[2-(5-tert-butyl-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 25);

[0397] -[[2-(5-tert-Butyl-2-hydroxy-phenyl)acetyl]amino]-N-(4-cyanotetrahydropyran-4-yl)pyridine-2-carboxamide (Compound 25.1);

[0398] N-tert-Butyl-4-[[2-(2-hydroxy-5-phenyl-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 26);

[0399] N-tert-Butyl-4-[[2-[5-chloro-2-hydroxy-4-(pyrrolidin-1-ylmethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 27);

[0400] N-tert-butyl-4-[[2-[4-[(tert-butylamino)methyl]-5-chloro-2-hydroxy-phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 27.1);

[0401] N-tert-butyl-4-[[2-[5-chloro-2-hydroxy-4-(morpholinomethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 27.2);

[0402] N-tert-Butyl-4-[[2-[5-chloro-4-[(3,3-difluoropyrrolidin-1-yl)methyl]-2-hydroxy-phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 27.3);

[0403] N-tert-Butyl-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-5-fluoro-pyridine-2-carboxamide (Compound 28);

[0404] N-tert-Butyl-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-3-fluoro-pyridine-2-carboxamide (Compound 28.1);

[0405] 4-[[2-(2-chlorophenyl)acetyl]amino]-N-(1-cyanocyclobutyl)pyridine-2-carboxamide (Compound 30);

[0406] 4-[[2-(2-chlorophenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 30.1);

[0407] 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(4-fluoro-1-bicyclo[2.1.1]hexyl)pyridine-2-carboxamide (Compound 30.2);

[0408] 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(1-cyclopropyl-1-methyl-ethyl)pyridine-2-carboxamide (Compound 30.3);

[0409] 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(1-cyano-1-methyl-ethyl)pyridine-2-carboxamide (Compound 30.3a);

[0410] 4-[[2-(2-chlorophenyl)acetyl]amino]-N-(1-methyl-3-bicyclo[1.1.1]pentyl)pyridine-2-carboxamide (Compound 30.4);

[0411] 4-[[2-(2-chlorophenyl)acetyl]amino]-N-(1-cyano-3-bicyclo[1.1.1]pentyl)pyridine-2-carboxamide (Compound 30.5);

[0412] 4-[[2-(2-chlorophenyl)acetyl]amino]-N-(2,2-difluorocyclopropyl)pyridine-2-carboxamide (Compound 30.6);

[0413] 4-[[2-(2-chlorophenyl)acetyl]amino]-N-(1-cyanocyclopropyl)pyridine-2-carboxamide (Compound 30.7);

[0414] 4-[[2-(2-chlorophenyl)acetyl]amino]-N-(1-methylcyclopropyl)pyridine-2-carboxamide (Compound 30.8);

[0415] 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(3-fluoro-1-bicyclo[1.1.1]pentyl)pyridine-2-carboxamide (Compound 30.9);

[0416] 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(2-fluoro-1,1-dimethyl-ethyl)pyridine-2-carboxamide (Compound 30.10);

[0417] 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(4-ethynyltetrahydropyran-4-yl)pyridine-2-carboxamide (Compound 30.11);

[0418] 4-[[2-(2-chlorophenyl)acetyl]amino]-N-(1-cyanocyclopentyl)pyridine-2-carboxamide (Compound 30.12);

[0419] 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(2,2-difluoro-1,1-dimethyl-ethyl)pyridine-2-carboxamide (Compound 30.13);

[0420] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4-cyanotetrahydropyran-4-yl)pyridine-2-carboxamide (Compound 31);

[0421] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-ethynylcyclopentyl)pyridine-2-carboxamide (Compound 31.2);

[0422] 4-[2-(5-chloro-2-hydroxyphenyl)acetylamino]-N-[(1s,2s)-2-hydroxycyclohexyl]pyridine-2-carboxamide (Compound 31.3);

[0423] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1S,2S)-2-hydroxycyclohexyl]pyridine-2-carboxamide or 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1R,2R)-2-hydroxycyclohexyl]pyridine-2-carboxamide (Compound 31.3a);

[0424] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4-ethynyltetrahydropyran-4-yl)pyridine-2-carboxamide (Compound 31.4);

[0425] N-[(6-amino-2-pyridinyl)methyl]-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 32);

[0426] 12-[[4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carbonyl]amino]dodecanoic acid (Compound 32.1);

[0427] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3-pyridylmethyl)pyridine-2-carboxamide (Compound 32.2);

[0428] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(2-pyridylmethyl)pyridine-2-carboxamide (Compound 32.3);

[0429] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4-pyridinylmethyl)pyridine-2-carboxamide (Compound 32.4);

[0430] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(2-hydroxyphenyl)methyl]pyridine-2-carboxamide (Compound 32.5);

[0431] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethyl-2-morpholino-ethyl)pyridine-2-carboxamide (Compound 32.6);

[0432] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(2-hydroxy-1,1-dimethyl-ethyl)pyridine-2-carboxamide (Compound 32.7);

[0433] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3,3-difluoro-4-piperidinyl)pyridine-2-carboxamide (Compound 32.8);

[0434] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1H-imidazol-2-yl)pyridine-2-carboxamide (Compound 32.9);

[0435] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1R,2R)-2-hydroxycyclopentyl]pyridine-2-carboxamide (Compound 33);

[0436] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-cyano-1-methyl-ethyl)pyridine-2-carboxamide (Compound 34);

[0437] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[3-(hydroxymethyl)tetrahydrofuran-3-yl]pyridine-2-carboxamide (Compound 35);

[0438] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(3R)-3-(hydroxymethyl)tetrahydrofuran-3-yl]pyridine-2-carboxamide or 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(3S)-3-(hydroxymethyl)tetrahydrofuran-3-yl]pyridine-2-carboxamide (Compound 35a);

[0439] -[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(3R)-3-(hydroxymethyl)tetrahydrofuran-3-yl]pyridine-2-carboxamide or 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(3S)-3-(hydroxymethyl)tetrahydrofuran-3-yl]pyridine-2-carboxamide (Compound 35b);

[0440] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4-hydroxy-4-methyl-cyclohexyl)pyridine-2-carboxamide as a 6:4 mixture of stereoisomers (Compound 35.1);

[0441] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1s,2r)-2-(hydroxymethyl)cyclohexyl]pyridine-2-carboxamide (Compound 35.2);

[0442] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1s,3r)-3-hydroxycyclopentyl]pyridine-2-carboxamide (Compound 35.3);

[0443] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[2-hydroxy-1-(hydroxymethyl)-1-methyl-ethyl]pyridine-2-carboxamide (Compound 35.4);

[0444] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3-hydroxycyclohexyl)pyridine-2-carboxamide as a mixture of stereoisomers (Compound 35.6);

[0445] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3-phenoxypropyl)pyridine-2-carboxamide (Compound 35.7);

[0446] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclopropyl)pyridine-2-carboxamide (Compound 35.8);

[0447] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[1-methyl-1-(2-pyridinyl)ethyl]pyridine-2-carboxamide (Compound 35.9);

[0448] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3-phenylpropyl)pyridine-2-carboxamide (Compound 35.10);

[0449] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[2-hydroxy-1-(2-pyridinyl)ethyl]pyridine-2-carboxamide (Compound 35.11);

[0450] 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(5-methoxy-2-pyridinyl)methyl]pyridine-2-carboxamide (Compound 35.12);

[0451] 3-[[4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carbonyl]amino]-3-methyl-butyric acid ethyl ester (Compound 35.13);

[0452] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3-hydroxy-1,1-dimethyl-propyl)pyridine-2-carboxamide (Compound 35.14);

[0453] N-benzyl-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 35.15);

[0454] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-phenyl-pyridine-2-carboxamide (Compound 35.16);

[0455] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1S,2S)-2-hydroxycyclopentyl]pyridine-2-carboxamide (Compound 35.17);

[0456] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1R,2S)-2-hydroxycyclopentyl]pyridine-2-carboxamide (Compound 35.18);

[0457] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1S,2R)-2-hydroxycyclopentyl]pyridine-2-carboxamide (Compound 35.19);

[0458] 3-[[2-(5-Fluoro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclohexyl)benzamide (Compound 35.20);

[0459] N-(1,1-dimethylprop-2-ynyl)-3-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 35.21);

[0460] N-cyclohexyl-3-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 35.22);

[0461] 3-[[2-(5-Fluoro-2-hydroxy-phenyl)acetyl]amino]-N-[3-(hydroxymethyl)tetrahydrofuran-3-yl]benzamide (Compound 35.23);

[0462] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-ethynylcyclohexyl)pyridine-2-carboxamide (Compound 35.24);

[0463] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[1-(hydroxymethyl)cyclobutyl]pyridine-2-carboxamide (Compound 35.25);

[0464] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[3-(hydroxymethyl)oxetan-3-yl]pyridine-2-carboxamide (Compound 35.26);

[0465] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-cyano-2-methoxy-1-methyl-ethyl)pyridine-2-carboxamide (Compound 35.27);

[0466] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1-hydroxycyclobutyl)methyl]pyridine-2-carboxamide (Compound 35.28);

[0467] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 36);

[0468] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-cyano-1,2-dimethyl-propyl)pyridine-2-carboxamide (Compound 37);

[0469] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclopentyl)pyridine-2-carboxamide (Compound 38);

[0470] N-(4-tert-Butylcyclohexyl)-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 39);

[0471] N-tert-Butyl-4-[[2-(2-chloro-3-fluoro-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 40);

[0472] N-tert-Butyl-4-[[2-(2-chloro-5-fluoro-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 40.1);

[0473] N-(4-cyanotetrahydropyran-4-yl)-3-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 41);

[0474] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[4-(2-hydroxyethyl)tetrahydropyran-4-yl]pyridine-2-carboxamide (Compound 42);

[0475] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[1,1-dimethyl-3-(2,2,2-trifluoroethylamino)propyl]pyridine-2-carboxamide (Compound 43);

[0476] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4-fluoro-1-bicyclo[2.1.1]hexyl)pyridine-2-carboxamide (Compound 44);

[0477] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[3-(2,2-dimethylpropionylamino)-1,1-dimethyl-propyl]pyridine-2-carboxamide (Compound 45);

[0478] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-cyano-2-hydroxy-1-methyl-ethyl)pyridine-2-carboxamide (Compound 46);

[0479] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1S)-1-cyano-2-hydroxy-1-methyl-ethyl]pyridine-2-carboxamide or 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1R)-1-cyano-2-hydroxy-1-methyl-ethyl]pyridine-2-carboxamide (Compound 46a);

[0480] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1S)-1-cyano-2-hydroxy-1-methyl-ethyl]pyridine-2-carboxamide or 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1R)-1-cyano-2-hydroxy-1-methyl-ethyl]pyridine-2-carboxamide (Compound 46b);

[0481] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3-cyanotetrahydrofuran-3-yl)pyridine-2-carboxamide (Compound 47);

[0482] 2-[4-[[4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carbonyl]amino]tetrahydropyran-4-yl]acetic acid methyl ester (Compound 47.1);

[0483] 4-[[4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carbonyl]amino]tetrahydropyran-4-carboxylic acid methyl ester (Compound 47.2);

[0484] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3-cyanooxetan-3-yl)pyridine-2-carboxamide (Compound 47.3);

[0485] 4-[[2-(5-Fluoro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclobutyl)pyridine-2-carboxamide (Compound 48);

[0486] N-(4-cyanotetrahydropyran-4-yl)-4-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 48.1);

[0487] N-[3-(tert-Butylamino)-1,1-dimethyl-3-oxo-propyl]-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 49);

[0488] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[3-(methylsulfonylamino)-1,1-dimethyl-propyl]pyridine-2-carboxamide (Compound 50);

[0489] N-(3-Acetylamino-1,1-dimethyl-propyl)-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 51);

[0490] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[4-(hydroxymethyl)tetrahydropyran-4-yl]pyridine-2-carboxamide (Compound 53);

[0491] N-tert-Butyl-4-[[2-[3-(1-hydroxyethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 54);

[0492] N-tert-Butyl-5-chloro-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 55);

[0493] N-tert-Butyl-4-[[2-[5-chloro-2-[(4-methoxyphenyl)methoxy]phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 56);

[0494] N-tert-butyl-4-[[(1S) or (1R)-4-chloro-7-hydroxy-indane-1-carbonyl]amino]pyridine-2-carboxamide and Example 57b: N-tert-butyl-4-[[(1S) or (1R)-4-chloro-7-hydroxy-indane-1-carbonyl]amino]pyridine-2-carboxamide (Compound 57a);

[0495] N-tert-butyl-4-[[(1S) or (1R)-4-chloro-7-hydroxy-indane-1-carbonyl]amino]pyridine-2-carboxamide and Example 57b: N-tert-butyl-4-[[(1S) or (1R)-4-chloro-7-hydroxy-indane-1-carbonyl]amino]pyridine-2-carboxamide (Compound 57b);

[0496] N-tert-Butyl-4-[[2-(2-cyclopropylphenyl)acetyl]amino]pyridine-2-carboxamide (Compound 58);

[0497] 4-[[2-(3-Bromo-5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (Compound 59);

[0498] N-(4-Fluoro-1-bicyclo[2.1.1]hexyl)-4-[[2-(2-fluorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 60);

[0499] N-(1-cyano-2-hydroxy-1-methyl-ethyl)-4-[[2-(2-fluorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 60.1);

[0500] N-(1,1-dimethylprop-2-ynyl)-4-[[2-(2-fluorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 60.2);

[0501] N-tert-Butyl-4-[[2-(5-chloro-2-hydroxy-3-isopropyl-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 61);

[0502] N-tert-Butyl-4-[[2-[5-chloro-2-hydroxy-3-(1-methoxyethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 62);

[0503] 4-[[2-(6-Quinolinyl)acetyl]amino]-N-tetrahydropyran-4-yl-pyridine-2-carboxamide (Compound 63);

[0504] 4-(Benzylcarbamoylamino)-N-tert-butyl-pyridine-2-carboxamide (Compound 64);

[0505] N-tert-Butyl-4-(cyclohexylmethylcarbamoylamino)pyridine-2-carboxamide (Compound 64.1);

[0506] N-tert-Butyl-4-(2-phenylethylcarbamoylamino)pyridine-2-carboxamide (Compound 64.2);

[0507] N-tert-Butyl-4-[[(1R)-1-phenylethyl]carbamoylamino]pyridine-2-carboxamide (Compound 64.3);

[0508] N-tert-Butyl-4-[[(1S)-1-phenylethyl]carbamoylamino]pyridine-2-carboxamide (Compound 64.4);

[0509] N-tert-Butyl-4-[(2-chlorophenyl)methylcarbamoylamino]pyridine-2-carboxamide (Compound 64.5);

[0510] N-tert-Butyl-4-(1H-indol-3-ylcarbamoylamino)pyridine-2-carboxamide (Compound 64.6);

[0511] N-tert-Butyl-4-[(3-chlorophenyl)methylcarbamoylamino]pyridine-2-carboxamide (Compound 64.7);

[0512] N-tert-Butyl-4-[(4-chlorophenyl)methylcarbamoylamino]pyridine-2-carboxamide (Compound 64.8);

[0513] N-tert-Butyl-4-[(2-hydroxyphenyl)carbamoylamino]pyridine-2-carboxamide (Compound 65);

[0514] N-tert-Butyl-4-[(2-methoxyphenyl)methylcarbamoylamino]pyridine-2-carboxamide (Compound 65.1);

[0515] N-tert-Butyl-4-[(2-hydroxyphenyl)methylcarbamoylamino]pyridine-2-carboxamide (Compound 65.2);

[0516] N-tert-Butyl-4-[(3-hydroxyphenyl)methylcarbamoylamino]pyridine-2-carboxamide (Compound 65.3);

[0517] N-tert-Butyl-4-[(4-hydroxyphenyl)methylcarbamoylamino]pyridine-2-carboxamide (Compound 65.4);

[0518] N-tert-Butyl-4-[[2-[2-hydroxy-5-(1-hydroxyethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 66);

[0519] N-tert-Butyl-4-[[2-[2-hydroxy-5-[1-(2,2,2-trifluoroethylamino)ethyl]phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 67);

[0520] N-tert-Butyl-4-[[2-[3-(cyanomethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 68);

[0521] N-tert-Butyl-4-[[2-[3-(methoxymethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 69);

[0522] N-tert-Butyl-4-[[2-[2-hydroxy-5-(morpholinomethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 70);

[0523] 3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3-cyanotetrahydrofuran-3-yl)benzamide (Compound 71);

[0524] 3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclohexyl)benzamide (Compound 71.1);

[0525] 4-[[2-(5-Fluoro-2-hydroxy-phenyl)acetyl]amino]-N-[3-(hydroxymethyl)tetrahydrofuran-3-yl]pyridine-2-carboxamide (Compound 72);

[0526] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[1-(hydroxymethyl)-2-methoxy-1-methyl-ethyl]pyridine-2-carboxamide (Compound 73);

[0527] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylbut-2-ynyl)pyridine-2-carboxamide (Compound 73.1);

[0528] 3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)benzamide (Compound 74);

[0529] 3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[3-(hydroxymethyl)tetrahydrofuran-3-yl]benzamide (Compound 74.1);

[0530] N-tert-Butyl-4-[[2-[2-hydroxy-5-(3-hydroxypropyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 75);

[0531] 4-[[2-(5-Chloro-4-fluoro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclobutyl)pyridine-2-carboxamide (Compound 76);

[0532] 4-[[2-(2,5-Difluorophenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 77);

[0533] 4-[[2-(2,5-Difluorophenyl)acetyl]amino]-N-(4-fluoro-1-bicyclo[2.1.1]hexyl)pyridine-2-carboxamide (Compound 77.1);

[0534] 4-[[2-(4-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 78);

[0535] N-(1,1-dimethylprop-2-ynyl)-4-[[2-[2-hydroxy-4-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 78.1);

[0536] N-(1,1-dimethylprop-2-ynyl)-4-[[2-[2-hydroxy-5-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 78.2);

[0537] 4-[(2-chroman-4-ylacetyl)amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 79);

[0538] N-(1,1-dimethylprop-2-ynyl)-4-[[2-(1-isopropyl-3,5-dimethyl-pyrazol-4-yl)acetyl]amino]pyridine-2-carboxamide (Compound 79.1);

[0539] N-(1,1-dimethylprop-2-ynyl)-4-[[2-(1H-indazol-4-yl)acetyl]amino]pyridine-2-carboxamide (Compound 79.2);

[0540] N-(1,1-dimethylprop-2-ynyl)-4-[[2-(1H-indol-7-yl)acetyl]amino]pyridine-2-carboxamide (Compound 79.3);

[0541] 3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4-cyanotetrahydropyran-4-yl)benzamide (Compound 80);

[0542] N-(1-cyano-1-methyl-ethyl)-4-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 81);

[0543] N-(1-cyano-2-hydroxy-1-methyl-ethyl)-4-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 81.1);

[0544] 4-[[2-(5-Fluoro-2-hydroxy-phenyl)acetyl]amino]-N-isopropyl-pyridine-2-carboxamide (Compound 81.2);

[0545] N-(1,1-dimethylprop-2-ynyl)-4-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 81.3);

[0546] N-(4-Fluoro-1-bicyclo[2.1.1]hexyl)-4-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 81.4);

[0547] 4-[[2-(5-Fluoro-2-hydroxy-phenyl)acetyl]amino]-N-[1-(hydroxymethyl)cyclobutyl]pyridine-2-carboxamide (Compound 81.5);

[0548] N-tert-Butyl-6-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]pyrimidine-4-carboxamide (Compound 82);

[0549] N-(1-cyano-1-methyl-ethyl)-4-(thiophene-3-carbonylamino)pyridine-2-carboxamide (Compound 83);

[0550] N-(1-cyano-1-methyl-ethyl)-4-[(2-cyclohexylacetyl)amino]pyridine-2-carboxamide (Compound 83.1);

[0551] N-(1-cyano-1-methyl-ethyl)-4-(cyclohexanecarbonylamino)pyridine-2-carboxamide (Compound 83.2);

[0552] N-(1-cyano-1-methyl-ethyl)-4-[(3,3-difluorocyclopentanecarbonyl)amino]pyridine-2-carboxamide (Compound 83.3);

[0553] N-(1-cyano-1-methyl-ethyl)-4-[(1-methylcyclopentanecarbonyl)amino]pyridine-2-carboxamide (Compound 83.4);

[0554] N-(1-cyano-1-methyl-ethyl)-4-(3-cyclohexylpropionylamino)pyridine-2-carboxamide (Compound 83.5);

[0555] 4-(2-{bicyclo[2.2.1]hept-2-yl}acetylamino)-N-(1-cyano-1-methylethyl)pyridine-2-carboxamide (Compound 83.6);

[0556] N-(1-cyano-1-methyl-ethyl)-4-[[2-(1-methylcyclohexyl)acetyl]amino]pyridine-2-carboxamide (Compound 83.7);

[0557] N-[2-[(1-cyano-1-methyl-ethyl)carbamoyl]-4-pyridinyl]-2-cyclopropyl-pyrimidine-5-carboxamide (Compound 83.8);

[0558] N-[2-[(1-cyano-1-methyl-ethyl)carbamoyl]-4-pyridinyl]-3-isobutyl-isoxazole-5-carboxamide (Compound 83.9);

[0559] N-(1-cyano-1-methyl-ethyl)-4-[[2-(4,4-difluorocyclohexyl)acetyl]amino]pyridine-2-carboxamide (Compound 83.10);

[0560] 4-[(1-Benzylcyclopropanecarbonyl)amino]-N-(1-cyano-1-methyl-ethyl)pyridine-2-carboxamide (Compound 83.11);

[0561] N-(1-cyano-1-methyl-ethyl)-4-[3-(2-methoxy-4-pyridinyl)propionylamino]pyridine-2-carboxamide (Compound 83.13);

[0562] 4-[(5-tert-Butyl-2-methyl-pyrazole-3-carbonyl)amino]-N-(1-cyano-1-methyl-ethyl)pyridine-2-carboxamide (Compound 83.14);

[0563] N-(1-cyano-1-methyl-ethyl)-4-[(2-pyrazol-1-ylbenzoyl)amino]pyridine-2-carboxamide (Compound 83.15);

[0564] N-[2-[(1-cyano-1-methyl-ethyl)carbamoyl]-4-pyridinyl]-6-(trifluoromethyl)pyridine-2-carboxamide (Compound 83.16);

[0565] N-[2-[(1-cyano-1-methyl-ethyl)carbamoyl]-4-pyridinyl]-3-oxo-4H-1,4-benzoxazine-7-carboxamide (Compound 83.17);

[0566] N-[2-[(1-cyano-1-methyl-ethyl)carbamoyl]-4-pyridinyl]-1-ethyl-indole-2-carboxamide (Compound 83.18);

[0567] N-(1-cyano-1-methyl-ethyl)-4-[[2-(2,2,2-trifluoroethyl)pyrazole-3-carbonyl]amino]pyridine-2-carboxamide (Compound 83.19);

[0568] N-[2-[(1-cyano-1-methyl-ethyl)carbamoyl]-4-pyridinyl]-3-phenyl-isoxazole-4-carboxamide (Compound 83.20);

[0569] 4-[(1-Benzylpyrazole-4-carbonyl)amino]-N-(1-cyano-1-methyl-ethyl)pyridine-2-carboxamide (Compound 83.21);

[0570] N-(1-cyano-1-methyl-ethyl)-4-[(2-methyl-5-phenyl-pyrazole-3-carbonyl)amino]pyridine-2-carboxamide (Compound 83.22);

[0571] N-(1-cyano-1-methyl-ethyl)-4-[[2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoyl]amino]pyridine-2-carboxamide (Compound 83.23);

[0572] N-(1-cyano-1-methyl-ethyl)-4-[(3-methyl-1-phenyl-pyrazole-4-carbonyl)amino]pyridine-2-carboxamide (Compound 83.24);

[0573] N-[2-[(1-cyano-1-methyl-ethyl)carbamoyl]-4-pyridinyl]-2-phenoxy-pyridine-3-carboxamide (Compound 83.25);

[0574] N-(1-cyano-1-methyl-ethyl)-4-[[2,5-dimethyl-1-(2-thienylmethyl)pyrrole-3-carbonyl]amino]pyridine-2-carboxamide (Compound 83.26);

[0575] N-[2-[(1-cyano-1-methyl-ethyl)carbamoyl]-4-pyridinyl]-5-(2-methoxyphenyl)isoxazole-3-carboxamide (Compound 83.27);

[0576] N-[2-[(1-cyano-1-methyl-ethyl)carbamoyl]-4-pyridinyl]-4-methyl-2-phenyl-thiazole-5-carboxamide (Compound 83.28);

[0577] 4-[(4-Acetylaminobenzoyl)amino]-N-(1-cyano-1-methyl-ethyl)pyridine-2-carboxamide (Compound 83.29);

[0578] N-[2-[(1-cyano-1-methyl-ethyl)carbamoyl]-4-pyridinyl]-1,3-benzothiazole-7-carboxamide (Compound 83.30);

[0579] N-(1-cyano-1-methyl-ethyl)-4-[3-(4-fluorophenyl)butyrylamino]pyridine-2-carboxamide (Compound 83.31);

[0580] N-[2-[(1-cyano-1-methyl-ethyl)carbamoyl]-4-pyridinyl]-1-methyl-2-oxo-quinoline-3-carboxamide (Compound 83.32);

[0581] N-tert-Butyl-3-[[2-(2-hydroxycyclohexyl)acetyl]amino]benzamide (Compound 84);

[0582] N-tert-Butyl-6-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyrimidine-4-carboxamide (Compound 85);

[0583] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[1-cyano-2-methoxy-1-(methoxymethyl)ethyl]pyridine-2-carboxamide (Compound 86);

[0584] 4-[[2-(3-Amino-4-tert-butyl-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (Compound 87);

[0585] 4-[[2-(2-Amino-4-tert-butyl-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (Compound 88);

[0586] N-tert-Butyl-4-[[2-(4-tert-butyl-3-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 89);

[0587] N-tert-Butyl-4-[[2-(4-tert-butyl-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 90);

[0588] N-tert-Butyl-4-[[2-(4-tert-butyl-2-fluoro-5-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 91);

[0589] 4-[[2-(4-Chloro-3-hydroxy-phenyl)acetyl]amino]-N-(4-cyanotetrahydropyran-4-yl)pyridine-2-carboxamide (Compound 92);

[0590] 4-[[2-(4-Chloro-3-hydroxy-phenyl)acetyl]amino]-N-(1-cyano-1-methyl-ethyl)pyridine-2-carboxamide (Compound 92.1);

[0591] 4-[[2-(4-Chloro-3-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 92.2);

[0592] 4-[[2-(4-Chloro-3-hydroxy-phenyl)acetyl]amino]-N-[(1s,2s)-2-hydroxycyclopentyl]pyridine-2-carboxamide (Compound 92.3);

[0593] 4-[[2-(4-tert-Butyl-3-hydroxy-phenyl)acetyl]amino]-N-[3-(hydroxymethyl)tetrahydrofuran-3-yl]pyridine-2-carboxamide (Compound 93);

[0594] 4-[[2-(4-tert-Butyl-3-hydroxy-phenyl)acetyl]amino]-N-[(2S)-2-hydroxycyclohexyl]pyridine-2-carboxamide (Compound 93.1);

[0595] 4-[[2-(4-tert-Butyl-3-hydroxy-phenyl)acetyl]amino]-N-[(2S)-2-hydroxycyclopentyl]pyridine-2-carboxamide (Compound 93.2);

[0596] 4-[[2-(4-tert-Butyl-3-hydroxy-phenyl)acetyl]amino]-N-(4-cyanotetrahydropyran-4-yl)pyridine-2-carboxamide (Compound 93.3);

[0597] 4-[[2-(4-tert-Butyl-3-hydroxy-phenyl)acetyl]amino]-N-(1-cyano-1-methyl-ethyl)pyridine-2-carboxamide (Compound 93.4);

[0598] 4-[[2-(4-tert-Butyl-3-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 93.5);

[0599] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methyl-1-phenyl-ethyl)pyridine-2-carboxamide (Compound 94); and salts and solvates of any of the foregoing.

[0600] Some compounds of general formula (I) are novel and therefore in another aspect of the present invention there is provided a compound of general formula (I) as defined above, provided that:

[0601] When X 1 N and X2 CR 8 , especially when X 1 N and X 2 When it is CH, Z is -C(O)- and Y is a bond, R 4 is not a 5- to 10-membered heteroaryl or heterocyclic ring that is linked to Y via a nitrogen atom; and

[0602] When X 1 and X 2 Both are CR 8 , and especially when X 1 and X 2 When both are CH, R 4 is phenyl having OH in the 2- or 3-position, and optionally having one or more further substituents as defined above; and

[0603] When X 1 CR 8 And X 2 For N, especially when X 1 is CH and X 2 When N is:

[0604] When Z is -C(O)-, Y is not a bond; and

[0605] When Z is -C(O)NH- and Y is a bond, R 4 is not a 12-membered heteroaryl ring system; and

[0606] When X 1 and X 2 Both are N, and when R 1 and R 2 One of them is H and R 1 and R 2 When the other is H or methyl, R 3 Unsubstituted or unsubstituted phenyl.

[0607] R 1 、R 2 、R 3 、R 4 、R 5 、X 1 、X 2 Suitable values ​​for , Y and Z are as defined above.

[0608] In some particularly suitable novel compounds of the present invention, X 1 is N and X 2 It's CR 8 , especially CH.

[0609] Examples of novel compounds according to the invention are:

[0610] N-tert-Butyl-4-[[2-(2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (Compound 1);

[0611] N-(1,1-dimethylpropyl)-3-[[2-(2-hydroxyphenyl)acetyl]amino]benzamide (Compound 1.1);

[0612] N-(1-adamantyl)-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 1.2);

[0613] N-(1-adamantyl)-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 1.3);

[0614] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3-methoxy-1,1-dimethyl-propyl)pyridine-2-carboxamide (Compound 1.4);

[0615] 3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylpropyl)benzamide (Compound 1.5);

[0616] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclobutyl)pyridine-2-carboxamide (Compound 1.6);

[0617] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclohexyl)pyridine-2-carboxamide (Compound 1.7);

[0618] N-[3-[[4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carbonyl]amino]-3-methyl-butyl]carbamic acid tert-butyl ester (Compound 1.8);

[0619] 3-[[2-(2-Hydroxyphenyl)acetyl]amino]-N-(2-methoxy-1,1-dimethyl-ethyl)benzamide (Compound 1.9);

[0620] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-cyclohexyl-pyridine-2-carboxamide (Compound 1.10);

[0621] N-tert-Butyl-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 2);

[0622] N-tert-Butyl-3-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 2.1);

[0623] N-tert-Butyl-3-[[2-(3-fluoro-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 2.2);

[0624] N-tert-Butyl-3-[[2-(4-fluoro-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 2.3);

[0625] N-tert-butyl-3-[[2-(2,6-dihydroxyphenyl)acetyl]amino]benzamide (Compound 2.4);

[0626] N-tert-butyl-3-[3-(2-hydroxyphenyl)propionylamino]benzamide (Compound 2.5);

[0627] N-tert-Butyl-3-[[2-(2-hydroxy-6-methoxy-phenyl)acetyl]amino]benzamide (Compound 2.6);

[0628] N-tert-butyl-3-[2-(2-hydroxyphenyl)propionylamino]benzamide (Compound 2.7);

[0629] N-tert-butyl-3-[[2-(2-hydroxy-3-methoxy-phenyl)acetyl]amino]benzamide (Compound 2.8);

[0630] N-tert-butyl-3-[[2-(3,5-difluoro-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 2.9);

[0631] 3-[[2-(5-Bromo-2-hydroxy-phenyl)acetyl]amino]-N-tert-butyl-benzamide (Compound 2.10);

[0632] N-tert-butyl-3-[[2-(2,3-difluoro-6-hydroxy-phenyl)acetyl]amino]benzamide (Compound 2.11);

[0633] N-tert-butyl-3-[[2-(4,5-difluoro-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 2.12);

[0634] N-(1,1-dimethylpropyl)-3-[[2-(4-fluoro-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 2.13);

[0635] N-tert-butyl-3-[[2-(2-hydroxy-4-methoxy-phenyl)acetyl]amino]benzamide (Compound 2.14);

[0636] N-tert-butyl-3-[[2-(2-fluoro-6-hydroxy-phenyl)acetyl]amino]benzamide (Compound 2.15);

[0637] N-tert-butyl-3-[[2-(2,3-dihydroxyphenyl)acetyl]amino]benzamide (Compound 2.16);

[0638] N-tert-butyl-3-[[2-[2-hydroxy-5-(trifluoromethyl)phenyl]acetyl]amino]benzamide (Compound 2.17);

[0639] 3-[2-[3-(tert-Butylcarbamoyl)anilino]-2-oxo-ethyl]-4-hydroxy-benzoic acid methyl ester (Compound 2.18);

[0640] N-tert-butyl-3-[[2-[2-hydroxy-4-(trifluoromethyl)phenyl]acetyl]amino]benzamide (Compound 2.19);

[0641] N-tert-Butyl-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3);

[0642] N-(1,1-dimethylpropyl)-4-[[2-(4-fluoro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.1a);

[0643] N-tert-Butyl-4-[[2-(4-fluoro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.2a);

[0644] N-tert-Butyl-4-[[2-(2-chloro-6-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.3a);

[0645] 4-[[2-(4-Bromo-5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (Compound 3.4a);

[0646] 4-[[2-(5-tert-Butyl-2-hydroxy-phenyl)acetyl]amino]-N-(1-cyanocyclobutyl)pyridine-2-carboxamide (Compound 3.5a);

[0647] 4-[[2-(5-tert-Butyl-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclobutyl)pyridine-2-carboxamide (Compound 3.6a);

[0648] N-tert-butyl-4-[2-(2,5-dibromo-3-fluoro-6-hydroxyphenyl)acetylamino]pyridine-2-carboxamide (Compound 3.7a);

[0649] N-tert-Butyl-4-[[2-[2-hydroxy-5-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 3.5b);

[0650] N-tert-Butyl-4-[[2-(4-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.6b);

[0651] N-tert-Butyl-4-[[2-[2-hydroxy-4-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 3.7b);

[0652] N-tert-Butyl-4-[[2-(2-hydroxy-5-methoxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.8b);

[0653] N-tert-butyl-4-[(6-hydroxyindane-1-carbonyl)amino]pyridine-2-carboxamide (Compound 3.9b);

[0654] N-tert-butyl-4-[(7-hydroxyindane-1-carbonyl)amino]pyridine-2-carboxamide (Compound 3.10b);

[0655] N-tert-Butyl-4-[[2-(2,5-dibromo-3-chloro-6-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.11b);

[0656] N-tert-Butyl-4-[[2-(3-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.12b);

[0657] N-tert-Butyl-4-[[2-(2-fluoro-5-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.13b);

[0658] N-tert-butyl-4-[[2-(4-chloro-3-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.14b);

[0659] N-tert-butyl-4-[[2-(2-chloro-3-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.15b);

[0660] N-tert-butyl-4-[[2-(2-chloro-5-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.16b);

[0661] N-tert-butyl-4-[[2-(3-chloro-5-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.17b);

[0662] N-tert-Butyl-3-[[2-(3-hydroxyphenyl)acetyl]amino]benzamide (Compound 4);

[0663] N-tert-butyl-3-[[2-(1H-indazol-3-yl)acetyl]amino]benzamide (Compound 4.1);

[0664] N-tert-butyl-3-[[2-(5-fluoro-1H-indol-3-yl)acetyl]amino]benzamide (Compound 4.2);

[0665] N-tert-Butyl-3-[[2-(2-hydroxyphenyl)acetyl]amino]benzamide (Compound 4.3);

[0666] N-tert-Butyl-4-[[2-(2-thienyl)acetyl]amino]pyridine-2-carboxamide (Compound 5);

[0667] 4-[[2-(2-adamantyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (Compound 5.1);

[0668] N-tert-Butyl-4-[[2-(4-fluoro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.2);

[0669] N-tert-Butyl-4-[[2-(5-chloro-2-fluoro-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.3);

[0670] N-tert-Butyl-4-[[2-(2-furyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.4);

[0671] N-tert-Butyl-4-[[2-(3-chlorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.5);

[0672] N-tert-Butyl-4-[[2-(1H-indol-3-yl)acetyl]amino]pyridine-2-carboxamide (Compound 5.6);

[0673] N-tert-Butyl-4-[[2-(o-tolyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.7);

[0674] N-tert-Butyl-4-[[2-(3,4-dichlorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.8);

[0675] N-tert-Butyl-4-[[2-(3-fluorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.9);

[0676] N-tert-Butyl-4-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.10);

[0677] N-tert-butyl-4-[[2-(p-tolyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.11);

[0678] N-tert-Butyl-4-[[2-(2-fluorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.12);

[0679] N-tert-Butyl-4-[[2-(4-fluorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.13);

[0680] N-tert-butyl-4-[[2-(m-tolyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.14);

[0681] 4-[[2-(1,3-Benzoxazol-6-yl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (Compound 5.15);

[0682] N-tert-butyl-4-[[2-(2-chloro-3-pyridinyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.16);

[0683] N-tert-Butyl-4-[[2-(2,6-dichlorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.17);

[0684] N-tert-butyl-4-[[2-(4-chloro-3-fluoro-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.18);

[0685] N-tert-butyl-4-[[2-(3,5-dichlorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.19);

[0686] N-tert-Butyl-4-[[2-(2-chlorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.20);

[0687] N-tert-Butyl-4-[[2-(3-chloro-4-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.21);

[0688] N-tert-Butyl-4-(indane-1-carbonylamino)pyridine-2-carboxamide (Compound 5.22);

[0689] N-tert-Butyl-4-[(2-quinoxalin-6-ylacetyl)amino]pyridine-2-carboxamide (Compound 5.23);

[0690] N-tert-Butyl-4-[[2-(2-naphthyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.24);

[0691] N-tert-butyl-4-(2,3-dihydrobenzofuran-3-carbonylamino)pyridine-2-carboxamide (Compound 5.25);

[0692] N-tert-butyl-4-(6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-carbonylamino)pyridine-2-carboxamide (Compound 5.26);

[0693] N-tert-butyl-4-(1,2,3,4-tetrahydronaphthalene-1-carbonylamino)pyridine-2-carboxamide (Compound 5.27);

[0694] N-tert-Butyl-4-[[2-(6-quinolinyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.29);

[0695] N-tert-butyl-4-[[1-(3-chlorophenyl)cyclopropanecarbonyl]amino]pyridine-2-carboxamide (Compound 5.31);

[0696] N-tert-butyl-4-[[2-(2,3-dihydro-1,4-benzodioxin-6-yl)acetyl]amino]pyridine-2-carboxamide (Compound 5.32);

[0697] N-(1,1-dimethylprop-2-ynyl)-4-[(2-isochroman-1-ylacetyl)amino]pyridine-2-carboxamide (Compound 5.33);

[0698] 4-[[2-(4,4-difluorocyclohexyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 5.34);

[0699] N-(1,1-dimethylprop-2-ynyl)-4-[[2-[4-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 5.35);

[0700] N-(1,1-dimethylprop-2-ynyl)-4-[[2-[3-(trifluoromethyl)-1H-pyrazol-4-yl]acetyl]amino]pyridine-2-carboxamide (Compound 5.36);

[0701] N-(1,1-dimethylprop-2-ynyl)-4-[[2-[3-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 5.37);

[0702] N-(1,1-dimethylprop-2-ynyl)-4-[[2-[2-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 5.38);

[0703] 4-[[2-(2,3-dihydro-1,4-benzoxazin-4-yl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 5.39);

[0704] N-tert-Butyl-4-[[2-(5-cyano-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 6);

[0705] 3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1,2,2-tetramethylpropyl)benzamide (Compound 7);

[0706] 3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylbutyl)benzamide (Compound 7.1);

[0707] 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylbutyl)pyridine-2-carboxamide (Compound 7.2);

[0708] 3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-cyclohexyl-benzamide (Compound 7.3);

[0709] 3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-tetrahydropyran-4-yl-benzamide (Compound 7.4);

[0710] 3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1,2-trimethylpropyl)benzamide (Compound 7.5);

[0711] 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1,2-trimethylpropyl)pyridine-2-carboxamide (Compound 7.6);

[0712] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-isopropyl-pyridine-2-carboxamide (Compound 7.7);

[0713] 3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4-methyltetrahydropyran-4-yl)benzamide (Compound 7.8);

[0714] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4-methyltetrahydropyran-4-yl)pyridine-2-carboxamide (Compound 7.9);

[0715] 3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclobutyl)benzamide (Compound 7.10);

[0716] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-tetrahydropyran-4-yl-pyridine-2-carboxamide (Compound 7.11);

[0717] 4-[2-(5-chloro-2-hydroxyphenyl)acetylamino]-N-[(1s,4s)-4-hydroxycyclohexyl]pyridine-2-carboxamide (Compound 7.12);

[0718] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-sec-butyl-pyridine-2-carboxamide (Compound 7.13);

[0719] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(2-hydroxy-1,1,2-trimethyl-propyl)pyridine-2-carboxamide (Compound 7.14);

[0720] N-(3-Bicyclo[1.1.1]pentyl)-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 7.15);

[0721] 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-cyanocyclobutyl)pyridine-2-carboxamide (Compound 7.16);

[0722] tert-Butyl 3-[[3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]benzoyl]amino]piperidine-1-carboxylate (Compound 8);

[0723] tert-Butyl 3-[[4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carbonyl]amino]piperidine-1-carboxylate (Compound 8.1);

[0724] 4-[[3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]benzoyl]amino]-4-methyl-piperidine-1-carboxylic acid tert-butyl ester (Compound 8.2);

[0725] (1r,5s,6s)-tert-butyl 6-{4-[2-(5-chloro-2-hydroxyphenyl)acetylamino]pyridine-2-amido}-3-azabicyclo[3.1.0]hexane-3-carboxylate (Compound 8.3);

[0726] N-tert-Butyl-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-4-fluoro-benzamide (Compound 9);

[0727] N-tert-Butyl-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-5-methyl-benzamide (Compound 9.1);

[0728] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylpropyl)pyridine-2-carboxamide (Compound 9.2);

[0729] N-tert-Butyl-4-[[2-(5-tert-butyl-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 10);

[0730] N-tert-Butyl-5-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-2-hydroxy-benzamide (Compound 11);

[0731] N-tert-Butyl-3-[[2-(5-cyano-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 12);

[0732] 3-[2-[[2-(tert-Butylcarbamoyl)-4-pyridinyl]amino]-2-oxo-ethyl]-4-hydroxy-benzoic acid methyl ester (Compound 13);

[0733] N-tert-Butyl-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-4-hydroxy-benzamide (Compound 14);

[0734] N-tert-Butyl-4-[[2-(2-hydroxy-5-methyl-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 15);

[0735] N-tert-Butyl-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-4-methoxy-benzamide (Compound 16);

[0736] N-tert-Butyl-5-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-2-fluoro-benzamide (Compound 17);

[0737] N-tert-Butyl-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-5-fluoro-benzamide (Compound 18);

[0738] N-tert-Butyl-4-[[2-(3-hydroxy-2-pyridinyl)acetyl]amino]pyridine-2-carboxamide (Compound 19);

[0739] N-tert-Butyl-4-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 20);

[0740] N-tert-butyl-4-[[(1R)-or (1S)-indane-1-carbonyl]amino]pyridine-2-carboxamide (Compound 21a);

[0741] N-tert-Butyl-4-[[(1R)-or (1S)-indane-1-carbonyl]amino]pyridine-2-carboxamide (Compound 21b);

[0742] N-tert-Butyl-4-[(2-phenylacetyl)amino]pyridine-2-carboxamide (Compound 22);

[0743] 4-(3,3-dimethylbutyrylamino)-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 22.1);

[0744] 4-[(2-cyclopentylacetyl)amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 22.2);

[0745] 4-[[2-(3-chloro-4-pyridinyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 22.3);

[0746] 4-[[2-(4-Chlorophenyl)acetyl]amino]-N-(1-cyanocyclopropyl)pyridine-2-carboxamide (Compound 23);

[0747] 4-[[2-(3-chlorophenyl)acetyl]amino]-N-(1-cyanocyclopropyl)pyridine-2-carboxamide (Compound 23.1);

[0748] 4-[[2-(2-Chloro-5-fluoro-phenyl)acetyl]amino]-N-(1-cyanocyclopropyl)pyridine-2-carboxamide (Compound 23.2);

[0749] N-tert-Butyl-4-(indane-2-carbonylamino)pyridine-2-carboxamide (Compound 23.3);

[0750] N-tert-Butyl-4-[[2-[2-(difluoromethoxy)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 23.4);

[0751] N-tert-Butyl-4-[[2-[2-(difluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 23.5);

[0752] N-tert-Butyl-4-[[2-(3,4-difluorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 23.6);

[0753] N-tert-Butyl-4-[[2-(3,5-difluorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 23.7);

[0754] N-tert-Butyl-4-[[2-(2,3-difluorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 23.8);

[0755] 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-tetrahydropyran-4-yl-pyridine-2-carboxamide (Compound 23.9);

[0756] N-(1-cyanocyclobutyl)-4-[[2-(6-quinolinyl)acetyl]amino]pyridine-2-carboxamide (Compound 23.11);

[0757] N-tert-Butyl-4-[[2-[2-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 23.12);

[0758] 4-[[2-(2-Bromophenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (Compound 23.13);

[0759] N-tert-Butyl-4-[[2-(2-cyanophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 23.14);

[0760] 4-[[2-(2-chlorophenyl)acetyl]amino]-N-(4-cyanotetrahydropyran-4-yl)pyridine-2-carboxamide (Compound 23.15);

[0761] N-(4-cyanotetrahydropyran-4-yl)-4-[[2-(6-quinolinyl)acetyl]amino]pyridine-2-carboxamide (Compound 23.16);

[0762] 4-[[2-(2-Chloro-5-methoxy-phenyl)acetyl]amino]-N-(1-cyanocyclopropyl)pyridine-2-carboxamide (Compound 24);

[0763] N-(3-Bicyclo[1.1.1]pentyl)-4-[[2-(5-tert-butyl-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 25);

[0764] -[[2-(5-tert-Butyl-2-hydroxy-phenyl)acetyl]amino]-N-(4-cyanotetrahydropyran-4-yl)pyridine-2-carboxamide (Compound 25.1);

[0765] N-tert-Butyl-4-[[2-(2-hydroxy-5-phenyl-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 26);

[0766] N-tert-Butyl-4-[[2-[5-chloro-2-hydroxy-4-(pyrrolidin-1-ylmethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 27);

[0767] N-tert-butyl-4-[[2-[4-[(tert-butylamino)methyl]-5-chloro-2-hydroxy-phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 27.1);

[0768] N-tert-butyl-4-[[2-[5-chloro-2-hydroxy-4-(morpholinomethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 27.2);

[0769] N-tert-Butyl-4-[[2-[5-chloro-4-[(3,3-difluoropyrrolidin-1-yl)methyl]-2-hydroxy-phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 27.3);

[0770] N-tert-Butyl-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-5-fluoro-pyridine-2-carboxamide (Compound 28);

[0771] N-tert-Butyl-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-3-fluoro-pyridine-2-carboxamide (Compound 28.1);

[0772] 4-[[2-(2-chlorophenyl)acetyl]amino]-N-(1-cyanocyclobutyl)pyridine-2-carboxamide (Compound 30);

[0773] 4-[[2-(2-chlorophenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 30.1);

[0774] 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(4-fluoro-1-bicyclo[2.1.1]hexyl)pyridine-2-carboxamide (Compound 30.2);

[0775] 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(1-cyclopropyl-1-methyl-ethyl)pyridine-2-carboxamide (Compound 30.3);

[0776] 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(1-cyano-1-methyl-ethyl)pyridine-2-carboxamide (Compound 30.3a);

[0777] 4-[[2-(2-chlorophenyl)acetyl]amino]-N-(1-methyl-3-bicyclo[1.1.1]pentyl)pyridine-2-carboxamide (Compound 30.4);

[0778] 4-[[2-(2-chlorophenyl)acetyl]amino]-N-(1-cyano-3-bicyclo[1.1.1]pentyl)pyridine-2-carboxamide (Compound 30.5);

[0779] 4-[[2-(2-chlorophenyl)acetyl]amino]-N-(2,2-difluorocyclopropyl)pyridine-2-carboxamide (Compound 30.6);

[0780] 4-[[2-(2-chlorophenyl)acetyl]amino]-N-(1-cyanocyclopropyl)pyridine-2-carboxamide (Compound 30.7);

[0781] 4-[[2-(2-chlorophenyl)acetyl]amino]-N-(1-methylcyclopropyl)pyridine-2-carboxamide (Compound 30.8);

[0782] 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(3-fluoro-1-bicyclo[1.1.1]pentyl)pyridine-2-carboxamide (Compound 30.9);

[0783] 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(2-fluoro-1,1-dimethyl-ethyl)pyridine-2-carboxamide (Compound 30.10);

[0784] 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(4-ethynyltetrahydropyran-4-yl)pyridine-2-carboxamide (Compound 30.11);

[0785] 4-[[2-(2-chlorophenyl)acetyl]amino]-N-(1-cyanocyclopentyl)pyridine-2-carboxamide (Compound 30.12);

[0786] 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(2,2-difluoro-1,1-dimethyl-ethyl)pyridine-2-carboxamide (Compound 30.13);

[0787] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4-cyanotetrahydropyran-4-yl)pyridine-2-carboxamide (Compound 31);

[0788] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-ethynylcyclopentyl)pyridine-2-carboxamide (Compound 31.2);

[0789] 4-[2-(5-chloro-2-hydroxyphenyl)acetylamino]-N-[(1s,2s)-2-hydroxycyclohexyl]pyridine-2-carboxamide (Compound 31.3);

[0790] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1S,2S)-2-hydroxycyclohexyl]pyridine-2-carboxamide or 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1R,2R)-2-hydroxycyclohexyl]pyridine-2-carboxamide (Compound 31.3a);

[0791] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4-ethynyltetrahydropyran-4-yl)pyridine-2-carboxamide (Compound 31.4);

[0792] N-[(6-amino-2-pyridinyl)methyl]-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 32);

[0793] 12-[[4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carbonyl]amino]dodecanoic acid (Compound 32.1);

[0794] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3-pyridylmethyl)pyridine-2-carboxamide (Compound 32.2);

[0795] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(2-pyridylmethyl)pyridine-2-carboxamide (Compound 32.3);

[0796] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4-pyridinylmethyl)pyridine-2-carboxamide (Compound 32.4);

[0797] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(2-hydroxyphenyl)methyl]pyridine-2-carboxamide (Compound 32.5);

[0798] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethyl-2-morpholino-ethyl)pyridine-2-carboxamide (Compound 32.6);

[0799] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(2-hydroxy-1,1-dimethyl-ethyl)pyridine-2-carboxamide (Compound 32.7);

[0800] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3,3-difluoro-4-piperidinyl)pyridine-2-carboxamide (Compound 32.8);

[0801] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1H-imidazol-2-yl)pyridine-2-carboxamide (Compound 32.9);

[0802] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1R,2R)-2-hydroxycyclopentyl]pyridine-2-carboxamide (Compound 33);

[0803] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-cyano-1-methyl-ethyl)pyridine-2-carboxamide (Compound 34);

[0804] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[3-(hydroxymethyl)tetrahydrofuran-3-yl]pyridine-2-carboxamide (Compound 35);

[0805] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(3R)-3-(hydroxymethyl)tetrahydrofuran-3-yl]pyridine-2-carboxamide or 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(3S)-3-(hydroxymethyl)tetrahydrofuran-3-yl]pyridine-2-carboxamide (Compound 35a);

[0806] -[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(3R)-3-(hydroxymethyl)tetrahydrofuran-3-yl]pyridine-2-carboxamide or 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(3S)-3-(hydroxymethyl)tetrahydrofuran-3-yl]pyridine-2-carboxamide (Compound 35b);

[0807] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4-hydroxy-4-methyl-cyclohexyl)pyridine-2-carboxamide as a 6:4 mixture of stereoisomers (Compound 35.1);

[0808] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1s,2r)-2-(hydroxymethyl)cyclohexyl]pyridine-2-carboxamide (Compound 35.2);

[0809] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1s,3r)-3-hydroxycyclopentyl]pyridine-2-carboxamide (Compound 35.3);

[0810] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[2-hydroxy-1-(hydroxymethyl)-1-methyl-ethyl]pyridine-2-carboxamide (Compound 35.4);

[0811] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3-hydroxycyclohexyl)pyridine-2-carboxamide as a mixture of stereoisomers (Compound 35.6);

[0812] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3-phenoxypropyl)pyridine-2-carboxamide (Compound 35.7);

[0813] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclopropyl)pyridine-2-carboxamide (Compound 35.8);

[0814] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[1-methyl-1-(2-pyridinyl)ethyl]pyridine-2-carboxamide (Compound 35.9);

[0815] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3-phenylpropyl)pyridine-2-carboxamide (Compound 35.10);

[0816] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[2-hydroxy-1-(2-pyridinyl)ethyl]pyridine-2-carboxamide (Compound 35.11);

[0817] 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(5-methoxy-2-pyridinyl)methyl]pyridine-2-carboxamide (Compound 35.12);

[0818] 3-[[4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carbonyl]amino]-3-methyl-butyric acid ethyl ester (Compound 35.13);

[0819] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3-hydroxy-1,1-dimethyl-propyl)pyridine-2-carboxamide (Compound 35.14);

[0820] N-benzyl-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 35.15);

[0821] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-phenyl-pyridine-2-carboxamide (Compound 35.16);

[0822] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1S,2S)-2-hydroxycyclopentyl]pyridine-2-carboxamide (Compound 35.17);

[0823] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1R,2S)-2-hydroxycyclopentyl]pyridine-2-carboxamide (Compound 35.18);

[0824] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1S,2R)-2-hydroxycyclopentyl]pyridine-2-carboxamide (Compound 35.19);

[0825] 3-[[2-(5-Fluoro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclohexyl)benzamide (Compound 35.20);

[0826] N-(1,1-dimethylprop-2-ynyl)-3-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 35.21);

[0827] N-cyclohexyl-3-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 35.22);

[0828] 3-[[2-(5-Fluoro-2-hydroxy-phenyl)acetyl]amino]-N-[3-(hydroxymethyl)tetrahydrofuran-3-yl]benzamide (Compound 35.23);

[0829] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-ethynylcyclohexyl)pyridine-2-carboxamide (Compound 35.24);

[0830] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[1-(hydroxymethyl)cyclobutyl]pyridine-2-carboxamide (Compound 35.25);

[0831] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[3-(hydroxymethyl)oxetan-3-yl]pyridine-2-carboxamide (Compound 35.26);

[0832] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-cyano-2-methoxy-1-methyl-ethyl)pyridine-2-carboxamide (Compound 35.27);

[0833] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1-hydroxycyclobutyl)methyl]pyridine-2-carboxamide (Compound 35.28);

[0834] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 36);

[0835] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-cyano-1,2-dimethyl-propyl)pyridine-2-carboxamide (Compound 37);

[0836] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclopentyl)pyridine-2-carboxamide (Compound 38);

[0837] N-(4-tert-Butylcyclohexyl)-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 39);

[0838] N-tert-Butyl-4-[[2-(2-chloro-3-fluoro-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 40);

[0839] N-tert-Butyl-4-[[2-(2-chloro-5-fluoro-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 40.1);

[0840] N-(4-cyanotetrahydropyran-4-yl)-3-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 41);

[0841] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[4-(2-hydroxyethyl)tetrahydropyran-4-yl]pyridine-2-carboxamide (Compound 42);

[0842] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[1,1-dimethyl-3-(2,2,2-trifluoroethylamino)propyl]pyridine-2-carboxamide (Compound 43);

[0843] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4-fluoro-1-bicyclo[2.1.1]hexyl)pyridine-2-carboxamide (Compound 44);

[0844] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[3-(2,2-dimethylpropionylamino)-1,1-dimethyl-propyl]pyridine-2-carboxamide (Compound 45);

[0845] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-cyano-2-hydroxy-1-methyl-ethyl)pyridine-2-carboxamide (Compound 46);

[0846] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1S)-1-cyano-2-hydroxy-1-methyl-ethyl]pyridine-2-carboxamide or 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1R)-1-cyano-2-hydroxy-1-methyl-ethyl]pyridine-2-carboxamide (Compound 46a);

[0847] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1S)-1-cyano-2-hydroxy-1-methyl-ethyl]pyridine-2-carboxamide or 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1R)-1-cyano-2-hydroxy-1-methyl-ethyl]pyridine-2-carboxamide (Compound 46b);

[0848] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3-cyanotetrahydrofuran-3-yl)pyridine-2-carboxamide (Compound 47);

[0849] 2-[4-[[4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carbonyl]amino]tetrahydropyran-4-yl]acetic acid methyl ester (Compound 47.1);

[0850] 4-[[4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carbonyl]amino]tetrahydropyran-4-carboxylic acid methyl ester (Compound 47.2);

[0851] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3-cyanooxetan-3-yl)pyridine-2-carboxamide (Compound 47.3);

[0852] 4-[[2-(5-Fluoro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclobutyl)pyridine-2-carboxamide (Compound 48);

[0853] N-(4-cyanotetrahydropyran-4-yl)-4-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 48.1);

[0854] N-[3-(tert-Butylamino)-1,1-dimethyl-3-oxo-propyl]-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 49);

[0855] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[3-(methylsulfonylamino)-1,1-dimethyl-propyl]pyridine-2-carboxamide (Compound 50);

[0856] N-(3-Acetylamino-1,1-dimethyl-propyl)-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 51);

[0857] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[4-(hydroxymethyl)tetrahydropyran-4-yl]pyridine-2-carboxamide (Compound 53);

[0858] N-tert-Butyl-4-[[2-[3-(1-hydroxyethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 54);

[0859] N-tert-Butyl-5-chloro-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 55);

[0860] N-tert-Butyl-4-[[2-[5-chloro-2-[(4-methoxyphenyl)methoxy]phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 56);

[0861] N-tert-butyl-4-[[(1S) or (1R)-4-chloro-7-hydroxy-indane-1-carbonyl]amino]pyridine-2-carboxamide and Example 57b: N-tert-butyl-4-[[(1S) or (1R)-4-chloro-7-hydroxy-indane-1-carbonyl]amino]pyridine-2-carboxamide (Compound 57a);

[0862] N-tert-butyl-4-[[(1S) or (1R)-4-chloro-7-hydroxy-indane-1-carbonyl]amino]pyridine-2-carboxamide and Example 57b: N-tert-butyl-4-[[(1S) or (1R)-4-chloro-7-hydroxy-indane-1-carbonyl]amino]pyridine-2-carboxamide (Compound 57b);

[0863] N-tert-Butyl-4-[[2-(2-cyclopropylphenyl)acetyl]amino]pyridine-2-carboxamide (Compound 58);

[0864] 4-[[2-(3-Bromo-5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (Compound 59);

[0865] N-(4-Fluoro-1-bicyclo[2.1.1]hexyl)-4-[[2-(2-fluorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 60);

[0866] N-(1-cyano-2-hydroxy-1-methyl-ethyl)-4-[[2-(2-fluorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 60.1);

[0867] N-(1,1-dimethylprop-2-ynyl)-4-[[2-(2-fluorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 60.2);

[0868] N-tert-Butyl-4-[[2-(5-chloro-2-hydroxy-3-isopropyl-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 61);

[0869] N-tert-Butyl-4-[[2-[5-chloro-2-hydroxy-3-(1-methoxyethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 62);

[0870] 4-[[2-(6-Quinolinyl)acetyl]amino]-N-tetrahydropyran-4-yl-pyridine-2-carboxamide (Compound 63);

[0871] 4-(Benzylcarbamoylamino)-N-tert-butyl-pyridine-2-carboxamide (Compound 64);

[0872] N-tert-Butyl-4-(cyclohexylmethylcarbamoylamino)pyridine-2-carboxamide (Compound 64.1);

[0873] N-tert-Butyl-4-(2-phenylethylcarbamoylamino)pyridine-2-carboxamide (Compound 64.2);

[0874] N-tert-Butyl-4-[[(1R)-1-phenylethyl]carbamoylamino]pyridine-2-carboxamide (Compound 64.3);

[0875] N-tert-Butyl-4-[[(1S)-1-phenylethyl]carbamoylamino]pyridine-2-carboxamide (Compound 64.4);

[0876] N-tert-Butyl-4-[(2-chlorophenyl)methylcarbamoylamino]pyridine-2-carboxamide (Compound 64.5);

[0877] N-tert-Butyl-4-(1H-indol-3-ylcarbamoylamino)pyridine-2-carboxamide (Compound 64.6);

[0878] N-tert-Butyl-4-[(3-chlorophenyl)methylcarbamoylamino]pyridine-2-carboxamide (Compound 64.7);

[0879] N-tert-Butyl-4-[(4-chlorophenyl)methylcarbamoylamino]pyridine-2-carboxamide (Compound 64.8);

[0880] N-tert-Butyl-4-[(2-hydroxyphenyl)carbamoylamino]pyridine-2-carboxamide (Compound 65);

[0881] N-tert-Butyl-4-[(2-methoxyphenyl)methylcarbamoylamino]pyridine-2-carboxamide (Compound 65.1);

[0882] N-tert-Butyl-4-[(2-hydroxyphenyl)methylcarbamoylamino]pyridine-2-carboxamide (Compound 65.2);

[0883] N-tert-Butyl-4-[(3-hydroxyphenyl)methylcarbamoylamino]pyridine-2-carboxamide (Compound 65.3);

[0884] N-tert-Butyl-4-[(4-hydroxyphenyl)methylcarbamoylamino]pyridine-2-carboxamide (Compound 65.4);

[0885] N-tert-Butyl-4-[[2-[2-hydroxy-5-(1-hydroxyethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 66);

[0886] N-tert-Butyl-4-[[2-[2-hydroxy-5-[1-(2,2,2-trifluoroethylamino)ethyl]phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 67);

[0887] N-tert-Butyl-4-[[2-[3-(cyanomethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 68);

[0888] N-tert-Butyl-4-[[2-[3-(methoxymethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 69);

[0889] N-tert-Butyl-4-[[2-[2-hydroxy-5-(morpholinomethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 70);

[0890] 3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3-cyanotetrahydrofuran-3-yl)benzamide (Compound 71);

[0891] 3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclohexyl)benzamide (Compound 71.1);

[0892] 4-[[2-(5-Fluoro-2-hydroxy-phenyl)acetyl]amino]-N-[3-(hydroxymethyl)tetrahydrofuran-3-yl]pyridine-2-carboxamide (Compound 72);

[0893] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[1-(hydroxymethyl)-2-methoxy-1-methyl-ethyl]pyridine-2-carboxamide (Compound 73);

[0894] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylbut-2-ynyl)pyridine-2-carboxamide (Compound 73.1);

[0895] 3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)benzamide (Compound 74);

[0896] 3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[3-(hydroxymethyl)tetrahydrofuran-3-yl]benzamide (Compound 74.1);

[0897] N-tert-Butyl-4-[[2-[2-hydroxy-5-(3-hydroxypropyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 75);

[0898] 4-[[2-(5-Chloro-4-fluoro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclobutyl)pyridine-2-carboxamide (Compound 76);

[0899] 4-[[2-(2,5-Difluorophenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 77);

[0900] 4-[[2-(2,5-Difluorophenyl)acetyl]amino]-N-(4-fluoro-1-bicyclo[2.1.1]hexyl)pyridine-2-carboxamide (Compound 77.1);

[0901] 4-[[2-(4-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 78);

[0902] N-(1,1-dimethylprop-2-ynyl)-4-[[2-[2-hydroxy-4-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 78.1);

[0903] N-(1,1-dimethylprop-2-ynyl)-4-[[2-[2-hydroxy-5-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 78.2);

[0904] 4-[(2-chroman-4-ylacetyl)amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 79);

[0905] N-(1,1-dimethylprop-2-ynyl)-4-[[2-(1-isopropyl-3,5-dimethyl-pyrazol-4-yl)acetyl]amino]pyridine-2-carboxamide (Compound 79.1);

[0906] N-(1,1-dimethylprop-2-ynyl)-4-[[2-(1H-indazol-4-yl)acetyl]amino]pyridine-2-carboxamide (Compound 79.2);

[0907] N-(1,1-dimethylprop-2-ynyl)-4-[[2-(1H-indol-7-yl)acetyl]amino]pyridine-2-carboxamide (Compound 79.3);

[0908] 3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4-cyanotetrahydropyran-4-yl)benzamide (Compound 80);

[0909] N-(1-cyano-1-methyl-ethyl)-4-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 81);

[0910] N-(1-cyano-2-hydroxy-1-methyl-ethyl)-4-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 81.1);

[0911] 4-[[2-(5-Fluoro-2-hydroxy-phenyl)acetyl]amino]-N-isopropyl-pyridine-2-carboxamide (Compound 81.2);

[0912] N-(1,1-dimethylprop-2-ynyl)-4-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 81.3);

[0913] N-(4-Fluoro-1-bicyclo[2.1.1]hexyl)-4-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 81.4);

[0914] 4-[[2-(5-Fluoro-2-hydroxy-phenyl)acetyl]amino]-N-[1-(hydroxymethyl)cyclobutyl]pyridine-2-carboxamide (Compound 81.5);

[0915] N-tert-Butyl-6-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]pyrimidine-4-carboxamide (Compound 82);

[0916] N-(1-cyano-1-methyl-ethyl)-4-(thiophene-3-carbonylamino)pyridine-2-carboxamide (Compound 83);

[0917] N-(1-cyano-1-methyl-ethyl)-4-[(2-cyclohexylacetyl)amino]pyridine-2-carboxamide (Compound 83.1);

[0918] N-(1-cyano-1-methyl-ethyl)-4-(cyclohexanecarbonylamino)pyridine-2-carboxamide (Compound 83.2);

[0919] N-(1-cyano-1-methyl-ethyl)-4-[(3,3-difluorocyclopentanecarbonyl)amino]pyridine-2-carboxamide (Compound 83.3);

[0920] N-(1-cyano-1-methyl-ethyl)-4-[(1-methylcyclopentanecarbonyl)amino]pyridine-2-carboxamide (Compound 83.4);

[0921] N-(1-cyano-1-methyl-ethyl)-4-(3-cyclohexylpropionylamino)pyridine-2-carboxamide (Compound 83.5);

[0922] 4-(2-{bicyclo[2.2.1]hept-2-yl}acetylamino)-N-(1-cyano-1-methylethyl)pyridine-2-carboxamide (Compound 83.6);

[0923] N-(1-cyano-1-methyl-ethyl)-4-[[2-(1-methylcyclohexyl)acetyl]amino]pyridine-2-carboxamide (Compound 83.7);

[0924] N-[2-[(1-cyano-1-methyl-ethyl)carbamoyl]-4-pyridinyl]-2-cyclopropyl-pyrimidine-5-carboxamide (Compound 83.8);

[0925] N-[2-[(1-cyano-1-methyl-ethyl)carbamoyl]-4-pyridinyl]-3-isobutyl-isoxazole-5-carboxamide (Compound 83.9);

[0926] N-(1-cyano-1-methyl-ethyl)-4-[[2-(4,4-difluorocyclohexyl)acetyl]amino]pyridine-2-carboxamide (Compound 83.10);

[0927] 4-[(1-Benzylcyclopropanecarbonyl)amino]-N-(1-cyano-1-methyl-ethyl)pyridine-2-carboxamide (Compound 83.11);

[0928] N-(1-cyano-1-methyl-ethyl)-4-[3-(2-methoxy-4-pyridinyl)propionylamino]pyridine-2-carboxamide (Compound 83.13);

[0929] 4-[(5-tert-Butyl-2-methyl-pyrazole-3-carbonyl)amino]-N-(1-cyano-1-methyl-ethyl)pyridine-2-carboxamide (Compound 83.14);

[0930] N-(1-cyano-1-methyl-ethyl)-4-[(2-pyrazol-1-ylbenzoyl)amino]pyridine-2-carboxamide (Compound 83.15);

[0931] N-[2-[(1-cyano-1-methyl-ethyl)carbamoyl]-4-pyridinyl]-6-(trifluoromethyl)pyridine-2-carboxamide (Compound 83.16);

[0932] N-[2-[(1-cyano-1-methyl-ethyl)carbamoyl]-4-pyridinyl]-3-oxo-4H-1,4-benzoxazine-7-carboxamide (Compound 83.17);

[0933] N-[2-[(1-cyano-1-methyl-ethyl)carbamoyl]-4-pyridinyl]-1-ethyl-indole-2-carboxamide (Compound 83.18);

[0934] N-(1-cyano-1-methyl-ethyl)-4-[[2-(2,2,2-trifluoroethyl)pyrazole-3-carbonyl]amino]pyridine-2-carboxamide (Compound 83.19);

[0935] N-[2-[(1-cyano-1-methyl-ethyl)carbamoyl]-4-pyridinyl]-3-phenyl-isoxazole-4-carboxamide (Compound 83.20);

[0936] 4-[(1-Benzylpyrazole-4-carbonyl)amino]-N-(1-cyano-1-methyl-ethyl)pyridine-2-carboxamide (Compound 83.21);

[0937] N-(1-cyano-1-methyl-ethyl)-4-[(2-methyl-5-phenyl-pyrazole-3-carbonyl)amino]pyridine-2-carboxamide (Compound 83.22);

[0938] N-(1-cyano-1-methyl-ethyl)-4-[[2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoyl]amino]pyridine-2-carboxamide (Compound 83.23);

[0939] N-(1-cyano-1-methyl-ethyl)-4-[(3-methyl-1-phenyl-pyrazole-4-carbonyl)amino]pyridine-2-carboxamide (Compound 83.24);

[0940] N-[2-[(1-cyano-1-methyl-ethyl)carbamoyl]-4-pyridinyl]-2-phenoxy-pyridine-3-carboxamide (Compound 83.25);

[0941] N-(1-cyano-1-methyl-ethyl)-4-[[2,5-dimethyl-1-(2-thienylmethyl)pyrrole-3-carbonyl]amino]pyridine-2-carboxamide (Compound 83.26);

[0942] N-[2-[(1-cyano-1-methyl-ethyl)carbamoyl]-4-pyridinyl]-5-(2-methoxyphenyl)isoxazole-3-carboxamide (Compound 83.27);

[0943] N-[2-[(1-cyano-1-methyl-ethyl)carbamoyl]-4-pyridinyl]-4-methyl-2-phenyl-thiazole-5-carboxamide (Compound 83.28);

[0944] 4-[(4-Acetylaminobenzoyl)amino]-N-(1-cyano-1-methyl-ethyl)pyridine-2-carboxamide (Compound 83.29);

[0945] N-[2-[(1-cyano-1-methyl-ethyl)carbamoyl]-4-pyridinyl]-1,3-benzothiazole-7-carboxamide (Compound 83.30);

[0946] N-(1-cyano-1-methyl-ethyl)-4-[3-(4-fluorophenyl)butyrylamino]pyridine-2-carboxamide (Compound 83.31);

[0947] N-[2-[(1-cyano-1-methyl-ethyl)carbamoyl]-4-pyridinyl]-1-methyl-2-oxo-quinoline-3-carboxamide (Compound 83.32);

[0948] N-tert-Butyl-3-[[2-(2-hydroxycyclohexyl)acetyl]amino]benzamide (Compound 84);

[0949] N-tert-Butyl-6-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyrimidine-4-carboxamide (Compound 85);

[0950] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[1-cyano-2-methoxy-1-(methoxymethyl)ethyl]pyridine-2-carboxamide (Compound 86);

[0951] 4-[[2-(3-Amino-4-tert-butyl-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (Compound 87);

[0952] 4-[[2-(2-Amino-4-tert-butyl-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (Compound 88);

[0953] N-tert-Butyl-4-[[2-(4-tert-butyl-3-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 89);

[0954] N-tert-Butyl-4-[[2-(4-tert-butyl-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 90);

[0955] N-tert-Butyl-4-[[2-(4-tert-butyl-2-fluoro-5-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 91);

[0956] 4-[[2-(4-Chloro-3-hydroxy-phenyl)acetyl]amino]-N-(4-cyanotetrahydropyran-4-yl)pyridine-2-carboxamide (Compound 92);

[0957] 4-[[2-(4-Chloro-3-hydroxy-phenyl)acetyl]amino]-N-(1-cyano-1-methyl-ethyl)pyridine-2-carboxamide (Compound 92.1);

[0958] 4-[[2-(4-Chloro-3-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 92.2);

[0959] 4-[[2-(4-Chloro-3-hydroxy-phenyl)acetyl]amino]-N-[(1s,2s)-2-hydroxycyclopentyl]pyridine-2-carboxamide (Compound 92.3);

[0960] 4-[[2-(4-tert-Butyl-3-hydroxy-phenyl)acetyl]amino]-N-[3-(hydroxymethyl)tetrahydrofuran-3-yl]pyridine-2-carboxamide (Compound 93);

[0961] 4-[[2-(4-tert-Butyl-3-hydroxy-phenyl)acetyl]amino]-N-[(2S)-2-hydroxycyclohexyl]pyridine-2-carboxamide (Compound 93.1);

[0962] 4-[[2-(4-tert-Butyl-3-hydroxy-phenyl)acetyl]amino]-N-[(2S)-2-hydroxycyclopentyl]pyridine-2-carboxamide (Compound 93.2);

[0963] 4-[[2-(4-tert-Butyl-3-hydroxy-phenyl)acetyl]amino]-N-(4-cyanotetrahydropyran-4-yl)pyridine-2-carboxamide (Compound 93.3);

[0964] 4-[[2-(4-tert-Butyl-3-hydroxy-phenyl)acetyl]amino]-N-(1-cyano-1-methyl-ethyl)pyridine-2-carboxamide (Compound 93.4);

[0965] 4-[[2-(4-tert-Butyl-3-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 93.5);

[0966] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methyl-1-phenyl-ethyl)pyridine-2-carboxamide (Compound 94);

[0967] and salts and solvates of any of the foregoing.

[0968] The compounds of general formula (I) may be prepared as described below, and methods for their preparation form a further aspect of the invention.

[0969] The compound of formula (I) wherein Z is -C(O)- is prepared by reacting the compound of formula (II):

[0970]

[0971] where R 1 、R 2 、R 3 、R 5a and R 5b 、X 1 and X 2 As defined in formula (I);

[0972] By reacting with a compound of formula (III):

[0973]

[0974] where R 4 and Y is as defined in the general formula (I).

[0975] The reaction is suitably carried out in the presence of a coupling agent, and this method is particularly suitable for the case where X 1 and X 2 Each is independently N or CR 8 A compound of formula (I), wherein R 8 is a halo group, and Y is a bond or an alkylene group.

[0976] An example of a suitable coupling agent is a carbodiimide, such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) and a triazole, such as 1-hydroxy-7-azabenzotriazole (HOAt) or hydroxybenzotriazole (HOBT). Suitably, the reaction is carried out under basic conditions, such as in the presence of an amine, such as diisopropylethylamine (DIPEA), and in an organic solvent, such as DMF.

[0977] Alternatively, the coupling agent can be propylphosphonic anhydride (T3P). When T3P is used as the coupling agent, the reaction can be carried out under basic conditions, for example, in the presence of an amine (e.g., diisopropylethylamine (DIPEA) or triethylamine (TEA)) and in an organic solvent (e.g., dioxane).

[0978] Other known peptide coupling agents can also be used, such as O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TATU), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), and the like.

[0979] The compound of formula (III) may be commercially available or may be prepared by methods known to those skilled in the art. For example, the synthesis of the compound of formula (III) wherein Y is -CH2- may be carried out by converting the nitrile of formula (XXIII):

[0980]

[0981] where R 4 As defined in formula (I);

[0982] This is accomplished by reaction with an aqueous base, for example a metal hydroxide such as lithium hydroxide, followed by acidification, for example with hydrochloric acid.

[0983] The reaction is suitably carried out in aqueous solution and heated to reflux temperature.

[0984] Nitriles of general formula (XXIII) can be prepared by reacting compounds of general formula (XXIV):

[0985]

[0986] where R 4 As defined in formula (I) and R 27 is halogen, for example fluorine, chlorine or bromine, especially chlorine;

[0987] This is done by reaction with a cyanide salt, such as sodium cyanide.

[0988] The reaction can be carried out at a temperature of about 15 to 25°C, typically at room temperature, in an organic solvent such as N,N-dimethylformamide.

[0989] The compound of general formula (XXIV) can be prepared by halogenating the compound of general formula (XXV) with a halogenating agent:

[0990]

[0991] where R 4 As defined in general formula (I).

[0992] The appropriate halogenating agent for the reaction depends on the type of halogen group R desired. 27 For example, when R 27 When chlorine is used, the halogenating agent may be thionyl chloride. The reaction can be carried out at a temperature of about 15 to 25°C, usually at room temperature, in an organic solvent (eg, dichloromethane).

[0993] Compounds of general formula (XXV) can be obtained by reducing compounds of general formula (III) wherein Y is a bond (ie, which has the formula:

[0994]

[0995] where R 4 As defined in general formula (I).

[0996] The reduction may be carried out using any suitable reducing agent, for example borane-THF, and is suitably carried out at elevated temperature, for example 30-60°C, typically around 50°C.

[0997] In another method for preparing compounds of formula (I), compounds of formula (II) as defined above may be reacted with an acid chloride of formula (IV):

[0998]

[0999] where R 4 and Y is as defined in the general formula (I).

[1000] The reaction is suitably carried out under basic conditions, for example in the presence of an amine such as DIPEA.

[1001] This method is particularly suitable for compounds where Y is a bond or an alkylene group.

[1002] The acid chloride of the general formula (IV) is commercially available or can be obtained by reacting a carboxylic acid of the general formula (III) with a chlorinating agent (eg thionyl chloride).

[1003] The compounds of general formula (III) may be known and commercially available or may be prepared by methods known to those skilled in the art.

[1004] Alternatively, for a compound of formula (I) wherein Z is -C(O)NH-, the compound of formula (II) can be reacted with a compound of formula (XIV):

[1005] O=C=NYR 4 (XIV)

[1006] where R 4 and Y is as defined in the general formula (I).

[1007] Suitably, the reaction is carried out in an anhydrous organic solvent (such as N,N-dimethylformamide) at elevated temperature, for example about 70 to 85°C.

[1008] Another method for preparing compounds of formula (Ia) or (Ib) is by reacting a compound of formula (II) with a compound of formula (XIII):

[1009]

[1010] where R 10 、R 11 and n is as defined in general formula (Ia).

[1011] For example, to prepare a 11a is Cl and R 11b The compound of formula (Ib) is H, and the compound of formula (XIII) may be 5-chloro-2(3H)-benzofuranone, which has the following structure:

[1012]

[1013] The reaction can be carried out in an organic solvent such as toluene, typically at elevated temperature, for example about 90 to 120°C, such as about 100 to 110°C, and under pressure, for example in a sealed tube.

[1014] The compounds of general formula (XIII) and (XIV) may be known and commercially available or may be prepared by methods known to those skilled in the art.

[1015] The compound of general formula (II) can be prepared by converting the compound of general formula (VIII):

[1016]

[1017] where R 5a 、R 5b 、X 1 and X 2 As defined in formula (I);

[1018] React with a compound of formula (VII) to form:

[1019]

[1020] where R 1 、R 2 and R 3 As defined in general formula (I).

[1021] Suitably, the reaction is carried out in the presence of a coupling agent as described above for the reaction between compounds of formula (II) and (III).TBTU is a particularly suitable coupling agent for this reaction, although EDCI and HOAt or HOBt may also be used.

[1022] In some cases, compounds of formula (VIII) may be protected as carbamates of formula (VI):

[1023]

[1024] where R 5a 、R 5b 、X 1 and X 2 As defined in formula (I); and R 20 C 1-8 Alkyl or benzyl.

[1025] In this case, the reaction with a compound of the general formula (VII) gives a carbamate of the general formula (V):

[1026]

[1027] where R 1 、R 2 、R 3 、R 5a 、R 5b 、X 1 and X 2 As defined in formula (I); and R 20 As defined in formula (VI).

[1028] The carbamate protecting group may be removed by hydrolysis, suitably acid hydrolysis, for example using hydrochloric acid, and may be carried out in an organic solvent such as dichloromethane.

[1029] The compounds of the general formula (VI), (VII) and (VIII) are known and are commercially available or can be prepared by methods known to those skilled in the art.

[1030] For example, where X 2 The compound of formula (VIII) is C-Cl and can be prepared by replacing X 2 The compound of formula (VIII) wherein CH is CH is reacted with a chlorinating agent (such as N-chlorosuccinimide). Suitably, the reaction can be carried out in an organic solvent (such as N,N-dimethylformamide) at an elevated temperature (such as about 50 to 70°C).

[1031] Furthermore, R 1 is ethynyl and R 2 With R 2The compounds of the general formula (VII) which together form a carbocyclic or heterocyclic ring can be prepared by reacting the compound of the general formula (XVII):

[1032]

[1033] where R 2 With R 3 form a carbocyclic or heterocyclic ring, and R 21 C 3-8 Alkyl groups, such as tert-butyl;

[1034] Reacting with a compound of formula (XVIII), suitably in the presence of an aluminum catalyst and a base:

[1035]

[1036] where R 23 Each independently is C 1-3 Alkyl; then prepared using acid deprotection.

[1037] Suitable bases include strong bases such as n-butyllithium, and a suitable acid for the deprotection step is hydrochloric acid, suitably in an organic solvent such as dioxane.

[1038] The compound of general formula (XVII) can be prepared by converting the compound of general formula (XIX):

[1039]

[1040] where R 21 As defined in formula (XVII);

[1041] Prepared by reacting with a compound of formula (XX):

[1042]

[1043] where R 2 With R 3 forming a carbocyclic or heterocyclic ring.

[1044] Suitably, the reaction is catalysed using a titanium (IV) catalyst, for example titanium (IV) ethoxide.

[1045] Compounds of general formula (XIX) and (XX) are known and readily available.

[1046] An alternative method for preparing compounds of general formula (II) is by reducing compounds of general formula (IX), for example by hydrogenation over a palladium catalyst:

[1047]

[1048] where R 1 、R 2 、R3 、R 5a 、R 5b 、X 1 and X 2 As defined in general formula (I).

[1049] The hydrogenation is typically carried out in an alcoholic solvent such as ethanol at a temperature of about 15 to 25° C., for example at room temperature.

[1050] The compound of general formula (IX) can be prepared by converting the compound of general formula (VIIIa):

[1051]

[1052] where R 5a 、R 5b 、X 1 and X 2 As defined in formula (I);

[1053] It is obtained by reacting with an amine of general formula (VII).

[1054] The reaction may be carried out in the presence of a coupling agent, such as one of the coupling agents described above for the reaction between compounds of formula (II) and (III).

[1055] An alternative method for preparing compounds of general formula (I) is to convert compounds of general formula (X):

[1056]

[1057] where X 1 、X 2 , Y, R 4 、R 5a and R 5b As defined in formula (I);

[1058] reacting with a compound of general formula (VII) as defined above.

[1059] This method is particularly suitable for 1 N or CR 8 A compound wherein R 8 is H or halogen, and / or X 2 N or CR 8 , where R 8 is H, OH or O(C 1-4 alkyl), and / or R 5a It is H or F.

[1060] Suitably, the reaction is carried out under basic conditions, for example in the presence of an amine (e.g., DIPEA or TEA), and in the presence of a coupling agent as described above for the reaction between compounds of formula (II) and (III). EDCI and HOAt or HOBt are suitable coupling agents for this reaction, as are HATU, TBTU, and HBTU.

[1061] The compound of general formula (X) can be prepared by deprotecting the compound of general formula (XI):

[1062]

[1063] where X 1 、X 2 , Y, R 4 、R 5a and R 5b As defined in formula (I); and R 25 C 1-8 Alkyl or benzyl.

[1064] Although other methods of deprotection of carboxylic acids are known in the art and / or discussed below, one example of a suitable deprotecting agent is boron tribromide.

[1065] When the target compound is R 4 is a compound of formula (I) substituted with OH, for example, a compound of formula (Ib), (Ic), (d) or (Ie) or a compound wherein R 10 and / or one or more R 11 The method of using boron tribromide for deprotection is particularly suitable for compounds of formula (Ia) wherein the group is OH. 4 The OH groups on the structural part can be protected, such as OR 26 Group, where R 26 C 1-8 The protecting group can also be removed using boron tribromide. Similarly, boron tribromide deprotection is also suitable for preparing 1 and / or X 2 CR 8 The compound of formula (X), wherein R 8 For OH.

[1066] On the other hand, if the desired compound of formula (I) is a compound containing an alkoxy group, for example, wherein R 4 For example, O(C 1-6 alkyl) or wherein X 1 and / or X 2 C(OC 1-4alkyl) compounds, deprotection is preferably carried out by hydrolysis, in particular alkaline hydrolysis, for example using an alkali metal hydroxide such as lithium hydroxide. This ensures that C(O)OR 25 The group hydrolyzes to C(O)OH without affecting the alkoxy substituents in the rest of the molecule.

[1067] The compound of general formula (XI) can be prepared by converting the compound of general formula (XII):

[1068]

[1069] where X 1 and X 2 、R 5a and R 5b As defined in formula (I); and R 25 As defined in formula (XI);

[1070] With the general formula (III) compound as defined above to prepare by reaction, or with the general formula (IV) compound as defined above to prepare by reaction, or with the general formula (XIII) compound (such as 5-chloro-2 (3H) -benzofuranone) to prepare, wherein R 11a is chlorine and R 11b is a compound of formula (Ib) wherein H is H.

[1071] The reaction with the compound of formula (III) is suitably carried out under basic conditions, for example in the presence of an amine such as DIPEA or TEA, and in the presence of a coupling agent as described above for the reaction between compounds of formula (II) and (III). EDCI and HOAt or HOBt are particularly suitable coupling agents.

[1072] The reaction with the compound of formula (IV) is generally carried out in an organic solvent such as dichloromethane.The compound of formula (IV) can be generated in situ by reacting the compound of formula (III) with thionyl chloride.

[1073] The reaction with the compound of formula (XIII) can be carried out in an organic solvent such as toluene, typically at elevated temperature, for example about 90 to 120°C, such as about 100 to 110°C, and under pressure, for example in a sealed tube.

[1074] Compounds of general formula (XII) are known and are commercially available or can be prepared by methods known to those skilled in the art.

[1075] In another alternative method, a compound of formula (I) can be prepared by reacting a compound of formula (XV) with a phosphorus ligand such as XantPhos and a palladium catalyst:

[1076]

[1077] where X 1 、X 2 , Y, R 4 、R 5a and R 5b As defined in formula (I), and R 22 is halogen, suitably chlorine or bromine;

[1078] Prepared by reaction with an amine of general formula (VII) as defined above and carbon monoxide.

[1079] The compound of formula (XV) can be prepared by reacting a compound of formula (XVI):

[1080]

[1081] where X 1 、X 2 、R 5a and R 5b As defined in formula (I), and R 22 As defined in formula (XV);

[1082] It can be prepared by reacting with a compound of the general formula (IV) as defined above or with a compound of the general formula (III) as defined above.

[1083] The reaction may be carried out under an inert atmosphere in an organic solvent such as N,N-dimethylformamide at a temperature of about 15 to 25°C, suitably at room temperature.

[1084] When a compound of formula (IV) is used, it can be generated in situ by reacting a compound of formula (III) with thionyl chloride.

[1085] Alternatively, the compound of formula (XVI) can be reacted with a lactone of formula (XIII).

[1086] Compounds of general formula (XVI) are well known and are commercially available or can be prepared by methods familiar to those skilled in the art.

[1087] The compounds of general formula (I) can be prepared as protected derivatives. For example, wherein R 4 Compounds of formula (I) having an OH substituent may be prepared by protecting the OH group (e.g., as a C 1-6 alkoxy, benzyloxy or substituted benzyloxy) equivalent compounds of general formula (I), wherein the benzyloxy can be C 1-6Alkoxy or halo substitution. Such protecting groups may be present in the precursors of formula (III), (IV), (X), (XI), (XIII), (XIV) and (XV) and may be removed using an aqueous acid such as aqueous hydrochloric acid, or by hydrogenation, for example under hydrogen pressure in the presence of a metal catalyst such as palladium on carbon.

[1088] Compounds of general formula (I) can also be converted into other compounds of general formula (I).

[1089] where R 4 For one or more -O(C 1-6 Compounds of formula (I) or (Ia) having an aryl or heteroaryl ring system substituted with an alkyl) substituent can be converted to a compound wherein -O(C 1-6 The method can be used to prepare compounds of formula (Ib), (Ic), (Id) and (Ie) wherein the substituent of the compound of formula (I) or (Ia) is replaced by an OH substituent.

[1090] where R 4 The compounds of formula (I) or (Ia) which are aryl or heteroaryl ring systems substituted with OH may also be prepared by combining an equivalent wherein R 4 The compounds of the general formula (I) having an NH2-substituted aryl or heteroaryl ring system are prepared by diazotization with nitrous acid (generated in situ from sodium nitrite and a strong acid such as sulfuric acid). The resulting diazonium salt is reacted with water in a reaction suitably catalyzed by copper (I) (e.g. in the form of copper (I) oxide) to give the compound R 4 An OH substituent is formed on the group.

[1091] where R 4 Compounds of formula (I) or (Ia) wherein R is an aryl or heteroaryl ring system substituted with NH2 can be prepared by reducing 4 The reduction is typically achieved by hydrogenation, suitably catalysed by palladium.

[1092] where R 4 Compounds of formula (I) or (Ia) having aryl or heteroaryl ring systems substituted with a nitro group can be prepared by nitration of an equivalent compound of formula (I), for example using concentrated nitric acid mixed with sulfuric acid. Alternatively, the nitration can be performed at an earlier stage of the process. For example, the nitration can be performed on compounds of formula (III) or formula (IV), and these nitrated derivatives can then be converted into compounds of formula (I).

[1093] The carbon-carbon coupling reaction wherein R4 The compound of formula (I) wherein the aryl or heteroaryl group has a halide substituent is converted into a compound of formula (I) wherein the halide substituent is replaced by CN, C(O)R 6 、C(O)OR 6 、C(O)N(R 6 )(R 7 )、N(R 7 )C(O)R 6 、R 19 or C 1-6 Alkyl is substituted, which is optionally substituted by one or more substituents selected from the group consisting of halogen, CN, nitro, cycloalkyl, OR 6 SR 6 NR 6 R 7 、C(O)R 6 C(O)OR 6 、C(O)N(R 6 )(R 7 ) and N(R 7 )C(O)R 6 , where R 6 and R 7 As defined above in formula (I). If desired, the alkenyl group can be reduced to an alkyl group by further methods such as hydrogenation.

[1094] For example, where R 4 Compounds of general formula (I) having a halo substituent can be converted into compounds wherein R 4 For analogs having a cyano substituent, the reaction is suitably catalyzed by a palladium / phosphine complex such as tetrakis(triphenylphosphine)palladium(0).

[1095] where R 4 With C(O)R 6 Substituted compounds of formula (I) can be prepared by reacting an equivalent halogen-substituted compound with a 1-vinyloxyalkane or vinyloxysilane via palladium / phosphine catalysis. Suitably, the reaction with the vinyloxyalkane can be carried out in the presence of a base (e.g., triethylamine) at elevated temperature (e.g., about 90 to 120° C.) under pressure (e.g., in a sealed tube). The reaction with the vinyloxysilane can be carried out in the presence of zinc fluoride in an anhydrous solvent (e.g., N,N-dimethylformamide) at elevated temperature (e.g., about 60 to 80° C.) under pressure (e.g., in a sealed tube). If desired, the carbonyl group can be reduced to an OH group, for example, using a hydride reducing agent such as sodium borohydride.

[1096] Similarly, where R 4The compound of formula (I) having a halogen substituent can be converted to a compound of formula (XXII) by a palladium / phosphine catalytic reaction followed by catalytic hydrogenation. 4 CH2CH2-C(O)OR 6 Substituted compounds:

[1097]

[1098] where R 6 As defined in general formula (I), but more suitably other than hydrogen.

[1099] The reaction with the compound of general formula (XXII) can be carried out under nitrogen pressure in the presence of a base such as triethylamine and at elevated temperature, for example about 60 to 80°C.

[1100] The hydrogenation can be catalyzed by palladium or palladium on carbon.

[1101] The obtained R 6 Compounds other than hydrogen can be converted by hydrolysis into 6 Compounds which are hydrogen are typically hydrolyzed by base, for example using aqueous alkali metal hydroxide solutions, such as lithium hydroxide.

[1102] R 4 The product of general formula (I) substituted by CH2CH2-C(O)OH is reduced to give 4 Compounds of formula (I) substituted with CH2CH2-CH2OH. Suitably, the acid may first be converted into a mixed anhydride using a suitable alkyl chloroformate reagent (e.g., methyl chloroformate), and then reduced in situ to the desired alcohol using a suitable reducing agent (e.g., sodium borohydride). The reaction may be carried out in the presence of a base such as triethylamine.

[1103] where R 4 With C(O)OR 6 Substituents (where R 6 The compound of formula (I) other than H) may be composed of 4 The halogen-substituted compound of formula (I) is prepared by reacting carbon monoxide with a suitable alcohol in a palladium / phosphine catalytic reaction. The catalyst can be prepared from a precatalyst, suitably a third generation Buchwald precatalyst such as XantPhos. Carbon monoxide can be prepared by reacting formic acid with a reagent such as methanesulfonyl chloride and a base such as triethylamine. The C(O)OR 6 The group can be converted to C(O)OH by hydrolysis, for example by base hydrolysis using an alkali metal hydroxide such as lithium hydroxide.

[1104] In a palladium catalyzed reaction, a compound of formula (XXa) or (XXb) can be used to convert R 4The compound of formula (I) having a halogen substituent is converted into a compound wherein R 4 C 1-6 Alkyl-substituted compound of formula (I), wherein the C 1-6 Alkyl is OR 6 or NR 6 R 7 Substituted, where R 6 and R 7 As defined in general formula (I):

[1105]

[1106] where R 6 and R 7 As defined in formula (I), M + is a metal ion, suitably a potassium ion, and Q is C 1-6 Alkylene is suitably -CH2-.

[1107] Suitably, the reaction is carried out under mild basic conditions, for example in the presence of sodium carbonate, at an elevated temperature, such as about 70 to 90°C.

[1108] where R 4 Compounds of formula (I) wherein R is substituted with halogen can be converted to compounds wherein R is substituted with halogen by reaction with a suitable arylboronic acid. 4 The compound of formula (I) is an aryl group substituted by an aryl group. The reaction is suitably catalyzed by a palladium / phosphine catalyst (e.g., 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride). Suitably, the reaction can be carried out in an organic solvent such as 1,4-dioxane and at an elevated temperature of, for example, about 90 to 120° C. and under pressurized conditions, for example, in a sealed tube.

[1109] where R 4 Compounds of formula (I) which are phenyl groups can be alkylated using a Friedel Crafts type alkylation reaction with a suitable alcohol or alkyl halide in the presence of a strong Lewis acid catalyst (e.g., sulfuric acid). The position of the alkylation will depend on the position of the other substituents in the ring. For example, when R 4 In the case of 2-fluoro-5-hydroxyphenyl, alkylation will occur at the 4-position as shown in Example 91.

[1110] In the compounds of general formula (I), substitution of halogen with methyl can be achieved via a Suzuki-Miyaura coupling reaction (Grey et al., Tetrahedron Letters, 41(32), 6237-6240; 2000); nitrile configuration can be achieved as described by Willardsen et al. in Journal of Medicinal Chemistry, 47(16), 4089-4099; 2004. Esters and amides can be configured by carbonylation as described by Veryser et al. in React. Chem. Eng., 2016, 1, 142-146.

[1111] where R 4 To be OR 6 In the compounds of formula (I) having substituted aryl or heteroaryl ring systems, R 4 The group can be halogenated by reaction with a halogenating agent, for example, N-halosuccinimide or bromine.

[1112] The reaction with N-halosuccinimide is carried out in a polar organic solvent such as acetonitrile at elevated temperature (e.g., about 50 to 70° C.) The reaction with bromine can occur in a solvent such as acetic acid at reduced temperature (e.g., about −5 to 5° C.).

[1113] where R 4 C(O)R 6’ Substitute (where R 6’ C 1-6 The compound of formula (I) wherein R is an alkyl or haloalkyl) can be converted to a compound of formula (I) by reacting with a compound of formula (XXI) under reducing conditions, such as in the presence of a borohydride (e.g. sodium triacetoxyborohydride), wherein R 4 C(R 6’ )-NR 6 R 7 Substituted, where R 6 and R 7 As defined in general formula (I):

[1114]

[1115] where R 6 and R 7 As defined in formula (I). The reaction can be carried out in an organic solvent, such as a halogenated solvent (such as dichloroethane or dichloromethane), in the presence of a suitable acid (such as acetic acid) catalyst, and the reaction temperature can be about 15 to 25°C, usually room temperature.

[1116] where R 4The compound of formula (I) substituted with a haloalkyl group can be converted into a compound wherein R 4 The reaction is suitably carried out at a temperature of about 15 to 80°C. In some cases, the reaction may require room temperature. The reaction solvent may be an aqueous solvent, typically a mixture of water and an organic solvent such as dichloromethane.

[1117] Make R 4 The reaction of the mutual conversion of the substituent groups on can also be carried out in the early stage of the method. For example, the compound of formula (III), (IV), (VI), (X), (XI) or (XV) can also be converted into each other in the same manner as the compound of formula (I).

[1118] In which R 1 C(O)OH or R 1 or R 3 is substituted by C(O)OH or R 4 In compounds having a substituent comprising a C(O)OH group, the C(O)OH group can be reduced to an OH group using any suitable method. Hydride reducing agents such as lithium aluminum hydride are particularly suitable.

[1119] In compounds of general formula (I) comprising an alkyl group substituted by a primary or secondary amino group N(R)2, the amino group can be converted into a group -N(R)-C(O)-alkyl (wherein R is a group R 6 、R 12 or R 15 , depending on the position of the amino group in the molecule).

[1120] The primary and secondary amines in these compounds can be converted to the group -N(R)-C(O)O-alkyl by reaction with a carboxylic anhydride. This process can be reversed to produce the primary and secondary amines by treating the compound containing the alkyloxycarbonylamino substituent with an acid or with boron tribromide.

[1121] where R 3 N(R 15 )S(O)2R 14 or N(R 15 )S(O)2R 16 The compound of the general formula (I) can be prepared by 3 N(R 15 )2 of the general formula (I) compound and sulfonyl halide WS (O) 2R 14 or WS(O)2R 16 Reaction, wherein W is a halide, especially a chloride, and R 14 、R15 and R 16 As defined above.

[1122] where R 1 、R 3 or R 4 Compounds of formula (I) comprising C(O)OR' (wherein R' is suitably R 6 、R 7 、R 12 or R 15 ) can be converted into a compound containing the group C(O)N(R')2 by reaction with a suitable amine in the presence of a coupling agent.

[1123] Other interconversions of various substituent groups can be carried out by methods familiar to those skilled in the art.

[1124] The compounds of the present invention are typically administered as part of a pharmaceutical composition. Therefore, the present invention further provides a pharmaceutical composition comprising formula (I), (Iz), (Iy), (Ix), (Ia), (Ib), (Ic), (Id) or (Ie) and a pharmaceutically acceptable excipient.

[1125] The pharmaceutical compositions may be formulated for oral, rectal, nasal, bronchial (inhalation), topical (including dermal, transdermal, eye drop, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration and may be prepared by any method well known in the art of pharmacy.

[1126] The composition can be prepared by combining the active agent defined above with an excipient. Generally speaking, the formulation is prepared by uniformly and tightly combining the active agent with a liquid carrier or a finely divided solid carrier or both, and then molding the product if necessary. The present invention also relates to a method for preparing a pharmaceutical composition, which comprises combining or combining a compound of formula (I) with a pharmaceutically acceptable carrier or vehicle.

[1127] The formulations of the present invention for oral administration may be in the form of discrete units such as capsules, sachets or tablets each containing a predetermined amount of the active agent; powders or granules; solutions or suspensions of the active agent in an aqueous liquid or a non-aqueous liquid; or oil-in-water liquid emulsions or water-in-oil liquid emulsions; or boluses, etc.

[1128] In compositions for oral administration (e.g., tablets and capsules), the term "acceptable carrier" includes carriers such as common excipients, such as binders, for example, syrup, gum arabic, gelatin, sorbitol, gum tragacanth, polyvinylpyrrolidone (povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sucrose, and starch; fillers and carriers, for example, corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride, and alginic acid; and lubricants, such as magnesium stearate, sodium stearate and other metal stearates, glyceryl stearate, stearic acid, silicone oil, talc, waxes, oils, and colloidal silica. Flavoring agents, such as peppermint, oil of wintergreen, cherry flavor, and the like, may also be used. Colorants may be added to make the dosage form easier to identify. Tablets may also be coated by methods well known in the art.

[1129] Tablets are optionally prepared by compression or molding with one or more auxiliary agents. Compressed tablets can be prepared by compressing the active agent in a free-flowing form, such as a powder or granules, in a suitable machine, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant or dispersant. Molded tablets can be prepared by molding a mixture of a powdered compound moistened with an inert liquid diluent in a suitable machine. Tablets can optionally be coated or scored and can be formulated to provide slow or controlled release of an active agent.

[1130] Other suitable formulations for oral administration include lozenges comprising the active agent in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active agent in an inert basis such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active agent in a suitable liquid carrier.

[1131] For topical application to the skin, the compounds of formula (I) may be formulated into creams, ointments, jellies, solutions or suspensions. Cream or ointment formulations useful for this drug are conventional formulations known in the art, for example, as described in standard textbooks of pharmacology such as the British Pharmacopoeia.

[1132] Aerosol formulations can be used for local administration to the lungs. Aerosol formulations typically comprise an active ingredient suspended or dissolved in a suitable aerosol propellant, such as a chlorofluorocarbon (CFC) or a hydrofluorocarbon (HFC). Suitable CFC propellants include trichloromonofluoromethane (propellant 11), dichlorotetrafluoromethane (propellant 114), and dichlorodifluoromethane (propellant 12). Suitable HFC propellants include tetrafluoroethane (HFC-134a) and heptafluoropropane (HFC-227). The propellant typically accounts for 40%-99.5% of the total inhalation composition weight, for example, 40%-90%. The formulation may comprise excipients, including cosolvents (e.g., ethanol) and surfactants (e.g., lecithin, sorbitan trioleate, etc.). Other possible excipients include polyethylene glycol, polyvinyl pyrrolidone, glycerol, etc. Aerosol formulations are packaged in canisters and delivered by means of a metering valve (for example, those supplied by Bespak, Valois or 3M, or by Aptar, Coster or Vari) to deliver a suitable dose.

[1133] Non-pressurized formulations such as aqueous solutions or suspensions can also be used to achieve local administration to the lungs. These can be administered using a nebulizer, for example, which can be handheld and portable or can be used at home or in hospitals (it can also be non-portable). The formulation can contain excipients such as water, buffers, tension adjusters, pH adjusters, surfactants and cosolvents. Suspensions and aerosol formulations (whether pressurized or not) generally contain the compound of the invention in fine powder form, such as D 50 The particle size distribution can be calculated using D 10 、D 50 With D 90 The value represents the particle size distribution D 50 The median value is defined as the particle size in micrometers when the distribution is cut in half. The values ​​measured from the laser particle size analyzer will be more accurately described as volume distributions, so the D obtained by this process is used. 50 The value is more meaningful in Dv 50 The Dv value used in this article refers to the particle size distribution measured by a laser particle size analyzer. Similarly, the Dv value used in this context is the median value of the volume distribution. 10 With D 90 The value is the average Dv 10 With Dv 90 value, and respectively means in D 10 10% distribution particle size below the value, and D 90 The 90% distribution particle size is below the value.

[1134] Dry powder formulations may also be used for local administration to the lungs. Dry powder formulations will contain the compound of the present disclosure in fine powder form, typically with a mass mean diameter (MMAD) of 1-10 μm or D50 The particle size distribution of the compound of the present invention is 0.5-10 μm, for example, about 1-5 μm. Powders of the compound of the present invention in fine powder form can be prepared by a micronization process or similar fine grinding methods. Micronization can be performed using a jet mill, such as those manufactured by Hosokawa Alpine. The resulting particle size distribution can be measured using a laser particle size analyzer (e.g., a Malvern Mastersizer 2000S instrument). The formulation typically contains a topically acceptable diluent, such as lactose, glucose, or mannitol (preferably lactose), and typically has a relatively large particle size, for example, a mass mean diameter (MMAD) of 50 μm or more, for example, 100 μm or more or D 50 The term "lactose" as used herein refers to lactose-containing components, including α-lactose monohydrate, β-lactose monohydrate, α-lactose anhydrate, β-lactose anhydrate and amorphous lactose. The lactose component can be processed by micronization, sieving, grinding, compression, agglomeration or spray drying. It also includes various commercially available lactose forms, such as (inhalation-grade lactose; DFE Pharma), 70 (sieved lactose for dry powder inhalers; Meggle), (DFE Pharma) and (sieved inhalation grade lactose; DFE Pharma) and other products. In one embodiment, the lactose component is selected from α-lactose monohydrate, α-lactose anhydrate and amorphous lactose, preferably, the lactose is α-lactose monohydrate.

[1135] The dry powder formulation may also contain other excipients. Thus, in one embodiment, the dry powder formulation according to the present disclosure comprises magnesium stearate or calcium stearate. The formulation may have excellent chemical and / or physical stability, particularly when the formulation also contains lactose.

[1136] Dry powder formulations are typically delivered using a dry powder inhaler (DPI) device. Examples of dry powder delivery systems include and Examples of other dry powder delivery systems include ECLIPSE, NEXT, ROTAHALER, HANDIHALER, AEROLISER, CYCLOHALER, BREEZHALER / NEOHALER, MONODOSE, FLOWCAPS, TWINCAPS, X-CAPS, TURBOSPIN, ELPENHALER, MIATHALER, TWISTHALER, NOVOLIZER, PRESSAIR, ELLIPTA, ORIEL dry powder inhaler, MICRODOSE, PULVINAL, EASYHALER, ULTRAHALER, TAIFUN, PULMOJET, OMNIHALER, GYROHALER, Taper, CONIX, XCELOVAIR, and PROHALER.

[1137] In one embodiment, the compound of formula (I) is provided as a micronized dry powder formulation, for example containing a suitable grade of lactose.

[1138] Thus, one aspect of the present invention is to provide a pharmaceutical composition comprising a compound of formula (I) in granular form and granular lactose, optionally comprising magnesium stearate.

[1139] In one embodiment, the compound of formula (I) is provided in the form of a micronized dry powder formulation comprising a suitable grade of lactose and magnesium stearate, which is filled into a device such as DISKUS. Suitably, the device is a multi-dose device, for example the formulation is filled into blisters for a multiple unit dose device such as DISKUS.

[1140] In another embodiment, the compound of formula (I) is provided as a micronized dry powder formulation, for example containing a suitable grade of lactose, filled into a hard shell capsule for use in a single dose device, such as AEROLISER.

[1141] In another embodiment, the compound of formula (I) is provided as a micronized dry powder formulation containing a suitable grade of lactose and magnesium stearate, filled into a hard shell capsule for use in a single-dose device, such as AEROLISER.

[1142] In another embodiment, there is provided a compound of formula (I) in fine powder form for inhalation, wherein the powder is D 50The fine particles of 0.5-10 μm, for example, about 1-5 μm, are obtained by fine grinding rather than jet mill micronization, such as spray drying, spray freezing, microfluidization, high pressure homogenization, supercritical fluid crystallization, ultrasonic crystallization or a combination of these methods, or other suitable particle formation methods known in the art can be used to produce fine particles with an aerodynamic particle size of 0.5-10 μm. The particle size distribution produced can be measured using a laser particle size analyzer (e.g., Malvern Mastersizer 2000S instrument). The particles can comprise only compound or be combined with other suitable excipients that contribute to processing. The fine particles produced can form a final formulation for delivery to humans or optionally further formulated with other suitable excipients to promote delivery in an acceptable dosage form.

[1143] The compounds of the present invention can also be administered rectally, for example, in the form of suppositories or enemas, including aqueous or oily solutions and suspensions, emulsions, and foams. Such compositions are prepared by standard methods well known to those skilled in the art. For example, suppositories can be prepared by mixing the active ingredient with a conventional suppository base (e.g., cocoa butter or other glycerides). In this case, the drug is mixed with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore melts in the rectum to release the drug. Such substances are cocoa butter and polyethylene glycol.

[1144] Typically, for compositions intended for topical application to the eye in the form of eye drops or eye ointments, the total amount of compounds of formula (I) will be from about 0.0001 to less than 4.0% (w / w).

[1145] Preferably, for topical ophthalmic administration, the compositions administered according to formula (I) will be formulated into solutions, suspensions, emulsions and other dosage forms. Aqueous solutions are generally preferred because they are easy to prepare and patients can easily administer the composition by dropping one or two drops of solution into the affected eye. However, the composition may also be a suspension, a viscous or semi-viscous gel or other solid or semisolid composition. For compounds that are poorly soluble in water, a suspension may be preferred.

[1146] Another method of administration to the eye is by intravitreal injection of a solution or suspension of a compound of formula (I).Alternatively, compounds of formula (I) may be delivered using ocular implants or inserts.

[1147] The compositions of formula (I) may also include various other ingredients, including but not limited to tonicity agents, buffers, surfactants, stabilizing polymers, preservatives, co-solvents, and viscosity building agents. Suitable pharmaceutical compositions of formula (I) include compounds of the invention formulated with tonicity agents and buffers. Pharmaceutical compositions of formula (I) may further optionally include surfactants and / or demulcents and / or stabilizing polymers.

[1148] A variety of tonicity agents can be used to adjust the tonicity of the composition, preferably to adjust the ophthalmic composition to the tonicity of natural tears. For example, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, simple sugars such as dextrose, fructose, galactose, and / or simple polyols such as sugar alcohols, mannitol, sorbitol, xylitol, lactitol, isomalt, maltitol, and hydrogenated starch hydrolysates can be added to the composition to approximate physiological tonicity. The amount of tonicity agent used will depend on the specific agent added. However, the composition generally contains a tonicity agent sufficient to provide the final composition with an ophthalmologically acceptable osmotic pressure (typically about 150-450 mOsm, preferably 250-350 mOsm, and optimally about 290 mOsm). Generally, the tonicity agent of the present invention will be present in an amount ranging from 2 to 4% w / w. Preferred tonicity agents of the present invention include simple sugars or sugar alcohols, such as D-mannitol.

[1149] A suitable buffer system (e.g., sodium phosphate, sodium acetate, sodium citrate, sodium borate, or boric acid) may be added to the composition to prevent pH drift under storage conditions. The specific concentration will depend on the pharmaceutical agent used. However, it is preferred to select a buffer that can maintain the target pH in the range of pH 5 to 8, more preferably maintaining the target pH at pH 5 to 7.

[1150] Surfactants may optionally be used to deliver higher concentrations of the compound of formula (I). The function of the surfactant is to solubilize the compound and stabilize colloidal dispersions, such as micellar solutions, microemulsions, emulsions, and suspensions. Examples of surfactants that may be used include polysorbates, poloxamers, polyosyl 40 stearate, polyoxyl castor oil, tyloxapol, Triton, and sorbitan monolaurate. Preferred surfactants for use in the present invention have a hydrophilicity / lipophilicity / balance "HLB" in the range of 12.4 to 13.2 and are ophthalmically acceptable, such as Triton X114 and tyloxapol.

[1151] Other agents that may be added to ophthalmic compositions of compounds of formula (I) are demulcents that act as stabilizing polymers. Stabilizing polymers should be ionic / charged, preferably for topical ophthalmic use, and more specifically, polymers with a negative charge on their surface, thereby exhibiting a zeta potential (-) of 10-50 mV and physical stability, and capable of forming a dispersion in water (i.e., water-soluble). Preferred stabilizing polymers of the present invention are polyelectrolytes, or, if more than one is present, polyelectrolytes from the family of cross-linked polyacrylates, such as carbomers and Pemulen®, specifically Carbomer 974p (polyacrylic acid), at 0.1-0.5% w / w.

[1152] Other compounds may also be added to the ophthalmic composition of the compound of formula (I) to increase the viscosity of the carrier. Examples of viscosity enhancers include, but are not limited to, polysaccharides, such as hyaluronic acid and its salts, chondroitin sulfate and its salts, dextran, various polymers of the cellulose family; vinyl polymers; and acrylic polymers.

[1153] Topical ophthalmic products are typically packaged in multidose formats and therefore require preservatives to prevent microbial contamination during use. Suitable preservatives include benzalkonium chloride, chlorobutanol, benzododecinium bromide, methylparaben, propylparaben, phenylethyl alcohol, disodium edetate, sorbic acid, polyquaternium-1, or other agents known to those skilled in the art. These preservatives are typically used in amounts of 0.001 to 1.0% w / v. Unit dose compositions of formula (I) are sterile but are typically not preservative-free. Therefore, such compositions typically do not contain a preservative.

[1154] Parenteral formulations are generally sterile.

[1155] A medical practitioner or other skilled artisan will be able to determine appropriate dosages of compounds of Formula (I), (Ia) or (Ib), and therefore the amount of the compound to be included in any particular pharmaceutical formulation, whether in unit dosage form or otherwise.

[1156] The compounds of general formula (I) may be used in combination with one or more other active agents useful in the treatment or prevention of respiratory diseases and disorders.

[1157] Such additional active agents may be included in the above-mentioned pharmaceutical compositions, but alternatively, they may be administered separately, either simultaneously or earlier or later than the compound of formula (I).

[1158] Therefore, another aspect of the present invention is to provide a product comprising a compound of formula (I) and another active agent for the treatment or prevention of respiratory disorders, as a combined preparation for simultaneous, sequential or separate use in the treatment of diseases or disorders affected by TMEM16A regulation, in particular respiratory diseases or disorders, such as one of the above-mentioned diseases and disorders.

[1159] Also provided are combinations of compounds of formula (I) and another active agent for treating or preventing respiratory disorders as a combined preparation for simultaneous, sequential or separate use in the treatment of a disease or disorder affected by TMEM16A regulation, in particular a respiratory disease or disorder, such as one of the diseases and disorders mentioned above.

[1160] Suitable additional active agents that may be included in the pharmaceutical compositions or combined preparations of the compounds of general formula (I) include:

[1161] β2-adrenergic receptor agonists, such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, indacaterol, terbutaline, orciprenaline, bitolterol mesylate, pirbuterol, olodaterol, vilanterol and abediterol;

[1162] Antihistamines, for example histamine H1 receptor antagonists, such as loratadine, cetirizine, desloratadine, levocetirizine, fexofenadine, astemizole, and chlorpheniramine, or H4 receptor antagonists; dornase alpha;

[1163] Corticosteroids, such as prednisone, corticosterone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, mometasone furoate, and fluticasone furoate;

[1164] Leukotriene antagonists, such as montelukast and zafirlukast;

[1165] Anticholinergic compounds, in particular muscarinic antagonists, such as ipratropium, tiotropium, glycopyrrolate, aclidinium and umeclidinium;

[1166] CFTR repair therapies (e.g., CFTR potentiators, modifiers, or amplifiers), such as ivacaftor, QBW251, VX659, VX445, VX561 / CPT-656, VX152, VX440, GLP2737, GLP2222, GLP2451, PTI438, PTI801, PTI808, FDL-169, and FDL-176, and CFTR modifiers, such as lumacaftor and tezacaftor;

[1167] ENaC modulators, particularly ENaC inhibitors;

[1168] antibiotic;

[1169] Respiratory tract moisturizers (osmolytes), such as hypertonic saline and mannitol and

[1170] Mucolytic agents, such as N-acetylcysteine.

[1171] When the additional active agent is an ENaC modulator, it may be an ENaC inhibitor, such as amiloride, VX-371, AZD5634, QBW276, SPX-101, BI443651, and ETD001. Other suitable ENaC blockers are described in our applications WO 2017 / 221008, WO 2018 / 096325, PCT / GB2018 / 052982, and GB1808093.7, and any of the exemplified compounds in these applications may be used in combination with the compound of formula (I). Compounds particularly suitable for use in combination with the compound of formula (I) include compounds having a cation selected from:

[1172] 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)ethyl]-6-(4-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}piperidine-1-carbonyl)-1,3-diethyl-1H-1,3-benzodiazol-3-ium;

[1173] 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}carboxamido)methyl]-6-{[2-(4-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}piperidin-1-yl)ethyl]carbamoyl}-1,3-diethyl-1H-1,3-benzodiazol-3-ium;

[1174] 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}carboxamido)methyl]-5-[4-({bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}methyl)piperidine-1-carbonyl]-1,3-diethyl-1H-1,3-benzodiazol-3-ium;

[1175] 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-[(3R)-3-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}pyrrolidine-1-carbonyl]-1,3-diethyl-1H-1,3-benzodiazol-3-ium;

[1176] 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}carboxamido)methyl]-6-[(3S)-3-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}pyrrolidine-1-carbonyl]-1,3-diethyl-1H-1,3-benzodiazol-3-ium;

[1177] 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}carboxamido)methyl]-1,3-diethyl-6-{[(1r,4r)-4-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}cyclohexyl]carbamoyl}-1H-1,3-benzodiazol-3-ium;

[1178] 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}carboxamido)methyl]-1,3-diethyl-6-{[(1s,4s)-4-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}cyclohexyl]carbamoyl}-1H-1,3-benzodiazol-3-ium;

[1179] and suitable anions such as halide, sulfate, nitrate, phosphate, formate, acetate, trifluoroacetate, fumarate, citrate, tartrate, oxalate, succinate, mandelate, methanesulfonate or p-toluenesulfonate.

[1180] The invention is illustrated by the following non-limiting examples and figures. BRIEF DESCRIPTION OF THE DRAWINGS

[1181] Figure 1 is an example trace from the whole-cell patch clamp (Qpatch) TMEM16A potentiator assay used in Biological Example 95 and illustrates the method used in the assay. Figure 1 Middle: S is saline; V is medium; #1 is test compound concentration #1; #2 is test compound concentration 2; #3 is test compound concentration 3; #4 is test compound concentration 4; #5 is test compound concentration 5; R is reference. The arrow in the V column indicates the baseline current, I BL The arrows in columns #1, #2, #3, #4, #5 and R represent the [#1] , I [#2] , I [#3] , I [#4] , I [#5] and I [Ref] , which are the peak currents of test compound concentrations #1 to #5 and the reference during the incubation period. Example

[1182] The invention is illustrated by the following examples.

[1183] General conditions:

[1184] Mass spectra were performed on LC-MS systems using electrospray ionization, these were run using a Waters Acquity uPLC system with a Waters PDA and ELS detector or a Shimadzu LCMS-2010EV system. [M+H]+ means monoisotopic molecular weight.

[1185] NMR spectra were recorded on a Bruker Avance III HD 500 MHz, Bruker Avance III HD 250 MHz, or a SmartProbe 400 MHz Avance III HD Nanobay with a 5 mm Broad Band Inverse probe, using the solvent as an internal deuterium lock. Unless otherwise stated, spectra were recorded at room temperature and referenced to the solvent peak.

[1186] Referring to the following examples, compounds of the preferred embodiments were synthesized using the methods described herein or other methods known in the art.

[1187] Where appropriate, conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation and chromatography can be used to separate and purify the various raw materials, intermediates and compounds of the preferred embodiments. Unless otherwise stated, all raw materials are obtained from commercial suppliers and can be used without further purification. Salts can be prepared from compounds by known salt-forming methods.

[1188] By Purify compounds by flash column chromatography on normal phase silica gel using an appropriate SNAP cartridge and gradient. Alternatively, use an Isolera system with an appropriate SNAP C18 cartridge and reverse phase eluent. Compounds were purified on reverse phase silica gel using the Isolera system or by preparative HPLC where indicated.

[1189] Preparative HPLC using acidic pH, early elution method

[1190] Purification was performed on a Gilson LC system using a Waters Sunfire C18 column (30 mm x 100 mm, 10 μM; temperature: RT) with a gradient of 10-95% B (A = water with 0.1% formic acid; B = acetonitrile with 0.1% formic acid) over 14.44 minutes, followed by 95% B for 2.11 minutes, with an injection volume of 1500 μL and a flow rate of 40 mL / min. UV spectra were recorded at 215 nm using a Gilson detector.

[1191] Preparative HPLC using acidic pH, standard elution method

[1192] Purification by preparative HPLC (acidic pH, standard elution method) was performed on a Gilson LC system using a Waters Sunfire C18 column (30 mm x 100 mm, 10 μM; temperature: RT) with a gradient of 30-95% B (A = water with 0.1% formic acid; B = acetonitrile with 0.1% formic acid) over 11 minutes, followed by 95% B for 2.11 minutes with an injection volume of 1500 μL and a flow rate of 40 mL / min. UV spectra were recorded at 215 nm using a Gilson detector.

[1193] Preparative HPLC using basic pH, early elution method

[1194] Purification by preparative HPLC (basic pH, early elution method) was performed on a Gilson LC system using a Waters Xbridge C18 column (30 mm x 100 mm, 10 μM; temperature: RT) and a gradient of 10-95% (A = water with 0.2% ammonium hydroxide; B = acetonitrile with 0.2% ammonium hydroxide) over 14.44 minutes, followed by 95% B for 2.11 minutes with an injection volume of 1500 μL and a flow rate of 40 mL / min. UV spectra were recorded at 215 nm using a Gilson detector.

[1195] Preparative HPLC using basic pH, standard elution method

[1196] Purification by preparative HPLC (basic pH, standard elution method) was performed on a Gilson LC system using a Waters Xbridge C18 column (30 mm x 100 mm, 10 μM; temperature: RT) with a gradient of 30-95% (A = water containing 0.2% ammonium hydroxide; B = acetonitrile containing 0.2% ammonium hydroxide) over 11 minutes, then 95% B for 2.11 minutes, with an injection volume of 1500 μL and a flow rate of 40 mL / min, UV spectra were recorded at 215 nm using a Gilson detector.

[1197] Unless otherwise stated, analytical HPLC conditions were as follows:

[1198] Method A

[1199] Column: Phenomenex Kinetix-XB C18 2.1x100mm, 1.7μm

[1200] Column temperature 40℃

[1201] Eluent: A: H20 0.1% formic acid, B: acetonitrile, 0.1% formic acid

[1202] Flow rate: 0.6 mL / min

[1203] Gradient: 0-5.3 min 5-100% B, 5.3-5.8 min 100% B, 5.8-5.82 min 100-5% B, 5.82-7.00 min 5% B

[1204] Method B

[1205] Column: Waters CSH TM C18 2.1x100mm 1.7μm

[1206] Column temperature 40℃

[1207] Eluent: A: 2 mM ammonium bicarbonate, buffered to pH 10, B: acetonitrile

[1208] Flow rate: 0.6 mL / min

[1209] Gradient: 0-5.3 min 5-100% B, 5.3-5.8 min 100% B, 5.8-5.82 min 100-5% B, 5.82-7.00 min 5% B

[1210] Method C

[1211] Column: Waters BEH TM C18 2.1x100mm 1.7μm

[1212] Column temperature 40℃

[1213] Eluent: A: 2 mM ammonium bicarbonate, buffered to pH 10, B: acetonitrile

[1214] Flow rate: 0.6 mL / min

[1215] Gradient: 0-5.3 min 5-100% B, 5.3-5.8 min 100% B, 5.8-5.82 min 100-5% B, 5.82-7.00 min 5% B

[1216] Method D

[1217] Column: Waters Atlantis dC18 2.1x100mm 3μm

[1218] Column temperature 40℃

[1219] Eluent: A: H20 + 0.1% formic acid, B: acetonitrile + 0.1% formic acid

[1220] Flow rate: 0.6 mL / min

[1221] Gradient: 0-5 min 5-100% B, 5-5.4 min 100% B, 5.4-5.42 min 100-5% B, 5.42-7.00 min 5% B

[1222] Method E

[1223] Column: Kinetex Core-Shell C18 2.1x50mm 5μm

[1224] Column temperature 40℃

[1225] Eluent: A: H20 + 0.1% formic acid, B: acetonitrile + 0.1% formic acid

[1226] Flow rate: 1.2 mL / min

[1227] Gradient: 0-1.20 min 5-100% B, 1.20-1.30 min 100% B, 1.30-1.31 min 100-5% B Method F

[1228] Column: Phenomenex Gemini-NX C18 2x50mm 3μm

[1229] Column temperature 40℃

[1230] Eluent: A: 2 mM ammonium bicarbonate, buffered to pH 10, B: acetonitrile

[1231] Flow rate: 1 mL / min

[1232] Gradient: 0-1.80 min 1-100% B, 1.80-2.10 min 100% B, 2.10-2.30 min 100-1% B

[1233] The following examples are intended to illustrate the present invention and should not be construed as limiting thereof. Temperatures are given in degrees Celsius. Unless otherwise stated, all evaporations were performed under vacuum, preferably between about 15 mm Hg and 100 mm Hg (=20-133 mbar). The structures of the final products, intermediates, and starting materials were confirmed by standard analytical methods, such as microanalysis and spectral characterization, such as MS, IR, and NMR. Abbreviations used are those conventional in the art. Unless otherwise defined, these terms have their generally accepted meanings.

[1234] abbreviation

[1235] aq. water-containing br width

[1236] d doublet

[1237] dd double peaks

[1238] DCM dichloromethane

[1239] DIPEA diisopropylethylamine

[1240] DMF N,N-dimethylformamide

[1241] EDCl 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

[1242] EtOAcEthyl acetate

[1243] HOAt 1-Hydroxy-7-azabenzotriazole

[1244] HATU 2-(7-Aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate

[1245] HPLC high pressure liquid chromatography

[1246] MeCNAcetonitrile

[1247] MeOH

[1248] MS

[1249] m multiplet

[1250] min

[1251] mL milliliters

[1252] m / z mass-to-charge ratio

[1253] NCS N-chlorosuccinimide

[1254] NMR nuclear magnetic resonance

[1255] PTFE polytetrafluoroethylene

[1256] Rt retention time

[1257] s single peak

[1258] tTriple Peak

[1259] TBME methyl tert-butyl ether

[1260] TBTU N,N,N′,N′-Tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate

[1261] TEA triethylamine

[1262] TFA (Trifluoroacetic acid)

[1263] THF Tetrahydrofuran

[1264] 1,2-Propylphosphonic anhydride

[1265] Preparation of Examples

[1266] Example 1

[1267] N-tert-Butyl-4-[[2-(2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide

[1268]

[1269] Step 1: Methyl 4-[[2-(2-methoxyphenyl)acetyl]amino]pyridine-2-carboxylate

[1270]

[1271] To a solution of 2-(2-methoxyphenyl)acetic acid (218 mg, 1.31 mmol) in DMF (4 mL) were added HOAt (179 mg, 1.31 mmol), EDCI (328 mg, 1.71 mmol), DIPEA (574 μL, 3.29 mmol), and methyl 4-aminopyridine-2-carboxylate (200 mg, 1.31 mmol), and the mixture was stirred at room temperature for 6 hours and 15 minutes. The resulting mixture was partitioned between H2O (30 mL) and DCM (30 mL), and the two phases were separated. The aqueous phase was further extracted with DCM (30 mL), and the combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography eluting with EtOAc in heptane to give the title compound as a light yellow gum.

[1272] 1H NMR (500 MHz, chloroform-d) δ 8.58 (d, J = 5.5 Hz, 1H), 8.10 (s, 1H), 7.92 (dd, J = 5.5, 2.2 Hz, 1H), 7.84 (d, J = 2.1 Hz, 1H), 7.37-7.32 (m, 1H), 7.29 (dd, J = 7.4, 1.5 Hz, 1H), 7.04-6.97 (m, 2H), 3.98 (s, 3H), 3.97 (s, 3H), 3.75 (s, 2H).

[1273] LC-MS (Method E): Rt 0.96 min; MS m / z 301.1 = [M+H]+ (99% @ 215 nm)

[1274] Step 2: 4-[[2-(2-Hydroxyphenyl)acetyl]amino]pyridine-2-carboxylic acid

[1275]

[1276] A solution of methyl 4-[[2-(2-methoxyphenyl)acetyl]amino]pyridine-2-carboxylate (step 1) (119 mg, 0.4 mmol) in DCM (1.2 mL) was cooled to 0 ° C, treated with 1 M BBr in DCM (2.38 mL, 2.38 mmol) for more than 15 minutes, and stirred at 0 ° C for 1 hour. After warming to room temperature, the reaction was stirred for a further 19 hours. Another portion of 1 M BBr in DCM (1.19 mL, 1.19 mmol) was added at room temperature and stirring was continued for another 72 hours. Water (25 mL) was slowly added to the reaction mixture, and the biphasic solution was then concentrated under vacuum to give the title compound as a brown solid.

[1277] 1H NMR (500 MHz, methanol-d4) δ 8.68-8.60 (m, 2H), 8.39 (dd, J = 6.7, 2.4 Hz, 1H), 7.18 (dd, J = 7.7, 1.6 Hz, 1H), 7.15-7.10 (m, 1H), 6.85-6.79 (m, 2H), 3.84 (s, 2H). (Compound purity 85%).

[1278] LC-MS (Method E): Rt 0.74 min; MS m / z 273.0 = [M+H]+ (92% @ 215 nm)

[1279] Step 3: N-tert-Butyl-4-[[2-(2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide

[1280] A solution of 4-[[2-(2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxylic acid (step 2) (138 mg, 0.43 mmol) in DMF (1.5 mL) was treated with EDCI (107 mg, 0.56 mmol), HOAt (59 mg, 0.43 mmol), DIPEA (113 μL, 0.65 mmol) and 2-methylpropan-2-amine (45 μL, 0.43 mmol). The reaction mixture was stirred at room temperature for 21 hours and then concentrated under vacuum. The crude residue was purified by preparative HPLC (acidic pH, early elution method) and the product-containing fractions were freeze-dried to give the title compound as a white solid.

[1281] 1H NMR (500MHz, DMSO-d6) δ10.65(s,1H),9.49(s,1H),8.43(d,J=5.5Hz,1H),8.18(d,J=2.0Hz,1H),8.03(s,1H),7.82(dd,J=5.5,2.2Hz,1H),7 .13(dd,J=7.5,1.5Hz,1H),7.07(td,J=7.8,1.7Hz,1H),6.79(dd,J=8.0,0.9Hz,1H),6.75(td,J=7.4,1.1Hz,1H),3.65(s,2H),1.39(s,9H).

[1282] LC-MS (Method A): Rt 2.86 min; MS m / z 328.2 = [M+H]+ (100% @ 215 nm)

[1283] Example 1.1

[1284] N-(1,1-Dimethylpropyl)-3-[[2-(2-hydroxyphenyl)acetyl]amino]benzamide

[1285]

[1286] Step 1: Methyl 3-[[2-(2-methoxyphenyl)acetyl]amino]benzoate

[1287]

[1288] 2-(2-Methoxyphenyl)acetic acid (1.09 g, 6.62 mmol) in DMF (1.5 mL) was treated with HOAt (900 mg, 6.62 mmol), EDCI (1.65 g, 8.6 mmol), DIPEA (2.89 mL, 16.54 mmol), and methyl 3-aminobenzoate (1.0 g, 6.62 mmol). The mixture was stirred at room temperature for 3.5 hours. The resulting mixture was partitioned between H2O (30 mL) and DCM (30 mL), and the two phases were separated. The aqueous phase was further extracted with DCM (30 mL), and the combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography eluting with EtOAc in heptane to give the title compound as a beige crystalline solid.

[1289] 1H NMR (500MHz, DMSO-d6) δ10.28(s,1H),8.30(t,J=1.8Hz,1H),7.86-7.80(m,1H),7.62(dt,J=7.7,1.2Hz,1H),7.44(t,J=7 .9Hz,1H),7.28-7.19(m,2H),6.98(d,J=7.9Hz,1H),6.90(td,J=7.4,0.9Hz,1H),3.84(s,3H),3.76(s,3H),3.64(s,2H).

[1290] LC-MS (Method E): Rt 1.10 min; MS m / z 300.0 = [M+H]+ (100% @ 215 nm)

[1291] Step 2: 3-[[2-(2-Hydroxyphenyl)acetyl]amino]benzoic acid

[1292]

[1293] A solution of methyl 3-[[2-(2-methoxyphenyl)acetyl]amino]benzoate (step 1) (1.21 g, 4.04 mmol) in DCM (15 mL) was cooled to 0°C and treated with 1M BBr in DCM (16.17 mL, 16.17 mmol) over 15 minutes. After the addition was complete, the mixture was stirred at 0°C for 1 hour and then at room temperature for 19 hours. Water (50 mL) was slowly added to the mixture and the DCM was concentrated under vacuum. The aqueous residue was extracted with EtOAc (2x50 mL) and the combined organic extracts were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The recovered material was suspended in DCM (7.5 mL), cooled to 0°C, and treated with 1M BBr in DCM (7.0 mL, 7.0 mmol) over 10 minutes. The reaction mixture was stirred at 0°C for 1 hour and then at room temperature for 4 hours. Water (100 mL) was slowly added to the reaction mixture and the DCM was concentrated under vacuum. The resulting mixture was extracted with EtOAc (2x100 mL) and the combined organic extracts were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give the title compound as a straw-colored solid.

[1294] 1H NMR (500MHz, DMSO-d6) δ12.89(s,1H),10.22(s,1H),9.47(s,1H),8.24(t,J=1.7Hz,1H),7.86-7.80(m,1H),7.60(dt,J=7.7,1.2Hz,1H),7.41(t ,J=7.9Hz,1H),7.14(dd,J=7.5,1.4Hz,1H),7.07(td,J=7.8,1.7Hz,1H),6.80(dd,J=8.0,0.9Hz,1H),6.75(td,J=7.4,1.1Hz,1H),3.61(s,2H).

[1295] LC-MS (Method E): Rt 0.93 min; MS m / z 272.1 = [M+H]+ (92% @ 215 nm)

[1296] Step 3: N-(1,1-dimethylpropyl)-3-[[2-(2-hydroxyphenyl)acetyl]amino]benzamide

[1297] To a solution of 3-[[2-(2-hydroxyphenyl)acetyl]amino]benzoic acid (step 2) (70 mg, 0.24 mmol) in DMF (1 mL) was added EDCI (59 mg, 0.31 mmol), HOAt (32 mg, 0.24 mmol), DIPEA (62.2 μL, 0.36 mmol) and 2-methylbutan-2-amine (36.1 μL, 0.31 mmol), and the mixture was stirred at room temperature for 17 hours. The resulting mixture was partitioned between water (5 mL) and DCM (5 mL), and the organic layer was collected using a hydrophobic frit and concentrated under vacuum. The residue was purified via preparative HPLC (acidic pH, early elution method), and the product fractions were lyophilized overnight to give the title compound as an off-white powder.

[1298] 1H NMR (500MHz, DMSO-d6) δ10.15(s,1H),9.49(s,1H),7.89(t,J=1.8Hz,1H),7.80-7.74(m,1 H),7.54(s,1H),7.40(dt,J=7.7,1.2Hz,1H),7.33(t,J=7.9Hz,1H),7.14(dd,J=7.5,1.6H z,1H),7.06(td,J=7.8,1.7Hz,1H),6.80(dd,J=8.0,1.0Hz,1H),6.75(td,J=7.4,1.1Hz,1 H), 3.60 (s, 2H), 1.77 (q, J = 7.5Hz, 2H), 1.30 (s, 6H), 0.80 (t, J = 7.5Hz, 3H). LC-MS (Method A): Rt 2.96min; MS m / z 341.2=[M+H]+(99%@215nm).

[1299] The compounds of the examples listed below (Table 1) were prepared analogously to Example 1 by replacing 2-(2-methoxyphenyl)acetic acid (step 1) and methyl 4-aminopyridine-2-carboxylate (step 1) with the appropriate commercially available acids and amines and by replacing 2-methylpropan-2-amine (step 3) with the appropriate amines.

[1300] Table 1

[1301]

[1302]

[1303] Example 1.6

[1304] 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclobutyl)pyridine-2-carboxamide

[1305]

[1306] To a solution of 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 31, Step 1) (800 mg, 2.61 mmol), 1-methylcyclobutanamine hydrochloride (381 mg, 3.13 mmol), and TEA (800 μL, 5.74 mmol) in DMF (15 mL) was added HATU (1.19 g, 3.13 mmol), and the mixture was stirred at room temperature overnight. The resulting mixture was concentrated under vacuum, and the residue was dissolved in EtOAc and washed sequentially with 1 M aqueous HCl, aqueous NaHCO, brine, and 1 M NaOH. The organic extract was dried over NaSO and concentrated under vacuum. The crude product was purified by silica gel chromatography eluting with 50-100% ethyl acetate in heptane to produce a light yellow foam. The isolated material was recrystallized by dissolving in methanol (15 mL) and heating to reflux until all solids dissolved. The mixture was allowed to slowly cool to room temperature and the resulting crystals were filtered to give the title compound as a pale yellow solid.

[1307] 1H NMR (500MHz, DMSO-d6) δ10.67(s,1H),9.81(s,1H),8.47(s,1H),8.45(d,J=5.5Hz,1H),8.15(d,J=1.9Hz,1H),7.82(dd,J=5.5,2.2Hz,1H),7.22(d,J =2.7Hz,1H),7.12(dd,J=8.6,2.7Hz,1H),6.80(d,J=8.6Hz,1H),3.67(s,2 H),2.42-2.36(m,2H),2.02-1.96(m,2H),1.84-1.77(m,2H),1.47(s,3H).

[1308] LC-MS (Method A): Rt 3.24 min; MS m / z 374.3 / 376.3 = [M+H]+ (100% @ 215 nm)

[1309] Example 1.10

[1310] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-cyclohexyl-pyridine-2-carboxamide

[1311]

[1312] Step 1: 4-[[2-(5-Chloro-2-methoxy-phenyl)acetyl]amino]-N-cyclohexyl-pyridine-2-carboxamide

[1313]

[1314] A solution of 4-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 8.1, Step 2) (3.0 g, 9.07 mmol), cyclohexylamine (1.25 mL, 10.89 mmol), EDCI (2.09 g, 10.89 mmol), HOAt (1.48 g, 10.89 mmol), and DIPEA (3.17 mL, 18.15 mmol) in DMF (30 mL) was stirred at room temperature for 19.5 hours. The resulting mixture was concentrated under vacuum, and the residue was partitioned between EtOAc (200 mL) and water (200 mL). The organic portion was separated, and the aqueous layer was extracted again with EtOAc (2 x 100 mL). The combined organic extracts were washed with water (2 x 100 mL), brine (2 x 100 mL), dried over Na2SO4, and concentrated under vacuum to give the title compound as a red / brown solid.

[1315] 1H NMR (500MHz, DMSO-d6) δ10.69(s,1H),8.47(d,J=5.5Hz,1H),8.38(d,J=8.6Hz,1H),8.18(d,J=2.1Hz,1H),7.81(dd,J=5.5,2.2Hz,1H),7. 35-7.27(m,2H),7.05-6.98(m,1H),3.76(s,3H),3.71(s,2H),1.85-1 .67(m,4H),1.64-1.53(m,1H),1.45-1.27(m,4H),1.25-1.03(m,2H).

[1316] LC-MS (Method E): Rt 1.26 min; MS m / z 402.0 / 404.1 = [M+H]+ (89% @ 215 nm)

[1317] Step 2: 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-cyclohexyl-pyridine-2-carboxamide

[1318] 1M BBr in DCM (21.26 mL, 21.26 mmol) was added to a stirred suspension of 4-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]-N-cyclohexyl-pyridine-2-carboxamide (step 1) (3.2 g, 7.09 mmol) in DCM (50 mL) at 0°C. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 2 hours. The reaction was quenched by the slow addition of water (-70 mL) and the mixture was partially concentrated under vacuum to remove volatile solvents. EtOAc (200 mL) was added followed by water (100 mL), the organic portion was separated, the aqueous layer was extracted with EtOAc (100 mL), and the combined organics were washed with saturated NaHCO (2 x 150 mL), brine (100 mL), dried over NaSO, and concentrated under vacuum. The crude product was purified by C18 reverse phase chromatography, eluting with 10-100% MeCN in water and 0.1% formic acid, to afford a dark brown / orange solid. The solid was dissolved in a minimum volume of boiling MeCN (~100 mL) and allowed to stand overnight. The resulting crystals were collected by vacuum filtration and dried in a vacuum oven at 40°C for 5 hours to afford the title compound as light beige needles.

[1319] 1H NMR(500MHz,DMSO-d6)δ10.68(br s,1H),9.81(br s,1H),8.46(d,J=5.5Hz,1H),8.38(d,J=8.6Hz,1H),8.18(d,J=2.1Hz,1H),7 .82(dd,J=5.5,2.2Hz,1H),7.21(d,J=2.7Hz,1H),7.12(dd,J=8.6,2.7Hz,1H ),6.80(d,J=8.6Hz,1H),3.83-3.70(m,1H),3.66(s,2H),1.85-1.75(m,2H), 1.75-1.65(m,2H),1.63-1.54(m,1H),1.45-1.25(m,4H),1.21-1.07(m,1H).

[1320] LC-MS (Method A): Rt 3.46 min; MS m / z 388.2 / 390.1 = [M+H]+ (100% @ 215 nm)

[1321] Example 2

[1322] N-tert-Butyl-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]benzamide

[1323]

[1324] Step 1a: tert-Butyl N-[3-(tert-butylcarbamoyl)phenyl]carbamate

[1325]

[1326] Commercially available 3-(tert-butoxycarbonylamino)benzoic acid (2.5 g, 10.54 mmol) in DMF (40 mL) was treated with HOAt (1.43 g, 10.54 mmol), EDCI (2.63 g, 13.7 mmol), TEA (1.9 mL, 13.7 mmol), and 2-methylpropan-2-amine (1.44 mL, 13.7 mmol) and stirred at room temperature for 2 hours. The resulting mixture was diluted with water (100 mL) and filtered to collect the resulting white suspension. The filter cake was washed with water (3 x 15 mL) and oven-dried to afford the title compound as an off-white solid.

[1327] 1H NMR (500 MHz, methanol-d4) δ 7.78-7.70 (m, 1H), 7.52-7.46 (m, 1H), 7.38-7.28 (m, 2H), 1.53 (s, 9H), 1.45 (s, 9H).

[1328] LC-MS (Method E): Rt 1.17 min; MS m / z 293.0 = [M+H]+ (100% @ 215 nm)

[1329] Step 1b: 3-Amino-N-tert-butyl-benzamide hydrochloride

[1330]

[1331] Tert-butyl N-[3-(tert-butylcarbamoyl)phenyl]carbamate (step 1a) (5.3 g, 18.13 mmol) was suspended in 1,4-dioxane (20 mL), followed by the addition of 4M HCl in dioxane (9.59 mL, 271.92 mmol). After stirring at room temperature for 24 hours, the resulting mixture was concentrated under vacuum and azeotroped with methanol. The resulting foam was dried in a vacuum oven at 40°C for another 3 hours to afford the title compound as a light orange foam.

[1332] 1H NMR(500MHz,DMSO-d6)δ10.25(br s,2H),7.91(s,1H),7.76(d,J=7.1Hz,1H),7.71-7.68(m,1H),7.50(t,J=7.8Hz,1H),7.47-7.43(m,1H),1.37(s,9H).

[1333] LC-MS (Method E): Rt 0.73 min; MS m / z 193.1 = [M+H]+ (99% @ 215 nm)

[1334] Step 2: 2-(5-Chloro-2-methoxy-phenyl)acetic acid

[1335]

[1336] To the solution of 2-(2-methoxyphenyl)acetic acid (2.0g, 12.04mmol) in THF (34.8mL) cooling (-10 ℃) stirring was added sulfonyl chloride (1.37mL, 16.85mmol) over 15 minutes, and continued stirring for 1 hour. The reaction was quenched with ice-cold water (34.8mL), and extracted in EtOAc (3x50mL). The organic layer merged was dried over Na2SO4, and concentrated under vacuum to give a pink solid of the title compound.

[1337] 1H NMR (250MHz, DMSO-d6) δ 12.24 (s, 1H), 7.30 (d, J = 2.7Hz, 2H), 6.99 (d, J = 8.8Hz, 1H), 3.76 (s, 3H), 3.51 (s, 2H).

[1338] LC-MS (Method E): Rt 1.01 min; no characteristic mass ion was observed at MS m / z

[1339] Step 3: N-tert-Butyl-3-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]benzamide

[1340]

[1341] To 2-(5-chloro-2-methoxy-phenyl)acetic acid (step 2) (114 mg, 0.57 mmol) in DMF (3 mL) was added HOAt (77 mg, 0.57 mmol), EDCI (142 mg, 0.74 mmol), DIPEA (248 μL, 1.42 mmol) and 3-amino-N-tert-butyl-benzamide hydrochloride (step 1b) (130 mg, 0.57 mmol). The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was partitioned between water (8 mL) and DCM (8 mL) and the phases were separated using a PTFE-sintered phase separator. The organic layer was concentrated under vacuum and the crude product was purified by silica gel chromatography eluting with EtOAc in heptane. The product fractions were placed under vacuum to give the title compound as a white solid.

[1342] 1H NMR (500 MHz, chloroform-d) δ 7.76-7.64 (m, 3H), 7.41-7.37 (m, 1H), 7.36-7.31 (m, 1H), 7.30-7.26 (m, 2H), 6.88 (d, J = 8.6 Hz, 1H), 5.97 (br. s, 1H), 3.92 (s, 3H), 3.68 (s, 2H), 1.45 (s, 9H).

[1343] LC-MS (Method E): Rt 1.20 min; MS m / z 375.0 / 377.0 = [M+H]+ (94% @ 215 nm)

[1344] Step 4: N-tert-Butyl-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]benzamide

[1345] A solution of N-tert-butyl-3-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]benzamide (step 3) (3.83 g, 10.2 mmol) in DCM (80 mL) was cooled to 0°C and 1 M BBr in DCM (20.4 mL, 20.4 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 4 hours. The resulting mixture was diluted with water (10 mL) and the volatile solvents were removed in vacuo to give a gummy residue. The residue was dissolved in EtOAc (60 mL) and saturated sodium bicarbonate (60 mL) and stirred for 1 hour to ensure complete dissolution. The biphasic mixture was separated and the organic portion was washed with saturated sodium bicarbonate solution (80 mL), brine (80 mL), dried over Na2SO4, and concentrated in vacuo to give a thick beige oil. The crude product was purified by silica gel chromatography eluting with heptane containing 0-100% EtOAc to produce a white foam. This material was azeotroped with MeCN (2x80 mL) and then dissolved in boiling MeCN (~30 mL) and allowed to cool to room temperature. After 3 hours, the resulting crystalline solid was collected by filtration and recrystallized again from boiling MeCN (40 mL) to give the title compound as a white crystalline solid.

[1346] 1H NMR (500MHz, DMSO-d6) δ10.22(s,1H),9.81(s,1H),7.90(t,J=1.7Hz,1H),7.78-7.72(m,1H),7.69(s,1H),7.42(dt,J=7.8,1.1Hz ,1H),7.33(t,J=7.9Hz,1H),7.20(d,J=2.7Hz,1H),7.10(dd,J=8.6,2.7Hz,1H),6.80(d,J=8.6Hz,1H),3.61(s,2H),1.36(s,9H).

[1347] LC-MS (Method A): Rt 3.19 min; MS m / z 361.1 / 363.2 = [M+H]+ (100% @ 215 nm)

[1348] The compounds of the following examples (Table 2) were prepared in analogy to Example 2 by replacing 2-(5-chloro-2-methoxy-phenyl)acetic acid (Step 2) with the appropriate commercially available acid.

[1349] Table 2

[1350]

[1351]

[1352]

[1353]

[1354]

[1355]

[1356] Example 3

[1357] N-tert-Butyl-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide

[1358]

[1359] Step 1: 4-Amino-N-tert-butyl-pyridine-2-carboxamide

[1360]

[1361] To a mixture of 4-aminopyridine-2-carboxylic acid (8.0 g, 57.92 mmol), TBTU (22.32 g, 69.5 mmol) and TEA (24.22 mL, 173.76 mmol) in DMF (100 mL) was added 2-methylpropane-2-amine (7.30 mL, 69.5 mmol) and the resulting mixture was stirred at room temperature for 22 hours, then concentrated under vacuum. The crude material was purified by silica gel chromatography eluting with 3.5 M methanolic ammonia in DCM, and the product fractions were combined and concentrated under vacuum to give a pale yellow solid of the title compound.

[1362] 1H NMR (500 MHz, methanol-d4) δ 7.99 (d, J = 5.6 Hz, 1H), 7.23 (d, J = 2.2 Hz, 1H), 6.62 (dd, J = 5.6, 2.4 Hz, 1H), 1.45 (s, 9H).

[1363] LC-MS (Method F): Rt 1.47 min; MS m / z 194.3 = [M+H]+ (100% @ 215 nm)

[1364] Step 2: N-tert-Butyl-4-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxamide

[1365]

[1366] A solution of 2-(5-chloro-2-methoxy-phenyl)acetic acid (2.26 g, 11.27 mmol) in thionyl chloride (8.13 mL, 92.21 mmol) was heated at 70°C for 30 minutes. After cooling to room temperature, the excess thionyl chloride was removed in vacuo and azeotroped with toluene. The resulting residue was dissolved in DCM (5 mL) and added to a solution of 4-amino-N-tert-butyl-pyridine-2-carboxamide (step 1) (2.0 g, 10.25 mmol) and DIPEA (2.15 mL, 12.29 mmol) in DCM (25 mL). The mixture was stirred at room temperature for 1 hour, then diluted with water (50 mL) and extracted with DCM. The combined organic extracts were washed with brine (50 mL), dried over Na2SO4, and concentrated under vacuum. The crude residue was purified by silica gel chromatography eluting with 0-50% EtOAc in heptane to give the title compound as a light orange powder.

[1367] 1H NMR (500MHz, chloroform-d) δ8.39 (d, J=5.6Hz, 1H), 8.20 (dd, J=5.6, 2.2Hz, 1H), 8.10 (br s, 1H), 7.98 (br s,1H),7.56(d,J=2.1Hz,1H),7.29-7.26(m,2H),6.89(d,J=9.5Hz,1H),3.94(s,3H),3.70(s,2H),1.47(s,9H).

[1368] LC-MS (Method E): Rt 1.21 min; MS m / z 376.1 / 378.1 = [M+H]+ (92% @ 215 nm)

[1369] Step 3: N-tert-Butyl-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide

[1370] To a solution of N-tert-butyl-4-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxamide (step 2) (2.7 g, 6.82 mmol, 95%) in DCM (10 mL) was added 1 M BBr in DCM (27.3 mL, 27.3 mmol) dropwise at 0°C. Once the addition was complete, the mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction was quenched by the slow addition of water (10 mL) and the DCM was removed in vacuo. The resulting residue was dissolved in EtOAc and washed with saturated NaHCO solution (50 mL) and brine (50 mL). The organic portion was separated, dried over NaSO, and concentrated in vacuo. The crude residue was purified by silica gel chromatography eluting with 0-70% EtOAc in heptane to give the product as an orange powder. This was further purified by reverse phase chromatography using 0-100% MeCN in water and 0.1% formic acid to afford the product as a colorless powder. The product was recrystallized from MeCN to afford the title compound, and a second crop of product was isolated by adding water dropwise to the MeCN filtrate followed by heating and cooling the mixture.

[1371] 1H NMR(500MHz,DMSO-d6)δ10.69(br s,1H),9.82(br s,1H),8.44(d,J=5.5Hz,1H),8.17(d,J=1.9Hz,1H),8.03(s,1H),7.82(dd,J=5.5,2.2Hz,1H),7. 22(d,J=2.7Hz,1H),7.12(dd,J=8.6,2.7Hz,1H),6.80(d,J=8.6Hz,1H),3.67(s,2H),1.40(s,9H).

[1372] LC-MS (Method A): Rt 3.28 min; MS m / z 362.1 / 364.1 = [M+H]+ (99% @ 215 nm)

[1373] The compounds of the examples listed in the table below (Table 3a) were prepared analogously to Example 3 by replacing 2-methylpropan-2-amine (step 1) with a suitable amine and by replacing 2-(5-chloro-2-methoxy-phenyl)acetic acid (step 2) with a suitable commercially available acid.

[1374] Table 3a

[1375]

[1376]

[1377] Example 3.5b

[1378] N-tert-Butyl-4-[[2-[2-hydroxy-5-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide

[1379]

[1380] Step 1: N-tert-Butyl-4-[[2-[2-methoxy-5-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide

[1381]

[1382] To a solution of 4-amino-N-tert-butyl-pyridine-2-carboxamide (Example 3, Step 1) (70 mg, 0.36 mmol), TEA (127 μL, 0.72 mmol) and 2-[2-methoxy-5-(trifluoromethyl)phenyl]acetic acid (102 mg, 0.43 mmol) in 1,4-dioxane (1 mL) was added 50% The mixture was stirred at room temperature for 1 hour and the resulting mixture was partitioned between water (25 mL) and EtOAc (25 mL). The organic layer was separated, washed with water (20 mL), dried over Na2SO4, and concentrated under vacuum. The crude residue was purified by silica gel chromatography eluting with EtOAc in heptane to give the title compound as a light yellow solid.

[1383] 1H NMR (500MHz, DMSO-d6) δ10.75(s,1H),8.44(d,J=5.5Hz,1H),8.17(d,J=2.1Hz,1H),8.03(s,1H),7.80( dd,J=5.5,2.2Hz,1H),7.69-7.61(m,2H),7.18(d,J=8.5Hz,1H),3.83(s,3H),3.81(s,2H),1.40(s,9H).

[1384] LC-MS (Method E): Rt 1.23 min; MS m / z 410.0 = [M+H]+ (93% @ 215 nm)

[1385] Step 2: N-tert-Butyl-4-[[2-[2-hydroxy-5-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide

[1386] The title compound was prepared in analogy to Example 3, Step 3, from N-tert-butyl-4-[[2-[2-methoxy-5-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Step 2).

[1387] 1H NMR (500MHz, DMSO-d6) δ11.32-9.82(m,2H),8.44(d,J=5.5Hz,1H),8.17(d,J=2.0Hz,1H),8.03(s,1H),7.82(dd,J=5 .5, 2.2Hz, 1H), 7.54 (d, J = 2.0Hz, 1H), 7.45 (dd, J = 8.5, 2.1Hz, 1H), 6.95 (d, J = 8.4Hz, 1H), 3.76 (s, 2H), 1.40 (s, 9H).

[1388] LC-MS (Method A): Rt 3.41 min; MS m / z 396.2 = [M+H]+ (100% @ 215 nm)

[1389] The compounds of the following examples (Table 3b) were prepared in analogy to Example 3.5b by replacing 2-[2-methoxy-5-(trifluoromethyl)phenyl]acetic acid (step 1) with the appropriate commercially available acid.

[1390] Table 3b

[1391]

[1392]

[1393]

[1394]

[1395] Example 4

[1396] N-tert-Butyl-3-[[2-(3-hydroxyphenyl)acetyl]amino]benzamide

[1397]

[1398] A mixture of 3-amino-N-tert-butyl-benzamide hydrochloride (Example 2, step 1b) (50 mg, 0.22 mmol), EDCI (50 mg, 0.26 mmol), HOAt (36 mg, 0.26 mmol), DIPEA (0.09 mL, 0.52 mmol) in DCM (1.25 mL) was treated with 2-(3-hydroxyphenyl)acetic acid (33 mg, 0.22 mmol) and stirred at room temperature for 1 hour. The resulting mixture was diluted with water (5 mL) and extracted with DCM (3 x 5 mL). The combined organics were passed through a PTFE phase separator and concentrated under vacuum. The crude product was purified by preparative HPLC (acidic pH, early elution method). The product fractions were concentrated and dried under vacuum to give the title compound as a white solid.

[1399] 1H NMR (500MHz, methanol-d4) δ7.90(t,J=1.8Hz,1H),7.72(s,1H),7.69(ddd,J=8.0,2.1,1.1Hz,1H),7.49-7.45(m,1H ),7.39(t,J=7.9Hz,1H),7.19-7.13(m,1H),6.87-6.81(m,2H),6.73-6.68(m,1H),3.63(s,2H),1.46(s,9H).

[1400] LC-MS (Method B): Rt 2.56 min; MS m / z 344.3 = [M+NH3]+ (99% @ 215 nm)

[1401] The compounds of the following examples (Table 4) were prepared analogously to Example 4 by replacing 2-(3-hydroxyphenyl)acetic acid with the appropriate commercially available acid.

[1402] Table 4

[1403]

[1404]

[1405]

[1406] Example 5

[1407] N-tert-Butyl-4-[[2-(2-thienyl)acetyl]amino]pyridine-2-carboxamide

[1408]

[1409] A solution of 4-amino-N-tert-butyl-pyridine-2-carboxamide (Example 3, Step 1) (50 mg, 0.26 mmol), 2-(2-thienyl)acetic acid (37 mg, 0.26 mmol) and TEA (0.09 mL, 0.52 mmol) in 1,4-dioxane (2 mL) was stirred with 50% To 4-[ ...

[1410] 1H NMR (500MHz, DMSO-d6) δ10.80(s,1H),8.46(d,J=5.5Hz,1H),8.19(d,J=2.0Hz,1H),8.03(s,1H),7. 80(dd,J=5.5,2.2Hz,1H),7.41(dd,J=5.0,1.4Hz,1H),7.03-6.94(m,2H),3.95(s,2H),1.40(s,9H)

[1411] LC-MS (Method A): Rt 3.19 min; MS m / z 318.2 = [M+H]+ (99% @ 215 nm).

[1412] Example 5.1

[1413] 4-[[2-(2-adamantyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide

[1414]

[1415] A solution of 2-(2-adamantyl)acetic acid (40 mg, 0.21 mmol) in thionyl chloride (160 μL, 1.82 mmol) was heated at 70° C. for 30 minutes. Excess thionyl chloride was removed under vacuum (azeotropic drying with DCM). The residue was treated with a mixture of 4-amino-N-tert-butyl-pyridine-2-carboxamide (Example 3, Step 1) (40 mg, 0.21 mmol) and DIPEA (43 μL, 0.25 mmol) in DCM (1.5 mL) and stirred at room temperature for 1 hour. The resulting mixture was partitioned between water (5 mL) and DCM (5 mL). The phases were separated using a PTFE-sintered separator, and the organic layer was concentrated under vacuum. The crude product was purified by preparative HPLC (acidic pH, standard elution method). The product fractions were concentrated under vacuum to give the title compound as a white crystalline solid.

[1416] 1H NMR(500MHz,DMSO-d6)δ10.50(s,1H),8.42(d,J=5.5Hz,1H),8.19(d,J=2.0Hz,1H),8.02(s,1H),7.79(dd,J=5.5,2.2Hz,1H),2.54-2.51(m,2H),2 .27-2.19(m,1H),1.94-1.87(m,2H),1.87-1.83(m,1H),1.83-1.77(m,3H ),1.77-1.71(m,2H),1.71-1.65(m,4H),1.54-1.49(m,2H),1.39(s,9H).

[1417] LC-MS (Method A): Rt 4.29 min; MS m / z 370.3 = [M+H]+ (100% @ 215 nm)

[1418] Similar to Example 5 (using ) or Example 5.1 (using thionyl chloride), the compounds of the following examples (Table 5) were prepared from 4-amino-N-tert-butyl-pyridine-2-carboxamide (Example 3, Step 1) and a suitable commercially available acid.

[1419] Table 5

[1420]

[1421]

[1422]

[1423]

[1424]

[1425]

[1426]

[1427]

[1428] Example 5.33

[1429] N-(1,1-Dimethylprop-2-ynyl)-4-[(2-isochroman-1-ylacetyl)amino]pyridine-2-carboxamide

[1430]

[1431] The title compound was prepared in analogy to Example 5.1 from 4-amino-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Example 78, Step 1) and 2-isochroman-1-ylacetic acid.

[1432] 1H NMR (500MHz, DMSO-d6) δ10.60(s,1H),8.49(d,J=5.5Hz,1H),8.33(s,1H),8.22(d,J= 2.0Hz,1H),7.87(dd,J=5.5,2.2Hz,1H),7.19(tdd,J=12.4,9.2,5.5Hz,4H),5.19(dd ,J=10.0,3.1Hz,1H),4.08-4.01(m,1H),3.72(ddd,J=11.4,9.0,4.1Hz,1H),3.21(s, 1H), 3.09 (dd, J=14.6, 3.4Hz, 1H), 2.92-2.84 (m, 1H), 2.75-2.67 (m, 2H), 1.65 (s, 6H).

[1433] LC-MS (Method A): Rt 3.22 min; MS m / z 378.3 = [M+H]+ (100% @ 215 nm)

[1434] Example 5.34

[1435] 4-[[2-(4,4-difluorocyclohexyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide

[1436]

[1437] The title compound was prepared in analogy to Example 5.1 from 4-amino-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Example 78, Step 1) and 2-(4,4-difluorocyclohexyl)acetic acid.

[1438] 1H NMR(500MHz,DMSO-d6)δ10.52(s,1H),8.46(d,J=5.5Hz,1H),8.30(s,1H),8.20(d,J=2.0Hz,1H),7.80(dd,J=5.5,2.2Hz,1H), 3.21(s,1H),2.34(d,J=7.1Hz,2H),2.05-1.90(m,3H),1.90-1.82(m,1H),1.82-1.75(m,3H),1.64(s,6H),1.32-1.18(m,2H).

[1439] LC-MS (Method A): Rt 3.26 min; MS m / z 364.3 = [M+H]+ (97% @ 215 nm)

[1440] Example 5.35

[1441] N-(1,1-Dimethylprop-2-ynyl)-4-[[2-[4-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide

[1442]

[1443] The title compound was prepared in analogy to Example 5 from 4-amino-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Example 78, Step 1) and 2-[4-(trifluoromethyl)phenyl]acetic acid.

[1444] 1H NMR (500MHz, DMSO-d6) δ10.84(s,1H),8.47(d,J=5.5Hz,1H),8.31(s,1H),8.19(d,J=2.0Hz,1H),7.82(dd ,J=5.5,2.2Hz,1H),7.70(d,J=8.1Hz,2H),7.56(d,J=8.1Hz,2H),3.86(s,2H),3.20(s,1H),1.64(s,6H).

[1445] LC-MS (Method A): Rt 3.53 min; MS m / z 390.2 = [M+H]+ (100% @ 215 nm)

[1446] Example 5.36

[1447] N-(1,1-Dimethylprop-2-ynyl)-4-[[2-[3-(trifluoromethyl)-1H-pyrazol-4-yl]acetyl]amino]pyridine-2-carboxamide

[1448] Step 1: 2-[3-(Trifluoromethyl)-1H-pyrazol-4-yl]acetic acid

[1449]

[1450] Periodic acid (278 mg, 1.22 mmol) was added to MeCN (4.5 mL) and stirred at room temperature for 20 minutes. To this solution was added 2-[3-(trifluoromethyl)-1H-pyrazol-4-yl]ethanol (100 mg, 0.56 mmol) in MeCN (0.93 mL), and the mixture was cooled to 0°C. Pyridinium chlorochromate (8 mg, 0.04 mmol) was added, the mixture was gradually warmed to room temperature and stirred for 90 hours, and the resulting mixture was diluted with excess water, acidified with 3M sulfuric acid, and quenched with saturated aqueous sodium thiosulfate solution. After 3 days, the mixture was filtered and washed with water to give the title compound as a light yellow solid.

[1451] 1H NMR (400 MHz, DMSO-d6) δ 13.44 (s, 1H), 12.38 (s, 1H), 7.85 (s, 1H), 3.53 (s, 2H). LC-MS (Method E): Rt 0.77 min; MS m / z 195.0 = [M+H]+ (95% @ 215 nm)

[1452] Step 2: N-(1,1-dimethylprop-2-ynyl)-4-[[2-[3-(trifluoromethyl)-1H-pyrazol-4-yl]acetyl]amino]pyridine-2-carboxamide

[1453] The title compound was prepared in analogy to Example 5 from 4-amino-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Example 78, Step 1) and 2-[3-(trifluoromethyl)-1H-pyrazol-4-yl]acetic acid (Step 1).

[1454] 1H NMR (400MHz, DMSO-d6) δ13.50(s,1H),10.74(s,1H),8.48(d,J=5.5Hz,1H),8.32(s,1H),8.20(d ,J=2.1Hz,1H),7.91(s,1H),7.80(dd,J=5.5,2.1Hz,1H),3.73(s,2H),3.21(s,1H),1.64(s,6H).

[1455] LC-MS (Method A): Rt 2.69 min; MS m / z 380.2 = [M+H]+ (100% @ 215 nm)

[1456] Example 5.37

[1457] N-(1,1-Dimethylprop-2-ynyl)-4-[[2-[3-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide

[1458]

[1459] The title compound was prepared in analogy to Example 5 from 4-amino-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Example 78, Step 1) and 2-[3-(trifluoromethyl)phenyl]acetic acid.

[1460] 1H NMR (500MHz, DMSO-d6) δ10.84(s,1H),8.48(d,J=5.5Hz,1H),8.31(s,1H),8.19(d,J=2.0Hz,1H),7.83(dd,J=5. 5,2.2Hz,1H),7.72-7.69(m,1H),7.66-7.61(m,2H),7.61-7.55(m,1H),3.88(s,2H),3.21(s,1H),1.64(s,6H).

[1461] LC-MS (Method A): Rt 3.51 min; MS m / z 390.2 = [M+H]+ (100% @ 215 nm)

[1462] Example 5.38

[1463] N-(1,1-Dimethylprop-2-ynyl)-4-[[2-[2-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide

[1464]

[1465] The title compound was prepared in analogy to Example 5 from 4-amino-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Example 78, Step 1) and 2-[2-(trifluoromethyl)phenyl]acetic acid.

[1466] 1H NMR (500MHz, DMSO-d6) δ10.84(s,1H),8.48(d,J=5.5Hz,1H),8.32(s,1H),8.18(d,J=2.0Hz,1H),7.80(dd,J=5.5,2.2Hz ,1H),7.73(d,J=7.8Hz,1H),7.67(t,J=7.6Hz,1H),7.52(dd,J=18.5,7.7Hz,2H),4.01(s,2H),3.21(s,1H),1.64(s,6H).

[1467] LC-MS (Method A): Rt 3.53 min; MS m / z 390.2 = [M+H]+ (100% @ 215 nm)

[1468] Example 5.39

[1469] 4-[[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide

[1470]

[1471] The title compound was prepared in analogy to Example 5 from 4-amino-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Example 78, Step 1) and 2-(2,3-dihydro-1,4-benzoxazin-4-yl)acetic acid.

[1472] 1H NMR (500MHz, DMSO-d6) δ10.65(s,1H),8.48(d,J=5.5Hz,1H),8.31(s,1H),8.20(d,J=2.1Hz,1H),7.86(dd,J=5.5,2.2Hz, 1H),6.74-6.67(m,2H),6.59-6.52(m,2H),4.26-4.21(m,2H),4.17(s,2H),3.52-3.47(m,2H),3.21(s,1H),1.64(s,6H).

[1473] LC-MS (Method A): Rt 3.32 min; MS m / z 379.2 = [M+H]+ (90% @ 215 nm)

[1474] Example 6

[1475] N-tert-Butyl-4-[[2-(5-cyano-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide

[1476]

[1477] Step 1: 4-[[2-(5-Bromo-2-methoxy-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide

[1478]

[1479] 2-(5-Bromo-2-methoxy-phenyl)acetic acid (348 mg, 1.42 mmol) in thionyl chloride (1.25 mL, 14.2 mmol) was stirred at 70° C. under an inert atmosphere for 1 hour. The resulting solution was cooled to room temperature and concentrated under vacuum (azeotroping with toluene and DCM). The dry acid chloride was dissolved in anhydrous DCM (10 mL) and added dropwise to a solution of 4-amino-N-tert-butyl-pyridine-2-carboxamide (Example 3, Step 1) (274 mg, 1.42 mmol) and DIPEA (0.5 mL, 2.84 mmol) in anhydrous DCM (10 mL). The reaction mixture was stirred at room temperature under an inert atmosphere. After 1 hour, the mixture was diluted with DCM (25 mL) and washed with water (2×25 mL). The organic extract was dried over Na 2 SO 4 and concentrated under vacuum. The resulting crude oil was purified by silica gel chromatography eluting with EtOAc in heptane, flushing the column with methanol, and collecting the eluent and concentrating it under vacuum to give a beige solid, which was again purified by silica gel chromatography eluting with 0-10% MeOH in DCM. The product fractions were concentrated under vacuum and dried in a vacuum oven at 40° C. for 2 hours to give the title compound.

[1480] 1H NMR(500MHz,DMSO-d6)δ10.70(s,1H),8.44(d,J=5.5Hz,1H),8.17(d,J=2.0Hz,1H),8.03(s,1H),7.80 (dd,J=5.5,2.2Hz,1H),7.47-7.38(m,2H),7.01-6.92(m,1H),3.74(s,3H),3.71(s,2H),1.40(s,9H).

[1481] LC-MS (Method A): Rt 3.62 min; MS m / z 420.2, 422.2 = [M+H]+ (100% @ 215 nm)

[1482] Step 2: N-tert-Butyl-4-[[2-(5-cyano-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxamide

[1483]

[1484] A solution of 4-[[2-(5-bromo-2-methoxy-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (step 1) (75 mg, 0.18 mmol) in DMF (2 mL) was degassed with nitrogen for 5 minutes before the addition of tetrakis(triphenylphosphine)palladium(0) (21 mg, 0.02 mmol). The mixture was purged with nitrogen for an additional 5 minutes and then treated with zinc cyanide (27 mg, 0.23 mmol), and the resulting mixture was stirred at 100° C. for 16 hours. Another portion of zinc cyanide (27 mg, 0.23 mmol) and tetrakis(triphenylphosphine)palladium(0) (21 mg, 0.02 mmol) were added, the mixture was purged with nitrogen, and stirring was continued at 100° C. for an additional 24 hours. The mixture was diluted with EtOAc (20 mL) and washed with water (20 mL), aqueous NaHCO 3 (sat.) solution (20 mL), and brine (20 mL). The organics were dried over Na2SO4 and concentrated under vacuum.The crude material was purified by silica gel chromatography eluting with EtOAc in heptane and the product fractions were concentrated under vacuum and dried in a vacuum oven to give the title compound as a yellow solid.

[1485] 1H NMR (500MHz, chloroform-d) δ8.40(d,J=5.6Hz,1H),8.39(br.s,1H),8.20(dd,J=5.6,2.2Hz,1H),8.04(s,1H),7.75-7.69(m,1 H),7.63(dd,J=8.6,2.1Hz,1H),7.58(d,J=2.0Hz,1H),6.99(d,J=8.6Hz,1H),3.95(s,3H),3.77(s,2H),1.47(s,9H).

[1486] LC-MS (Method E): Rt 1.13 min; MS m / z 367.1 = [M+H]+ (95% @ 215 nm)

[1487] Step 3: N-tert-Butyl-4-[[2-(5-cyano-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide

[1488]

[1489] To a solution of N-tert-butyl-4-[[2-(5-cyano-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxamide (step 2) (20 mg, 0.05 mmol) in DCM (2 mL) was added 1 M BBr in DCM (164 μL, 0.16 mmol) and the resulting mixture was stirred under an inert atmosphere for 2 hours. Additional 1 M BBr in DCM (164 μL, 0.16 mmol) was added and the mixture was stirred at room temperature for another 16 hours. Additional 1 M BBr in DCM (164 μL, 0.16 mmol) was added and the mixture was stirred at room temperature under nitrogen for 24 hours. The mixture was diluted with DCM (20 mL) and washed with water (2 x 20 mL), and the organic portion was dried over NaSO and concentrated under vacuum. The crude product was purified by C18 reverse phase chromatography eluting with 0-100% MeCN in water and 0.1% formic acid and the product fractions were freeze-dried to afford the title compound as a white solid.

[1490] 1H NMR(500MHz,DMSO-d6)δ10.78(br s,1H),10.75(s,1H),10.90-10.60(m,2H),8.44(d,J=5.5Hz,1H),8.16(d,J=1.9Hz,1H),8.03(s,1H),7.81(dd,J=5.5,2.2H z,1H),7.63(d,J=2.1Hz,1H),7.57(dd,J=8.4,2.2Hz,1H),6.93(d,J=8.4Hz,1H),3.72(s,2H),1.40(s,9H).LC-MS (Method A): Rt 2.84min; MS m / z 353.3=[M+H]+(94%@215nm)

[1491] Example 7

[1492] 3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1,2,2-tetramethylpropyl)benzamide

[1493]

[1494] Step 1: Methyl 3-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]benzoate

[1495]

[1496] A solution of 2-(5-chloro-2-methoxy-phenyl)acetic acid (1200 mg, 5.98 mmol), EDCI (1376 mg, 7.18 mmol), HOAt (814 mg, 5.98 mmol), DIPEA (2.61 mL, 14.95 mmol) and methyl 3-aminobenzoate (904 mg, 5.98 mmol) in DMF (5 mL) was stirred at room temperature for 17 hours. The reaction mixture was diluted with water (35 mL) and extracted with EtOAc (2x40 mL). The combined organic fractions were washed with water (2x40 mL), dried over Na2SO4, and concentrated under vacuum. The crude material was purified by silica gel chromatography eluting with heptane containing 10-70% EtOAc, and the product fractions were concentrated under vacuum to give the title compound as an off-white solid.

[1497] 1H NMR (500MHz, DMSO-d6) δ10.32(s,1H),8.29(t,J=1.8Hz,1H),7.82(ddd,J=8.1,2.1,1.0Hz,1H),7.63(dt,J=7.7, 1.2Hz,1H),7.45(t,J=7.9Hz,1H),7.32-7.28(m,2H),7.05-6.95(m,1H),3.84(s,3H),3.76(s,3H),3.66(s,2H).

[1498] LC-MS (Method E): Rt 1.21 min; MS m / z 334.1 / 336.1 = [M+H]+ (96% @ 215 nm)

[1499] Step 2: 3-[[2-(5-Chloro-2-methoxy-phenyl)acetyl]amino]benzoic acid

[1500]

[1501] 2M LiOH (7.71 mL, 15.42 mmol) was added to a solution of methyl 3-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]benzoate (step 1) (1751 mg, 5.14 mmol) in THF (8 mL). The reaction mixture was stirred at room temperature for 7 hours, and the resulting mixture was concentrated under vacuum, diluted with water (8 mL), and acidified to pH 2 with 2M aqueous HCl. The formed precipitate was collected by vacuum filtration and washed with EtO (2 x 20 mL), and the solid was dried in a vacuum oven at 40 ° C for 3 hours to give the title compound as a light beige solid.

[1502] 1H NMR(500MHz,DMSO-d6)δ10.32(s,1H),8.23(s,1H),7.87-7.74(m,1H),7.61(d,J=7.7Hz,1 H),7.41(t,J=7.9Hz,1H),7.31-7.27(m,2H),7.03-6.95(m,1H),3.76(s,3H),3.66(s,2H).

[1503] LC-MS (Method E): Rt 1.07 min; MS m / z 320.1 / 322.1 = [M+H]+ (100% @ 215 nm)

[1504] Step 3: 3-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]-N-(1,1,2,2-tetramethylpropyl)benzamide

[1505]

[1506] A solution of 3-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]benzoic acid (step 2) (70 mg, 0.22 mmol), EDCI (50 mg, 0.26 mmol), HOAt (36 mg, 0.26 mmol), DIPEA (0.11 mL, 0.66 mmol) and 2,3,3-trimethylbutan-2-amine hydrochloride (33 mg, 0.22 mmol) in DMF (0.5 mL) was stirred at room temperature for 3 hours. The resulting mixture was diluted with EtOAc (5 mL) and water (5 mL), the aqueous layer was extracted with EtOAc (5 mL), and the combined organic extracts were washed with water (5 mL), brine (5 mL), dried over Na2SO4, and concentrated under vacuum. The crude residue was purified by preparative HPLC (acidic pH, early elution method) and the product fractions were concentrated under vacuum to give the title compound as an off-white powder.

[1507] 1H NMR (500MHz, DMSO-d6) δ10.19(s,1H),7.85(s,1H),7.74(dt,J=6.8,2.1Hz,1H),7.37-7.32(m,2H),7. 32-7.26(m,2H),7.09(s,1H),7.02-6.98(m,1H),3.76(s,3H),3.65(s,2H),1.39(s,6H),0.97(s,9H).

[1508] LC-MS (Method E): Rt 1.32 min; MS m / z 417.2 / 419.2 = [M+H]+ (97% @ 215 nm)

[1509] Step 4: 3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1,2,2-tetramethylpropyl)benzamide

[1510] To a cooled (0°C) solution of 3-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]-N-(1,1,2,2-tetramethylpropyl)benzamide (step 3) (53 mg, 0.13 mmol) in DCM (0.5 mL) was added 1 M BBr in DCM (0.38 mL, 0.38 mmol) and the mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted with water (5 mL) and extracted with EtOAc (2 x 8 mL). The combined organic extracts were dried over NaSO and concentrated under vacuum. The crude residue was purified by preparative HPLC (acidic pH, early elution method) and the product fractions were concentrated under vacuum to give the title compound as an off-white powder.

[1511] 1H NMR(500MHz,DMSO-d6)δ10.19(s,1H),9.81(br s,1H),7.86(s,1H),7.75(dt,J=6.6,2.2Hz,1H),7.38-7.31(m,2H),7.20(d,J=2.7Hz, 1H),7.13-7.05(m,2H),6.80(d,J=8.6Hz,1H),3.61(s,2H),1.39(s,6H),0.97(s,9H).

[1512] LC-MS (Method D): Rt 4.52 min; MS m / z 403.2 / 405.2 = [M+H]+ (100% @ 215 nm).

[1513] The compounds of the following examples (Table 6) were prepared analogously to Example 7 from the appropriate amino ester and acid (Step 1) and by substituting the appropriate commercially available amine for 2,3,3-trimethylbutan-2-amine hydrochloride (Step 3). / TEA for the amide coupling step.

[1514] Table 6

[1515]

[1516]

[1517]

[1518]

[1519]

[1520]

[1521] Example 8

[1522] tert-Butyl 3-[[3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]benzoyl]amino]piperidine-1-carboxylate

[1523] Step 1: 3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3-piperidinyl)benzamide

[1524]

[1525] The title compound was prepared in analogy to Example 7 by substituting tert-butyl 3-aminopiperidine-1-carboxylate for 2,3,3-trimethylbutan-2-amine hydrochloride (step 3).

[1526] 1H NMR(500MHz,DMSO-d6)δ10.22(s,1H),8.15(d,J=7.9Hz,1H),7.98(s,1H),7.82-7.70(m, 1H),7.50-7.46(m,1H),7.36(t,J=7.9Hz,1H),7.20(d,J=2.7Hz,1H),7.11(dd,J=8.6,2.7 Hz,1H),6.80(d,J=8.6Hz,1H),3.88-3.80(m,1H),3.61(s,2H),3.02-2.95(m,1H),2.88- 2.80(m,1H),2.48-2.42(m,2H),1.90-1.77(m,1H),1.74-1.59(m,1H),1.54-1.37(m,2H).

[1527] LC-MS (Method A): Rt 1.66 min; MS m / z 388.2 / 390.2 = [M+H]+ (96% @ 215 nm)

[1528] Step 2: tert-Butyl 3-[[3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]benzoyl]amino]piperidine-1-carboxylate

[1529] To a solution of 3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3-piperidinyl)benzamide (step 1) (19 mg, 0.05 mmol) in THF (0.5 mL) was added BOC anhydride (12 mg, 0.06 mmol) and the resulting mixture was stirred at room temperature for 3 hours. Additional BOC anhydride (12 mg, 0.06 mmol) was added and stirring continued for another hour. The reaction mixture was concentrated under vacuum and the crude product was purified by silica gel chromatography eluting with EtOAc in heptane to give the title compound as an off-white powder.

[1530] 1H NMR(500MHz,DMSO-d6)δ10.26(br s,1H),9.81(br s,1H),8.24(d,J=7.0Hz,1H),7.99(s,1H),7.83-7.74(m,1H),7.49(d,J=7. 8Hz,1H),7.37(m,1H),7.20(d,J=2.7Hz,1H),7.11(dd,J=8.6,2.7Hz,1H),6 .80(d,J=8.6Hz,1H),4.05-3.67(m,3H),3.61(s,2H),3.03-2.70(m,2H),1. 91-1.81(m,1H),1.76-1.67(m,1H),1.60-1.46(m,1H),1.45-1.31(m,10H).

[1531] LC-MS (Method A): Rt 3.41 min; MS m / z 488.3 / 490.4 = [M+H]+ (99% @ 215 nm)

[1532] Example 8.1

[1533] tert-Butyl 3-[[4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carbonyl]amino]piperidine-1-carboxylate

[1534] Step 1: 4-[[2-(5-Chloro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid methyl ester

[1535]

[1536] 2-(5-Chloro-2-methoxy-phenyl)acetic acid (24.19 g, 120.59 mmol) was suspended in thionyl chloride (103.68 mL, 1427.48 mmol) and heated at 70°C for 1.5 hours. After cooling to room temperature, the mixture was concentrated under vacuum, and the residue was then dissolved in DCM (135 mL) and concentrated again. The resulting brown viscous oil was dissolved in DCM (135 mL) and added dropwise to a cooled (ice bath) suspension of methyl 4-aminopyridine-2-carboxylate (17.9 g, 117.65 mmol) and DIPEA (30.82 mL, 176.47 mmol) in DCM (225 mL). The reaction mixture was allowed to warm to room temperature and stirred overnight. The resulting mixture was diluted with water (180 mL) and stirred for 10 minutes. The organic portion was separated, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography eluting with EtOAc to give the title compound as an orange glassy solid.

[1537] 1H NMR (500MHz, DMSO-d6) δ10.72(s,1H),8.54(d,J=5.5Hz,1H),8.30(d,J=1.9Hz,1H),7.77(dd,J =5.5,2.2Hz,1H),7.32-7.29(m,2H),7.02-6.99(m,1H),3.86(s,3H),3.75(s,3H),3.71(s,2H).

[1538] LC-MS (Method E): Rt 1.04 min; MS m / z 335.0 / 337.0 = [M+H]+ (98% @ 215 nm)

[1539] Step 2: 4-[[2-(5-Chloro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid

[1540]

[1541] To a solution of methyl 4-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxylate (step 1) (95%, 38.09 g, 108.1 mmol) in THF (200 mL) was added 2 M aqueous lithium hydroxide hydrate (162.15 mL, 324.29 mmol) and the resulting mixture was stirred at room temperature for 1 hour. The volatile organics were removed under vacuum and the aqueous residue was cooled (ice bath) and treated with slowly added 3 M aqueous HCl (150 mL). The resulting suspension was filtered, washed with water (3 x 200 mL), diethyl ether (2 x 250 mL), suction dried and then further dried in a high vacuum oven at 40 °C to give the title compound as a beige solid.

[1542] 1H NMR(500MHz,DMSO-d6)δ10.78(s,1H),8.53(d,J=5.6Hz,1H),8.27(d,J=2.0Hz,1H),7.81 (dd,J=5.6,2.2Hz,1H),7.34-7.28(m,2H),7.04-6.98(m,1H),3.75(s,3H),3.72(s,2H).

[1543] LC-MS (Method E): Rt 0.88 min; MS m / z 320.9 / 323.0 = [M+H]+ (97% @ 215 nm)

[1544] Step 3: tert-Butyl 3-[[4-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carbonyl]amino]piperidine-1-carboxylate

[1545]

[1546] A solution of 4-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (step 2) (70 mg, 0.22 mmol), EDCI (50 mg, 0.26 mmol), HOAt (36 mg, 0.26 mmol), DIPEA (0.08 mL, 0.44 mmol) and tert-butyl 3-aminopiperidine-1-carboxylate (27.2 μL, 0.26 mmol) in DMF (0.5 mL) was stirred at room temperature for 20 hours. The resulting mixture was diluted with EtOAc (5 mL) and water (5 mL). The aqueous layer was extracted with EtOAc (5 mL). The combined organic extracts were washed with water (5 mL), brine (5 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by preparative HPLC (acidic pH, early elution method) to give the title compound as an off-white solid.

[1547] 1H NMR(500MHz,DMSO-d6)δ10.71(br s,1H),8.52(br s,1H),8.46(m,1H),8.19(br s,1H),7.87-7.79(m,1H),7.35-7.26(m,2H),7.08-6.93(m,1H),3.87-3.78(m,1H),3.75(s,3 H),3.71(s,2H),3.17-2.83(m,2H),1.87-1.77(m,1H),1.77-1.58(m,2H),1.57-1.20(m,10H).

[1548] LC-MS (Method E): Rt 1.28 min; MS m / z 503.3 / 505.2 = [M+H]+ (93% @ 215 nm)

[1549] Steps 4 and 5: tert-Butyl 3-[[4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carbonyl]amino]piperidine-1-carboxylate

[1550] The title compound was prepared in analogy to Example 8 from tert-butyl 3-[[4-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carbonyl]amino]piperidine-1-carboxylate (step 3).

[1551] 1H NMR(500MHz,DMSO-d6)δ10.71(br s,1H),9.83(br s,1H),8.61-8.40(m,2H),8.20(s,1H),7.83(dd,J=5.5,2.0Hz,1H),7.21(d,J=2.7Hz,1H),7.12(dd,J=8.6,2.7Hz,1H),6.80(d,J=8.6H z,1H),3.90-3.76(m,2H),3.66(s,2H),3.57-3.49(m,1H),3.11-2.80(m,1H),1.87-1.76(m,1H),1.75-1.57(m,2H),1.45-1.27(m,10H).

[1552] LC-MS (Method A): Rt 3.51 min; MS m / z 489.3 / 491.3 = [M+H]+ (99% @ 215 nm)

[1553] The compounds of the following examples (Table 7) were prepared analogously to Example 8 starting from the appropriate aryl acid and by replacing tert-butyl 3-aminopiperidine-1-carboxylate (Example 8, Step 1) with the appropriate commercially available amine.

[1554] Table 7

[1555]

[1556] Example 9

[1557] N-tert-Butyl-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-4-fluoro-benzamide

[1558]

[1559] Step 1: 3-Amino-N-tert-butyl-4-fluoro-benzamide

[1560]

[1561] To a solution of 3-amino-4-fluoro-benzoic acid (205 mg, 1.32 mmol) in DCM (5 mL) were added 2-methylpropan-2-amine (306 μL, 2.91 mmol), DIPEA (0.92 mL, 5.29 mmol) and HATU (553 mg, 1.46 mmol) in sequence, and the mixture was shaken at room temperature overnight. The resulting mixture was washed with 2M HCl (5 mL) and saturated NaHCO 3 solution (5 mL), and the organic phase was separated by passing through a hydrophobic frit and concentrated under vacuum. Purification by flash chromatography on silica gel eluting with 0-100% EtOAc in heptane gave the title compound as an off-white solid.

[1562] 1H NMR (500 MHz, chloroform-d) δ 7.25-7.19 (m, 1H), 6.99-6.95 (m, 2H), 5.82 (s, 1H), 3.82 (s, 2H), 1.45 (s, 9H).

[1563] LC-MS (Method E): Rt 0.95 min; MS m / z 211.1 = [M+H]+ (97% @ 215 nm)

[1564] Step 2: N-tert-Butyl-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-4-fluoro-benzamide

[1565] A suspension of 3-amino-N-tert-butyl-4-fluoro-benzamide (step 1) (105 mg, 0.5 mmol) and 5-chloro-3H-benzofuran-2-one (84 mg, 0.5 mmol) in toluene (3 mL) was heated to 110° C. in a sealed tube for 4 days. After cooling to room temperature, the mixture was concentrated under vacuum and the crude residue was purified by preparative HPLC (acidic pH, early elution method) to give the title compound as an off-white powder.

[1566] 1H NMR(500MHz,MeOD)δ8.28(dd,J=7.4,2.1Hz,1H),7.56-7.49(m,1H),7.24-7.18(m,2H),7. 10(dd,J=8.6,2.6Hz,1H),6.81(d,J=8.6Hz,1H),3.74(s,2H),1.43(s,9H).LC-MS(Method A): Rt 3.18min; MS m / z 379.1 / 381.1=[M+H]+(97%@215nm)

[1567] Example 9.1

[1568] N-tert-Butyl-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-5-methyl-benzamide

[1569]

[1570] The title compound was prepared in analogy to Example 9 by substituting 3-amino-5-methyl-benzoic acid for 3-amino-4-fluoro-benzoic acid (step 1).

[1571] 1H NMR (500MHz, methanol-d4) δ7.67(s,1H),7.50(s,1H),7.28(s,1H),7.19(d,J=2.6Hz,1H),7.0 8(dd,J=8.6,2.6Hz,1H),6.78(d,J=8.6Hz,1H),3.67(s,2H),2.36(s,3H),1.44(s,9H).

[1572] LC-MS (Method A): Rt 3.32 min; MS m / z 375.2 / 377.2 = [M+H]+ (99% @ 215 nm).

[1573] Example 9.2

[1574] 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-(1,1-dimethylpropyl)pyridine-2-carboxamide

[1575]

[1576] Step 1: 4-amino-N-(1,1-dimethylpropyl)pyridine-2-carboxamide

[1577]

[1578] To a mixture of 2-methylbutan-2-amine (1.69 mL, 14.48 mmol), TBTU (1023 mg, 3.19 mmol) and TEA (0.81 mL, 5.79 mmol) was added 4-aminopyridine-2-carboxylic acid (400 mg, 2.9 mmol) and the mixture was stirred at room temperature for 5 hours.

[1579] The resulting mixture was partitioned between water (40 mL) and DCM (40 mL), the phases were separated, the organic portion was concentrated in vacuo, and the crude product was purified by C18 reverse phase chromatography eluting with MeCN in H2O and 0.1% ammonium hydroxide to give the title compound as a white solid.

[1580] 1H NMR(500MHz,DMSO-d6)δ7.97(d,J=5.6Hz,1H),7.92(s,1H),7.17(d,J=2.3Hz,1H),6.56(dd ,J=5.6,2.4Hz,1H),6.32(s,2H),1.74(q,J=7.5Hz,2H),1.31(s,6H),0.80(t,J=7.5Hz,3H).

[1581] LC-MS (Method F): Rt 1.55 min; MS m / z 208.3 = [M+H]+ (100% @ 215 nm)

[1582] Step 2: 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylpropyl)pyridine-2-carboxamide

[1583] The title compound was prepared in analogy to Example 9 (step 2) from 4-amino-N-(1,1-dimethylpropyl)pyridine-2-carboxamide and 5-chloro-3H-benzofuran-2-one.

[1584] 1 H NMR (500MHz, methanol-d4) δ8.42(d,J=5.6Hz,1H),8.13-8.08(m,1H),7.91(dd,J=5.5,2.2Hz,1H),7.19(d,J=2.6Hz,1H),7.0 9(dd,J=8.6,2.6Hz,1H),6.77(d,J=8.6Hz,1H),3.71(s,2H),1.86(q,J=7.5Hz,2H),1.42(s,6H),0.91(t,J=7.5Hz,3H).

[1585] LC-MS (Method A): Rt 3.50 min; MS m / z 376.0 / 378.0 = [M+H]+ (98% @ 215 nm).

[1586] Example 10

[1587] N-tert-Butyl-4-[[2-(5-tert-butyl-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide

[1588]

[1589] Step 1: N-tert-Butyl-4-[[2-(5-tert-butyl-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxamide

[1590]

[1591] The title compound was prepared in analogy to Example 4 from 4-amino-N-tert-butyl-pyridine-2-carboxamide (Example 3, Step 1) and commercially available 2-(5-tert-butyl-2-methoxy-phenyl)acetic acid.

[1592] 1H NMR (500MHz, chloroform-d) δ8.45(br s,1H),8.38(d,J=5.7Hz,1H),8.29(d,J=5.3Hz,1H),8.16(br s,1H),7.57(s,1H),7.34(dd,J=8.6,2.5Hz,1H),7.28(d,J=2.5Hz,1H),6 .92(d,J=8.6Hz,1H),3.98(s,3H),3.75(s,2H),1.48(s,9H),1.30(s,9H).

[1593] LC-MS (Method E): Rt 1.31 min; MS m / z 398.2 = [M+H]+ (85% @ 215 nm)

[1594] Step 2: N-tert-Butyl-4-[[2-(5-tert-butyl-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide

[1595] The title compound was prepared in analogy to Example 3 (step 3) from N-tert-butyl-4-[[2-(5-tert-butyl-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxamide.

[1596] 1H NMR (500MHz, methanol-d4) δ8.42(d,J=5.5Hz,1H),8.09(d,J=1.8Hz,1H),7.91(dd,J=5.5,2.2Hz,1H),7.21(d, J=2.5Hz,1H),7.15(dd,J=8.4,2.5Hz,1H),6.75(d,J=8.4Hz,1H),3.72(s,2H),1.47(s,9H),1.28(s,9H).

[1597] LC-MS (Method A): Rt 3.81 min; MS m / z 384.3 = [M+H]+ (97% @ 215 nm)

[1598] Example 11

[1599] N-tert-Butyl-5-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-2-hydroxy-benzamide

[1600]

[1601] Step 1: 5-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-2-methoxy-benzoic acid methyl ester

[1602]

[1603] A mixture of 5-chloro-3H-benzofuran-2-one (75 mg, 0.44 mmol) and 5-amino-2-methoxy-benzoic acid methyl ester (81 mg, 0.44 mmol) in toluene (2 mL) was stirred in a sealed tube at 100 °C for 2 hours. The resulting mixture was allowed to cool to room temperature, toluene was added, and the suspension was filtered, washed with toluene, and the solid was dried under vacuum to give the title compound as an off-white solid.

[1604] 1H NMR (500MHz, chloroform-d) δ7.79(s,1H),7.77(d,J=2.8Hz,1H),7.72(dd,J=9.0,2.8Hz,1H),7.14(dd,J=8.6,2.6Hz,1 H),7.08(d,J=2.6Hz,1H),6.93(d,J=9.0Hz,1H),6.90(d,J=8.6Hz,1H),3.88(s,3H),3.87(s,3H),3.67(s,2H).

[1605] LC-MS (Method E): Rt 1.05 min; MS m / z 350.0 / 351.9 = [M+H]+ (98% @ 215 nm)

[1606] Step 2: 5-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-2-methoxy-benzoic acid

[1607]

[1608] To a solution of 5-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-2-methoxy-benzoic acid methyl ester (step 1) (105 mg, 0.29 mmol) in 1,4-dioxane (2 mL) was added 2M aqueous LiOH (0.29 mL, 0.59 mmol) and the mixture was shaken at room temperature for 5 hours. Another equivalent of 2M aqueous LiOH (0.15 mL, 0.29 mmol) was added and shaking continued for 1 hour. The dioxane was removed under vacuum and the resulting mixture was acidified to pH 1 with 1M HCl (1 mL). The mixture was extracted with EtOAc (2 x 5 mL), and the combined extracts were dried over Na2SO4 and concentrated under vacuum to give the title compound as an off-white solid.

[1609] 1H NMR(500MHz,DMSO-d6)δ12.60(br s,1H),10.05(s,1H),9.79(s,1H),7.89(d,J=2.7Hz,1H),7.70(dd,J=9.0,2.8Hz,1H),7.19(d,J=2.7Hz, 1H),7.10(dd,J=8.6,2.7Hz,1H),7.07(d,J=9.1Hz,1H),6.80(d,J=8.6Hz,1H),3.77(s,3H),3.57(s,2H).

[1610] LC-MS (Method E): Rt 0.99 min; MS m / z 336.0 / 338.0 = [M+H]+ (99% @ 215 nm)

[1611] Step 3: N-tert-Butyl-5-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-2-methoxy-benzamide

[1612]

[1613] The title compound was prepared in analogy to Example 1, Step 3, from 5-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-2-methoxy-benzoic acid (Step 2).

[1614] 1H NMR (500MHz, DMSO-d6) δ10.13(s,1H),9.80(s,1H),7.90(d,J=2.8Hz,1H),7.85(s,1H),7.74(dd,J=8.9,2.8Hz,1H),7.18(d,J =2.7Hz,1H),7.09(dd,J=8.6,2.7Hz,1H),7.07(d,J=9.0Hz,1H),6.79(d,J=8.6Hz,1H),3.86(s,3H),3.56(s,2H),1.36(s,9H).

[1615] LC-MS (Method A): Rt 3.34 min; MS m / z 391.2 / 393.2 = [M+H]+ (99% @ 215 nm)

[1616] Step 4: N-tert-Butyl-5-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-2-hydroxy-benzamide

[1617] The title compound was prepared in analogy to Example 3, Step 3, from N-tert-butyl-5-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-2-methoxy-benzamide (Step 3).

[1618] 1H NMR(500MHz,DMSO-d6)δ11.50(br.s,1H),9.94(s,1H),9.82(s,1H),8.24(s,1H),7.98-7.88(m,1H),7.60-7.53(m,1H),7 .19(d,J=2.6Hz,1H),7.10(dd,J=8.6,2.7Hz,1H),6.83(d,J=8.7Hz,1H),6.80(d,J=8.6Hz,1H),3.56(s,2H),1.38(s,9H).

[1619] LC-MS (Method A): Rt 3.29 min; MS m / z 377.2 / 379.2 = [M+H]+ (95% @ 215 nm)

[1620] Example 12

[1621] N-tert-Butyl-3-[[2-(5-cyano-2-hydroxy-phenyl)acetyl]amino]benzamide

[1622]

[1623] Step 1: 3-[[2-(5-Bromo-2-methoxy-phenyl)acetyl]amino]-N-tert-butyl-benzamide

[1624]

[1625] The title compound was prepared in analogy to Example 4 from 3-amino-N-tert-butyl-benzamide hydrochloride (Example 2, Step 1b) and 2-(5-bromo-2-methoxy-phenyl)acetic acid.

[1626] 1H NMR(500MHz,DMSO-d6)δ10.19(s,1H),7.89(s,1H),7.74(d,1H),7.70(s,1H),7.44-7.40 (m,3H),7.33(t,J=7.9Hz,1H),6.99-6.92(m,1H),3.76(s,3H),3.65(s,2H),1.36(s,9H).

[1627] LC-MS (Method A): Rt 3.41 min; MS m / z 419.2, 421.2 = [M+H]+ (100% @ 215 nm)

[1628] Step 2-3: N-tert-Butyl-3-[[2-(5-cyano-2-hydroxy-phenyl)acetyl]amino]benzamide

[1629] The title compound was prepared in analogy to Example 6 steps 2 and 3 from 3-[[2-(5-bromo-2-methoxy-phenyl)acetyl]amino]-N-tert-butyl-benzamide (step 1).

[1630] 1H NMR (500MHz, DMSO-d6) δ10.76(br.S,1H),10.23(s,1H),7.89(t,J=1.8Hz,1H),7.80-7.72(m,1H),7.70(s,1H),7.61(d,J=2.1Hz,1H ),7.56(dd,J=8.4,2.2Hz,1H),7.42(d,J=7.8Hz,1H),7.33(m,1H),6.93(d,J=8.4Hz,1H),3.66(s,2H),1.36(s,9H).LC-MS (Method A): Rt 2.66min; MS m / z 352.2=[M+H]+(98%@215nm)

[1631] Example 13

[1632] 3-[2-[[2-(tert-Butylcarbamoyl)-4-pyridinyl]amino]-2-oxo-ethyl]-4-hydroxy-benzoic acid methyl ester

[1633] Step 1: 4-[[2-(5-Bromo-2-hydroxy-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide

[1634]

[1635] A solution of 4-[[2-(5-bromo-2-methoxy-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (Example 6, Step 1) (500 mg, 1.19 mmol) in DCM (25 mL) was treated with 1 M BBr in DCM (3.57 mL, 3.57 mmol) and stirred at room temperature under nitrogen overnight. The resulting mixture was diluted with DCM (50 mL) and washed with water (25 mL x 2). The organic extracts were dried over NaSO and concentrated under vacuum. The crude solid was purified by C18 reverse phase chromatography eluting with 0-100% MeCN in water and 0.1% formic acid to give the title compound as a light yellow solid.

[1636] 1H NMR (500MHz, DMSO-d6) δ10.69(s,1H),9.86(s,1H),8.44(d,J=5.5Hz,1H),8.17(d,J=2.0Hz,1H),8.03(s,1H),7.81(dd, J=5.5,2.2Hz,1H),7.34(d,J=2.5Hz,1H),7.24(dd,J=8.6,2.6Hz,1H),6.76(d,J=8.6Hz,1H),3.67(s,2H),1.40(s,9H).

[1637] LC-MS (Method A): Rt 3.34 min; MS m / z 406.1 / 408.1 = [M+H]+ (90% @ 215 nm)

[1638] Step 2: 3-[2-[[2-(tert-Butylcarbamoyl)-4-pyridinyl]amino]-2-oxo-ethyl]-4-hydroxy-benzoic acid methyl ester

[1639] All reagents were charged to a Coware apparatus (carbon monoxide generation system) according to the following procedure; sodium carbonate (53 mg, 0.50 mmol), 4-[[2-(5-bromo-2-hydroxy-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (step 1) (75 mg, 0.16 mmol), XantPhos Pd-G3 (third generation (G3) Buchwald precatalyst) (8 mg, 0.01 mmol) and toluene (2 mL) were added to chamber A. The reaction mixture was degassed for 5 minutes and MeOH (0.25 mL) was added. Toluene (2 mL) containing formic acid (19 μL, 0.50 mmol) was added to chamber B, followed by methanesulfonyl chloride (39 μL, 0.50 mmol). Both chambers were sealed, and TEA (139 μL, 0.99 mmol) was added to chamber B to generate carbon monoxide. This Coware equipment was heated 75 ℃ for 7 hours, and the mixture that obtains is concentrated under vacuum, is dissolved among the EtOAc (20mL), and washs with water (2x20mL).Under vacuum, concentrate organic moiety, and use preparation HPLC (acidic pH, early stage elution method) purifying.Separate this product fraction and lyophilize, obtain the off-white solid of title compound.

[1640] 1H NMR(500MHz,DMSO-d6)δ10.78(br s,1H),10.55(br s,1H),8.44(d,J=5.5Hz,1H),8.17(d,J=2.0Hz,1H),8.03(s,1H),7.83-7.80(m,2H),7. 74(dd,J=8.5,2.2Hz,1H),6.88(d,J=8.5Hz,1H),3.79(s,3H),3.72(s,2H),1.40(s,9H).

[1641] LC-MS (Method A): Rt 2.94 min; MS m / z 386.3 = [M+H]+ (95% @ 215 nm)

[1642] Example 14

[1643] N-tert-Butyl-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-4-hydroxy-benzamide

[1644]

[1645] Step 1: 3-[[2-(5-Chloro-2-methoxy-phenyl)acetyl]amino]-4-methoxy-benzoic acid methyl ester

[1646]

[1647] The title compound was prepared in analogy to Example 6 (step 1) from 3-amino-4-methoxy-benzoic acid methyl ester and 2-(5-chloro-2-methoxy-phenyl)acetic acid.

[1648] 1H NMR (500MHz, chloroform-d) δ8.98(m,1H),8.28(s,1H),7.77(dd,J=8.6,2.1Hz,1H),7.31(d,J=2.6Hz,1H),7.24( dd,J=8.7,2.6Hz,1H),6.86(dd,J=8.7,6.1Hz,2H),3.90(s,3H),3.90(s,3H),3.86(s,3H),3.71(s,2H).

[1649] LC-MS (Method E): Rt 1.20 min; MS m / z 364.1 / 366.1 = [M+H]+ (72% @ 215 nm)

[1650] Step 2: 3-[[2-(5-Chloro-2-methoxy-phenyl)acetyl]amino]-4-methoxy-benzoic acid

[1651]

[1652] To a solution of 3-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]-4-methoxy-benzoic acid methyl ester (step 1) (301 mg, 0.83 mmol) in 1,4-dioxane (4 mL) was added 2M aqueous LiOH (1.24 mL, 2.48 mmol), the mixture was shaken at room temperature overnight, the dioxane was removed under vacuum, and the resulting mixture was acidified with 1M HCl to pH 1. The mixture was washed with EtOAc (2 x 5 mL), the aqueous phase was concentrated under vacuum, and the resulting solid was sonicated with MeOH (20 mL), the suspension was filtered, washed with additional MeOH (5 mL), and the combined filtrates were concentrated under vacuum to give an off-white solid.

[1653] 1H NMR (500MHz, DMSO-d6) δ9.26 (s, 1H), 8.56 (s, 1H), 7.68 (dd, J = 8.5, 2.1Hz, 1H), 7.35-7.20 ( m,3H),7.13(d,J=8.6Hz,1H),7.03(d,J=8.5Hz,1H),3.92(s,3H),3.82(s,2H),3.80(s,3H).

[1654] LC-MS (Method E): Rt 1.08 min; MS m / z 350.1 / 352.1 = [M+H]+ (85% @ 215 nm)

[1655] Step 3: N-tert-Butyl-3-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]-4-methoxy-benzamide

[1656]

[1657] To a solution of 3-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]-4-methoxy-benzoic acid (step 2) (201 mg, 0.57 mmol) in DMF (2 mL) was added EDCI (110 mg, 0.57 mmol), HOAt (78 mg, 0.57 mmol), DIPEA (251 μL, 1.44 mmol) and 2-methylpropan-2-amine (79 μL, 0.75 mmol). The reaction mixture was shaken at room temperature overnight and then partitioned between DCM (6 mL) and water (6 mL). The organic layer was collected using a hydrophobic frit, concentrated under vacuum, and chromatographed on silica gel eluting with EtOAc in heptane to give the title compound as a colorless glass.

[1658] 1H NMR (500MHz, chloroform-d) δ8.63(d,J=2.2Hz,1H),8.36(s,1H),7.64(dd,J=8.6,2.3Hz,1H),7.30(d,J=2.6Hz,1H),7.25(dd ,J=8.8,2.6Hz,1H),6.87(dd,J=10.9,8.7Hz,2H),5.99(s,1H),3.90(s,3H),3.88(s,3H),3.70(s,2H),1.43(s,9H).

[1659] LC-MS (Method E): Rt 1.20 min; MS m / z 405.1 / 407.1 = [M+H]+ (62% @ 215 nm)

[1660] Step 4: N-tert-Butyl-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-4-hydroxy-benzamide

[1661] The title compound was prepared in analogy to Example 3, Step 3, from N-tert-butyl-3-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]-4-methoxy-benzamide (Step 3).

[1662] 1H NMR (500MHz, methanol-d4) δ8.23(d,J=2.2Hz,1H),7.48(s,1H),7.39(dd,J=8.4,2.2Hz,1H),7.24(d,J=2.6Hz, 1H),7.11(dd,J=8.6,2.6Hz,1H),6.86(d,J=8.4Hz,1H),6.82(d,J=8.6Hz,1H),3.72(s,2H),1.43(s,9H).

[1663] LC-MS (Method A): Rt 2.93 min; MS m / z 377.3 / 379.2 = [M+H]+ (99% @ 215 nm).

[1664] Example 15

[1665] N-tert-Butyl-4-[[2-(2-hydroxy-5-methyl-phenyl)acetyl]amino]pyridine-2-carboxamide

[1666]

[1667] Step 1: N-tert-Butyl-4-[[2-(2-methoxy-5-methyl-phenyl)acetyl]amino]pyridine-2-carboxamide

[1668]

[1669] To a solution of 4-[[2-(5-bromo-2-methoxy-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (Example 6, Step 1) (200 mg, 0.48 mmol) and potassium carbonate (132 mg, 0.95 mmol) in diglyme (5 mL) was added Pd(dppf)2Cl2 (17 mg, 0.02 mmol) followed by the addition of 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane in THF (50%, 0.16 mL, 0.57 mmol). The resulting mixture was degassed with nitrogen for 5 minutes and then stirred at 100° C. in a pressure tube for 16 hours. The resulting mixture was diluted with EtOAc (25 mL) and washed with water (2×25 mL) and brine (2×25 mL). The organic portion was dried over Na 2 SO 4 , concentrated under vacuum, and purified by silica gel chromatography eluting with EtOAc in heptane. The product fractions were concentrated under vacuum to give the title compound as a beige solid.

[1670] 1H NMR (500MHz, DMSO-d6) δ10.65(s,1H),8.43(d,J=5.5Hz,1H),8.18(d,J=2.0Hz,1H),8.03(s,1H),7.81(dd,J=5 .5,2.2Hz,1H),7.06-7.01(m,2H),6.86(d,J=8.2Hz,1H),3.71(s,3H),3.65(s,2H),2.23(s,3H),1.40(s,9H).

[1671] LC-MS (Method E): Rt 1.22 min; MS m / z 356.2 = [M+H]+ (97% @ 215 nm)

[1672] Step 2: N-tert-Butyl-4-[[2-(2-hydroxy-5-methyl-phenyl)acetyl]amino]pyridine-2-carboxamide

[1673] The title compound was prepared in analogy to Example 3 (step 3) from N-tert-butyl-4-[[2-(2-methoxy-5-methyl-phenyl)acetyl]amino]pyridine-2-carboxamide (step 1).

[1674] 1H NMR (500MHz, DMSO-d6) δ10.63(s,1H),9.25(s,1H),8.43(d,J=5.5Hz,1H),8.18(d,J=2.0Hz,1H),8.03(s,1H),7.82(dd,J=5.5 ,2.2Hz,1H),6.94(d,J=1.9Hz,1H),6.87(dd,J=8.1,1.9Hz,1H),6.68(d,J=8.1Hz,1H),3.61(s,2H),2.18(s,3H),1.40(s,9H).

[1675] LC-MS (Method A): Rt 3.19 min; MS m / z 342.3 = [M+H]+ (100% @ 215 nm)

[1676] Example 16

[1677] N-tert-Butyl-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-4-methoxy-benzamide

[1678]

[1679] The title compound was prepared in analogy to Example 11, steps 1-3, from 3-amino-4-methoxy-benzoic acid methyl ester and 5-chloro-3H-benzofuran-2-one.

[1680] 1H NMR (500MHz, methanol-d4) δ8.36(d,J=2.1Hz,1H),7.51(dd,J=8.6,2.2Hz,1H),7.24(d,J=2.6Hz,1H),7.12(dd ,J=8.6,2.6Hz,1H),7.03(d,J=8.6Hz,1H),6.83(d,J=8.6Hz,1H),3.91(s,3H),3.72(s,2H),1.43(s,9H).

[1681] LC-MS (Method A): Rt 3.18 min; MS m / z 391.2 / 393.2 = [M+H]+ (95% @ 215 nm)

[1682] Example 17

[1683] N-tert-Butyl-5-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-2-fluoro-benzamide

[1684]

[1685] Step 1-2: 5-[[2-(5-Chloro-2-methoxy-phenyl)acetyl]amino]-2-fluoro-benzoic acid

[1686]

[1687] The title compound was prepared in analogy to Example 7, steps 1 and 2, from 5-amino-2-fluoro-benzoate and 2-(5-chloro-2-methoxy-phenyl)acetic acid.

[1688] 1H NMR(500MHz,DMSO-d6)δ13.25(br s,1H),10.29(s,1H),8.14(dd,J=6.6,2.8Hz,1H),7.83-7.76(m,1H),7.32-7.28( m,2H),7.25(dd,J=10.5,9.0Hz,1H),7.03-6.98(m,1H),3.77(s,3H),3.65(s,2H).

[1689] LC-MS (Method E): Rt 1.04 min; MS m / z 338.0, 340.1 = [M+H]+ (95% @ 215 nm)

[1690] Step 3: N-tert-Butyl-5-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]-2-fluoro-benzamide

[1691]

[1692] To a mixture of 5-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]-2-fluoro-benzoic acid (step 2) (100 mg, 0.28 mmol), TBTU (108 mg, 0.34 mmol) and TEA (0.08 mL, 0.56 mmol) in DMF (1.5 mL) was added 2-methylpropan-2-amine (35 μL, 0.34 mmol) and the mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated under vacuum and the residue was partitioned between water (10 mL) and DCM (10 mL). The organic phase was separated and concentrated under vacuum and the crude product was purified by silica gel chromatography eluting with EtOAc in heptane to give the title compound as a white solid.

[1693] 1H NMR (500MHz, DMSO-d6) δ10.21(s,1H),7.83(s,1H),7.73(dd,J=6.3,2.7Hz,1H),7.65(ddd,J=8.8,4.4,2.8Hz,1H),7. 32-7.29(m,1H),7.29-7.27(m,1H),7.17(t,J=9.4Hz,1H),7.02-6.98(m,1H),3.76(s,3H),3.63(s,2H),1.34(s,9H).

[1694] LC-MS (Method E): Rt 1.22 min; MS m / z 393.2, 395.1 = [M+H]+ (99% @ 215 nm)

[1695] Step 4: N-tert-Butyl-5-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-2-fluoro-benzamide

[1696] The title compound was prepared in analogy to Example 7, Step 4, from N-tert-butyl-5-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]-2-fluoro-benzamide (Step 3).

[1697] 1H NMR (500MHz, DMSO-d6) δ10.21(s,1H),9.84(s,1H),7.83(s,1H),7.73(dd,J=6.3,2.7Hz,1H),7.66(ddd,J=8.9,4 .4,2.8Hz,1H),7.24-7.13(m,2H),7.11(dd,J=8.6,2.7Hz,1H),6.80(d,J=8.6Hz,1H),3.59(s,2H),1.34(s,9H).

[1698] LC-MS (Method A): Rt 3.30 min; MS m / z 379.2 / 381.1 = [M+H]+ (99% @ 215 nm)

[1699] Example 18

[1700] N-tert-Butyl-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-5-fluoro-benzamide

[1701]

[1702] Step 1: 3-Amino-N-tert-butyl-5-fluoro-benzamide

[1703] The title compound was prepared in analogy to Example 9, Step 1, from 3-amino-5-fluoro-benzoic acid.

[1704] 1H NMR (500 MHz, chloroform-d) δ 6.85-6.80 (m, 1H), 6.69 (dt, J = 9.1, 1.8 Hz, 1H), 6.45 (dt, J = 10.2, 2.2 Hz, 1H), 5.81 (s, 1H), 3.89 (s, 2H), 1.45 (s, 9H).

[1705] LC-MS (Method E): Rt 0.96 min; MS m / z 211.1 = [M+H]+ (100% @ 215 nm)

[1706] Step 2-3: N-tert-Butyl-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-5-fluoro-benzamide

[1707] The title compound was prepared in analogy to Example 3 Steps 2 and 3 from 3-amino-N-tert-butyl-5-fluoro-benzamide (Step 1).

[1708] 1H NMR (500MHz, DMSO-d6) δ10.41(s,1H),9.81(s,1H),7.81(s,1H),7.75(dt,J=11.2,2.0Hz,1H),7.66(s,1H),7.32- 7.24(m,1H),7.20(d,J=2.7Hz,1H),7.11(dd,J=8.6,2.7Hz,1H),6.80(d,J=8.6Hz,1H),3.62(s,2H),1.36(s,9H).

[1709] LC-MS (Method A): Rt 3.34 min; MS m / z 379.1 / 381.1 = [M+H]+ (97% @ 215 nm)

[1710] Example 19

[1711] N-tert-Butyl-4-[[2-(3-hydroxy-2-pyridinyl)acetyl]amino]pyridine-2-carboxamide

[1712]

[1713] Step 1: N-tert-Butyl-4-[[2-(3-methoxy-2-pyridinyl)acetyl]amino]pyridine-2-carboxamide

[1714]

[1715] The title compound was prepared in analogy to Example 5 from 4-amino-N-tert-butyl-pyridine-2-carboxamide (Example 3, Step 1) and 2-(3-methoxy-2-pyridyl)acetic acid.

[1716] 1H NMR (500MHz, DMSO-d6) δ10.75(s,1H),8.44(d,J=5.5Hz,1H),8.18(d,J=2.1Hz,1H),8.07(dd,J=4.7,1.3Hz,1H),8.03(s,1H),7.80(d d,J=5.5,2.2Hz,1H),7.42(dd,J=8.3,1.2Hz,1H),7.30(dd,J=8.3,4.7Hz,1H),3.88(s,2H),3.81(s,3H),1.40(s,9H).LC-MS (Method A): Rt 2.11min; MS m / z 343.2=[M+H]+(100%@215nm)

[1717] Step 2: N-tert-Butyl-4-[[2-(3-hydroxy-2-pyridinyl)acetyl]amino]pyridine-2-carboxamide

[1718] The title compound was prepared in analogy to Example 7, Step 4, from N-tert-butyl-4-[[2-(3-methoxy-2-pyridinyl)acetyl]amino]pyridine-2-carboxamide (Step 1).

[1719] 1H NMR(500MHz,DMSO-d6)δ10.73(s,1H),10.01(br s,1H),8.44(d,J=5.5Hz,1H),8.18(d,J=2.1Hz,1H),8.03(s,1H),7.95(dd,J=4.4,1 .6Hz,1H),7.81(dd,J=5.5,2.2Hz,1H),7.20-7.09(m,2H),3.84(s,2H),1.40(s,9H).

[1720] LC-MS (Method A): Rt 1.60 min; MS m / z 329.1 = [M+H]+ (98% @ 215 nm)

[1721] Example 20

[1722] N-tert-Butyl-4-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide

[1723]

[1724] Step 1: N-tert-Butyl-4-[[2-(5-fluoro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxamide

[1725]

[1726] A solution of 2-(5-fluoro-2-methoxy-phenyl)acetic acid (57 mg, 0.31 mmol) in thionyl chloride (246 μL, 2.79 mmol) was heated at 70°C for 1 hour. Excess thionyl chloride was removed under vacuum and azeotroped with DCM. The residue was added to a mixture of 4-amino-N-tert-butyl-pyridine-2-carboxamide (Example 3, Step 1) (60 mg, 0.31 mmol) and DIPEA (65 μL, 0.37 mmol) in DCM (30 mL), and the mixture was stirred at room temperature. After 1 hour, the mixture was partitioned between water (25 mL) and DCM (25 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by silica gel chromatography, eluting with EtOAc in heptane, and the product fractions were freeze-dried to give the title compound as a white solid.

[1727] 1H NMR (500MHz, DMSO-d6) δ10.68(s,1H),8.44(d,J=5.5Hz,1H),8.17(d,J=2.0Hz,1H),8.03(s,1H),7.81(dd,J=5.5,2.2Hz,1H), 7.12(dd,J=9.2,3.2Hz,1H),7.08(td,J=8.6,3.2Hz,1H),6.98(dd,J=9.0,4.6Hz,1H),3.74(s,3H),3.71(s,2H),1.40(s,9H).

[1728] LC-MS (Method E): Rt 1.16 min; MS m / z 360.1 = [M+H]+ (98% @ 215 nm)

[1729] Step 2: N-tert-Butyl-4-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide

[1730] To a solution of N-tert-butyl-4-[[2-(5-fluoro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxamide (step 1) (54.1 mg, 0.15 mmol) in DCM (1.3 mL) was slowly added 1 M BBr in DCM (452 ​​μL, 0.45 mmol) at room temperature. The reaction was stirred at room temperature for 2.5 hours and then concentrated under vacuum. The residue was partitioned between H O (10 mL) and EtOAc (10 mL), the organic portion separated, and concentrated under vacuum. The crude product was purified by preparative HPLC (acidic pH, early elution method) to give the title compound as a white solid.

[1731] 1H NMR (500MHz, DMSO-d6) δ10.67(s,1H),9.52(s,1H),8.44(d,J=5.5Hz,1H),8.18(d,J=2.1Hz,1H),8.03(s,1H),7.82(dd,J=5.5 ,2.2Hz,1H),7.01(dd,J=9.4,3.2Hz,1H),6.91(td,J=8.6,3.2Hz,1H),6.77(dd,J=8.8,4.9Hz,1H),3.67(s,2H),1.40(s,9H).

[1732] LC-MS (Method A): Rt 3.01 min; MS m / z 346.1 = [M+H]+ (98% @ 215 nm)

[1733] Example 21

[1734] Racemic N-tert-butyl-4-[[-indane-1-carbonyl]amino]pyridine-2-carboxamide

[1735]

[1736] A mixture of 4-amino-N-tert-butyl-pyridine-2-carboxamide (Example 3, Step 1) (100 mg, 0.52 mmol) and indane-1-carboxylic acid (84 mg, 0.52 mmol) in 1,4-dioxane (1 mL) was stirred with 50% The solution was treated with EtOAc (616 μL, 1.03 mmol) and TEA (181 μL, 1.03 mmol) and stirred at room temperature for 1.5 hours. The resulting mixture was diluted with EtOAc (20 mL) and water (20 mL), the organic portion was separated, dried over Na SO , filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography, eluting with EtOAc in heptane to give racemic N-tert-butyl-4-[[-indane-1-carbonyl] amino] pyridine-2-carboxamide.

[1737] Example 21a: N-tert-butyl-4-[[(1R) or (1S)-indane-1-carbonyl]amino]pyridine-2-carboxamide and Example 21b: N-tert-butyl-4-[[(1R) or (1S)-indane-1-carbonyl]amino]pyridine-2-carboxamide

[1738]

[1739] Chiral separation of racemic N-tert-butyl-4-[[-indane-1-carbonyl]amino]pyridine-2-carboxamide was performed using supercritical fluid chromatography (SCFC) on a chiral column (25% IPA:75% CO2 on a Chiralcel OD-H 25 cm column at 15 ml / min) to afford the individual enantiomers:

[1740] Example 21a: First eluting peak: N-tert-butyl-4-[[(1R)-indane-1-carbonyl]amino]pyridine-2-carboxamide or N-tert-butyl-4-[[(1S)-indane-1-carbonyl]amino]pyridine-2-carboxamide

[1741] SFC retention time: 5.46 min, MS m / z 338.3 = [M+H]+ (100% @ 215 nm)

[1742] 1H NMR (500MHz, DMSO-d6) δ10.85(s,1H),8.46(d,J=5.5Hz,1H),8.23(d,J=2.0Hz,1H),8.03(s,1H),7.87(dd,J=5.5,2.2Hz,1H),7.32(d,J=7.4 Hz,1H),7.28(d,J=7.3Hz,1H),7.20(m,1H),7.16(m,1H),4.16(m,1H), 3.11-3.03(m,1H),2.95-2.87(m,1H),2.40-2.27(m,2H),1.40(s,9H).

[1743] ee 100%

[1744] Example 21b: Second eluting peak: N-tert-butyl-4-[[(1R)-indane-1-carbonyl]amino]pyridine-2-carboxamide or N-tert-butyl-4-[[(1S)-indane-1-carbonyl]amino]pyridine-2-carboxamide

[1745] SFC retention time: 8.00 min, MS m / z 338.3 = [M+H]+ (91% @ 215 nm)

[1746] 1H NMR (500MHz, DMSO-d6) δ10.85(s,1H),8.46(d,J=5.5Hz,1H),8.23(d,J=2.0Hz,1H),8.03(s,1H),7.87(dd,J=5.5,2.2Hz,1H),7.32(d,J=7.3 Hz,1H),7.28(d,J=7.3Hz,1H),7.20(m,1H),7.16(m,1H),4.16(m,1H), 3.11-3.03(m,1H),2.95-2.87(m,1H),2.39-2.27(m,2H),1.40(s,9H).

[1747] ee 88%

[1748] Example 22

[1749] N-tert-Butyl-4-[(2-phenylacetyl)amino]pyridine-2-carboxamide

[1750]

[1751] To a mixture of 4-amino-N-tert-butyl-pyridine-2-carboxamide (Example 3, Step 1) (50 mg, 0.26 mmol) in DCM (2.59 mL) was added TEA (113 μL, 0.65 mmol) and 2-phenylacetyl chloride (41 μL, 0.31 mmol), and the mixture was stirred for 16 hours. The resulting mixture was diluted with DCM (10 mL) and washed with water (2 x 10 mL) and then with a saturated aqueous solution of NaHCO (10 mL). The organic layer was separated, dried over NaSO, filtered, and concentrated under vacuum. The crude residue was dissolved in a mixture of DMSO:MeCN (800 μL, 1:1), filtered, and purified by preparative HPLC (acidic pH, early elution method). The product fractions were combined, the pH of the mixture was adjusted to pH 7 using a saturated aqueous solution of NaHCO (20 mL), and extracted with DCM (3 x 20 mL). The combined organic extracts were dried over Na 2 SO 4 , filtered, and concentrated in vacuo to give the title compound as an off-white solid.

[1752] 1H NMR(500MHz,DMSO-d6)δ10.75(s,1H),8.44(d,J=5.5Hz,1H),8.18(d,J=1.9Hz,1H),8.02(s,1H), 7.81(dd,J=5.5,2.2Hz,1H),7.33(d,J=4.4Hz,4H),7.29-7.23(m,1H),3.71(s,2H),1.39(s,9H).

[1753] LC-MS (Method A): Rt 3.23 min; MS m / z 312.2 = [M+H]+ (100% @ 215 nm)

[1754] Example 22.1

[1755] 4-(3,3-Dimethylbutyrylamino)-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide

[1756]

[1757] The title compound was prepared in analogy to Example 22 from 4-amino-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Example 78, Step 1) and 3,3-dimethylbutyryl chloride.

[1758] 1H NMR (500MHz, DMSO-d6) δ10.41(s,1H),8.45(d,J=5.5Hz,1H),8.31(s,1H),8.22(d,J=2.1 Hz,1H),7.81(dd,J=5.5,2.2Hz,1H),3.21(s,1H),2.25(s,2H),1.64(s,6H),1.02(s,9H).

[1759] LC-MS (Method A): Rt 3.22 min; MS m / z 302.2 = [M+H]+ (100% @ 215 nm)

[1760] Example 22.2

[1761] 4-[(2-Cyclopentylacetyl)amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide

[1762]

[1763] The title compound was prepared in analogy to Example 22 from 4-amino-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Example 78, Step 1) and 2-cyclopentylacetyl chloride.

[1764] 1H NMR (500MHz, DMSO-d6) δ10.47(s,1H),8.45(d,J=5.5Hz,1H),8.31(s,1H),8.21(d,J=2.1Hz,1H),7.81(dd,J=5.5,2.2Hz,1H),3.21(s ,1H),2.39-2.35(m,2H),2.28-2.19(m,1H),1.80-1.72(m,2H),1.64(s,6H),1.63-1.56(m,2H),1.56-1.47(m,2H),1.23-1.13(m,2H).

[1765] LC-MS (Method A): Rt 3.33 min; MS m / z 314.2 = [M+H]+ (97% @ 215 nm)

[1766] Example 22.3

[1767] 4-[[2-(3-chloro-4-pyridinyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide

[1768]

[1769] The title compound was prepared in analogy to Example 22 from 4-amino-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Example 78, Step 1) and 2-(3-chloro-4-pyridyl)acetic acid hydrochloride.

[1770] 1H NMR (500MHz, DMSO-d6) δ10.95(s,1H),8.63(s,1H),8.49(t,J=5.3Hz,2H),8.32(s,1H),8.19(d,J=2. 0Hz,1H),7.81(dd,J=5.5,2.2Hz,1H),7.51(d,J=4.9Hz,1H),3.99(s,2H),3.21(s,1H),1.64(s,6H).

[1771] LC-MS (Method A): Rt 2.53 min; MS m / z 357.1 / 359.1 = [M+H]+ (100% @ 215 nm)

[1772] Example 23

[1773] 4-[[2-(4-Chlorophenyl)acetyl]amino]-N-(1-cyanocyclopropyl)pyridine-2-carboxamide

[1774]

[1775] Step 1: 4-amino-N-(1-cyanocyclopropyl)pyridine-2-carboxamide

[1776]

[1777] To a mixture of 4-aminopyridine-2-carboxylic acid (1 g, 7.24 mmol), TBTU (2.79 g, 8.69 mmol) and TEA (1.21 mL, 8.69 mmol) in DMF (8 mL) was added 1-aminocyclopropanecarbonitrile (22.82 mL, 8.69 mmol) and the mixture was stirred for 2 days at 40° C. The resulting mixture was concentrated under vacuum and the crude residue was dissolved in EtOAc (15 mL) and the mixture was washed with water (20 mL), NaHCO (15 mL), dried over Na SO and concentrated under vacuum to give the title compound as an orange solid.

[1778] 1H NMR (500MHz, DMSO-d6) δ9.41(s,1H),8.01(d,J=5.6Hz,1H),7.22(d,J=2.3Hz,1H),6.62( dd,J=5.6,2.4Hz,1H),6.37(s,2H),1.51-1.47(m,2H),1.31-1.27(m,2H).LC-MS(Method E): Rt 0.25min; MS m / z 203.1=[M+H]+

[1779] Step 2: 4-[[2-(4-chlorophenyl)acetyl]amino]-N-(1-cyanocyclopropyl)pyridine-2-carboxamide

[1780] To a solution of 4-amino-N-(1-cyanocyclopropyl)pyridine-2-carboxamide (step 1) (100 mg, 0.45 mmol), 2-(4-chlorophenyl)acetic acid (83.52 mg, 0.49 mmol) and TEA (155 μL, 0.89 mmol) in 1,4-dioxane (2 mL) was slowly added 50% To the 4-nitro-2-oxo-2-oxo-4 ...

[1781] 1H NMR (500MHz, DMSO-d6) δ=10.80(s,1H),9.65(s,1H),8.49(d,J=5.5,1H),8.21(d,J=1.9,1H),7 .86(dd,J=5.5,2.2,1H),7.41-7.34(m,4H),3.74(s,2H),1.55-1.51(m,2H),1.34-1.30(m,2H).

[1782] LC-MS (Method A): Rt 2.92 min; MS m / z 355.3 = [M+H]+ (98% @ 215 nm)

[1783] The compounds of the examples listed below (Table 8) were prepared in analogy to Example 23 by replacing 1-aminocyclopropane (step 1) with a suitable amine and by replacing 2-(4-chlorophenyl)acetic acid (step 2) with a suitable commercially available acid.

[1784] Table 8

[1785]

[1786]

[1787]

[1788]

[1789] Example 24

[1790] 4-[[2-(2-chloro-5-methoxy-phenyl)acetyl]amino]-N-(1-cyanocyclopropyl)pyridine-2-carboxamide

[1791]

[1792] Steps 1 and 2: N-(1-cyanocyclopropyl)-4-[[2-(3-methoxyphenyl)acetyl]amino]pyridine-2-carboxamide

[1793] The title compound was prepared in analogy to Example 23 by substituting 2-(3-methoxyphenyl)acetic acid for 2-(4-chlorophenyl)acetic acid (step 2).

[1794] 1H NMR (500MHz, DMSO-d6) δ=10.77(s,1H),9.65(s,1H),8.49(d,J=5.5,1H),8.21(d,J=2.1,1H),7.86(dd,J=5.5,2.2,1H),7.24( t,J=7.8,1H),6.92-6.88(m,2H),6.83(dd,J=8.0,2.1,1H),3.74(s,3H),3.68,(s,2H),1.55-1.51(m,2H),1.34-1.30(m,2H).

[1795] LC-MS (Method E): Rt 1.03 min; MS m / z 351.0 = [M+H]+ (97% @ 215 nm)

[1796] Step 2: 4-[[2-(2-chloro-5-methoxy-phenyl)acetyl]amino]-N-(1-cyanocyclopropyl)pyridine-2-carboxamide

[1797] To a solution of N-(1-cyanocyclopropyl)-4-[[2-(3-methoxyphenyl)acetyl]amino]pyridine-2-carboxamide (step 1) (81 mg, 0.23 mmol) in MeCN (33.7 mL) was added NCS (77 mg, 0.58 mmol) and the mixture was stirred at 60° C. for 16 h. The resulting mixture was concentrated under vacuum to give a crude dry residue which was dissolved in EtOAc (10 mL), washed with water (10 mL), NaHCO3 (10 ml) and concentrated under vacuum and purified by preparative HPLC (acidic pH, standard elution method) to give the title compound as an off-white solid.

[1798] 1H NMR (500MHz, DMSO-d6) δ10.84(s,1H),9.66(s,1H),8.50(d,J=5.5Hz,1H),8.21(d,J=2.0Hz,1H),7.86(dd,J=5.5,2.2Hz,1H),7.35(d ,J=8.8Hz,1H),7.04(d,J=3.1Hz,1H),6.90(dd,J=8.8,3.1)Hz,1H),3.87(s,2H),3.76(s,3H),1.55-1.51(m,2H),1.35-1.30(m,2H).

[1799] LC-MS (Method A): Rt 2.84 min; MS m / z 385.2 / 387.2 = [M+H]+ (100% @ 215 nm)

[1800] Example 25

[1801] N-(3-Bicyclo[1.1.1]pentyl)-4-[[2-(5-tert-butyl-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide

[1802] Step 1: 4-[[2-(5-tert-Butyl-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid methyl ester

[1803]

[1804] 2-(5-tert-Butyl-2-methoxy-phenyl)acetic acid (700 mg, 3.15 mmol) was dissolved in thionyl chloride (2.5 mL, 28.37 mmol) and stirred at 70° C. for 30 minutes. The resulting mixture was concentrated under vacuum and azeotroped with toluene (3×5 mL). The residue was dissolved in DCM (15 mL) to form an acid chloride solution and added to a stirred solution of methyl 4-aminopyridine-2-carboxylate (527 mg, 3.46 mmol) in DCM (15 mL). After stirring for 10 minutes, the mixture was concentrated under vacuum to give a brown gum which was chromatographed on silica gel eluting with 25-100% EtOAc in heptane to give the title compound as a dark yellow glass.

[1805] 1H NMR (250MHz, DMSO-d6) δ10.68(s,1H),8.54(d,J=5.5Hz,1H),8.31(d,J=2.0Hz,1H),7.77(dd,J=5.5,2. 1Hz,1H),7.29-7.20(m,2H),6.89(d,J=9.3Hz,1H),3.86(s,3H),3.72(s,3H),3.68(s,2H),1.26(s,9H).

[1806] LC-MS (Method E): Rt 1.17 min; MS m / z 357 = [M+H] +

[1807] Step 2: 4-[[2-(5-tert-Butyl-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid

[1808]

[1809] To a solution of methyl 4-[[2-(5-tert-butyl-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxylate (step 1) (594 mg, 1.55 mmol) in THF (12 mL) was added 1 M sodium hydroxide solution (1.86 mL, 1.86 mmol), the mixture was stirred for 30 minutes, and the pH of the resulting mixture was adjusted to pH 4 by the addition of hydrochloric acid. The mixture was partitioned between EtOAc (20 mL) and water (20 mL), at which point a precipitate formed in the organic layer. The organic suspension was washed with water (20 mL), brine (20 mL), filtered through a phase separator, and dried to give the title compound as a fine powder.

[1810] 1H NMR (250MHz, DMSO-d6) δ10.70(s,1H),8.52(d,J=5.6Hz,1H),8.28(d,J=1.9Hz,1H),7.80(dd,J=5 .6,2.2Hz,1H),7.29-7.20(m,2H),6.89(d,J=9.4Hz,1H),3.72(s,3H),3.69(s,2H),1.26(s,9H).

[1811] LC-MS (Method E): Rt 0.98 min; MS m / z 343 = [M+H] +

[1812] Step 3: 4-[[2-(5-tert-Butyl-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid

[1813]

[1814] An ice-cold suspension of 4-[[2-(5-tert-butyl-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (step 2) (330 mg, 0.93 mmol) in DCM (9 mL) was treated with 1 M BBr in DCM (1.85 mL, 1.85 mmol) and stirred for 70 minutes. The reaction was quenched with methanol (1 mL) and the mixture was partitioned between EtOAc (20 mL) and water (20 mL), resulting in the formation of a fine white precipitate, which was filtered and dried to give the title compound as a solid.

[1815] 1H NMR (250MHz, DMSO-d6) δ11.51(s,1H),8.65(d,J=6.4Hz,1H),8.51(d,J=2.2Hz,1H),8.14(dd,J=6.4,2.3Hz ,1H),7.18(d,J=2.4Hz,1H),7.10(dd,J=8.4,2.5Hz,1H),6.74(d,J=8.4Hz,1H),3.75(s,2H),1.23(s,9H).

[1816] LC-MS (Method E): Rt 0.97 min; MS m / z 329 = [M+H]+ (91% @ 215 nm)

[1817] Step 4: N-(3-Bicyclo[1.1.1]pentyl)-4-[[2-(5-tert-butyl-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide

[1818] To a suspension of 4-[[2-(5-tert-butyl-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (step 3) (25 mg, 0.08 mmol) in DMF (0.5 mL) was added bicyclo[1.1.1]pentan-3-amine hydrochloride (11 mg, 0.09 mmol), DIPEA (0.05 mL, 0.3 mmol), and HATU (43 mg, 0.11 mmol). After stirring at room temperature for 18 hours, the mixture was partitioned between EtOAc (10 mL) and water (10 mL). The aqueous portion was extracted with EtOAc (2 x 20 mL), and the combined organic extracts were washed with water (20 mL), brine (20 mL), dried over NaSO, and concentrated under vacuum. The crude residue was purified by C18 reverse phase chromatography, eluting with 45-65% MeCN in water and 0.1% formic acid to give the title compound as a white powder.

[1819] 1H NMR (500MHz, DMSO-d6) δ10.70(s,1H),9.28(s,1H),9.07(s,1H),8.44(d,J=5.5Hz,1H),8.16(d,J=2.1Hz,1H),7.84(dd,J=5.5,2.2Hz ,1H),7.16(d,J=2.5Hz,1H),7.08(dd,J=8.4,2.5Hz,1H),6.72(d,J=8.4Hz,1H),3.65(s,2H),2.44(s,1H),2.09(s,6H),1.23(s,9H).

[1820] LC-MS (Method A): Rt 3.71 min; MS m / z 394 = [M+H] +

[1821] Example 25.1

[1822] 4-[[2-(5-tert-Butyl-2-hydroxy-phenyl)acetyl]amino]-N-(4-cyanotetrahydropyran-4-yl)pyridine-2-carboxamide

[1823]

[1824] The title compound was prepared in analogy to Example 25, Step 4, from 4-[[2-(5-tert-butyl-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 25, Step 3) and 4-aminotetrahydropyran-4-carbonitrile.

[1825] 1H NMR (500MHz, methanol-d4) δ8.47(d,J=5.5Hz,1H),8.17(d,J=1.8Hz,1H),7.94(dd,J=5.5,2.2Hz,1H),7.22(d,J=2.4Hz,1H),7.15(dd,J=8.4,2.5Hz ,1H),6.75(d,J=8.4Hz,1H),3.96(dt,J=12.5,4.0Hz,2H),3.80-3.74( m,2H),3.72(s,2H),2.49-2.43(m,2H),2.14-2.07(m,2H),1.28(s,9H).

[1826] LC-MS (Method A): Rt 3.22 min; MS m / z 437 = [M+H]+ (100% @ 215 nm)

[1827] Example 26

[1828] N-tert-Butyl-4-[[2-(2-hydroxy-5-phenyl-phenyl)acetyl]amino]pyridine-2-carboxamide

[1829]

[1830] Step 1: N-tert-Butyl-4-[[2-(2-methoxy-5-phenyl-phenyl)acetyl]amino]pyridine-2-carboxamide

[1831]

[1832] The pressure tube was filled with 4-[[2-(5-bromo-2-methoxy-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (Example 6, Step 1) (250 mg, 0.59 mmol), tripotassium phosphate (379 mg, 1.78 mmol), phenylboronic acid (80 mg, 0.65 mmol) in 1,4-dioxane (4 mL), and the suspension was degassed with nitrogen. Bis[3-(diphenylphosphino)cyclopenta-2,4-dien-1-yl]iron; dichloromethane; dichloropalladium (24 mg, 0.03 mmol) were added under a nitrogen atmosphere, and the sealed tube was heated to 80 ° C for 23 hours. The reaction mixture was concentrated under vacuum, and the crude residue was redissolved in EtOAc and the mixture was passed through Filtration through (filtrate) and concentration of the filtrate in vacuo afforded a brown oil which was purified by silica gel chromatography eluting with 25-100% EtOAc in heptane to afford the title compound as a white solid.

[1833] 1H NMR (250 MHz, chloroform-d) δ 8.38 (d, J = 5.6 Hz, 1H), 8.26-8.14 (m, 2H), 7.97 (s, 1H), 7.59-7.50 (m, 5H), 7.46-7.37 (m, 2H), 7.37-7.28 (m, 1H), 7.05 (d, J = 8.3 Hz, 1H), 4.01 (s, 3H), 3.80 (s, 2H), 1.47 (s, 9H).

[1834] LC-MS (Method E): Rt 1.29 min; MS m / z 418 = [M+H] +

[1835] Step 2: N-tert-Butyl-4-[[2-(2-hydroxy-5-phenyl-phenyl)acetyl]amino]pyridine-2-carboxamide

[1836] To an ice-cold solution of N-tert-butyl-4-[[2-(2-methoxy-5-phenyl-phenyl)acetyl]amino]pyridine-2-carboxamide (step 1) (160 mg, 0.38 mmol) in DCM (2.5 mL) was added 1 M BBr in DCM (1.92 mL, 1.92 mmol) dropwise. After stirring for 10 minutes, the reaction was quenched by the addition of methanol (1 mL). The resulting mixture was concentrated under vacuum, and the residue was partitioned between EtOAc (20 mL) and water (20 mL). The organic layer was separated, and the aqueous portion was extracted again with EtOAc (2 x 20 mL). The combined organic extracts were washed with water (20 mL), brine (20 mL), dried over NaSO, and concentrated under vacuum to give the title compound as an amber glass.

[1837] 1H NMR (500 MHz, CHLOROFORM-d) δ 10.14-9.39 (m, 2H), 8.32 (d, J = 5.6 Hz, 1H), 8.16 (s, 1H), 8.04 (dd, J = 5.6, 1.9 Hz, 1H), 7.94 (s, 1H), 7.42 (d, J = 7.3 Hz, 2H), 7.39 (d, J = 2.1 Hz, 1H), 7.36-7.29 (m, 3H), 7.25 (t, J = 7.3 Hz, 1H), 7.00 (d, J = 8.3 Hz, 1H), 3.83 (s, 2H), 1.49 (s, 9H). LC-MS (Method A): Rt 3.64 min; MS m / z 404 = [M+H]+

[1838] Example 27

[1839] N-tert-Butyl-4-[[2-[5-chloro-2-hydroxy-4-(pyrrolidin-1-ylmethyl)phenyl]acetyl]amino]pyridine-2-carboxamide

[1840] Step 1: 2-(4-Bromo-5-chloro-2-methoxy-phenyl)acetic acid

[1841]

[1842] 2-(4-Bromo-2-methoxy-phenyl)acetic acid (2 g, 8.16 mmol) and NCS (1.14 g, 8.57 mmol) were dissolved in MeCN (40.8 mL) and stirred at 50° C. for 22 hours. The resulting mixture was concentrated under vacuum, and the residue was purified by silica gel chromatography, eluting with 20-100% EtOAc in heptane. The product was further purified by dissolving in EtOAc (100 mL) and extracting into saturated aqueous NaHCO (3×100 mL). The combined aqueous extracts were acidified with 1 M HCl and extracted with EtOAc (3×150 mL). The combined organic extracts were dried over NaSO, filtered, and concentrated under vacuum to afford the title compound as a colorless solid.

[1843] 1H NMR (250MHz, DMSO-d6) δ11.97(s,1H),7.46(s,1H),7.34(s,1H),3.79(s,3H),3.50(s,2H).

[1844] LC-MS (Method E): Rt 1.07 min; MS m / z not observed = [M+H]+

[1845] Step 2: 4-[[2-(4-Bromo-5-chloro-2-methoxy-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide

[1846]

[1847] The title compound was prepared in analogy to Example 3.5b Step 1 from 4-amino-N-tert-butyl-pyridine-2-carboxamide and 2-(4-bromo-5-chloro-2-methoxy-phenyl)acetic acid (Step 1).

[1848] 1H NMR(250MHz,DMSO-d6)δ10.70(s,1H),8.44(d,J=5.6Hz,1H),8.16(d,J=1.9Hz,1H),8.03(s,1H) ,7.79(dd,J=5.5,2.2Hz,1H),7.51(s,1H),7.36(s,1H),3.78(s,3H),3.71(s,2H),1.40(s,9H).

[1849] LC-MS (Method E): Rt 1.28 min; MS m / z 454 = [M+H] + 97% @ 215 nm)

[1850] Step 3: N-tert-butyl-4-[[2-[5-chloro-2-methoxy-4-(pyrrolidin-1-ylmethyl)phenyl]acetyl]amino]pyridine-2-carboxamide

[1851]

[1852] A tube was charged with 4-[[2-(4-bromo-5-chloro-2-methoxy-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (Step 2) (100 mg, 0.21 mmol), potassium trifluoropyrrolin-1-ylmethyl)borate (45 mg, 0.23 mmol), Xphos (6 mg, 0.01 mmol), Pd(Oac)2 (1.4 mg, 0.01 mmol), and Cs2CO3 (209 mg, 0.64 mmol) and placed under a nitrogen atmosphere. THF:water (1 mL of a 10:1 mixture) was added, and the mixture was heated at 80°C for 20 hours. The resulting mixture was diluted with water (2 mL) and extracted with DCM (3 x 10 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography eluting with 0-100% EtOAc in heptane to provide the title compound as a colorless solid.

[1853] 1H NMR (500MHz, DMSO-d6) δ10.68(s,1H),8.44(d,J=5.5Hz,1H),8.16(dd,J=6.4,2.0Hz,1H),8.03(s,1H),7.80( dd,J=5.5,2.2Hz,1H),7.29(s,1H),7.07(s,1H),3.75(s,3H),3.69(s,2H),3.65(s,2H),2.51-2.49(obscured m,4H),1.73-1.71(m,4H),1.40(s,9H).

[1854] LC-MS (Method E): Rt 1.04 min; MS m / z 459 / 461 = [M+H]+ (78% @ 215 nm)

[1855] Step 4: N-tert-butyl-4-[[2-[5-chloro-2-hydroxy-4-(pyrrolidin-1-ylmethyl)phenyl]acetyl]amino]pyridine-2-carboxamide

[1856] The title compound was prepared in analogy to Example 26, Step 2, from N-tert-butyl-4-[[2-[5-chloro-2-methoxy-4-(pyrrolidin-1-ylmethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Step 3).

[1857] 1H NMR (500MHz, DMSO-d6) δ10.72(s,1H),9.70(s,1H),8.44(d,J=5.5Hz,1H),8.17(d,J=2.0Hz,1H),8.03(s,1 H),7.81(dd,J=5.5,2.2Hz,1H),7.18(s,1H),6.97(s,1H),3.64(s,2H),3.57(s,2H),2.51-2.49(obscured m,4H),1.72-1.70(m,4H),1.40(s,9H).

[1858] LC-MS (Method A): Rt 2.08 min; MS m / z 445.3 / 447.3 = [M+H]+ (99% @ 215 nm)

[1859] The compounds of the following examples (Table 9) were prepared in analogy to Example 27 by substituting the appropriate boranuide for potassium trifluoropyrrolidine-1-ylmethyl)borate (Step 3).

[1860] Table 9

[1861]

[1862]

[1863] Example 28

[1864] N-tert-Butyl-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-5-fluoro-pyridine-2-carboxamide

[1865]

[1866] Step 1: N-(2-chloro-5-fluoro-4-pyridinyl)-2-(5-chloro-2-methoxy-phenyl)acetamide

[1867]

[1868] Thionyl chloride (6.01mL, 68.24mmol) solution containing 2-(5-chloro-2-methoxy-phenyl) acetic acid (753mg, 3.75mmol) was stirred at 70 ℃ for 1 hour, the mixture obtained was concentrated to dryness, and with toluene (2x10mL) azeotrope.Crude residue is dissolved in DMF (10mL), and dropwise processed with DMF (3mL) solution containing 2-chloro-5-fluoro-pyridine-4-amine (500mg, 3.41mmol), then processed with DIPEA (1.49mL, 8.53mmol).After room temperature stirred under inert atmosphere for 16 hours, mixture was diluted with EtOAc (100mL), and washed with water (2x50mL) and salt solution (2x50mL). The organic portion was dried over Na2SO4 and concentrated in vacuo, and the crude material was purified by C18 reverse phase chromatography, eluting with 0-100% MeCN in water with a 0.1% formic acid modifier, to afford the title compound as a light yellow solid.

[1869] 1H NMR(250MHz,DMSO-d6)δ10.58(s,1H),8.41(d,J=2.7Hz,1H),8.24(d,J=5.6 Hz,1H),7.33-7.28(m,2H),7.01(d,J=9.5Hz,1H),3.83(s,2H),3.75(s,3H).

[1870] LC-MS (Method E): Rt 1.25 min; MS m / z 328.9, 330.9 = [M+H] +

[1871] Step 2: N-tert-Butyl-4-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]-5-fluoro-pyridine-2-carboxamide

[1872]

[1873] All reagents were charged to a Coware apparatus (carbon monoxide generation system) according to the following procedure; N-(2-chloro-5-fluoro-4-pyridyl)-2-(5-chloro-2-methoxy-phenyl)acetamide (step 1) (170 mg, 0.52 mmol), sodium carbonate (164 mg, 1.55 mmol), XantPhos Pd-G3 (third generation (G3) Buchwald precatalyst) (49 mg, 0.05 mmol) and toluene (5 mL) were added to chamber A, followed by the addition of 2-methylpropane-2-amine (64 mg, 0.88 mmol). The resulting solution was degassed with nitrogen for 5 minutes. Toluene (5 mL) containing formic acid (49 μL, 1.29 mmol) was added to chamber B, followed by the addition of methanesulfonyl chloride (100 μL, 1.29 mmol). The vessel was sealed, and TEA (288 μL, 2.07 mmol) was added to chamber B to generate carbon monoxide. This Coware equipment is heated overnight at 100 ℃, and it is cooled to room temperature.The mixture that obtains is concentrated under vacuum, is dissolved in EtOAc (30mL) and washs with water (2x25mL), with organic part through Na SO Dry, and under vacuum, concentrate.By preparation HPLC (acidic pH, early stage elution method) purifying crude resistates, obtain the beige solid of title compound.

[1874] 1H NMR (250 MHz, methanol-d4) δ 8.91 (d, J = 6.5 Hz, 1H), 8.41 (d, J = 2.6 Hz, 1H), 7.29-7.23 (m, 2H), 7.00-6.94 (m, 1H), 3.84 (s, 3H), 3.79 (s, 2H), 1.45 (s, 9H).

[1875] LC-MS (Method E): Rt 1.25 min; MS m / z 394.1, 396.1 = [M+H]+ (97% @ 215 nm)

[1876] Step 3: N-tert-Butyl-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-5-fluoro-pyridine-2-carboxamide

[1877] To a cooled (0° C.) solution of N-tert-butyl-4-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]-5-fluoro-pyridine-2-carboxamide (step 2) (30 mg, 0.08 mmol) in DCM (2 mL) was added 1 M BBr in DCM (190 μL, 0.19 mmol). The reaction mixture was allowed to warm to room temperature and stirring was continued for another hour. The reaction was quenched by the addition of water (0.5 mL) and concentrated under vacuum. The crude material was redissolved in EtOAc (2 mL) and washed with saturated NaHCO (2 mL). The organic portion was concentrated under vacuum and the crude residue was purified by C18 reverse phase chromatography (0-100% MeCN in water with 0.1% formic acid modifier). The product fractions were concentrated under vacuum and freeze-dried to give the title compound as a white solid.

[1878] 1H NMR (500MHz, DMSO-d6) δ10.02(br.S,1H),8.82(d,J=6.6Hz,1H),8.54(d,J=2.5Hz,1H),7.91(s,1H),7. 22(d,J=2.7Hz,1H),7.12(dd,J=8.6,2.7Hz,1H),6.81(d,J=8.6Hz,1H),3.79-3.74(m,2H),1.38(s,9H).

[1879] LC-MS (Method A): Rt 3.37 min; MS m / z 380.3 / 381.3 / 382.3 = [M+H]+ (99% @ 215 nm)

[1880] Example 28.1

[1881] N-tert-Butyl-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-3-fluoro-pyridine-2-carboxamide

[1882]

[1883] The title compound was prepared in analogy to Example 28 Steps 1-3 from 2-chloro-3-fluoro-pyridin-4-amine and 2-(5-chloro-2-methoxy-phenyl)acetic acid.

[1884] 1H NMR(500MHz,DMSO-d6)δ8.29-8.25(m,2H),8.02(s,1H),7.21(d,J=2.7Hz,1H) ,7.12(dd,J=8.6,2.7Hz,1H),6.81(d,J=8.6Hz,1H),3.78(s,2H),1.38(s,9H).

[1885] LC-MS (Method A): Rt 3.30 min; MS m / z 380.2 / 382.2 = [M+H] +

[1886] Example 30

[1887] 4-[[2-(2-chlorophenyl)acetyl]amino]-N-(1-cyanocyclobutyl)pyridine-2-carboxamide

[1888]

[1889] Step 1: Methyl 4-[[2-(2-chlorophenyl)acetyl]amino]pyridine-2-carboxylate

[1890]

[1891] To a stirred solution of 2-(2-chlorophenyl)acetic acid (3.08 g, 18.07 mmol), methyl 4-aminopyridine-2-carboxylate (2.5 g, 16.43 mmol) and TEA (4.3 mL, 24.65 mmol) in 1,4-dioxane (40 mL) was added 50% The resulting mixture was stirred at room temperature for 2 hours and then diluted with EtOAc (100 mL) and water (100 mL). The organic layer was separated, dried over Na2SO4, and concentrated under vacuum. The crude residue was purified by silica gel chromatography eluting with 10-100% EtOAc in heptane to give the title compound as a light orange solid.

[1892] 1H NMR(500MHz,DMSO-d6)δ10.85(s,1H),8.55(d,J=5.5Hz,1H),8.31(d,J=1.9Hz,1H),7.77 (dd,J=5.5,2.2Hz,1H),7.48-7.40(m,2H),7.36-7.28(m,2H),3.91(s,2H),3.86(s,3H).

[1893] LC-MS (Method E): Rt 1.00 min; MS m / z 305.0 / 307.0 = [M+H]+ (96% @ 215 nm)

[1894] Step 2: 4-[[2-(2-chlorophenyl)acetyl]amino]pyridine-2-carboxylic acid

[1895]

[1896] 2M LiOH (16.07 mL, 32.13 mmol) was added to a stirred solution of methyl 4-[[2-(2-chlorophenyl)acetyl]amino]pyridine-2-carboxylate (step 2) (3.4 g, 10.71 mmol) in THF (40 mL) and stirred at room temperature for 20 minutes. The resulting mixture was partially concentrated under vacuum to remove volatile solvents and acidified to pH 2 with 2M aq HCl. The resulting suspension was filtered and dried in a vacuum oven at 40°C to give the title compound as an off-white solid.

[1897] 1H NMR (500 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.53 (d, J = 5.5 Hz, 1H), 8.27 (d, J = 2.1 Hz, 1H), 7.79 (dd, J = 5.5, 2.2 Hz, 1H), 7.49-7.41 (m, 2H), 7.35-7.29 (m, 2H), 3.92 (s, 2H). LC-MS (Method E): Rt 0.89 min; MS m / z 290.9 / 292.9 = [M+H]+ (100% @ 215 nm)

[1898] Step 3: 4-[[2-(2-chlorophenyl)acetyl]amino]-N-(1-cyanocyclobutyl)pyridine-2-carboxamide

[1899] A solution of 1-aminocyclobutanecarbonitrile (33 mg, 0.34 mmol), DIPEA (0.07 mL, 0.41 mmol), HATU (131 mg, 0.34 mmol) and 4-[[2-(2-chlorophenyl)acetyl]amino]pyridine-2-carboxylic acid (step 2) (100 mg, 0.34 mmol) in DMF (2 mL) was stirred at room temperature for 2 hours. The resulting mixture was concentrated under vacuum and the residue was partitioned between EtOAc (10 mL) and water (10 mL). The organic layer was separated, dried over Na2SO4, and concentrated under vacuum. The residue was purified by preparative HPLC (acidic pH, early elution method) and the product fractions were lyophilized overnight to give the title compound as an off-white powder.

[1900] 1H NMR (500MHz, DMSO-d6) δ10.87(s,1H),9.60(s,1H),8.53(d,J=5.5Hz,1H),8.20(d,J=1.9Hz,1H),7.87(dd,J=5.5,2.2 Hz,1H),7.52-7.38(m,2H),7.38-7.24(m,2H),3.92(s,2H),2.70-2.62(m,2H),2.59-2.52(m,2H),2.09-1.93(m,2H).

[1901] LC-MS (Method A): Rt 3.02 min; MS m / z 369.2 = [M+H]+ (100% @ 215 nm)

[1902] Example 30.1

[1903] 4-[[2-(2-chlorophenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide

[1904]

[1905] A solution of 2-methylbut-3-yn-2-amine (14 mg, 0.17 mmol), DIPEA (0.08 mL, 0.43 mmol), HATU (65 mg, 0.17 mmol), and 4-[[2-(2-chlorophenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 30, Step 2) (50 mg, 0.17 mmol) in DMF (1 mL) was stirred at room temperature for 2 hours. The resulting mixture was concentrated under vacuum, and the residue was then partitioned between EtOAc (10 mL) and water (10 mL). The organic layer was separated, dried over NaSO, and concentrated under vacuum. The residue was purified by preparative HPLC (acidic pH, early elution method), and the product fractions were combined and lyophilized overnight to give the title compound as an off-white powder.

[1906] 1H NMR (500MHz, DMSO-d6) δ10.85(s,1H),8.48(d,J=5.5Hz,1H),8.32(s,1H),8.19(d,J=2.0Hz,1H),7.83 (dd,J=5.5,2.2Hz,1H),7.49-7.39(m,2H),7.37-7.29(m,2H),3.92(s,2H),3.21(s,1H),1.64(s,6H).

[1907] LC-MS (Method A): Rt 3.25 min; MS m / z 356.3 / 358.2 = [M+H]+ (100% @ 215 nm)

[1908] Example 30.2

[1909] 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(4-fluoro-1-bicyclo[2.1.1]hexyl)pyridine-2-carboxamide

[1910]

[1911] A solution of 4-fluorobicyclo[2.1.1]hexan-1-amine hydrochloride (26 mg, 0.17 mmol), DIPEA (0.08 mL, 0.43 mmol), HATU (65 mg, 0.17 mmol) and 4-[[2-(2-chlorophenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 30, Step 2) (50 mg, 0.17 mmol) in DMF (1 mL) was stirred at room temperature for 2 hours. The resulting mixture was concentrated under vacuum and the residue was partitioned between EtOAc (10 mL) and water (10 mL). The organic layer was separated, dried over Na2SO4, and concentrated under vacuum. The residue was purified by preparative HPLC (acidic pH, early elution method) and the product fractions were combined and lyophilized overnight to give the title compound as an off-white powder.

[1912] 1H NMR (500MHz, DMSO-d6) δ10.83(s,1H),9.05(s,1H),8.48(d,J=5.5Hz,1H),8.16(d,J=2.0Hz,1H),7.83(dd,J=5.5,2.2Hz,1H),7.54-7. 40(m,2H),7.40-7.25(m,2H),3.91(s,2H),2.14-2.08(m,2H),2.08-2.04(m,2H),2.00-1.94(m,2H),1.87-1.81(m,2H).LC-MS (Method A): Rt 3.39min; MS m / z 388.3 / 390.3=[M+H]+(99%@215nm)

[1913] Example 30.3

[1914] 4-[[2-(2-chlorophenyl)acetyl]amino]-N-(1-cyclopropyl-1-methyl-ethyl)pyridine-2-carboxamide

[1915]

[1916] The title compound was prepared in analogy to Example 30, Step 3, from 4-[[2-(2-chlorophenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 30, Step 2) and 2-cyclopropylpropan-2-amine.

[1917] 1H NMR (500MHz, DMSO-d6) δ10.84(s,1H),8.47(d,J=5.5Hz,1H),8.20(d,J=2.1Hz,1H),8.03(s,1H),7.81(dd,J=5.5, 2.2Hz,1H),7.49-7.42(m,2H),7.35-7.31(m,2H),3.92(s,2H),1.41-1.34(m,1H),1.31(s,6H),0.43-0.36(m,4H).

[1918] LC-MS (Method A): Rt 3.73 min; MS m / z 372.2 / 374.2 = [M+H]+ (100% @ 215 nm)

[1919] The compounds of the following examples (Table 9a) were prepared in analogy to Example 30 by replacing 1-aminocyclobutanecarbonitrile (Step 3) with the appropriate commercially available amine.

[1920] Table 9a

[1921]

[1922]

[1923]

[1924] *Example 30.11: The amine, 4-ethynyltetrahydropyran-4-amine hydrochloride was prepared according to the procedure described in Journal of Organic Chemistry, 71(18), 7110-7112; 2006.

[1925] Example 31

[1926] 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4-cyanotetrahydropyran-4-yl)pyridine-2-carboxamide

[1927] Step 1: 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid

[1928]

[1929] 1 M BBr in DCM (308.67 mL, 308.67 mmol) was slowly added to a suspension of 4-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 8.1, Step 2) (25.0 g, 77.17 mmol, 99%) in DCM (500 mL) at 0-5° C. under an inert atmosphere of N over a period of 1 hour. The mixture was allowed to warm to room temperature and stirred for another hour. The reaction mixture was concentrated under vacuum, and the residue was suspended in EtOAc (500 mL) and water (500 mL) at 0° C. The resulting mixture was allowed to warm to room temperature, and the aqueous layer was adjusted to pH 4 by portionwise addition of saturated aqueous NaHCO (350 mL). The precipitate was collected by filtration, washed with water (2 x 100 mL), EtOAc (2 x 100 mL), diethyl ether (2 x 150 mL), and dried in a high vacuum oven at 40 °C to give the title compound as a beige solid.

[1930] 1H NMR (500MHz, DMSO-d6) δ10.72(s,1H),9.82(br.s,1H),8.53(d,J=5.5Hz,1H),8.27(d,J=2.0Hz,1H),7.80(d d,J=5.6,2.2Hz,1H),7.22(d,J=2.7Hz,1H),7.13(dd,J=8.6,2.7Hz,1H),6.80(d,J=8.6Hz,1H),3.67(s,2H).

[1931] LC-MS (Method E): Rt 0.86 min; MS m / z 306.9 / 308.9 = [M+H] + (97% @ 215 nm)

[1932] Step 2: 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4-cyanotetrahydropyran-4-yl)pyridine-2-carboxamide

[1933]

[1934] HATU (19.34 g, 50.86 mmol) was added to a stirred solution of 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 31, Step 1) (13 g, 42.39 mmol), 4-aminotetrahydropyran-4-carbonitrile (8.02 g, 63.58 mmol), and DIPEA (18.51 mL, 105.97 mmol) in DMF (150 mL). The reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was diluted with 0.5 M aq. NaOH (100 mL) and stirred at room temperature for 30 minutes. Water (500 mL) and EtOAc (500 mL) were added, and the resulting precipitate was removed by filtration. The aqueous solution was partially extracted with EtOAc (250 mL), and the combined organic matter was washed with water (2x750 mL), saturated NaHCO (500 mL), brine (700 mL), dried over Na SO, and concentrated under vacuum to give a yellow oil. The material was purified by silica gel chromatography, eluting with the heptane containing 0-100% EtOAc, then with the EtOAc containing 0-15% MeOH. The product fractions were combined and concentrated under vacuum. The residue was subsequently purified by KP-NH silica gel, eluting with the heptane containing 50-100% EtOAc, then with the EtOAc containing 0-15% MeOH, the clear product fractions were combined, concentrated under vacuum, and azeotroped with MeCN (3x500 mL) to give the title compound.

[1935] 1H NMR(500MHz,DMSO-d6)δ10.74(br s,1H),9.83(s,1H),9.00(s,1H),8.52(d,J=5.5Hz,1H),8.23(d,J=2.1Hz,1H),7.87(dd,J=5.5,2.2Hz,1H),7.22(d,J=2.7Hz,1H),7.13(dd,J= 8.6, 2.7Hz, 1H), 6.81 (d, J = 8.6Hz, 1H), 3.86 (td, J = 12.5Hz, 3.9Hz, 2H), 3.68 (s, 2H), 3.64-3.53 (m, 2H), 2.41-2.32 (m, 2H), 2.12-2.00 (m, 2H).

[1936] LC-MS (Method A): Rt 2.67 min; MS m / z 415.2 / 417.2 = [M+H] +

[1937] Step 3: Recrystallization of 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4-cyanotetrahydropyran-4-yl)pyridine-2-carboxamide

[1938] 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4-cyanotetrahydropyran-4-yl)pyridine-2-carboxamide (Step 2) (1881 mg, 4.44 mmol) was suspended in MeCN (16 mL) and heated to reflux for 10 minutes. Additional MeCN (2 mL) was added, and the mixture was heated to reflux for 30 minutes, at which point all material was observed to have dissolved into solution. The heating temperature was reduced to 55°C, and the mixture was seeded with crystals of 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4-cyanotetrahydropyran-4-yl)pyridine-2-carboxamide. The temperature of the mixture was maintained at 55°C for 1 hour, then allowed to slowly cool to room temperature overnight. The resulting crystals were collected by filtration, washed with a minimal amount of ice-cold MeCN (~5 mL), and dried in a vacuum oven at 40°C for 2 hours to provide the title compound as an off-white crystalline solid.

[1939] 1H NMR(500MHz,DMSO-d6)δ10.74(br s,1H),9.82(br s,1H),9.00(s,1H),8.53(d,J=5.5Hz,1H),8.23(d,J=2.0Hz,1H),7.87(dd,J=5.5,2.2Hz,1H),7.22(d,J=2.7Hz,1H),7.13(dd,J=8.6,2 .7Hz,1H),6.81(d,J=8.6Hz,1H),3.86(td,J=12.5Hz,3.9Hz,2H),3.68(s,2H),3.63-3.54(m,2H),2.40-2.34(m,2H),2.12-2.03(m,2H).

[1940] LC-MS (Method A): Rt 2.68 min; MS m / z 415.3 / 417.2 = [M+H]+ (99% @ 215 nm)

[1941] Example 31.2

[1942] 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-(1-ethynylcyclopentyl)pyridine-2-carboxamide

[1943]

[1944] The title compound was prepared in analogy to Example 31 Step 2 from 4-[[2-(5-chloro-2-hydroxy-...

Claims

1. Compounds of the general formula (I), including all tautomeric forms, all enantiomers and isotopic variants and salts and solvates thereof: in: R 1 H、CN、C(O)OR 12 , C 1-3 Alkyl, C 2-3 Alkenyl or C 2-3 Alkynyl, any of the alkyl, alkenyl or alkynyl groups is optionally substituted by one or more substituents, suitably one substituent, selected from: fluorine, OR 12 、N(R 12 )2. C(O)OR 12 、C(O)N(R 12 )2. C(O)R 12 and N(R 13 )C(O)R 12 ; Where R 12 and R 13 Each independently selected from H, C 1-6 Alkyl and C 1-6 Fluoroalkyl R 2 Is H or C 1-6 Alkyl, which is optionally replaced by OR 12 replace; R 3 yes: C 1-10 Alkyl, C 2-10 Alkenyl or C 2-10 Alkynyl, any of which is optionally substituted by one or more substituents, suitably by one substituent, selected from fluorine, CN, R 14 OR 14 , OR 15 、N(R 15 )2. C(O)OR 15 、C(O)N(R 15 )2、N(R 16 )C(O)R 15 、N(R 15 )S(O)2R 14 、N(R 15 )S(O)2R 16 and N(R 15 )C(O)OR 16； or A 3- to 7-membered carbocyclic or heterocyclic ring system or a 6- to 10-membered aryl or 5- to 10-membered heteroaryl ring system, each of which is optionally substituted with one or more substituents selected from the group consisting of halo, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, OR 17 and N(R 17 )2; Where R 14 is a 6- to 10-membered aryl or 5- to 10-membered heteroaryl ring system or a 3- to 7-membered carbocyclic or heterocyclic ring system, any of which is optionally substituted by one or more substituents selected from the group consisting of halo, C 1-4 Alkyl, C 1-4 Haloalkyl, OR 17 and N(R 17 )2; where R 17 Each independently is H, C 1-4 Alkyl or C 1-4 Haloalkyl; R 15 and R 16 Each independently is H, C 1-6 Alkyl or C 1-6 haloalkyl; or R 2 and R 3 Together with the carbon atoms to which they are attached, they form a 3- to 10-membered carbocyclic or heterocyclic ring system, which is optionally substituted by one or more substituents selected from the group consisting of halo, CN, OR 9 、N(R 9 )2. C(O)OR 9 、C(O)N(R 9 )2. C(O)R 9 、N(R 9 )C(O)R 9 and optionally halogenated, OR 9 or N(R 9 )2 substituted C 1-4 Alkyl; or R 1 , R 2 and R 3 Together with the carbon atoms to which they are attached, they form a bridged 5- to 10-membered carbocyclic or heterocyclic ring system or phenyl, any of which is optionally substituted with one or more substituents selected from the group consisting of halo, CN, OR 9 、N(R 9 )2. C(O)OR 9 、C(O)N(R 9 )2. C(O)R 9 、N(R 9 )C(O)R 9 and optionally halogenated, OR 9 or N(R 9 )2 substituted C 1-4 alkyl; R 9 Each independently selected from H, C 1-6 Alkyl or C 1-6 Haloalkyl; X 1 and X 2 Each of the 8 ; R 8 H, halide, OH, O(C 1-4 Alkyl), CN or NH2; Y is a bond or a straight chain of C 1-6 An alkylene chain, which is optionally substituted by one or more substituents R 18 Substitution, where two substituents R 18 can be attached to the same or different carbon atoms; Where R 18 Each is independently C 1-3 Alkyl or C 1-3 A haloalkyl group wherein -CH2- is optionally replaced by -NH- or -O-, and wherein both R 18 The groups may be combined with the atom or atoms to which they are attached to form a 3- to 6-membered carbocyclic or heterocyclic ring system; Z is -C(O)- or -C(O)NH-; R 4 is a 6- to 14-membered aryl, a 5- to 14-membered heteroaryl, or a 5- to 10-membered carbocyclic ring system, any of which is optionally substituted with one or more substituents selected from: halogen group, CN, nitro, R 19 、OR 19 、OR 6 、SR 6 、NR 6 R 7 、C(O)R 6 、C(O)R 19 、C(O)OR 6 、C(O)N(R 6 )(R 7 )、N(R 7 )C(O)R 6 ; C 1-6 Alkyl or O(C 1-6 alkyl), any of which is optionally substituted by one or more substituents selected from the group consisting of halo, CN, nitro, R 19 , OR 6 , SR 6 NR 6 R 7 、C(O)R 6 C(O)OR 6 、C(O)N(R 6 )(R 7 ) and N(R 7 )C(O)R 6 ;and Oxo, when R 4 This is true when not completely aromatic in nature; Where R 19 is a 5- or 6-membered aryl or heteroaryl ring system or a 3- to 7-membered carbocyclic or heterocyclic ring system, any of which is optionally substituted by one or more substituents selected from the group consisting of halo, C 1-4 Alkyl, C 1-4 Haloalkyl, OH, O(C 1-4 alkyl), O(C 1-4 haloalkyl); R 6 It is H, C 1-6 Alkyl, C 1-6 haloalkyl, benzyl, 3- to 7-membered carbocyclic group or 3- to 7-membered heterocyclic group; R 7 It is H, C 1-6 Alkyl or C 1-6 haloalkyl; or R 6 and R 7 Together with the nitrogen atom to which they are attached, may form a 4 to 7-membered heterocyclic ring, which optionally contains one or more additional heteroatoms and is optionally substituted by one or more substituents selected from oxo and halo; and R 5a and R 5b Each of which is independently H, C 1-4 Alkyl or halo; It is used in medical applications.

2. Compounds for use according to claim 1 for the treatment or prevention of diseases and disorders which are affected by the modulation of TMEM16A.

3. Use of a compound of formula (I) as defined in claim 1 for the preparation of a medicament for the treatment or prevention of diseases and disorders affected by TMEM16A regulation.

4. A method for the treatment or prevention of diseases and disorders affected by TMEM16A modulation, said method comprising administering to a patient in need of said treatment an effective amount of a compound of general formula (I) as defined in claim 1.

5. A compound for use, use or method according to any one of claims 2 to 4, wherein the disease or condition affected by TMEM16A modulation is selected from respiratory diseases and conditions, dry mouth (xerostomia), overactive intestine, cholestasis and ocular symptoms.

6. A compound for use, use or method according to claim 5, wherein the respiratory diseases and disorders are selected from cystic fibrosis, chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema, bronchiectasis, bronchiectasis including non-cystic fibrosis, asthma and primary ciliary dyskinesia.

7. A compound for use, use or method according to claim 5, wherein the dry mouth (xerostomia) is caused by Sjögren's syndrome, radiation therapy or a drug that causes dry mouth.

8. A compound for use, use or method according to claim 5, wherein the intestinal overactivity is associated with gastric dyspepsia, gastroparesis, chronic constipation or irritable bowel syndrome.

9. The compound for use, use or method according to claim 5, wherein the ocular disease is dry eye.

10. A compound for use, a use or a method according to any one of claims 1 to 9, wherein: In the compound of general formula (I), Z is -C(O)-, and R 5b is H, so that the compound has the formula (Iz): Where R 1 , R 2 , R 3 , R 4 , R 5a , X 1 , X 2 and Y as defined in claim 1; or In the compound of the general formula (I), Z is -C(O)NH-, and R 5b is H, so that the compound has the general formula (Iy): Where R 1 , R 2 , R 3 , R 4 , R 5a , X 1 , X 2 and Y is as defined in claim 1; or The compound of general formula (I) is a compound of general formula (Ix), including all tautomeric forms, all enantiomers and isotopic variants and salts and solvates thereof: in: R 1 is H, CN or C 1-3 Alkyl, which is optionally substituted by one or more substituents selected from the group consisting of halo, OR 12 、N(R 12 )2. C(O)OR 12 、C(O)N(R 12 )2. C(O)R 12 and N(R 13 )C(O)R 12 ; Where R 12 and R 13 Each independently selected from H, C 1-6 Alkyl or C 1-6 Haloalkyl; R 2 It is C 1-6 alkyl; R 3 It is C 1-6 Alkyl, which is optionally substituted by one or more substituents selected from the group consisting of halo, OH, O(C 1-6 alkyl), C(O)O-(C 1-6 alkyl) and N(H)C(O)O-(C 1-6 alkyl); or R 2 and R 3 Together with the carbon atoms to which they are attached, they form a 3- to 10-membered carbocyclic or heterocyclic ring system, which is optionally substituted by one or more substituents selected from the group consisting of halo, OR 9 、N(R 9 )2. C(O)OR 9 、C(O)N(R 9 )2. C(O)R 9 and N(R 9 )C(O)R 9 ;or R 1 , R 2 and R 3 Together with the carbon atoms to which they are attached, they form a bridged 5- to 10-membered carbocyclic or heterocyclic ring system, which is optionally substituted with one or more substituents selected from the group consisting of halo, OR 9 、N(R 9 )2. C(O)OR 9 、C(O)N(R 9 )2. C(O)R 9 、N(R 9 )C(O)R 9 ; R 9 Each independently selected from H, C 1-6 Alkyl or C 1-6 Haloalkyl; X 1 and X 2 Each of the 8 ; R 8 is H, halo, OH, CN or NH2; Y is a bond or C 1-6 Alkylene; R 4 is a 6- to 10-membered aryl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered carbocyclic or heterocyclic ring system, any of which is optionally substituted with one or more substituents selected from: Halo, CN, nitro; OR 6 、SR 6 、NR 6 R 7 、C(O)R 6 C(O)OR 6 、C(O)N(R 6 )(R 7 )、N(R 7 )C(O)R 6 ; C 1-6 Alkyl, optionally substituted by one or more substituents selected from the group consisting of halo, CN, nitro, OR 6 , SR 6 NR 6 R 7 、C(O)R 6 C(O)OR 6 、C(O)N(R 6 )(R 7 ) and N(R 7 )C(O)R 6 ;and Oxo, when R 4 This is true when not completely aromatic in nature; Where R 6 It is H, C 1-6 Alkyl, C 1-6 Haloalkyl, 3-7 membered carbocyclic group or 3-7 membered heterocyclic group; R 7 It is H, C 1-6 Alkyl or C 1-6 haloalkyl; or R 6 and R 7 Together with the nitrogen atom to which they are attached, may form a 4 to 7-membered heterocyclic ring, which optionally contains one or more additional heteroatoms and is optionally substituted with one or more oxo substituents; and R 5 It is H, C 1-4 Alkyl or halo.

11. A compound for use, use or method according to any one of claims 1 to 10, wherein in the compound of general formula (I), R 1 H、CN、C(O)OR 12 or methyl, ethyl or ethynyl, which is optionally substituted by one or more substituents selected from the group consisting of fluorine, OR 12 、N(R 12 )2. C(O)OR 12 、C(O)N(R 12 )2. C(O)R 12 and N(R 13 )C(O)R 12 ; Where R 12 and R 13 Each independently as defined in claim 1.

12. The compound, use or method according to claim 11, wherein in the compound of formula (I), R 1 is H, CN, ethynyl or methyl, any of which is unsubstituted or substituted by OH.

13. The compound for use, use or method according to any one of claims 1 to 12, wherein in the compound of general formula (I): R 2 is methyl or ethyl; and R 3 It is C 1-4 Alkyl, which is optionally substituted by one or more substituents selected from the group consisting of hydroxy, methoxy, ethoxy, -C(O)O-(C 1-4 alkyl) and -N(H)C(O)O-(C 1-4 alkyl); or R 2 It is H, methyl or ethyl.

14. The compound for use, use or method according to any one of claims 1 to 13, wherein in the compound of general formula (I): R 3 It is C 1-10 Alkyl or C 2-3 Alkynyl, any one of which is unsubstituted or substituted with a single substituent selected from the group consisting of fluorine, R 14 OR 14 , OR 15 、C(O)OR 15 、N(R 16 )S(O)2R 15 and N(R 16 )C(O)OR 15 ;in R 14 is selected from phenyl, pyridyl and a 5- or 6-membered heterocyclic ring; R 15 Select from H or C 1-4 Alkyl; and R 16 is H; or R 3 is a 3- to 7-membered carbocyclic or heterocyclic ring system which is unsubstituted or substituted as defined in claim 1; or R 3 is phenyl or pyridyl, either of which is unsubstituted or substituted by one or more selected from OR 17 and N(R 17 )2 is substituted by a substituent, wherein R 17 Each is H or methyl.

15. The compound for use, use or method according to claim 14, wherein in the compound of general formula (I): R 1 is methyl or CN, and R 2 and R 3 are all methyl; or R 2 and R 3 Combined with the carbon atoms to which they are attached, they form a carbocyclic or heterocyclic ring system, and R 1 is H, methyl, methyl substituted by OH, CN, ethynyl, or C(O)OR 12 , where R 12 As defined in claim 1.

16. The compound for use, use or method according to any one of claims 1 to 15, wherein in the compound of general formula (I): X 1 is N, and X 2 CR 8 , where R 8 as defined in claim 1; or X 1 and X 2 All CR 8 , where R 8 Each independently as defined in claim 1.

17. A compound for use, a use or a method according to any one of claims 1 to 16, wherein in the compound of formula (I), Y is -CH2-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)- or -CH2CH2CH2-.

18. A compound for use, use or method according to any one of claims 1 to 17, wherein in the compound of formula (I), R 5a and R 5b All are H.

19. The compound for use, use or method according to any one of claims 1 to 18, wherein in the compound of general formula (I): R 4 is a 6- to 11-membered aryl group selected from phenyl, naphthyl, indanyl, 1,2,3,4-tetrahydronaphthyl and benzocycloheptyl, any of which is optionally substituted as defined in claim 1; or R 4 is a 5- to 10-membered heteroaryl group selected from pyridyl, quinolyl, quinoxalinyl, indazolyl, indolyl, benzoxazolyl, dihydrobenzofuranyl, furanyl and thienyl, any of which is optionally substituted as defined in claim 1; R 4 is a carbocyclyl selected from cyclohexyl and adamantyl, either of which is optionally substituted as defined in claim 1; or R 4 is phenyl, which is optionally substituted by one or more substituents as defined in claim 1; or R 4 is a 5-10-membered heteroaryl group selected from pyridyl, pyrrolyl, thienyl, furanyl, benzoxazolyl, imidazolyl, indolyl or indazolyl, any of which is optionally substituted as defined in claim 1.

20. The compound, use or method according to any one of claims 1 to 19, wherein in the compound of formula (I), Y is -CH2-, R 4 is phenyl, and the compound is a compound of general formula (Ia): in R 1 , R 2 , R 3 , R 5a , X 1 and X 2 As defined in claim 1; R 10 H, OH, halogen, C 1-6 Alkyl, -O(C 1-6 alkyl); R 11 are independently H, halo, OH, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -O(C 1-6 alkyl) or C(O)O-(C 1-6 alkyl); and n is 1 or 2.

21. The compound for use, use or method according to claim 20, wherein the compound of general formula (I) is a compound of general formula (Ib) or (Ic): in R 1 , R 2 , R 3 , R 5a , X 1 and X 2 As defined in claim 1; R 11a is H, halide, C 1-4 Alkyl, C 1-4 Haloalkyl or C(O)O(C 1-4 alkyl); R 11b is H, halide, C 1-4 Alkyl or C 1-4 Haloalkyl; R 11c H, halide, CN, C 1-4 Alkyl or C 1-4 haloalkyl; or The compound of general formula (I) is a compound of general formula (Id) or (Ie): Where R 1 , R 2 , R 3 , R 11a , R 11b and R 11c As defined above for the compounds of formula (Ib) and (Ic).

22. The compound for use, use or method according to any one of claims 1 to 9, wherein the compound of general formula (I) is selected from: N-tert-butyl-4-[[2-(2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (Compound 1); N-(1,1-dimethylpropyl)-3-[[2-(2-hydroxyphenyl)acetyl]amino]benzamide (Compound 1.1); N-(1-adamantyl)-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 1.2); N-(1-adamantyl)-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 1.3); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3-methoxy-1,1-dimethyl-propyl)pyridine-2-carboxamide (Compound 1.4); 3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylpropyl)benzamide (Compound 1.5); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclobutyl)pyridine-2-carboxamide (Compound 1.6); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclohexyl)pyridine-2-carboxamide (Compound 1.7); N-[3-[[4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carbonyl]amino]-3-methyl-butyl]carbamic acid tert-butyl ester (Compound 1.8); 3-[[2-(2-Hydroxyphenyl)acetyl]amino]-N-(2-methoxy-1,1-dimethyl-ethyl)benzamide (Compound 1.9); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-cyclohexyl-pyridine-2-carboxamide (Compound 1.10); N-tert-butyl-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 2); N-tert-butyl-3-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 2.1); N-tert-butyl-3-[[2-(3-fluoro-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 2.2); N-tert-butyl-3-[[2-(4-fluoro-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 2.3); N-tert-butyl-3-[[2-(2,6-dihydroxyphenyl)acetyl]amino]benzamide (Compound 2.4); N-tert-butyl-3-[3-(2-hydroxyphenyl)propionylamino]benzamide (Compound 2.5); N-tert-butyl-3-[[2-(2-hydroxy-6-methoxy-phenyl)acetyl]amino]benzamide (Compound 2.6); N-tert-butyl-3-[2-(2-hydroxyphenyl)propionylamino]benzamide (Compound 2.7); N-tert-butyl-3-[[2-(2-hydroxy-3-methoxy-phenyl)acetyl]amino]benzamide (Compound 2.8); N-tert-butyl-3-[[2-(3,5-difluoro-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 2.9); 3-[[2-(5-Bromo-2-hydroxy-phenyl)acetyl]amino]-N-tert-butyl-benzamide (Compound 2.10); N-tert-butyl-3-[[2-(2,3-difluoro-6-hydroxy-phenyl)acetyl]amino]benzamide (Compound 2.11); N-tert-butyl-3-[[2-(4,5-difluoro-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 2.12); N-(1,1-dimethylpropyl)-3-[[2-(4-fluoro-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 2.13); N-tert-butyl-3-[[2-(2-hydroxy-4-methoxy-phenyl)acetyl]amino]benzamide (Compound 2.14); N-tert-butyl-3-[[2-(2-fluoro-6-hydroxy-phenyl)acetyl]amino]benzamide (Compound 2.15); N-tert-butyl-3-[[2-(2,3-dihydroxyphenyl)acetyl]amino]benzamide (Compound 2.16); N-tert-butyl-3-[[2-[2-hydroxy-5-(trifluoromethyl)phenyl]acetyl]amino]benzamide (Compound 2.17); 3-[2-[3-(tert-Butylcarbamoyl)anilino]-2-oxo-ethyl]-4-hydroxy-benzoic acid methyl ester (Compound 2.18); N-tert-butyl-3-[[2-[2-hydroxy-4-(trifluoromethyl)phenyl]acetyl]amino]benzamide (Compound 2.19); N-tert-butyl-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3); N-(1,1-dimethylpropyl)-4-[[2-(4-fluoro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.1a); N-tert-butyl-4-[[2-(4-fluoro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.2a); N-tert-butyl-4-[[2-(2-chloro-6-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.3a); 4-[[2-(4-bromo-5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (Compound 3.4a); 4-[[2-(5-tert-butyl-2-hydroxy-phenyl)acetyl]amino]-N-(1-cyanocyclobutyl)pyridine-2-carboxamide (Compound 3.5a); 4-[[2-(5-tert-butyl-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclobutyl)pyridine-2-carboxamide (Compound 3.6a); N-tert-butyl-4-[2-(2,5-dibromo-3-fluoro-6-hydroxyphenyl)acetylamino]pyridine-2-carboxamide (Compound 3.7a); N-tert-butyl-4-[[2-[2-hydroxy-5-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 3.5b); N-tert-butyl-4-[[2-(4-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.6b); N-tert-butyl-4-[[2-[2-hydroxy-4-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 3.7b); N-tert-butyl-4-[[2-(2-hydroxy-5-methoxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.8b); N-tert-butyl-4-[(6-hydroxyindane-1-carbonyl)amino]pyridine-2-carboxamide (Compound 3.9b); N-tert-butyl-4-[(7-hydroxyindane-1-carbonyl)amino]pyridine-2-carboxamide (Compound 3.10b); N-tert-butyl-4-[[2-(2,5-dibromo-3-chloro-6-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.11b); N-tert-butyl-4-[[2-(3-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.12b); N-tert-butyl-4-[[2-(2-fluoro-5-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.13b); N-tert-butyl-4-[[2-(4-chloro-3-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.14b); N-tert-butyl-4-[[2-(2-chloro-3-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.15b); N-tert-butyl-4-[[2-(2-chloro-5-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.16b); N-tert-butyl-4-[[2-(3-chloro-5-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.17b); N-tert-butyl-3-[[2-(3-hydroxyphenyl)acetyl]amino]benzamide (Compound 4); N-tert-butyl-3-[[2-(1H-indazol-3-yl)acetyl]amino]benzamide (Compound 4.1); N-tert-butyl-3-[[2-(5-fluoro-1H-indol-3-yl)acetyl]amino]benzamide (Compound 4.2); N-tert-butyl-3-[[2-(2-hydroxyphenyl)acetyl]amino]benzamide (Compound 4.3); N-tert-butyl-3-[[2-(7-fluoro-2-methyl-1H-indol-3-yl)acetyl]amino]benzamide (Compound 4.4); N-tert-butyl-3-[[2-(1H-indol-3-yl)acetyl]amino]benzamide (Compound 4.5); N-tert-butyl-3-[(2-phenylacetyl)amino]benzamide (Compound 4.6); N-tert-butyl-3-[[2-(2-fluoro-6-methoxy-phenyl)acetyl]amino]benzamide (Compound 4.7); N-tert-butyl-3-[[2-(2,3-difluoro-6-methoxy-phenyl)acetyl]amino]benzamide (Compound 4.8); N-tert-butyl-3-[[2-[2-methoxy-4-(trifluoromethyl)phenyl]acetyl]amino]benzamide (Compound 4.9); N-tert-butyl-4-[[2-(2-thienyl)acetyl]amino]pyridine-2-carboxamide (Compound 5); 4-[[2-(2-adamantyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (Compound 5.1); N-tert-butyl-4-[[2-(4-fluoro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.2); N-tert-butyl-4-[[2-(5-chloro-2-fluoro-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.3); N-tert-butyl-4-[[2-(2-furyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.4); N-tert-butyl-4-[[2-(3-chlorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.5); N-tert-butyl-4-[[2-(1H-indol-3-yl)acetyl]amino]pyridine-2-carboxamide (Compound 5.6); N-tert-butyl-4-[[2-(o-tolyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.7); N-tert-butyl-4-[[2-(3,4-dichlorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.8); N-tert-butyl-4-[[2-(3-fluorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.9); N-tert-butyl-4-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.10); N-tert-butyl-4-[[2-(p-methylphenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.11); N-tert-butyl-4-[[2-(2-fluorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.12); N-tert-butyl-4-[[2-(4-fluorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.13); N-tert-butyl-4-[[2-(m-tolyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.14); 4-[[2-(1,3-Benzoxazol-6-yl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (Compound 5.15); N-tert-butyl-4-[[2-(2-chloro-3-pyridinyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.16); N-tert-butyl-4-[[2-(2,6-dichlorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.17); N-tert-butyl-4-[[2-(4-chloro-3-fluoro-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.18); N-tert-butyl-4-[[2-(3,5-dichlorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.19); N-tert-butyl-4-[[2-(2-chlorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.20); N-tert-butyl-4-[[2-(3-chloro-4-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.21); N-tert-butyl-4-(indane-1-carbonylamino)pyridine-2-carboxamide (Compound 5.22); N-tert-butyl-4-[(2-quinoxalin-6-ylacetyl)amino]pyridine-2-carboxamide (Compound 5.23); N-tert-butyl-4-[[2-(2-naphthyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.24); N-tert-butyl-4-(2,3-dihydrobenzofuran-3-carbonylamino)pyridine-2-carboxamide (Compound 5.25); N-tert-butyl-4-(6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-carbonylamino)pyridine-2-carboxamide (Compound 5.26); N-tert-butyl-4-(1,2,3,4-tetrahydronaphthalene-1-carbonylamino)pyridine-2-carboxamide (Compound 5.27); N-tert-butyl-4-[[2-(6-quinolinyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.29); N-tert-butyl-4-[[1-(3-chlorophenyl)cyclopropanecarbonyl]amino]pyridine-2-carboxamide (Compound 5.31); N-tert-butyl-4-[[2-(2,3-dihydro-1,4-benzodioxin-6-yl)acetyl]amino]pyridine-2-carboxamide (Compound 5.32); N-(1,1-dimethylprop-2-ynyl)-4-[(2-isochroman-1-ylacetyl)amino]pyridine-2-carboxamide (Compound 5.33); 4-[[2-(4,4-difluorocyclohexyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 5.34); N-(1,1-dimethylprop-2-ynyl)-4-[[2-[4-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 5.35); N-(1,1-dimethylprop-2-ynyl)-4-[[2-[3-(trifluoromethyl)-1H-pyrazol-4-yl]acetyl]amino]pyridine-2-carboxamide (Compound 5.36); N-(1,1-dimethylprop-2-ynyl)-4-[[2-[3-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 5.37); N-(1,1-dimethylprop-2-ynyl)-4-[[2-[2-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 5.38); 4-[[2-(2,3-dihydro-1,4-benzoxazin-4-yl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 5.39); N-tert-butyl-4-[[2-(5-cyano-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 6); 3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1,2,2-tetramethylpropyl)benzamide (Compound 7); 3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylbutyl)benzamide (Compound 7.1); 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylbutyl)pyridine-2-carboxamide (Compound 7.2); 3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-cyclohexyl-benzamide (Compound 7.3); 3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-tetrahydropyran-4-yl-benzamide (Compound 7.4); 3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1,2-trimethylpropyl)benzamide (Compound 7.5); 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1,2-trimethylpropyl)pyridine-2-carboxamide (Compound 7.6); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-isopropyl-pyridine-2-carboxamide (Compound 7.7); 3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4-methyltetrahydropyran-4-yl)benzamide (Compound 7.8); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4-methyltetrahydropyran-4-yl)pyridine-2-carboxamide (Compound 7.9); 3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclobutyl)benzamide (Compound 7.10); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-tetrahydropyran-4-yl-pyridine-2-carboxamide (Compound 7.11); 4-[2-(5-chloro-2-hydroxyphenyl)acetylamino]-N-[(1s,4s)-4-hydroxycyclohexyl]pyridine-2-carboxamide (Compound 7.12); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-sec-butyl-pyridine-2-carboxamide (Compound 7.13); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(2-hydroxy-1,1,2-trimethyl-propyl)pyridine-2-carboxamide (Compound 7.14); N-(3-Bicyclo[1.1.1]pentyl)-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 7.15); 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-cyanocyclobutyl)pyridine-2-carboxamide (Compound 7.16); 3-[[3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]benzoyl]amino]piperidine-1-carboxylic acid tert-butyl ester (Compound 8); 3-[[4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carbonyl]amino]piperidine-1-carboxylic acid tert-butyl ester (Compound 8.1); 4-[[3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]benzoyl]amino]-4-methyl-piperidine-1-carboxylic acid tert-butyl ester (Compound 8.2); (1r,5s,6s)-6-{4-[2-(5-chloro-2-hydroxyphenyl)acetylamino]pyridine-2-amido}-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (Compound 8.3); N-tert-butyl-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-4-fluoro-benzamide (Compound 9); N-tert-butyl-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-5-methyl-benzamide (Compound 9.1); 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylpropyl)pyridine-2-carboxamide (Compound 9.2); N-tert-butyl-4-[[2-(5-tert-butyl-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 10); N-tert-butyl-5-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-2-hydroxy-benzamide (Compound 11); N-tert-butyl-3-[[2-(5-cyano-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 12); 3-[2-[[2-(tert-Butylcarbamoyl)-4-pyridinyl]amino]-2-oxo-ethyl]-4-hydroxy-benzoic acid methyl ester (Compound 13); N-tert-butyl-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-4-hydroxy-benzamide (Compound 14); N-tert-butyl-4-[[2-(2-hydroxy-5-methyl-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 15); N-tert-butyl-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-4-methoxy-benzamide (Compound 16); N-tert-Butyl-5-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-2-fluoro-benzamide (Compound 17); N-tert-butyl-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-5-fluoro-benzamide (Compound 18); N-tert-butyl-4-[[2-(3-hydroxy-2-pyridinyl)acetyl]amino]pyridine-2-carboxamide (Compound 19); N-tert-butyl-4-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 20); N-tert-butyl-4-[[(1R) or (1S)-indane-1-carbonyl]amino]pyridine-2-carboxamide (Compound 21a); N-tert-butyl-4-[[(1R) or (1S)-indane-1-carbonyl]amino]pyridine-2-carboxamide (Compound 21b); N-tert-Butyl-4-[(2-phenylacetyl)amino]pyridine-2-carboxamide (Compound 22); 4-(3,3-dimethylbutyrylamino)-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 22.1); 4-[(2-Cyclopentylacetyl)amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 22.2); 4-[[2-(3-chloro-4-pyridinyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 22.3); 4-[[2-(4-chlorophenyl)acetyl]amino]-N-(1-cyanocyclopropyl)pyridine-2-carboxamide (Compound 23); 4-[[2-(3-chlorophenyl)acetyl]amino]-N-(1-cyanocyclopropyl)pyridine-2-carboxamide (Compound 23.1); 4-[[2-(2-Chloro-5-fluoro-phenyl)acetyl]amino]-N-(1-cyanocyclopropyl)pyridine-2-carboxamide (Compound 23.2); N-tert-butyl-4-(indane-2-carbonylamino)pyridine-2-carboxamide (Compound 23.3); N-tert-butyl-4-[[2-[2-(difluoromethoxy)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 23.4); N-tert-butyl-4-[[2-[2-(difluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 23.5); N-tert-butyl-4-[[2-(3,4-difluorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 23.6); N-tert-butyl-4-[[2-(3,5-difluorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 23.7); N-tert-butyl-4-[[2-(2,3-difluorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 23.8); 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-tetrahydropyran-4-yl-pyridine-2-carboxamide (Compound 23.9); N-(1-cyanocyclobutyl)-4-[[2-(6-quinolinyl)acetyl]amino]pyridine-2-carboxamide (Compound 23.11); N-tert-butyl-4-[[2-[2-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 23.12); 4-[[2-(2-bromophenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (Compound 23.13); N-tert-butyl-4-[[2-(2-cyanophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 23.14); 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(4-cyanotetrahydropyran-4-yl)pyridine-2-carboxamide (Compound 23.15); N-(4-cyanotetrahydropyran-4-yl)-4-[[2-(6-quinolinyl)acetyl]amino]pyridine-2-carboxamide (Compound 23.16); 4-[[2-(2-Chloro-5-methoxy-phenyl)acetyl]amino]-N-(1-cyanocyclopropyl)pyridine-2-carboxamide (Compound 24); N-(3-Bicyclo[1.1.1]pentyl)-4-[[2-(5-tert-butyl-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 25); -[[2-(5-tert-butyl-2-hydroxy-phenyl)acetyl]amino]-N-(4-cyanotetrahydropyran-4-yl)pyridine-2-carboxamide (Compound 25.1); N-tert-butyl-4-[[2-(2-hydroxy-5-phenyl-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 26); N-tert-butyl-4-[[2-[5-chloro-2-hydroxy-4-(pyrrolidin-1-ylmethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 27); N-tert-butyl-4-[[2-[4-[(tert-butylamino)methyl]-5-chloro-2-hydroxy-phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 27.1); N-tert-butyl-4-[[2-[5-chloro-2-hydroxy-4-(morpholinomethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 27.2); N-tert-butyl-4-[[2-[5-chloro-4-[(3,3-difluoropyrrolidin-1-yl)methyl]-2-hydroxy-phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 27.3); N-tert-Butyl-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-5-fluoro-pyridine-2-carboxamide (Compound 28); N-tert-butyl-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-3-fluoro-pyridine-2-carboxamide (Compound 28.1); 4-[[2-(2-chlorophenyl)acetyl]amino]-N-(1-cyanocyclobutyl)pyridine-2-carboxamide (Compound 30); 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 30.1); 4-[[2-(2-chlorophenyl)acetyl]amino]-N-(4-fluoro-1-bicyclo[ 2.1.1]hexyl)pyridine-2-carboxamide (compound 30.2); 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(1-cyclopropyl-1-methyl-ethyl)pyridine-2-carboxamide (Compound 30.3); 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(1-cyano-1-methyl-ethyl)pyridine-2-carboxamide (Compound 30.3a); 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(1-methyl-3-bicyclo[1.1.1]pentyl)pyridine-2-carboxamide (Compound 30.4); 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(1-cyano-3-bicyclo[1.1.1]pentyl)pyridine-2-carboxamide (Compound 30.5); 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(2,2-difluorocyclopropyl)pyridine-2-carboxamide (Compound 30.6); 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(1-cyanocyclopropyl)pyridine-2-carboxamide (Compound 30.7); 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(1-methylcyclopropyl)pyridine-2-carboxamide (Compound 30.8); 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(3-fluoro-1-bicyclo[1.1.1]pentyl)pyridine-2-carboxamide (Compound 30.9); 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(2-fluoro-1,1-dimethyl-ethyl)pyridine-2-carboxamide (Compound 30.10); 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(4-ethynyltetrahydropyran-4-yl)pyridine-2-carboxamide (Compound 30.11); 4-[[2-(2-chlorophenyl)acetyl]amino]-N-(1-cyanocyclopentyl)pyridine-2-carboxamide (Compound 30.12); 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(2,2-difluoro-1,1-dimethyl-ethyl)pyridine-2-carboxamide (Compound 30.13); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4-cyanotetrahydropyran-4-yl)pyridine-2-carboxamide (Compound 31); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-ethynylcyclopentyl)pyridine-2-carboxamide (Compound 31.2); 4-[2-(5-chloro-2-hydroxyphenyl)acetylamino]-N-[(1s,2s)-2-hydroxycyclohexyl]pyridine-2-carboxamide (Compound 31.3); 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1S,2S)-2-hydroxycyclohexyl]pyridine-2-carboxamide or 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1R,2R)-2-hydroxycyclohexyl]pyridine-2-carboxamide (Compound 31.3a); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4-ethynyltetrahydropyran-4-yl)pyridine-2-carboxamide (Compound 31.4); N-[(6-amino-2-pyridinyl)methyl]-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 32); 12-[[4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carbonyl]amino]dodecanoic acid (Compound 32.1); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3-pyridylmethyl)pyridine-2-carboxamide (Compound 32.2); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(2-pyridinylmethyl)pyridine-2-carboxamide (Compound 32.3); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4-pyridinylmethyl)pyridine-2-carboxamide (Compound 32.4); 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(2-hydroxyphenyl)methyl]pyridine-2-carboxamide (Compound 32.5); 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethyl-2-morpholino-ethyl)pyridine-2-carboxamide (Compound 32.6); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(2-hydroxy-1,1-dimethyl-ethyl)pyridine-2-carboxamide (Compound 32.7); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3,3-difluoro-4-piperidinyl)pyridine-2-carboxamide (Compound 32.8); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1H-imidazol-2-yl)pyridine-2-carboxamide (Compound 32.9); 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1R,2R)-2-hydroxycyclopentyl]pyridine-2-carboxamide (Compound 33); 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-cyano-1-methyl-ethyl)pyridine-2-carboxamide (Compound 34); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[3-(hydroxymethyl)tetrahydrofuran-3-yl]pyridine-2-carboxamide (Compound 35); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(3R)-3-(hydroxymethyl)tetrahydrofuran-3-yl]pyridine-2-carboxamide or 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(3S)-3-(hydroxymethyl)tetrahydrofuran-3-yl]pyridine-2-carboxamide (Compound 35a); -[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(3R)-3-(hydroxymethyl)tetrahydrofuran-3-yl]pyridine-2-carboxamide or 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(3S)-3-(hydroxymethyl)tetrahydrofuran-3-yl]pyridine-2-carboxamide (Compound 35b); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4-hydroxy-4-methyl-cyclohexyl)pyridine-2-carboxamide as a 6:4 mixture of stereoisomers (Compound 35.1); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1s,2r)-2-(hydroxymethyl)cyclohexyl]pyridine-2-carboxamide (Compound 35.2); 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1s,3r)-3-hydroxycyclopentyl]pyridine-2-carboxamide (Compound 35.3); 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-[2-hydroxy-1-(hydroxymethyl)-1-methyl-ethyl]pyridine-2-carboxamide (Compound 35.4); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3-hydroxycyclohexyl)pyridine-2-carboxamide as a mixture of stereoisomers (Compound 35.6); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3-phenoxypropyl)pyridine-2-carboxamide (Compound 35.7); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclopropyl)pyridine-2-carboxamide (Compound 35.8); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[1-methyl-1-(2-pyridinyl)ethyl]pyridine-2-carboxamide (Compound 35.9); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3-phenylpropyl)pyridine-2-carboxamide (Compound 35.10); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[2-hydroxy-1-(2-pyridinyl)ethyl]pyridine-2-carboxamide (Compound 35.11); 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(5-methoxy-2-pyridinyl)methyl]pyridine-2-carboxamide (Compound 35.12); 3-[[4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carbonyl]amino]-3-methyl-butyric acid ethyl ester (Compound 35.13); 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3-hydroxy-1,1-dimethyl-propyl)pyridine-2-carboxamide (Compound 35.14); N-benzyl-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 35.15); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-phenyl-pyridine-2-carboxamide (Compound 35.16); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1S,2S)-2-hydroxycyclopentyl]pyridine-2-carboxamide (Compound 35.17); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1R,2S)-2-hydroxycyclopentyl]pyridine-2-carboxamide (Compound 35.18); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1S,2R)-2-hydroxycyclopentyl]pyridine-2-carboxamide (Compound 35.19); 3-[[2-(5-Fluoro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclohexyl)benzamide (Compound 35.20); N-(1,1-dimethylprop-2-ynyl)-3-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 35.21); N-cyclohexyl-3-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 35.22); 3-[[2-(5-Fluoro-2-hydroxy-phenyl)acetyl]amino]-N-[3-(hydroxymethyl)tetrahydrofuran-3-yl]benzamide (Compound 35.23); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-ethynylcyclohexyl)pyridine-2-carboxamide (Compound 35.24); 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-[1-(hydroxymethyl)cyclobutyl]pyridine-2-carboxamide (Compound 35.25); 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-[3-(hydroxymethyl)oxetane-3-yl]pyridine-2-carboxamide (Compound 35.26); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-cyano-2-methoxy-1-methyl-ethyl)pyridine-2-carboxamide (Compound 35.27); 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1-hydroxycyclobutyl)methyl]pyridine-2-carboxamide (Compound 35.28); 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 36); 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-cyano-1,2-dimethyl-propyl)pyridine-2-carboxamide (Compound 37); 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclopentyl)pyridine-2-carboxamide (Compound 38); N-(4-tert-Butylcyclohexyl)-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 39); N-tert-butyl-4-[[2-(2-chloro-3-fluoro-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 40); N-tert-butyl-4-[[2-(2-chloro-5-fluoro-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 40.1); N-(4-cyanotetrahydropyran-4-yl)-3-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 41); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[4-(2-hydroxyethyl)tetrahydropyran-4-yl]pyridine-2-carboxamide (Compound 42); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[1,1-dimethyl-3-(2,2,2-trifluoroethylamino)propyl]pyridine-2-carboxamide (Compound 43); 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4-fluoro-1-bicyclo[ 2.1.1]hexyl)pyridine-2-carboxamide (Compound 44); 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-[3-(2,2-dimethylpropionylamino)-1,1-dimethyl-propyl]pyridine-2-carboxamide (Compound 45); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-cyano-2-hydroxy-1-methyl-ethyl)pyridine-2-carboxamide (Compound 46); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1S)-1-cyano-2-hydroxy-1-methyl-ethyl]pyridine-2-carboxamide or 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1R)-1-cyano-2-hydroxy-1-methyl-ethyl]pyridine-2-carboxamide (Compound 46a); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1S)-1-cyano-2-hydroxy-1-methyl-ethyl]pyridine-2-carboxamide or 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1R)-1-cyano-2-hydroxy-1-methyl-ethyl]pyridine-2-carboxamide (Compound 46b); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3-cyanotetrahydrofuran-3-yl)pyridine-2-carboxamide (Compound 47); 2-[4-[[4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carbonyl]amino]tetrahydropyran-4-yl]acetic acid methyl ester (Compound 47.1); 4-[[4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carbonyl]amino]tetrahydropyran-4-carboxylic acid methyl ester (Compound 47.2); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3-cyanoxetan-3-yl)pyridine-2-carboxamide (Compound 47.3); 4-[[2-(5-Fluoro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclobutyl)pyridine-2-carboxamide (Compound 48); N-(4-cyanotetrahydropyran-4-yl)-4-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 48.1); N-[3-(tert-butylamino)-1,1-dimethyl-3-oxo-propyl]-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 49); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[3-(methylsulfonylamino)-1,1-dimethyl-propyl]pyridine-2-carboxamide (Compound 50); N-(3-Acetylamino-1,1-dimethyl-propyl)-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 51); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[4-(hydroxymethyl)tetrahydropyran-4-yl]pyridine-2-carboxamide (Compound 53); N-tert-butyl-4-[[2-[3-(1-hydroxyethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 54); N-tert-Butyl-5-chloro-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 55); N-tert-butyl-4-[[2-[5-chloro-2-[(4-methoxyphenyl)methoxy]phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 56); N-tert-butyl-4-[[(1S) or (1R)-4-chloro-7-hydroxy-indane-1-carbonyl]amino]pyridine-2-carboxamide and Example 57b: N-tert-butyl-4-[[(1S) or (1R)-4-chloro-7-hydroxy-indane-1-carbonyl]amino]pyridine-2-carboxamide (Compound 57a); N-tert-butyl-4-[[(1S) or (1R)-4-chloro-7-hydroxy-indane-1-carbonyl]amino]pyridine-2-carboxamide and Example 57b: N-tert-butyl-4-[[(1S) or (1R)-4-chloro-7-hydroxy-indane-1-carbonyl]amino]pyridine-2-carboxamide (Compound 57b); N-tert-butyl-4-[[2-(2-cyclopropylphenyl)acetyl]amino]pyridine-2-carboxamide (Compound 58); 4-[[2-(3-Bromo-5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (Compound 59); N-(4-fluoro-1-bicyclo[ 2.1.1]hexyl)-4-[[2-(2-fluorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 60); N-(1-cyano-2-hydroxy-1-methyl-ethyl)-4-[[2-(2-fluorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 60.1); N-(1,1-dimethylprop-2-ynyl)-4-[[2-(2-fluorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 60.2); N-tert-butyl-4-[[2-(5-chloro-2-hydroxy-3-isopropyl-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 61); N-tert-butyl-4-[[2-[5-chloro-2-hydroxy-3-(1-methoxyethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 62); 4-[[2-(6-quinolyl)acetyl]amino]-N-tetrahydropyran-4-yl-pyridine-2-carboxamide (Compound 63); 4-(Benzylcarbamoylamino)-N-tert-butyl-pyridine-2-carboxamide (Compound 64); N-tert-butyl-4-(cyclohexylmethylcarbamoylamino)pyridine-2-carboxamide (Compound 64.1); N-tert-butyl-4-(2-phenylethylcarbamoylamino)pyridine-2-carboxamide (Compound 64.2); N-tert-butyl-4-[[(1R)-1-phenylethyl]carbamoylamino]pyridine-2-carboxamide (Compound 64.3); N-tert-butyl-4-[[(1S)-1-phenylethyl]carbamoylamino]pyridine-2-carboxamide (Compound 64.4); N-tert-butyl-4-[(2-chlorophenyl)methylcarbamoylamino]pyridine-2-carboxamide (Compound 64.5); N-tert-butyl-4-(1H-indol-3-ylcarbamoylamino)pyridine-2-carboxamide (Compound 64.6); N-tert-butyl-4-[(3-chlorophenyl)methylcarbamoylamino]pyridine-2-carboxamide (Compound 64.7); N-tert-butyl-4-[(4-chlorophenyl)methylcarbamoylamino]pyridine-2-carboxamide (Compound 64.8); N-tert-butyl-4-[(2-hydroxyphenyl)carbamoylamino]pyridine-2-carboxamide (Compound 65); N-tert-butyl-4-[(2-methoxyphenyl)methylcarbamoylamino]pyridine-2-carboxamide (Compound 65.1); N-tert-butyl-4-[(2-hydroxyphenyl)methylcarbamoylamino]pyridine-2-carboxamide (Compound 65.2); N-tert-butyl-4-[(3-hydroxyphenyl)methylcarbamoylamino]pyridine-2-carboxamide (Compound 65.3); N-tert-butyl-4-[(4-hydroxyphenyl)methylcarbamoylamino]pyridine-2-carboxamide (Compound 65.4); N-tert-butyl-4-[[2-[2-hydroxy-5-(1-hydroxyethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 66); N-tert-butyl-4-[[2-[2-hydroxy-5-[1-(2,2,2-trifluoroethylamino)ethyl]phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 67); N-tert-butyl-4-[[2-[3-(cyanomethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 68); N-tert-butyl-4-[[2-[3-(methoxymethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 69); N-tert-butyl-4-[[2-[2-hydroxy-5-(morpholinomethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 70); 3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3-cyanotetrahydrofuran-3-yl)benzamide (Compound 71); 3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclohexyl)benzamide (Compound 71.1); 4-[[2-(5-Fluoro-2-hydroxy-phenyl)acetyl]amino]-N-[3-(hydroxymethyl)tetrahydrofuran-3-yl]pyridine-2-carboxamide (Compound 72); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[1-(hydroxymethyl)-2-methoxy-1-methyl-ethyl]pyridine-2-carboxamide (Compound 73); 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylbut-2-ynyl)pyridine-2-carboxamide (Compound 73.1); 3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)benzamide (Compound 74); 3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-[3-(hydroxymethyl)tetrahydrofuran-3-yl]benzamide (Compound 74.1); N-tert-butyl-4-[[2-[2-hydroxy-5-(3-hydroxypropyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 75); 4-[[2-(5-Chloro-4-fluoro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclobutyl)pyridine-2-carboxamide (Compound 76); 4-[[2-(2,5-Difluorophenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 77); 4-[[2-(2,5-difluorophenyl)acetyl]amino]-N-(4-fluoro-1-bicyclo[ 2.1.1]hexyl)pyridine-2-carboxamide (compound 77.1); 4-[[2-(4-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 78); N-(1,1-dimethylprop-2-ynyl)-4-[[2-[2-hydroxy-4-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 78.1); N-(1,1-dimethylprop-2-ynyl)-4-[[2-[2-hydroxy-5-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 78.2); 4-[(2-Chroman-4-ylacetyl)amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 79); N-(1,1-dimethylprop-2-ynyl)-4-[[2-(1-isopropyl-3,5-dimethyl-pyrazol-4-yl)acetyl]amino]pyridine-2-carboxamide (Compound 79.1); N-(1,1-dimethylprop-2-ynyl)-4-[[2-(1H-indazol-4-yl)acetyl]amino]pyridine-2-carboxamide (Compound 79.2); N-(1,1-dimethylprop-2-ynyl)-4-[[2-(1H-indol-7-yl)acetyl]amino]pyridine-2-carboxamide (Compound 79.3); 3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4-cyanotetrahydropyran-4-yl)benzamide (Compound 80); N-(1-cyano-1-methyl-ethyl)-4-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 81); N-(1-cyano-2-hydroxy-1-methyl-ethyl)-4-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 81.1); 4-[[2-(5-Fluoro-2-hydroxy-phenyl)acetyl]amino]-N-isopropyl-pyridine-2-carboxamide (Compound 81.2); N-(1,1-dimethylprop-2-ynyl)-4-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 81.3); N-(4-fluoro-1-bicyclo[ 2.1.1]hexyl)-4-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 81.4); 4-[[2-(5-Fluoro-2-hydroxy-phenyl)acetyl]amino]-N-[1-(hydroxymethyl)cyclobutyl]pyridine-2-carboxamide (Compound 81.5); N-tert-butyl-6-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]pyrimidine-4-carboxamide (Compound 82); N-(1-cyano-1-methyl-ethyl)-4-(thiophene-3-carbonylamino)pyridine-2-carboxamide (Compound 83); N-(1-cyano-1-methyl-ethyl)-4-[(2-cyclohexylacetyl)amino]pyridine-2-carboxamide (Compound 83.1); N-(1-cyano-1-methyl-ethyl)-4-(cyclohexanecarbonylamino)pyridine-2-carboxamide (Compound 83.2); N-(1-cyano-1-methyl-ethyl)-4-[(3,3-difluorocyclopentanecarbonyl)amino]pyridine-2-carboxamide (Compound 83.3); N-(1-cyano-1-methyl-ethyl)-4-[(1-methylcyclopentanecarbonyl)amino]pyridine-2-carboxamide (Compound 83.4); N-(1-cyano-1-methyl-ethyl)-4-(3-cyclohexylpropionylamino)pyridine-2-carboxamide (Compound 83.5); 4-(2-{Bicyclo[2.2.1]hept-2-yl}acetylamino)-N-(1-cyano-1-methylethyl)pyridine-2-carboxamide (Compound 83.6); N-(1-cyano-1-methyl-ethyl)-4-[[2-(1-methylcyclohexyl)acetyl]amino]pyridine-2-carboxamide (Compound 83.7); N-[2-[(1-cyano-1-methyl-ethyl)carbamoyl]-4-pyridinyl]-2-cyclopropyl-pyrimidine-5-carboxamide (Compound 83.8); N-[2-[(1-cyano-1-methyl-ethyl)carbamoyl]-4-pyridinyl]-3-isobutyl-isoxazole-5-carboxamide (Compound 83.9); N-(1-cyano-1-methyl-ethyl)-4-[[2-(4,4-difluorocyclohexyl)acetyl]amino]pyridine-2-carboxamide (Compound 83.10); 4-[(1-benzylcyclopropanecarbonyl)amino]-N-(1-cyano-1-methyl-ethyl)pyridine-2-carboxamide (Compound 83.11); N-(1-cyano-1-methyl-ethyl)-4-[3-(2-methoxy-4-pyridinyl)propionylamino]pyridine-2-carboxamide (Compound 83.13); 4-[(5-tert-butyl-2-methyl-pyrazole-3-carbonyl)amino]-N-(1-cyano-1-methyl-ethyl)pyridine-2-carboxamide (Compound 83.14); N-(1-cyano-1-methyl-ethyl)-4-[(2-pyrazol-1-ylbenzoyl)amino]pyridine-2-carboxamide (Compound 83.15); N-[2-[(1-cyano-1-methyl-ethyl)carbamoyl]-4-pyridinyl]-6-(trifluoromethyl)pyridine-2-carboxamide (Compound 83.16); N-[2-[(1-cyano-1-methyl-ethyl)carbamoyl]-4-pyridinyl]-3-oxo-4H-1,4-benzoxazine-7-carboxamide (Compound 83.17); N-[2-[(1-cyano-1-methyl-ethyl)carbamoyl]-4-pyridinyl]-1-ethyl-indole-2-carboxamide (Compound 83.18); N-(1-cyano-1-methyl-ethyl)-4-[[2-(2,2,2-trifluoroethyl)pyrazole-3-carbonyl]amino]pyridine-2-carboxamide (Compound 83.19); N-[2-[(1-cyano-1-methyl-ethyl)carbamoyl]-4-pyridinyl]-3-phenyl-isoxazole-4-carboxamide (Compound 83.20); 4-[(1-benzylpyrazole-4-carbonyl)amino]-N-(1-cyano-1-methyl-ethyl)pyridine-2-carboxamide (Compound 83.21); N-(1-cyano-1-methyl-ethyl)-4-[(2-methyl-5-phenyl-pyrazole-3-carbonyl)amino]pyridine-2-carboxamide (Compound 83.22); N-(1-cyano-1-methyl-ethyl)-4-[[2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoyl]amino]pyridine-2-carboxamide (Compound 83.23); N-(1-cyano-1-methyl-ethyl)-4-[(3-methyl-1-phenyl-pyrazole-4-carbonyl)amino]pyridine-2-carboxamide (Compound 83.24); N-[2-[(1-cyano-1-methyl-ethyl)carbamoyl]-4-pyridinyl]-2-phenoxy-pyridine-3-carboxamide (Compound 83.25); N-(1-cyano-1-methyl-ethyl)-4-[[2,5-dimethyl-1-(2-thienylmethyl)pyrrole-3-carbonyl]amino]pyridine-2-carboxamide (Compound 83.26); N-[2-[(1-cyano-1-methyl-ethyl)carbamoyl]-4-pyridinyl]-5-(2-methoxyphenyl)isoxazole-3-carboxamide (Compound 83.27); N-[2-[(1-cyano-1-methyl-ethyl)carbamoyl]-4-pyridinyl]-4-methyl-2-phenyl-thiazole-5-carboxamide (Compound 83.28); 4-[(4-Acetylaminobenzoyl)amino]-N-(1-cyano-1-methyl-ethyl)pyridine-2-carboxamide (Compound 83.29); N-[2-[(1-cyano-1-methyl-ethyl)carbamoyl]-4-pyridinyl]-1,3-benzothiazole-7-carboxamide (Compound 83.30); N-(1-cyano-1-methyl-ethyl)-4-[3-(4-fluorophenyl)butyrylamino]pyridine-2-carboxamide (Compound 83.31); N-[2-[(1-cyano-1-methyl-ethyl)carbamoyl]-4-pyridinyl]-1-methyl-2-oxo-quinoline-3-carboxamide (Compound 83.32); N-tert-butyl-3-[[2-(2-hydroxycyclohexyl)acetyl]amino]benzamide (Compound 84); N-tert-Butyl-6-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyrimidine-4-carboxamide (Compound 85); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[1-cyano-2-methoxy-1-(methoxymethyl)ethyl]pyridine-2-carboxamide (Compound 86); 4-[[2-(3-Amino-4-tert-butyl-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (Compound 87); 4-[[2-(2-Amino-4-tert-butyl-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (Compound 88); N-tert-butyl-4-[[2-(4-tert-butyl-3-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 89); N-tert-butyl-4-[[2-(4-tert-butyl-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 90); N-tert-butyl-4-[[2-(4-tert-butyl-2-fluoro-5-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 91); 4-[[2-(4-Chloro-3-hydroxy-phenyl)acetyl]amino]-N-(4-cyanotetrahydropyran-4-yl)pyridine-2-carboxamide (Compound 92); 4-[[2-(4-Chloro-3-hydroxy-phenyl)acetyl]amino]-N-(1-cyano-1-methyl-ethyl)pyridine-2-carboxamide (Compound 92.1); 4-[[2-(4-chloro-3-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 92.2); 4-[[2-(4-chloro-3-hydroxy-phenyl)acetyl]amino]-N-[(1s,2s)-2-hydroxycyclopentyl]pyridine-2-carboxamide (Compound 92.3); 4-[[2-(4-tert-butyl-3-hydroxy-phenyl)acetyl]amino]-N-[3-(hydroxymethyl)tetrahydrofuran-3-yl]pyridine-2-carboxamide (Compound 93); 4-[[2-(4-tert-Butyl-3-hydroxy-phenyl)acetyl]amino]-N-[(2S)-2-hydroxycyclohexyl]pyridine-2-carboxamide (Compound 93.1); 4-[[2-(4-tert-Butyl-3-hydroxy-phenyl)acetyl]amino]-N-[(2S)-2-hydroxycyclopentyl]pyridine-2-carboxamide (Compound 93.2); 4-[[2-(4-tert-Butyl-3-hydroxy-phenyl)acetyl]amino]-N-(4-cyanotetrahydropyran-4-yl)pyridine-2-carboxamide (Compound 93.3); 4-[[2-(4-tert-Butyl-3-hydroxy-phenyl)acetyl]amino]-N-(1-cyano-1-methyl-ethyl)pyridine-2-carboxamide (Compound 93.4); 4-[[2-(4-tert-Butyl-3-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 93.5); and 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methyl-1-phenyl-ethyl)pyridine-2-carboxamide (Compound 94); and salts and solvates of any of the above.

23. The compound for use, use or method according to any one of claims 1 to 22, wherein the general formula (I), (Iz), (Iy), The compound of (Ix), (Ia), (Ib), (Ic), (Id) or (Ie) is used in combination with another active agent for treating or preventing respiratory disorders.

24. A compound of formula (I), (Iz), (Iy), (Ix), (Ia), (Ib), (Ic), (Id) or (Ie) as defined in any one of claims 1 or 10 to 22, provided that: When X 1 N and X 2 When CH, Z is -C(O)- and Y is a bond, R 4 is not a 5- to 10-membered heteroaryl or heterocyclic ring connected to Y via a nitrogen atom; and When X 1 and X 2 When both are CH, R 4 is phenyl having OH in the 2- or 3-position and optionally having one or more further substituents as defined in claim 1; and When X 1 is CH and X 2 When N is: When Z is -C(O)-, Y is not a bond; and When Z is -C(O)NH- and Y is a bond, R 4 is not a 12-membered heteroaryl ring system; and When X 1 and X 2 are all N, and when R 1 and R 2 One of them is H and R 1 and R 2 When the other is H or methyl, R 3 It is not substituted or unsubstituted phenyl.

25. A compound according to claim 24, selected from: N-tert-butyl-4-[[2-(2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (Compound 1); N-(1,1-dimethylpropyl)-3-[[2-(2-hydroxyphenyl)acetyl]amino]benzamide (Compound 1.1); N-(1-adamantyl)-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 1.2); N-(1-adamantyl)-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 1.3); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3-methoxy-1,1-dimethyl-propyl)pyridine-2-carboxamide (Compound 1.4); 3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylpropyl)benzamide (Compound 1.5); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclobutyl)pyridine-2-carboxamide (Compound 1.6); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclohexyl)pyridine-2-carboxamide (Compound 1.7); N-[3-[[4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carbonyl]amino]-3-methyl-butyl]carbamic acid tert-butyl ester (Compound 1.8); 3-[[2-(2-Hydroxyphenyl)acetyl]amino]-N-(2-methoxy-1,1-dimethyl-ethyl)benzamide (Compound 1.9); 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-cyclohexyl-pyridine-2-carboxamide (Compound 1.10); N-tert-butyl-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 2); N-tert-butyl-3-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 2.1); N-tert-butyl-3-[[2-(3-fluoro-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 2.2); N-tert-butyl-3-[[2-(4-fluoro-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 2.3); N-tert-butyl-3-[[2-(2,6-dihydroxyphenyl)acetyl]amino]benzamide (Compound 2.4); N-tert-butyl-3-[3-(2-hydroxyphenyl)propionylamino]benzamide (Compound 2.5); N-tert-butyl-3-[[2-(2-hydroxy-6-methoxy-phenyl)acetyl]amino]benzamide (Compound 2.6); N-tert-butyl-3-[2-(2-hydroxyphenyl)propionylamino]benzamide (Compound 2.7); N-tert-butyl-3-[[2-(2-hydroxy-3-methoxy-phenyl)acetyl]amino]benzamide (Compound 2.8); N-tert-butyl-3-[[2-(3,5-difluoro-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 2.9); 3-[[2-(5-Bromo-2-hydroxy-phenyl)acetyl]amino]-N-tert-butyl-benzamide (Compound 2.10); N-tert-butyl-3-[[2-(2,3-difluoro-6-hydroxy-phenyl)acetyl]amino]benzamide (Compound 2.11); N-tert-butyl-3-[[2-(4,5-difluoro-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 2.12); N-(1,1-dimethylpropyl)-3-[[2-(4-fluoro-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 2.13); N-tert-butyl-3-[[2-(2-hydroxy-4-methoxy-phenyl)acetyl]amino]benzamide (Compound 2.14); N-tert-butyl-3-[[2-(2-fluoro-6-hydroxy-phenyl)acetyl]amino]benzamide (Compound 2.15); N-tert-butyl-3-[[2-(2,3-dihydroxyphenyl)acetyl]amino]benzamide (Compound 2.16); N-tert-butyl-3-[[2-[2-hydroxy-5-(trifluoromethyl)phenyl]acetyl]amino]benzamide (Compound 2.17); 3-[2-[3-(tert-Butylcarbamoyl)anilino]-2-oxo-ethyl]-4-hydroxy-benzoic acid methyl ester (Compound 2.18); N-tert-butyl-3-[[2-[2-hydroxy-4-(trifluoromethyl)phenyl]acetyl]amino]benzamide (Compound 2.19); N-tert-butyl-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3); N-(1,1-dimethylpropyl)-4-[[2-(4-fluoro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.1a); N-tert-butyl-4-[[2-(4-fluoro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.2a); N-tert-butyl-4-[[2-(2-chloro-6-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.3a); 4-[[2-(4-bromo-5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (Compound 3.4a); 4-[[2-(5-tert-butyl-2-hydroxy-phenyl)acetyl]amino]-N-(1-cyanocyclobutyl)pyridine-2-carboxamide (Compound 3.5a); 4-[[2-(5-tert-butyl-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclobutyl)pyridine-2-carboxamide (Compound 3.6a); N-tert-butyl-4-[2-(2,5-dibromo-3-fluoro-6-hydroxyphenyl)acetylamino]pyridine-2-carboxamide (Compound 3.7a); N-tert-butyl-4-[[2-[2-hydroxy-5-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 3.5b); N-tert-butyl-4-[[2-(4-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.6b); N-tert-butyl-4-[[2-[2-hydroxy-4-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 3.7b); N-tert-butyl-4-[[2-(2-hydroxy-5-methoxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.8b); N-tert-butyl-4-[(6-hydroxyindane-1-carbonyl)amino]pyridine-2-carboxamide (Compound 3.9b); N-tert-butyl-4-[(7-hydroxyindane-1-carbonyl)amino]pyridine-2-carboxamide (Compound 3.10b); N-tert-butyl-4-[[2-(2,5-dibromo-3-chloro-6-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.11b); N-tert-butyl-4-[[2-(3-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.12b); N-tert-butyl-4-[[2-(2-fluoro-5-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.13b); N-tert-butyl-4-[[2-(4-chloro-3-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.14b); N-tert-butyl-4-[[2-(2-chloro-3-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.15b); N-tert-butyl-4-[[2-(2-chloro-5-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.16b); N-tert-butyl-4-[[2-(3-chloro-5-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.17b); N-tert-butyl-3-[[2-(3-hydroxyphenyl)acetyl]amino]benzamide (Compound 4); N-tert-butyl-3-[[2-(1H-indazol-3-yl)acetyl]amino]benzamide (Compound 4.1); N-tert-butyl-3-[[2-(5-fluoro-1H-indol-3-yl)acetyl]amino]benzamide (Compound 4.2); N-tert-butyl-3-[[2-(2-hydroxyphenyl)acetyl]amino]benzamide (Compound 4.3); N-tert-butyl-4-[[2-(2-thienyl)acetyl]amino]pyridine-2-carboxamide (Compound 5); 4-[[2-(2-adamantyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (Compound 5.1); N-tert-butyl-4-[[2-(4-fluoro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.2); N-tert-butyl-4-[[2-(5-chloro-2-fluoro-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.3); N-tert-butyl-4-[[2-(2-furyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.4); N-tert-butyl-4-[[2-(3-chlorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.5); N-tert-butyl-4-[[2-(1H-indol-3-yl)acetyl]amino]pyridine-2-carboxamide (Compound 5.6); N-tert-butyl-4-[[2-(o-tolyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.7); N-tert-butyl-4-[[2-(3,4-dichlorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.8); N-tert-butyl-4-[[2-(3-fluorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.9); N-tert-butyl-4-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.10); N-tert-butyl-4-[[2-(p-methylphenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.11); N-tert-butyl-4-[[2-(2-fluorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.12); N-tert-butyl-4-[[2-(4-fluorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.13); N-tert-butyl-4-[[2-(m-tolyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.14); 4-[[2-(1,3-Benzoxazol-6-yl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (Compound 5.15); N-tert-butyl-4-[[2-(2-chloro-3-pyridinyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.16); N-tert-butyl-4-[[2-(2,6-dichlorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.17); N-tert-butyl-4-[[2-(4-chloro-3-fluoro-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.18); N-tert-butyl-4-[[2-(3,5-dichlorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.19); N-tert-butyl-4-[[2-(2-chlorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.20); N-tert-butyl-4-[[2-(3-chloro-4-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.21); N-tert-butyl-4-(indane-1-carbonylamino)pyridine-2-carboxamide (Compound 5.22); N-tert-butyl-4-[(2-quinoxalin-6-ylacetyl)amino]pyridine-2-carboxamide (Compound 5.23); N-tert-butyl-4-[[2-(2-naphthyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.24); N-tert-butyl-4-(2,3-dihydrobenzofuran-3-carbonylamino)pyridine-2-carboxamide (Compound 5.25); N-tert-butyl-4-(6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-carbonylamino)pyridine-2-carboxamide (Compound 5.26); N-tert-butyl-4-(1,2,3,4-tetrahydronaphthalene-1-carbonylamino)pyridine-2-carboxamide (Compound 5.27); N-tert-butyl-4-[[2-(6-quinolinyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.29); N-tert-butyl-4-[[1-(3-chlorophenyl)cyclopropanecarbonyl]amino]pyridine-2-carboxamide (Compound 5.31); N-tert-butyl-4-[[2-(2,3-dihydro-1,4-benzodioxin-6-yl)acetyl]amino]pyridine-2-carboxamide (Compound 5.32); N-(1,1-dimethylprop-2-ynyl)-4-[(2-isochroman-1-ylacetyl)amino]pyridine-2-carboxamide (Compound 5.33); 4-[[2-(4,4-difluorocyclohexyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 5.34); N-(1,1-dimethylprop-2-ynyl)-4-[[2-[4-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 5.35); N-(1,1-dimethylprop-2-ynyl)-4-[[2-[3-(trifluoromethyl)-1H-pyrazol-4-yl]acetyl]amino]pyridine-2-carboxamide (Compound 5.36); N-(1,1-dimethylprop-2-ynyl)-4-[[2-[3-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 5.37); N-(1,1-dimethylprop-2-ynyl)-4-[[2-[2-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 5.38); 4-[[2-(2,3-dihydro-1,4-benzoxazin-4-yl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 5.39); N-tert-butyl-4-[[2-(5-cyano-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 6); 3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1,2,2-tetramethylpropyl)benzamide (Compound 7); 3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylbutyl)benzamide (Compound 7.1); 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylbutyl)pyridine-2-carboxamide (Compound 7.2); 3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-cyclohexyl-benzamide (Compound 7.3); 3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-tetrahydropyran-4-yl-benzamide (Compound 7.4); 3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1,2-trimethylpropyl)benzamide (Compound 7.5); 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1,2-trimethylpropyl)pyridine-2-carboxamide (Compound 7.6); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-isopropyl-pyridine-2-carboxamide (Compound 7.7); 3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4-methyltetrahydropyran-4-yl)benzamide (Compound 7.8); 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4-methyltetrahydropyran-4-yl)pyridine-2-carboxamide (Compound 7.9); 3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclobutyl)benzamide (Compound 7.10); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-tetrahydropyran-4-yl-pyridine-2-carboxamide (Compound 7.11); 4-[2-(5-chloro-2-hydroxyphenyl)acetylamino]-N-[(1s,4s)-4-hydroxycyclohexyl]pyridine-2-carboxamide (Compound 7.12); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-sec-butyl-pyridine-2-carboxamide (Compound 7.13); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(2-hydroxy-1,1,2-trimethyl-propyl)pyridine-2-carboxamide (Compound 7.14); N-(3-Bicyclo[1.1.1]pentyl)-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 7.15); 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-cyanocyclobutyl)pyridine-2-carboxamide (Compound 7.16); 3-[[3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]benzoyl]amino]piperidine-1-carboxylic acid tert-butyl ester (Compound 8); 3-[[4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carbonyl]amino]piperidine-1-carboxylic acid tert-butyl ester (Compound 8.1); 4-[[3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]benzoyl]amino]-4-methyl-piperidine-1-carboxylic acid tert-butyl ester (Compound 8.2); (1r,5s,6s)-6-{4-[2-(5-chloro-2-hydroxyphenyl)acetylamino]pyridine-2-amido}-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (Compound 8.3); N-tert-butyl-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-4-fluoro-benzamide (Compound 9); N-tert-butyl-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-5-methyl-benzamide (Compound 9.1); 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylpropyl)pyridine-2-carboxamide (Compound 9.2); N-tert-butyl-4-[[2-(5-tert-butyl-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 10); N-tert-butyl-5-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-2-hydroxy-benzamide (Compound 11); N-tert-butyl-3-[[2-(5-cyano-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 12); 3-[2-[[2-(tert-Butylcarbamoyl)-4-pyridinyl]amino]-2-oxo-ethyl]-4-hydroxy-benzoic acid methyl ester (Compound 13); N-tert-butyl-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-4-hydroxy-benzamide (Compound 14); N-tert-butyl-4-[[2-(2-hydroxy-5-methyl-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 15); N-tert-butyl-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-4-methoxy-benzamide (Compound 16); N-tert-Butyl-5-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-2-fluoro-benzamide (Compound 17); N-tert-butyl-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-5-fluoro-benzamide (Compound 18); N-tert-butyl-4-[[2-(3-hydroxy-2-pyridinyl)acetyl]amino]pyridine-2-carboxamide (Compound 19); N-tert-butyl-4-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 20); N-tert-butyl-4-[[(1R) or (1S)-indane-1-carbonyl]amino]pyridine-2-carboxamide (Compound 21a); N-tert-butyl-4-[[(1R) or (1S)-indane-1-carbonyl]amino]pyridine-2-carboxamide (Compound 21b); N-tert-Butyl-4-[(2-phenylacetyl)amino]pyridine-2-carboxamide (Compound 22); 4-(3,3-dimethylbutyrylamino)-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 22.1); 4-[(2-Cyclopentylacetyl)amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 22.2); 4-[[2-(3-chloro-4-pyridinyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 22.3); 4-[[2-(4-Chlorophenyl)acetyl]amino]-N-(1-cyanocyclopropyl)pyridine-2-carboxamide (Compound 23); 4-[[2-(3-chlorophenyl)acetyl]amino]-N-(1-cyanocyclopropyl)pyridine-2-carboxamide (Compound 23.1); 4-[[2-(2-Chloro-5-fluoro-phenyl)acetyl]amino]-N-(1-cyanocyclopropyl)pyridine-2-carboxamide (Compound 23.2); N-tert-butyl-4-(indane-2-carbonylamino)pyridine-2-carboxamide (Compound 23.3); N-tert-butyl-4-[[2-[2-(difluoromethoxy)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 23.4); N-tert-butyl-4-[[2-[2-(difluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 23.5); N-tert-butyl-4-[[2-(3,4-difluorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 23.6); N-tert-butyl-4-[[2-(3,5-difluorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 23.7); N-tert-butyl-4-[[2-(2,3-difluorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 23.8); 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-tetrahydropyran-4-yl-pyridine-2-carboxamide (Compound 23.9); N-(1-cyanocyclobutyl)-4-[[2-(6-quinolinyl)acetyl]amino]pyridine-2-carboxamide (Compound 23.11); N-tert-butyl-4-[[2-[2-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 23.12); 4-[[2-(2-bromophenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (Compound 23.13); N-tert-butyl-4-[[2-(2-cyanophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 23.14); 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(4-cyanotetrahydropyran-4-yl)pyridine-2-carboxamide (Compound 23.15); N-(4-cyanotetrahydropyran-4-yl)-4-[[2-(6-quinolinyl)acetyl]amino]pyridine-2-carboxamide (Compound 23.16); 4-[[2-(2-Chloro-5-methoxy-phenyl)acetyl]amino]-N-(1-cyanocyclopropyl)pyridine-2-carboxamide (Compound 24); N-(3-Bicyclo[1.1.1]pentyl)-4-[[2-(5-tert-butyl-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 25); -[[2-(5-tert-butyl-2-hydroxy-phenyl)acetyl]amino]-N-(4-cyanotetrahydropyran-4-yl)pyridine-2-carboxamide (Compound 25.1); N-tert-butyl-4-[[2-(2-hydroxy-5-phenyl-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 26); N-tert-butyl-4-[[2-[5-chloro-2-hydroxy-4-(pyrrolidin-1-ylmethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 27); N-tert-butyl-4-[[2-[4-[(tert-butylamino)methyl]-5-chloro-2-hydroxy-phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 27.1); N-tert-butyl-4-[[2-[5-chloro-2-hydroxy-4-(morpholinomethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 27.2); N-tert-butyl-4-[[2-[5-chloro-4-[(3,3-difluoropyrrolidin-1-yl)methyl]-2-hydroxy-phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 27.3); N-tert-Butyl-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-5-fluoro-pyridine-2-carboxamide (Compound 28); N-tert-butyl-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-3-fluoro-pyridine-2-carboxamide (Compound 28.1); 4-[[2-(2-chlorophenyl)acetyl]amino]-N-(1-cyanocyclobutyl)pyridine-2-carboxamide (Compound 30); 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 30.1); 4-[[2-(2-chlorophenyl)acetyl]amino]-N-(4-fluoro-1-bicyclo[ 2.1.1]hexyl)pyridine-2-carboxamide (compound 30.2); 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(1-cyclopropyl-1-methyl-ethyl)pyridine-2-carboxamide (Compound 30.3); 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(1-cyano-1-methyl-ethyl)pyridine-2-carboxamide (Compound 30.3a); 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(1-methyl-3-bicyclo[1.1.1]pentyl)pyridine-2-carboxamide (Compound 30.4); 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(1-cyano-3-bicyclo[1.1.1]pentyl)pyridine-2-carboxamide (Compound 30.5); 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(2,2-difluorocyclopropyl)pyridine-2-carboxamide (Compound 30.6); 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(1-cyanocyclopropyl)pyridine-2-carboxamide (Compound 30.7); 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(1-methylcyclopropyl)pyridine-2-carboxamide (Compound 30.8); 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(3-fluoro-1-bicyclo[1.1.1]pentyl)pyridine-2-carboxamide (Compound 30.9); 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(2-fluoro-1,1-dimethyl-ethyl)pyridine-2-carboxamide (Compound 30.10); 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(4-ethynyltetrahydropyran-4-yl)pyridine-2-carboxamide (Compound 30.11); 4-[[2-(2-chlorophenyl)acetyl]amino]-N-(1-cyanocyclopentyl)pyridine-2-carboxamide (Compound 30.12); 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(2,2-difluoro-1,1-dimethyl-ethyl)pyridine-2-carboxamide (Compound 30.13); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4-cyanotetrahydropyran-4-yl)pyridine-2-carboxamide (Compound 31); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-ethynylcyclopentyl)pyridine-2-carboxamide (Compound 31.2); 4-[2-(5-chloro-2-hydroxyphenyl)acetylamino]-N-[(1s,2s)-2-hydroxycyclohexyl]pyridine-2-carboxamide (Compound 31.3); 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1S,2S)-2-hydroxycyclohexyl]pyridine-2-carboxamide or 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1R,2R)-2-hydroxycyclohexyl]pyridine-2-carboxamide (Compound 31.3a); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4-ethynyltetrahydropyran-4-yl)pyridine-2-carboxamide (Compound 31.4); N-[(6-amino-2-pyridinyl)methyl]-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 32); 12-[[4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carbonyl]amino]dodecanoic acid (Compound 32.1); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3-pyridylmethyl)pyridine-2-carboxamide (Compound 32.2); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(2-pyridinylmethyl)pyridine-2-carboxamide (Compound 32.3); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4-pyridinylmethyl)pyridine-2-carboxamide (Compound 32.4); 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(2-hydroxyphenyl)methyl]pyridine-2-carboxamide (Compound 32.5); 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethyl-2-morpholino-ethyl)pyridine-2-carboxamide (Compound 32.6); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(2-hydroxy-1,1-dimethyl-ethyl)pyridine-2-carboxamide (Compound 32.7); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3,3-difluoro-4-piperidinyl)pyridine-2-carboxamide (Compound 32.8); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1H-imidazol-2-yl)pyridine-2-carboxamide (Compound 32.9); 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1R,2R)-2-hydroxycyclopentyl]pyridine-2-carboxamide (Compound 33); 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-cyano-1-methyl-ethyl)pyridine-2-carboxamide (Compound 34); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[3-(hydroxymethyl)tetrahydrofuran-3-yl]pyridine-2-carboxamide (Compound 35); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(3R)-3-(hydroxymethyl)tetrahydrofuran-3-yl]pyridine-2-carboxamide or 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(3S)-3-(hydroxymethyl)tetrahydrofuran-3-yl]pyridine-2-carboxamide (Compound 35a); -[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(3R)-3-(hydroxymethyl)tetrahydrofuran-3-yl]pyridine-2-carboxamide or 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(3S)-3-(hydroxymethyl)tetrahydrofuran-3-yl]pyridine-2-carboxamide (Compound 35b); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4-hydroxy-4-methyl-cyclohexyl)pyridine-2-carboxamide as a 6:4 mixture of stereoisomers (Compound 35.1); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1s,2r)-2-(hydroxymethyl)cyclohexyl]pyridine-2-carboxamide (Compound 35.2); 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1s,3r)-3-hydroxycyclopentyl]pyridine-2-carboxamide (Compound 35.3); 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-[2-hydroxy-1-(hydroxymethyl)-1-methyl-ethyl]pyridine-2-carboxamide (Compound 35.4); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3-hydroxycyclohexyl)pyridine-2-carboxamide as a mixture of stereoisomers (Compound 35.6); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3-phenoxypropyl)pyridine-2-carboxamide (Compound 35.7); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclopropyl)pyridine-2-carboxamide (Compound 35.8); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[1-methyl-1-(2-pyridinyl)ethyl]pyridine-2-carboxamide (Compound 35.9); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3-phenylpropyl)pyridine-2-carboxamide (Compound 35.10); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[2-hydroxy-1-(2-pyridinyl)ethyl]pyridine-2-carboxamide (Compound 35.11); 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(5-methoxy-2-pyridinyl)methyl]pyridine-2-carboxamide (Compound 35.12); 3-[[4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carbonyl]amino]-3-methyl-butyric acid ethyl ester (Compound 35.13); 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3-hydroxy-1,1-dimethyl-propyl)pyridine-2-carboxamide (Compound 35.14); N-benzyl-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 35.15); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-phenyl-pyridine-2-carboxamide (Compound 35.16); 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1S,2S)-2-hydroxycyclopentyl]pyridine-2-carboxamide (Compound 35.17); 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1R,2S)-2-hydroxycyclopentyl]pyridine-2-carboxamide (Compound 35.18); 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1S,2R)-2-hydroxycyclopentyl]pyridine-2-carboxamide (Compound 35.19); 3-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclohexyl)benzamide (Compound 35.20); N-(1,1-dimethylprop-2-ynyl)-3-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 35.21); N-cyclohexyl-3-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 35.22); 3-[[2-(5-Fluoro-2-hydroxy-phenyl)acetyl]amino]-N-[3-(hydroxymethyl)tetrahydrofuran-3-yl]benzamide (Compound 35.23); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-ethynylcyclohexyl)pyridine-2-carboxamide (Compound 35.24); 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-[1-(hydroxymethyl)cyclobutyl]pyridine-2-carboxamide (Compound 35.25); 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-[3-(hydroxymethyl)oxetane-3-yl]pyridine-2-carboxamide (Compound 35.26); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-cyano-2-methoxy-1-methyl-ethyl)pyridine-2-carboxamide (Compound 35.27); 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1-hydroxycyclobutyl)methyl]pyridine-2-carboxamide (Compound 35.28); 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 36); 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-cyano-1,2-dimethyl-propyl)pyridine-2-carboxamide (Compound 37); 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclopentyl)pyridine-2-carboxamide (Compound 38); N-(4-tert-Butylcyclohexyl)-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 39); N-tert-butyl-4-[[2-(2-chloro-3-fluoro-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 40); N-tert-butyl-4-[[2-(2-chloro-5-fluoro-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 40.1); N-(4-cyanotetrahydropyran-4-yl)-3-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 41); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[4-(2-hydroxyethyl)tetrahydropyran-4-yl]pyridine-2-carboxamide (Compound 42); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[1,1-dimethyl-3-(2,2,2-trifluoroethylamino)propyl]pyridine-2-carboxamide (Compound 43); 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4-fluoro-1-bicyclo[ 2.1.1]hexyl)pyridine-2-carboxamide (Compound 44); 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-[3-(2,2-dimethylpropionylamino)-1,1-dimethyl-propyl]pyridine-2-carboxamide (Compound 45); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-cyano-2-hydroxy-1-methyl-ethyl)pyridine-2-carboxamide (Compound 46); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1S)-1-cyano-2-hydroxy-1-methyl-ethyl]pyridine-2-carboxamide or 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1R)-1-cyano-2-hydroxy-1-methyl-ethyl]pyridine-2-carboxamide (Compound 46a); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1S)-1-cyano-2-hydroxy-1-methyl-ethyl]pyridine-2-carboxamide or 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1R)-1-cyano-2-hydroxy-1-methyl-ethyl]pyridine-2-carboxamide (Compound 46b); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3-cyanotetrahydrofuran-3-yl)pyridine-2-carboxamide (Compound 47); 2-[4-[[4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carbonyl]amino]tetrahydropyran-4-yl]acetic acid methyl ester (Compound 47.1); 4-[[4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carbonyl]amino]tetrahydropyran-4-carboxylic acid methyl ester (Compound 47.2); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3-cyanoxetan-3-yl)pyridine-2-carboxamide (Compound 47.3); 4-[[2-(5-Fluoro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclobutyl)pyridine-2-carboxamide (Compound 48); N-(4-cyanotetrahydropyran-4-yl)-4-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 48.1); N-[3-(tert-butylamino)-1,1-dimethyl-3-oxo-propyl]-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 49); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[3-(methylsulfonylamino)-1,1-dimethyl-propyl]pyridine-2-carboxamide (Compound 50); N-(3-Acetylamino-1,1-dimethyl-propyl)-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 51); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[4-(hydroxymethyl)tetrahydropyran-4-yl]pyridine-2-carboxamide (Compound 53); N-tert-butyl-4-[[2-[3-(1-hydroxyethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 54); N-tert-Butyl-5-chloro-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 55); N-tert-butyl-4-[[2-[5-chloro-2-[(4-methoxyphenyl)methoxy]phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 56); N-tert-butyl-4-[[(1S) or (1R)-4-chloro-7-hydroxy-indane-1-carbonyl]amino]pyridine-2-carboxamide and Example 57b: N-tert-butyl-4-[[(1S) or (1R)-4-chloro-7-hydroxy-indane-1-carbonyl]amino]pyridine-2-carboxamide (Compound 57a); N-tert-butyl-4-[[(1S) or (1R)-4-chloro-7-hydroxy-indane-1-carbonyl]amino]pyridine-2-carboxamide and Example 57b: N-tert-butyl-4-[[(1S) or (1R)-4-chloro-7-hydroxy-indane-1-carbonyl]amino]pyridine-2-carboxamide (Compound 57b); N-tert-butyl-4-[[2-(2-cyclopropylphenyl)acetyl]amino]pyridine-2-carboxamide (Compound 58); 4-[[2-(3-Bromo-5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (Compound 59); N-(4-fluoro-1-bicyclo[ 2.1.1]hexyl)-4-[[2-(2-fluorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 60); N-(1-cyano-2-hydroxy-1-methyl-ethyl)-4-[[2-(2-fluorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 60.1); N-(1,1-dimethylprop-2-ynyl)-4-[[2-(2-fluorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 60.2); N-tert-butyl-4-[[2-(5-chloro-2-hydroxy-3-isopropyl-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 61); N-tert-butyl-4-[[2-[5-chloro-2-hydroxy-3-(1-methoxyethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 62); 4-[[2-(6-quinolyl)acetyl]amino]-N-tetrahydropyran-4-yl-pyridine-2-carboxamide (Compound 63); 4-(Benzylcarbamoylamino)-N-tert-butyl-pyridine-2-carboxamide (Compound 64); N-tert-butyl-4-(cyclohexylmethylcarbamoylamino)pyridine-2-carboxamide (Compound 64.1); N-tert-butyl-4-(2-phenylethylcarbamoylamino)pyridine-2-carboxamide (Compound 64.2); N-tert-butyl-4-[[(1R)-1-phenylethyl]carbamoylamino]pyridine-2-carboxamide (Compound 64.3); N-tert-butyl-4-[[(1S)-1-phenylethyl]carbamoylamino]pyridine-2-carboxamide (Compound 64.4); N-tert-butyl-4-[(2-chlorophenyl)methylcarbamoylamino]pyridine-2-carboxamide (Compound 64.5); N-tert-butyl-4-(1H-indol-3-ylcarbamoylamino)pyridine-2-carboxamide (Compound 64.6); N-tert-butyl-4-[(3-chlorophenyl)methylcarbamoylamino]pyridine-2-carboxamide (Compound 64.7); N-tert-butyl-4-[(4-chlorophenyl)methylcarbamoylamino]pyridine-2-carboxamide (Compound 64.8); N-tert-butyl-4-[(2-hydroxyphenyl)carbamoylamino]pyridine-2-carboxamide (Compound 65); N-tert-butyl-4-[(2-methoxyphenyl)methylcarbamoylamino]pyridine-2-carboxamide (Compound 65.1); N-tert-butyl-4-[(2-hydroxyphenyl)methylcarbamoylamino]pyridine-2-carboxamide (Compound 65.2); N-tert-butyl-4-[(3-hydroxyphenyl)methylcarbamoylamino]pyridine-2-carboxamide (Compound 65.3); N-tert-butyl-4-[(4-hydroxyphenyl)methylcarbamoylamino]pyridine-2-carboxamide (Compound 65.4); N-tert-butyl-4-[[2-[2-hydroxy-5-(1-hydroxyethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 66); N-tert-butyl-4-[[2-[2-hydroxy-5-[1-(2,2,2-trifluoroethylamino)ethyl]phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 67); N-tert-butyl-4-[[2-[3-(cyanomethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 68); N-tert-butyl-4-[[2-[3-(methoxymethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 69); N-tert-butyl-4-[[2-[2-hydroxy-5-(morpholinomethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 70); 3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3-cyanotetrahydrofuran-3-yl)benzamide (Compound 71); 3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclohexyl)benzamide (Compound 71.1); 4-[[2-(5-Fluoro-2-hydroxy-phenyl)acetyl]amino]-N-[3-(hydroxymethyl)tetrahydrofuran-3-yl]pyridine-2-carboxamide (Compound 72); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[1-(hydroxymethyl)-2-methoxy-1-methyl-ethyl]pyridine-2-carboxamide (Compound 73); 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylbut-2-ynyl)pyridine-2-carboxamide (Compound 73.1); 3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)benzamide (Compound 74); 3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-[3-(hydroxymethyl)tetrahydrofuran-3-yl]benzamide (Compound 74.1); N-tert-butyl-4-[[2-[2-hydroxy-5-(3-hydroxypropyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 75); 4-[[2-(5-Chloro-4-fluoro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclobutyl)pyridine-2-carboxamide (Compound 76); 4-[[2-(2,5-Difluorophenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 77); 4-[[2-(2,5-difluorophenyl)acetyl]amino]-N-(4-fluoro-1-bicyclo[ 2.1.1]hexyl)pyridine-2-carboxamide (compound 77.1); 4-[[2-(4-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 78); N-(1,1-dimethylprop-2-ynyl)-4-[[2-[2-hydroxy-4-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 78.1); N-(1,1-dimethylprop-2-ynyl)-4-[[2-[2-hydroxy-5-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 78.2); 4-[(2-Chroman-4-ylacetyl)amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 79); N-(1,1-dimethylprop-2-ynyl)-4-[[2-(1-isopropyl-3,5-dimethyl-pyrazol-4-yl)acetyl]amino]pyridine-2-carboxamide (Compound 79.1); N-(1,1-dimethylprop-2-ynyl)-4-[[2-(1H-indazol-4-yl)acetyl]amino]pyridine-2-carboxamide (Compound 79.2); N-(1,1-dimethylprop-2-ynyl)-4-[[2-(1H-indol-7-yl)acetyl]amino]pyridine-2-carboxamide (Compound 79.3); 3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4-cyanotetrahydropyran-4-yl)benzamide (Compound 80); N-(1-cyano-1-methyl-ethyl)-4-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 81); N-(1-cyano-2-hydroxy-1-methyl-ethyl)-4-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 81.1); 4-[[2-(5-Fluoro-2-hydroxy-phenyl)acetyl]amino]-N-isopropyl-pyridine-2-carboxamide (Compound 81.2); N-(1,1-dimethylprop-2-ynyl)-4-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 81.3); N-(4-fluoro-1-bicyclo[ 2.1.1]hexyl)-4-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 81.4); 4-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]-N-[1-(hydroxymethyl)cyclobutyl]pyridine-2-carboxamide (Compound 81.5); N-tert-butyl-6-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]pyrimidine-4-carboxamide (Compound 82); N-(1-cyano-1-methyl-ethyl)-4-(thiophene-3-carbonylamino)pyridine-2-carboxamide (Compound 83); N-(1-cyano-1-methyl-ethyl)-4-[(2-cyclohexylacetyl)amino]pyridine-2-carboxamide (Compound 83.1); N-(1-cyano-1-methyl-ethyl)-4-(cyclohexanecarbonylamino)pyridine-2-carboxamide (Compound 83.2); N-(1-cyano-1-methyl-ethyl)-4-[(3,3-difluorocyclopentanecarbonyl)amino]pyridine-2-carboxamide (Compound 83.3); N-(1-cyano-1-methyl-ethyl)-4-[(1-methylcyclopentanecarbonyl)amino]pyridine-2-carboxamide (Compound 83.4); N-(1-cyano-1-methyl-ethyl)-4-(3-cyclohexylpropionylamino)pyridine-2-carboxamide (Compound 83.5); 4-(2-{Bicyclo[2.2.1]hept-2-yl}acetylamino)-N-(1-cyano-1-methylethyl)pyridine-2-carboxamide (Compound 83.6); N-(1-cyano-1-methyl-ethyl)-4-[[2-(1-methylcyclohexyl)acetyl]amino]pyridine-2-carboxamide (Compound 83.7); N-[2-[(1-cyano-1-methyl-ethyl)carbamoyl]-4-pyridinyl]-2-cyclopropyl-pyrimidine-5-carboxamide (Compound 83.8); N-[2-[(1-cyano-1-methyl-ethyl)carbamoyl]-4-pyridinyl]-3-isobutyl-isoxazole-5-carboxamide (Compound 83.9); N-(1-cyano-1-methyl-ethyl)-4-[[2-(4,4-difluorocyclohexyl)acetyl]amino]pyridine-2-carboxamide (Compound 83.10); 4-[(1-Benzylcyclopropanecarbonyl)amino]-N-(1-cyano-1-methyl-ethyl)pyridine-2-carboxamide (Compound 83.11); N-(1-cyano-1-methyl-ethyl)-4-[3-(2-methoxy-4-pyridinyl)propionylamino]pyridine-2-carboxamide (Compound 83.13); 4-[(5-tert-butyl-2-methyl-pyrazole-3-carbonyl)amino]-N-(1-cyano-1-methyl-ethyl)pyridine-2-carboxamide (Compound 83.14); N-(1-cyano-1-methyl-ethyl)-4-[(2-pyrazol-1-ylbenzoyl)amino]pyridine-2-carboxamide (Compound 83.15); N-[2-[(1-cyano-1-methyl-ethyl)carbamoyl]-4-pyridinyl]-6-(trifluoromethyl)pyridine-2-carboxamide (Compound 83.16); N-[2-[(1-cyano-1-methyl-ethyl)carbamoyl]-4-pyridinyl]-3-oxo-4H-1,4-benzoxazine-7-carboxamide (Compound 83.17); N-[2-[(1-cyano-1-methyl-ethyl)carbamoyl]-4-pyridinyl]-1-ethyl-indole-2-carboxamide (Compound 83.18); N-(1-cyano-1-methyl-ethyl)-4-[[2-(2,2,2-trifluoroethyl)pyrazole-3-carbonyl]amino]pyridine-2-carboxamide (Compound 83.19); N-[2-[(1-cyano-1-methyl-ethyl)carbamoyl]-4-pyridinyl]-3-phenyl-isoxazole-4-carboxamide (Compound 83.20); 4-[(1-Benzylpyrazole-4-carbonyl)amino]-N-(1-cyano-1-methyl-ethyl)pyridine-2-carboxamide (Compound 83.21); N-(1-cyano-1-methyl-ethyl)-4-[(2-methyl-5-phenyl-pyrazole-3-carbonyl)amino]pyridine-2-carboxamide (Compound 83.22); N-(1-cyano-1-methyl-ethyl)-4-[[2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoyl]amino]pyridine-2-carboxamide (Compound 83.23); N-(1-cyano-1-methyl-ethyl)-4-[(3-methyl-1-phenyl-pyrazole-4-carbonyl)amino]pyridine-2-carboxamide (Compound 83.24); N-[2-[(1-cyano-1-methyl-ethyl)carbamoyl]-4-pyridinyl]-2-phenoxy-pyridine-3-carboxamide (Compound 83.25); N-(1-cyano-1-methyl-ethyl)-4-[[2,5-dimethyl-1-(2-thienylmethyl)pyrrole-3-carbonyl]amino]pyridine-2-carboxamide (Compound 83.26); N-[2-[(1-cyano-1-methyl-ethyl)carbamoyl]-4-pyridinyl]-5-(2-methoxyphenyl)isoxazole-3-carboxamide (Compound 83.27); N-[2-[(1-cyano-1-methyl-ethyl)carbamoyl]-4-pyridinyl]-4-methyl-2-phenyl-thiazole-5-carboxamide (Compound 83.28); 4-[(4-Acetylaminobenzoyl)amino]-N-(1-cyano-1-methyl-ethyl)pyridine-2-carboxamide (Compound 83.29); N-[2-[(1-cyano-1-methyl-ethyl)carbamoyl]-4-pyridinyl]-1,3-benzothiazole-7-carboxamide (Compound 83.30); N-(1-cyano-1-methyl-ethyl)-4-[3-(4-fluorophenyl)butyrylamino]pyridine-2-carboxamide (Compound 83.31); N-[2-[(1-cyano-1-methyl-ethyl)carbamoyl]-4-pyridinyl]-1-methyl-2-oxo-quinoline-3-carboxamide (Compound 83.32); N-tert-butyl-3-[[2-(2-hydroxycyclohexyl)acetyl]amino]benzamide (Compound 84); N-tert-Butyl-6-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyrimidine-4-carboxamide (Compound 85); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[1-cyano-2-methoxy-1-(methoxymethyl)ethyl]pyridine-2-carboxamide (Compound 86); 4-[[2-(3-Amino-4-tert-butyl-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (Compound 87); 4-[[2-(2-Amino-4-tert-butyl-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (Compound 88); N-tert-butyl-4-[[2-(4-tert-butyl-3-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 89); N-tert-butyl-4-[[2-(4-tert-butyl-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 90); N-tert-butyl-4-[[2-(4-tert-butyl-2-fluoro-5-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 91); 4-[[2-(4-Chloro-3-hydroxy-phenyl)acetyl]amino]-N-(4-cyanotetrahydropyran-4-yl)pyridine-2-carboxamide (Compound 92); 4-[[2-(4-Chloro-3-hydroxy-phenyl)acetyl]amino]-N-(1-cyano-1-methyl-ethyl)pyridine-2-carboxamide (Compound 92.1); 4-[[2-(4-chloro-3-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 92.2); 4-[[2-(4-chloro-3-hydroxy-phenyl)acetyl]amino]-N-[(1s,2s)-2-hydroxycyclopentyl]pyridine-2-carboxamide (Compound 92.3); 4-[[2-(4-tert-butyl-3-hydroxy-phenyl)acetyl]amino]-N-[3-(hydroxymethyl)tetrahydrofuran-3-yl]pyridine-2-carboxamide (Compound 93); 4-[[2-(4-tert-butyl-3-hydroxy-phenyl)acetyl]amino]-N-[(2S)-2-hydroxycyclohexyl]pyridine-2-carboxamide (Compound 93.1); 4-[[2-(4-tert-butyl-3-hydroxy-phenyl)acetyl]amino]-N-[(2S)-2-hydroxycyclopentyl]pyridine-2-carboxamide (Compound 93.2); 4-[[2-(4-tert-butyl-3-hydroxy-phenyl)acetyl]amino]-N-(4-cyanotetrahydropyran-4-yl)pyridine-2-carboxamide (Compound 93.3); 4-[[2-(4-tert-Butyl-3-hydroxy-phenyl)acetyl]amino]-N-(1-cyano-1-methyl-ethyl)pyridine-2-carboxamide (Compound 93.4); 4-[[2-(4-tert-Butyl-3-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 93.5); and 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methyl-1-phenyl-ethyl)pyridine-2-carboxamide (Compound 94); and Salts and solvates of any of the above.

26. A process for preparing a compound as claimed in claim 24, said process comprising: A. For compounds of formula (I) wherein Z is -C(O)-: In the presence of a coupling agent, the compound of general formula (II): Where R 1 , R 2 , R 3 , R 5a , R 5b , X 1 and X 2 As defined in claim 24; Reaction with a compound of general formula (III): Where R 4 and Y is as defined in claim 24; or The compound of general formula (II) is reacted with an acid chloride of general formula (IV): Where R 4 and Y is as defined in claim 24; or B. For the case where Z is C(O)NH and Y is -C 1-2 Alkylene-compounds of formula (I): The compound of general formula (II) is reacted with the compound of general formula (XIV): O=C=N-Y 1 -R 4 (XIV) Where R 4 As defined in claim 24, and Y 1 is -CH2- or -CH2CH2-; C. For the compound of general formula (Ib) as defined in claim 21, wherein R 11a is Cl and R 11b is H: reacting the compound of general formula (II) with 5-chloro-2(3H)-benzofuranone having the following structure: or D. Compound of general formula (X): Where X 1 , X 2 , Y, R 4 , R 5a and R 5b As defined in claim 24; Reaction with a compound of general formula (VII): Where R 1 , R 2 and R 3 as defined in claim 24; or E. Compound of general formula (X): Where X 1 , X 2 , Y, R 4 , R 5a and R 5b As defined in claim 24, with a compound of formula (VII) as defined above; or F. In the presence of a phosphorus ligand and a palladium catalyst, the compound of formula (XV): Where X 1 , X 2 , Y, R 4 , R 5a and R 5b As defined in claim 24, and R 22 is a halo group; with an amine of formula (VII) as defined above and carbon monoxide; or G. Converting a compound of general formula (I) into another compound of general formula (I).

27. A pharmaceutical composition comprising a compound according to claims 24 and 25 and a pharmaceutically acceptable excipient.

28. A pharmaceutical composition according to claim 27, formulated for oral, rectal, nasal, bronchial (inhalation), topical (including dermal, transdermal, eye drop, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.

29. A pharmaceutical composition according to claim 27 or 28, further comprising an additional active agent for the treatment or prevention of a respiratory disorder.

30. A product comprising a compound of formula (I) and another active agent for the treatment or prevention of respiratory disorders as a combined preparation for simultaneous, sequential or separate use in the treatment of diseases or disorders affected by TMEM16A modulation.

31. A compound for use, use or method according to claim 23, a pharmaceutical composition according to claim 29 or a The product of claim 30, wherein the additional active agent for treating or preventing respiratory disorders is selected from: beta-2 adrenergic receptor agonists, such as metaproterenol, isoproterenol, isoproterenol, albuterol, salbutamol, formoterol, salmeterol, indacaterol, terbutaline, metaproterenol, bitolterol mesylate, pirbuterol, olodaterol, vilanterol, and abeterol; Antihistamines, for example histamine H1 receptor antagonists, for example loratadine, cetirizine, desloratadine, levocetirizine, fexofenadine, astemizole, astemizole and chlorpheniramine, or H4 receptor antagonists; Streptodornase alpha; Corticosteroids, such as prednisone, corticosterone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, mometasone furoate, and fluticasone furoate; Leukotriene antagonists, such as montelukast and zafirlukast; Anticholinergic compounds, in particular muscarinic antagonists, such as ipratropium, tiotropium, glycopyrrolate, aclidinium and umeclidinium; CFTR repair therapies (e.g., CFTR potentiators, modifiers, or amplifiers), such as ivacaftor, QBW251, VX659, VX445, VX561 / CPT-656, VX152, VX440, GLP2737, GLP2222, GLP2451, PTI438, PTI801, PTI808, FDL-169, and FDL-176, and CFTR modifiers, such as lumacaftor and tizacaftor; ENaC modulators, particularly ENaC inhibitors, such as: Amiloride, VX-371, AZD5634, QBW276, SPX-101, BI443651, ETD001, and a compound having a cation selected from: 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}carboxamido)ethyl]-6-(4-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}piperidine-1-carbonyl)-1,3-diethyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}carboxamido)methyl]-6-{[2-(4-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}piperidin-1-yl)ethyl]carbamoyl}-1,3-diethyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}carboxamido)methyl]-5-[4-({bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}methyl)piperidine-1-carbonyl]-1,3-diethyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}carboxamido)methyl]-6-[(3R)-3-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}pyrrolidine-1-carbonyl]-1,3-diethyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}carboxamido)methyl]-6-[(3S)-3-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}pyrrolidine-1-carbonyl]-1,3-diethyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}carboxamido)methyl]-1,3-diethyl-6-{[(1r,4r)-4-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}cyclohexyl]carbamoyl}-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-1,3-diethyl-6-{[(1s,4s)-4-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}cyclohexyl]carbamoyl}-1H-1,3-benzodiazol-3-ium; and a suitable anion, for example, halide, sulfate, nitrate, phosphate, formate, acetate, trifluoroacetate, fumarate, citrate, tartrate, oxalate, succinate, mandelate, methanesulfonate or p-toluenesulfonate; antibiotic; Airway moisturizers (osmolytes), such as hypertonic saline and mannitol and Mucolytics, such as N-acetylcysteine.

32. A process for the preparation of a pharmaceutical composition according to claim 27 or 28, said process comprising combining a compound according to claim 24 or 25 with an excipient.

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