WO2009027283A1 - Triazolopyridine compounds and their use as ask inhibitors - Google Patents

Triazolopyridine compounds and their use as ask inhibitors Download PDF

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Publication number
WO2009027283A1
WO2009027283A1 PCT/EP2008/060884 EP2008060884W WO2009027283A1 WO 2009027283 A1 WO2009027283 A1 WO 2009027283A1 EP 2008060884 W EP2008060884 W EP 2008060884W WO 2009027283 A1 WO2009027283 A1 WO 2009027283A1
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Prior art keywords
alkyl
pyridin
triazolo
optionally substituted
nicotinamide
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PCT/EP2008/060884
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French (fr)
Inventor
Dominique Swinnen
Catherine Jorand-Lebrun
Tania Grippi - Vallotton
Mathilde Muzerelle
Amanda Royle
Jacqueline Macritchie
Richard Hill
Jeffrey P. Shaw
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Merck Serono S.A.
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Priority to MX2010002312A priority Critical patent/MX2010002312A/en
Priority to CA002691448A priority patent/CA2691448A1/en
Priority to US12/666,445 priority patent/US8263595B2/en
Priority to AU2008291075A priority patent/AU2008291075A1/en
Priority to BRPI0816476A priority patent/BRPI0816476A2/en
Priority to JP2010522319A priority patent/JP2010536917A/en
Application filed by Merck Serono S.A. filed Critical Merck Serono S.A.
Priority to EA201070328A priority patent/EA201070328A1/en
Priority to CN200880104471XA priority patent/CN101878212A/en
Priority to EP08787340A priority patent/EP2181112A1/en
Publication of WO2009027283A1 publication Critical patent/WO2009027283A1/en
Priority to ZA2009/09152A priority patent/ZA200909152B/en
Priority to US13/483,324 priority patent/US20120238565A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
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    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • R3 is selected from a. hydrogen; b. halogen; and c. Ci-C 6 -alkyl optionally substituted with at least one fluoro;
  • heterocycloalkyl means a non-aromatic monocyclic or polycyclic ring comprising carbon and hydrogen atoms and at least one heteroatom selected from nitrogen, oxygen, and sulfur.
  • Cs-Cs-heterocycloalkyl, "C3- C10” etc. refers to the size of the corresponding heterocycloalkyl.
  • Particular examples of heterocycloalkyl groups include e.g. tetrahydrofuranyl, tetrahydro-2H-pyranyl, morpholinyl, pyrrolidinyl, piperidinyl, 2- oxopyrrolidinyl, piperazinyl.
  • R 2 is selected from a. hydrogen; b. halogen; c. aryl optionally substituted with Rio, Rn and/or Ri 2 ; and d. 5 to 10-membered heteroaryl having at least one heteroatom selected from N, S and O and optionally substituted with Ci-C 6 alkyl;
  • R3 is selected from a. hydrogen; b. halogen; and c. Ci-C ⁇ -alkyl optionally substituted with at least one fluoro;
  • R5 is selected from a. Ci-C ⁇ -alkyl optionally substituted with at least one of the following groups i. alkoxycarbonyl, ii. Ci-C ⁇ -alkoxy, iii. -NC(O)R' wherein R' is aryl optionally substituted with Ci-C ⁇ -alkyl, iv. benzyloxy; b. aryl-Ci-Ce-alkyl; c. 5 or 6-membered heteroaryl-Ci-C ⁇ -alkyl having a heteroatom selected from N, S and O optionally substituted with Ci-C ⁇ -alkyl, halogen or Ci-C ⁇ -alkoxy; d.
  • Ci-C ⁇ -alkyl optionally substituted with at least one of the following groups i. alkoxycarbonyl, ii. Ci-C ⁇ -alkoxy, iii. -NC(O)R' wherein R' is aryl optionally substituted with Ci-C ⁇ -al
  • R5 is selected from a. Ci-C ⁇ -alkyl optionally substituted with at least one of the following groups i. alkoxycarbonyl, ii. Ci-C ⁇ -alkoxy, iii. -NHC(O)R' wherein R' is aryl optionally substituted with Ci-C ⁇ -alkyl, iv. benzyloxy; b. aiyl-Ci-Ce-alkyl; c. 5 or 6-membered heteroaryl-Ci-C ⁇ -alkyl having a heteroatom selected from N, S and O optionally substituted with Ci-C ⁇ -alkyl, halogen or Ci-C ⁇ -alkoxy; d.
  • Ci-C ⁇ -alkyl optionally substituted with at least one of the following groups i. alkoxycarbonyl, ii. Ci-C ⁇ -alkoxy, iii. -NHC(O)R' wherein R' is aryl optionally substituted with Ci-
  • R3 is selected from a. hydrogen; b. halogen; and cCi-C ⁇ -alkyl optionally substituted with at least one fluoro;
  • R 3 is Cl, Br, -CH 3 or -CF 3;
  • Ri is selected from a. hydrogen; b. unsubstituted Ci-C ⁇ -alkyl; c. C 2 -C 6 -alkenyl optionally substituted with Ci-C ⁇ -alkyl; d. -NR 6 R 7 ; e. unsubstituted Cs-Cs-cycloalkoxy; f. unsubstituted Cs-Cs-cycloalkyl sulfanyl; and g. 5 or 6 membered heteroaryl having at least one heteroatom selected from N, S and O optionally substituted with Ci-C 6 alkyl;
  • the compounds according to the invention may be used for the preparation of a medicament for modulating and/or inhibiting the activity or function of ASK, in particular ASK-I, in a subject and in particular for preventing and/or treating autoimmune disorderes, inflammatory diseases, cardiovascular disceases and/or neurodegenerative diseases
  • Another aspect of the invention is a pharmaceutical composition containing at least one triazolopyridine compound according to the invention and a pharmaceutically acceptable carrier, diluent or excipient.
  • Another aspect of the invention is a process for the preparation of a triazolopyridine compound according to formula (I), comprising the step of reacting a compound of Formula (II) with an acylating agent of Formulas (Ilia or IHb) in a presence of a base or a coupling agent:
  • triazolopyridine compounds (Ib) and boronic acid (IVa) or ester (IVb) are heated at various temperature by traditional thermic methods or using microwave technology in presence of a base such as K2CO3, K3PO4 or CsF and a catalytic amount of palladium catalyst such as PdCl 2 (PPl ⁇ ) 2 or Pd(OAc) 2 with a ligand such as DPPF in an appropriate solvent such as DMF or a combination of water with THF or dioxane such as those described hereinafter in the Examples.
  • a base such as K2CO3, K3PO4 or CsF
  • palladium catalyst such as PdCl 2 (PPl ⁇ ) 2 or Pd(OAc) 2 with a ligand such as DPPF
  • a ligand such as DPPF
  • R 1 is F, Cl, Br, I, OMs, OTf, SR 13
  • the compounds of invention have been named according the standards used in the program "ACD/Name Batch” from Advanced Chemistry Development Inc., ACD/Labs (7.00 Release). Product version: 7.10, build: 15 Sep 2003.
  • Benzoyl chloride (4.40 g; 31.4 mmol; 2.0 eq.) was added to a suspension of 5- bromo[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A3), 3.34 g; 15.7 mmol; 1.0 eq.) in pyridine (2.53 mL; 31.4 mmol; 2.0 eq.) and DCM (60 mL). The reaction mixture was then heated at reflux for 4 hours, after which it was cooled down to rt. Diethyl ether was added to the reaction mixture and the solid which precipitated was filtered off.
  • N-(5-chloro[l,2,4]triazolo[l,5-a]pyridin-2-yl)nicotinamide ((B4), 141.00 mg; 0.52 mmol; 1.00 eq.), 2,2-dimethylethenylboronic acid (Synthonix, 102.96 mg; 1.03 mmol; 2.00 eq.), cesium fluoride (156.53 mg; 1.03 mmol; 2.00 eq.) and bis(triphenylphosphine)palladium(II) chloride (36.16 mg; 0.05 mmol; 0.10 eq.) were flushed with nitrogen in a sealed vial.

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Abstract

The present invention relates to triazolopyridine compounds according to Formula (I), their use as medicament, for treating autoimmune disorders, inflammatorydiseases, cardiovascular disceases and/or neurodegenerative diseases and a process for their preparation.

Description

TRIAZOLOPYRIDINE COMPOUNDS AND THEIR USE AS ASK INHIBITORS
Field of the invention
The present invention relates to triazolopyridine compounds according to Formula (I), their use as medicament, for treating autoimmune disorders, inflammatory diseases, cardiovascular disceases and/or neurodegenerative diseases and a process for their preparation.
Background of the invention
ASK (apoptosis signal-regulating kinase) has been described as a mitogen-activated protein kinase. ASK-I and ASK-2 have been described as members of the ASK family. ASK-I is a MAPKKK (mitogen-activated protein kinase kinase kinase). Human and mouse ASK-I consist of 1374 and 1380 amino acids, respectively, and possess a serine/threonine kinase domain. ASK-I is activated by environmental stress. The stimuli include inter alia H2O2, LPS, ROS (reactive oxygen species), ER stress, influx of calcium ions, and various cytokines such as TNF (tumor necrosis factor) have been described to be stimuli. ASK-I in turn induces various stress responses including apoptosis and has been described to mediate various cellular responses including survival and differentiation. ASK-I is a member of the MAPKKK family that constitutes the JNK and p38 MAP kinase (MAPK) cascades. Trx (thioredoxin) was identified as a repressor of ASK-I and also forms part of the "ASK-I signalosome", a high molecular mass complex. ASK has been described to be involved in various diseases associated with autoimmune disorders and neurodegenerative disorders (e.g. H. Nagai et al, J. Biochem. and MoI. Biol, Vol. 40, No. 1, January 2007, pp. 1 - 6).
Summary of the invention
According to one aspect of the invention, are provided triazolopyridine compounds according to Formula (I):
Figure imgf000003_0001
Formula (I) wherein Ri is selected from a. hydrogen; b. Ci-Ce-alkyl; c. C2-C6-alkenyl optionally substituted with Ci-C6-alkyl; d. -NR6R7; e. C3-C8-cycloalkoxy, Ci-C6-alkoxy; f. C3-C8-cycloalkyl sulfanyl, Ci-C6-alkyl sulfanyl; and g. 5 or 6-membered heteroaryl having at least one heteroatom selected from N, S and O, said heteroaryl being optionally substituted with Ci-C6 alkyl, halogen, or Ci-C6 alkoxy;
R2 is selected from a. hydrogen; b. halogen; c. aryl optionally substituted with Rio, Rn and/or Ri2; and d. 5 to 10-membered heteroaryl having at least one heteroatom selected from N, S and O and optionally substituted with Ci-C6 alkyl;
or Ri and R2 taken together form a -C=C-C=C- group-;
R3 is selected from a. hydrogen; b. halogen; and c. Ci-C6-alkyl optionally substituted with at least one fluoro;
R4 is selected from a.hydrogen; and b.5 or 6-membered heteroaryl having at least one heteroatom selected from N, S and
O;
R5 is selected from a. Ci-Cβ-alkyl optionally substituted with at least one of the following groups i. alkoxycarbonyl, ii. Ci-Cβ-alkoxy, iii. -NC(O)R' wherein R' is aryl optionally substituted with Ci-Cβ-alkyl, iv. benzyloxy; b. aiyl-Ci-Ce-alkyl; c. 5 or 6-membered heteroaryl-Ci-Cβ-alkyl having a heteroatom selected from N, S and O optionally substituted with Ci-Cβ-alkyl, halogen or Ci-Cβ-alkoxy; d. C3-C6-cycloalkyl optionally substituted with phenyl; e. 3 to 8-membered heterocycloalkyl having a heteroatom selected from N, S and O optionally substituted with an acyl group; f. aryl optionally substituted with at least one of the following groups i. Ci-Ce-alkyl, ii. perfluoro-Ci-C6-alkyl, iii. at least one Ci-Cβ-alkoxy optionally substituted with Ci-Cβ-alkoxy carbonyl, iv. phenyl, v. Ci-Cβ-alkyl sulfonyl, vi. -NHC(O) Ci-Ce-alkyl, vii. amino-Ci-Cβ-alkyl wherein amino is selected from -NH2, -NHCi-Cβ-alkyl,
-N(Ci-C6-alkyl)2, N(Ci-C6-alkyl)(Ci-C6-alkoxy-Ci-C6-alkyl), and the two substituents Ci-Cβ-alkyl can be the same or different, and wherein the two substituents may form a 3 to 8-membered heterocycloalkyl with the N to which they are attached to and wherein the heterocycloalkyl is optionally substituted with Ci-Cβ-alkyl or with hydroxy, viii. -N(Ci-C6-alkyl) (Ci-Ce-alkoxy-Ci-Ce-alkyl), ix. 5 to 6-membered heterocycloalkyl-Ci-Cβ-alkyl having a heteroatom selected from N and O, x. amido-Ci-Cβ-alkyl, xi. Ci-Cδ-alkoxy, xii. halogen; g. 5 to 10-memberedheteroaryl having at least one heteroatom selected from N, O or S optionally substituted with halogen; and h. pyridinyl optionally substituted with at least one of the following groups i. halogen, ii. Ci-Ce-alkyl, iii. amino-Ci-C6-alkyl wherein amino is selected from -NH2, -NHCi-Cδ-alkyl or -N(Ci-C6-alkyl)2, wherein the two substituents Ci-Cδ-alkyl can be the same or different, and wherein the two substituents may form a 3 to 8-membered heterocycloalkyl with the N to which they are attached to and wherein the heterocycloalkyl is optionally substituted with Ci-C6-alkyl or hydroxy; iv. -NH(hydroxy-Ci-C6-alkyl), v. -NH-(5-membered heteroaryl-Ci-Cδ-alkyl having as heteroatom O), vi. 5 or 6-membered heterocycloalkyl-Ci-Cδ-alkyl having at least one heteroatom selected from O and N; vii. 5 or 6-membered heterocycloalkyl having at least one heteroatom selected from O and N optionally substituted with hydroxy, -C(O)OR' wherein R' is
Ci-Cδ-alkyl, halogen or Ci-C6-alkyl; viii. amino; ix. -NH(amino-Ci-C6-alkyl); x. -N(C1-C6-alkyl)2;
R6 is selected from a. Ci-Cδ-alkyl optionally substituted with one or two hydroxy groups, b. phenyl optionally substituted with at least one of the following groups i. halogen ii. Ci-C6-alkyl,or iii. Ci-Cδ-alkoxy; c. 5 or 6-membered heterocycloalkyl having a heteroatom selected from O and N optionally substituted with Ci-Cβ-alkyl; d. C3-Cs-cycloalkyl optionally substituted with R8; and e. -(CH2)nR9 wherein n equals 1, 2 or 3; R7 is a. hydrogen or b. Ci-Ce-alkyl;
or R6 and R7 can form a 3 to 8-membered heterocycloalkyl with the N to which they are attached to and wherein the heterocycloalkyl is optionally substituted with C1-C6- alkyl;
Rs is selected from a.hydrogen; b. hydroxy; c. Ci-Cβ-alkyl optionally substituted with hydroxy; d.C(O)O-Ci-C6-alkyl; and e.-NH2;
R9 is selected from a. C3-Cs-cycloalkyl optionally substituted with an unsubstituted d-C6-alkyl; b. 5 or 6-membered heterocycloalkyl having a heteroatom selected from N and O optionally substituted with d-C6-alkyl; c.5 or 6-membered heteroaryl having a heteroatom selected from N and O optionally substituted with d-C6-alkyl; d. phenyl;
Rio, Rn and R12 are each independently selected from a. hydrogen; b. halogen; c. hydroxy; d. Ci-Ce-alkyl; e. Ci-Cβ-alkoxy; f. cyano; g. -C(O)NH(C i-C6-alkyl)amino wherein the amino is -N(CH3)2); and L-NH2. Any of the above chemical groups can be optionally substituted as laid out in the below definitions.
According to another aspect of the invention, are provided triazolopyridine compound intermediates.
According to another aspect of the invention, are provided triazolopyridine compounds according to Formula (I) for use as medicament.
According to another aspect of the invention, are provided pharmaceutical formulations comprising triazolopyridine compounds according to Formula (I).
According to another aspect of the invention, are provided triazolopyridine compounds according to Formula (I), which are able to modulate, especially inhibit the activity or function of ASK, in particular ASK-I, in disease states in mammals, especially in humans.
According to another aspect of the invention, are provided methods for the prevention or treatment of autoimmune diseases, inflammatory diseases, cardiovascular diseases and/or neurodegenerative diseases by administering an effective amount of a triazolopyridine compounds according to Formula (I) to a subject in need thereof.
According to another aspect of the invention, are provided methods for the prevention or treatment of autoimmune diseases, inflammatory diseases, cardiovascular diseases and/or neurodegenerative diseases by administering an effective amount of a triazolopyridine compounds according to Formula (I) to a subject in need thereof, by modulating, especially inhibiting the activity or function of ASK.
According to another aspect of the invention, is provided a process for the preparation of a triazolopyridine compound according to Formula (I).
Detailed description of the invention
The following paragraphs provide definitions of the various chemical moieties that make up the compounds according to the invention and are intended to apply uniformly through-out the specification and claims unless an otherwise expressly set out definition provides a broader definition.
The term "alkyl" refers to a linear or branched saturated hydrocarbon chain; this term is exemplified by groups such as methyl; ethyl; n-propyl; isopropyl; n-butyl; isobutyl; tert-butyl; n-hexyl. The term "Ci-Cβ-alkyl" refers to alkyl groups having 1 to 6 carbon atoms.
The term "alkenyl" refers to unsaturated alkyl groups having at least one double bond and includes both linear- and branched alkenyl groups; this term is exemplified by groupssuch as propenyl, but-3-enyl, pent-4-enyl. The term "C2-C6 alkenyl" refers to alkenyl groups having from 2 to 6 carbon atoms.
The term "aryl" refers to an aromatic carbocyclic group having at least one aromatic ring (e.g. phenyl or biphenyl) or multiple condensed rings in which at least one ring is aromatic, (e.g. naphthyl, anthryl, or phenanthryl).
The term "heteroaryl" refers to a monocyclic heteroaromatic, or a bicyclic or a tricyclic fused- ring heteroaromatic group, wherein the at least one heteroatom selected from nitrogen, oxygen, and sulfur. Cs-Cs-heteroaryl, C3-Cio-heteroaryl etc. refers to the size of the corresponding heteroaryl. Particular examples of heteroaromatic groups include e.g., 2,3- dihydro benzofuranyl, 1-oxidopyridinyl, 2,3-dihydro-l,4-benzodioxinyl,quinoxalinyl, 2,2- difluoro-l,3-benzodioxolyl, pyridinyl, pyrrolyl, furanyl, thiophenyl, isoxazolyl, pyrazolyl, benzofuryl, [2,3-dihydro]benzofuryl, benzoxazolyl, quinoxalinyl.
The term "cycloalkyl" refers to alkyl groups having a monocyclic ring, bicyclic or multiple fused alkyl rings; such cycloalkyl rings include e.g. cyclopropyl, cyclobutyl, cyclopentyl; cyclohexyl, cycloheptyl, cyclooctyl; and the like; such multiple ring structures include e.g. adamantanyl; and bicyclo[2.2. ljheptane. "C3-C8", "C3-C10" etc. refers to the cycle size of the corresponding cycloalkyl.
The term "heterocycloalkyl" means a non-aromatic monocyclic or polycyclic ring comprising carbon and hydrogen atoms and at least one heteroatom selected from nitrogen, oxygen, and sulfur. "Cs-Cs-heterocycloalkyl, "C3- C10" etc. refers to the size of the corresponding heterocycloalkyl. Particular examples of heterocycloalkyl groups include e.g. tetrahydrofuranyl, tetrahydro-2H-pyranyl, morpholinyl, pyrrolidinyl, piperidinyl, 2- oxopyrrolidinyl, piperazinyl.
The term "halogen" refers to Br, Cl, I, F.
The term "cyano" refers to a -C≡N group.
The term "perfluoroCi-Ce-alkyl" refers to a Ci-Cβ-alkyl group wherein each hydrogen atom has been replaced by a fluoro atom.
The term "amino" refers to a-NRR' group wherein R and R' are each independently selected from a) hydrogen, b) Ci-Cβ-alkyl optionally substituted with hydroxy, Ci-Cβ-alkoxy, c) heteroaryl-Ci-Cβ-alkyl wherein the heteroatom is O, d) acylamino-Ci-Cβ-alkyl, e) -C(O)OC1- Ce-alkyl.
The term "acyl" refers to a group -C(O)R wherein R is H, Ci-Cβ-alkyl or phenyl.
The term "amido" refers to a group -C(O)-NRR' wherein R and R' are independently H or Ci-Cβ-alkyl, and may form a cycle with the N to which they are attached.
The term "Ci-Cβ-alkylamino" refers to a Ci-Cβ-alkyl group attached to the parent molecular group through an amino.
The term "amino-Ci-Cβ-alkyl" refers to an amino group attached to the parent molecular group through a Ci-Cβ-alkyl wherein the amino group is selected from -NH2, -NHC1-C6- alkyl, and -N(Ci-C6-alkyl)2 wherein the two substituents Ci-Cβ-alkyl can be the same or different, and wherein the two substitutents may form a 3 to 8-membered heterocycloalkyl with the N to which they are attached to and which heterocycloalkyl may be optionally substituted with Ci-Cβ-alkyl.
The term "alkyloxy" or "alkoxy" refers to the group -OR (e.g methoxy, ethoxy) wherein R is alkyl.
The term "cycloalkyl-oxy" or "cycloalkoxy" refers to a group -0-R (e.g cyclohexyloxy) wherein R is a cycloalkyl. The term "cycloalkyl-sulfanyl" refers to a group -S-R (e.g cyclohexylsulfanyl) wherein R is a cycloalkyl.
The term "cycloalkyl-Ci-Cβ-alkyl" refers to a cycloalkyl group attached to the parent molecular group through a Ci-Cβ-alkyl.
The term "aryl-Ci-Cβ-alkyl" refers to an aryl group attached to the parent molecular group through a Ci-Cβ-alkyl (e.g. benzyl).
The term "aryl-Ci-Cβ-alkyloxy" refers to a -O-R group wherein R is aryl Ci-Cβ-alkyl (e.g. benzyloxy).
The term "heteroaryl-Ci-Cβ-alkyl" refers to a heteroaryl group attached to the parent molecular group through a Ci-Cβalkyl.
The term "-C(O)Oalkyl" or "alkoxycarbonyl"refers to a group -C(O)-O-R wherein R is a Ci- Ce-alkyl.
The term carboxylic acid refers to a -COOH.
The term "hydroxy-Ci-Cβ-alkyl" refers to a Ci-Cβ-alkyl substituted by a hydroxyl.
The term "heterocycloalkyl-Ci-Cβ-alkyl" refers to a heterocycloalkyl group attached to the parent molecular group through a Ci-Cβ-alkyl.
The term "halogen-aryl" refers to a group aryl (e.g phenyl) substituted by a halogen (e.g. 4- chloro-phenyl, 3-iodo-phenyl, 4-fluoro-phenyl, 4-bromo-phenyl, 3-chloro-phenyl, 2-bromo- phenyl).
The term "Ci-Cβ-alkyl-sulfonyl" refers to a group -S(O)2-R wherein R is Ci-Cβ-alkyl.
The term "acylamino-Ci-Ce-alkyl" refers to an acylamino group attached to the parent molecular group through a Ci-Cβ-alkyl. The term "acylamino" refers to a group -NH-acyl group which may also be defined as - NHC(O)R wherein R is a Ci-Ce-alkyl.
The above defined residues can be substituted or unsubstituted; the term "unsubstituted or substituted" or "optionally substituted" means that unless otherwise constrained by the definition of the individual substituent, the above set out groups, like "alkyl", "alkenyl", "alkynyl", "aryl", "heteroaryl", "cycloalkyl", "heterocycloalkyl" etc. can be substituted with at least one substituent selected from the group consisting of "d-Cβ-alkyl", "C2-C6-alkenyl", "C2-C6-alkynyl", "cycloalkyl", "heterocycloalkyl", "Ci-C6-alkyl aryl", "Ci-C6-alkyl heteroaryl", "Ci-C6-alkyl cycloalkyl", "Ci-Ce-alkyl heterocycloalkyl", "amino", "ammonium", "acyl", "acyloxy", "acylamino", "aminocarbonyl", "alkoxycarbonyl", "ureido", "aryl", "-C(O)OC i-C6-alkyl", "heteroaryl", "sulfonyl", "alkoxy", in particular "Ci-C6- alkoxy", "sulfanyl", "halogen", "carboxy", "trihalomethyl", "cyano", "hydroxy", "mercapto", "nitro", "halogen-aryl", "lactam", in particular "γ-lactam" or "δ-lactam", and the like.
"Pharmaceutically acceptable salts or complexes" refer to salts or complexes of the compounds disclosed herein. Examples of such salts include, but are not limited to, salts which are formed with inorganic acids (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), as well as salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, palmoic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid, methane sulfonic acid, naphthalene disulfonic acid, and poly- galacturonic acid, as well as salts formed with basic amino acids such as lysine or arginine.
Additionally, salts of compounds containing a carboxylic acid or other acidic functional group(s) can be prepared by reacting with a suitable base. Such a pharmaceutically acceptable salt may be made with a base which affords a pharmaceutically acceptable cation, which includes alkali metal salts (especially sodium and potassium), alkaline earth metal salts (especially calcium and magnesium), aluminum salts and ammonium salts, as well as salts made from physiologically acceptable organic bases such as trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline, dicyclohexylamine, N,N'-dibenzylethylenediamine, 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine, tri-(2-hydroxyethyl)amine, procaine, dibenzylpiperidine, N-benzyl-β-phenethylamine, dehydroabietylamine, N5N'- bisdehydroabietylamine, glucamine, N-methylglucamine, collidine, quinine, quinoline, and basic amino acid such as lysine and arginine.
According to one aspect of the invention, are provided triazolopyridine compounds according to Formula (I):
Figure imgf000012_0001
Formula (I) wherein Ri is selected from a. hydrogen; b. Ci-Ce-alkyl; c. C2-C6-alkenyl optionally substituted with Ci-C6-alkyl; d. -NR6R7; e. C3-C8-cycloalkoxy, Ci-C6-alkoxy; f. C3-C8-cycloalkyl sulfanyl, Ci-C6-alkyl sulfanyl; and g. 5 or 6-membered heteroaryl having at least one heteroatom selected from N, S and O, said heteroaryl being optionally substituted with Ci-C6 alkyl, halogen, or Ci-C6 alkoxy;
R2 is selected from a. hydrogen; b. halogen; c. aryl optionally substituted with Rio, Rn and/or Ri2; and d. 5 to 10-membered heteroaryl having at least one heteroatom selected from N, S and O and optionally substituted with Ci-C6 alkyl;
or Ri and R2 taken together form a -C=C-C=C- group-;
R3 is selected from a. hydrogen; b. halogen; and c. Ci-Cβ-alkyl optionally substituted with at least one fluoro;
R4 is selected from a.hydrogen; and b.5 or 6-membered heteroaryl having at least one heteroatom selected from N, S and
O;
R5 is selected from a. Ci-Cβ-alkyl optionally substituted with at least one of the following groups i. alkoxycarbonyl, ii. Ci-Cβ-alkoxy, iii. -NC(O)R' wherein R' is aryl optionally substituted with Ci-Cβ-alkyl, iv. benzyloxy; b. aryl-Ci-Ce-alkyl; c. 5 or 6-membered heteroaryl-Ci-Cβ-alkyl having a heteroatom selected from N, S and O optionally substituted with Ci-Cβ-alkyl, halogen or Ci-Cβ-alkoxy; d. C3-C6-cycloalkyl optionally substituted with phenyl; e. 3 to 8-membered heterocycloalkyl having a heteroatom selected from N, S and O optionally substituted with an acyl group; f. aryl optionally substituted with at least one of the following groups i. Ci-Ce-alkyl, ii. perfluoro-Ci-C6-alkyl, iii. at least one Ci-Cβ-alkoxy optionally substituted with Ci-Cβ-alkoxy carbonyl, iv. phenyl, v. Ci-Cβ-alkyl sulfonyl, vi. -NHC(O) Ci-Ce-alkyl, vii. amino-Ci-Cβ-alkyl wherein amino is selected from -NH2, -NHCi-Cβ-alkyl,
-N(Ci-C6-alkyl)2, N(Ci-C6-alkyl)(Ci-C6-alkoxy-Ci-C6-alkyl), and the two substituents Ci-Cβ-alkyl can be the same or different, and wherein the two substituents may form a 3 to 8-membered heterocycloalkyl with the N to which they are attached to and wherein the heterocycloalkyl is optionally substituted with Ci-Cβ-alkyl or with hydroxy; viii. -N(Ci-C6-alkyl) (Ci-Ce-alkoxy-Ci-Ce-alkyl), ix. 5 to 6-membered heterocycloalkyl-Ci-Cβ-alkyl having a heteroatom selected from N and O; x. amido-Ci-Cβ-alkyl, xi. Ci-Cβ-alkoxy, xii. halogen; g. 5 to 10-memberedheteroaryl having at least one heteroatom selected from N, O or S optionally substituted with halogen; and h. pyridinyl optionally substituted with at least one of the following groups i. halogen, ii. Ci-Ce-alkyl, iii. amino-Ci-Cβ-alkyl wherein amino is selected from -NH2, -NHCi-Cβ-alkyl or -N(Ci-C6-alkyl)2, wherein the two substituents Ci-Cβ-alkyl can be the same or different, and wherein the two substituents may form a 3 to 8-membered heterocycloalkyl with the N to which they are attached to and wherein the heterocycloalkyl is optionally substituted with Ci-Cβ-alkyl or hydroxy; iv. -NH(hydroxy-Ci-C6-alkyl), v. -NH-(5-membered heteroaryl-Ci-Cβ-alkyl having as heteroatom O), vi. 5 or 6-membered heterocycloalkyl-Ci-Cβ-alkyl having at least one heteroatom selected from O and N; vii. 5 or 6-membered heterocycloalkyl having at least one heteroatom selected from O and N optionally substituted with hydroxy, -C(O)OR' wherein R' is
Ci-Ce-alkyl, halogen or Ci-C6-alkyl; viii. amino; ix. -NH(amino-Ci-C6-alkyl); x. -N(C1-C6^IkVl)2;
R6 is selected from a. Ci-Cβ-alkyl optionally substituted with one or two hydroxy groups, b. phenyl optionally substituted with at least one of the following groups i. halogen ii. Ci-C6-alkyl,or iii. Ci-Cδ-alkoxy; c. 5 or 6-membered heterocycloalkyl having a heteroatom selected from O and N optionally substituted with Ci-C6-alkyl; d. C3-C8-cycloalkyl optionally substituted with Rs; and e. -(CH2)nR9 wherein n equals 1, 2 or 3;
R7 is a. hydrogen or b. Ci-Ce-alkyl;
or R6 and R7 can form a 3 to 8-membered heterocycloalkyl with the N to which they are attached to and wherein the heterocycloalkyl is optionally substituted with C1-C6- alkyl;
Rs is selected from a.hydrogen; b. hydroxy; c. Ci-Cδ-alkyl optionally substituted with hydroxy; d.C(O)O-Ci-C6-alkyl; and e.-NH2;
R9 is selected from a. C3-Cs-cycloalkyl optionally substituted with an unsubstituted Ci-Cβ-alkyl; b. 5 or 6-membered heterocycloalkyl having a heteroatom selected from N and O optionally substituted with Ci-Cβ-alkyl; c.5 or 6-membered heteroaryl having a heteroatom selected from N and O optionally substituted with Ci-C6-alkyl; d. phenyl;
Rio, Rn and R12 are each independently selected from a. hydrogen; b. halogen; c. hydroxy; d. Ci-Ce-alkyl; e. Ci-Cδ-alkoxy; f. cyano; g. -C(O)NH(C i-C6-alkyl)amino wherein the amino is -N(CH3)2); and L-NH2.
Any of the above chemical groups can be optionally substituted.
The compounds according to the invention advantageously inhibit ASK, preferably ASKl. The inventors could achieve good IC50 values by the particular design of the compounds according to the invention.
The IC50 value of the compounds of the invention measured according to the procedure as outlined in the experiments is 30 μM or less, preferably 20 μM or less, more preferably 15 μM or less, even more preferably 10 μM or less, still more preferably 5 μM or less, and more preferablyl μM or less.
It was found by the inventors that by refining the design of the compounds in particular positions with a selection of chemical groups as will be evident from the below description advantageous IC50 values in the nanomolar range could be achieved. Preferred compounds of the invention exhibit an IC50 value of, e.g. 90OnM or less, 70OnM or less, 50OnM or less, 20OnM or less, 10OnM or less, 5OnM or less.
The compounds according to the invention are also characterized by their positive inhibitory effect in the Lipopolysaccharide (LPS)-induced TNFα release assay in mice as described in the below experimental section. Preferrably the compounds of the invention exhibit an inhibition of 30% or more, preferably 40% or more, and more preferably 50% or more.
The dosage of a compound according to the invention applied in this assay is usually between 10 and 80mg/kg body weight. Another dosage that may be used is between 20 and 60, preferably between 30 and 40mg/kg.
Other in vitro and in vivo assays known to the person skilled in the art may be applied to show the positive effects of the compounds of the invention and their relevance for various diseases. These models are apparent and well known to the person skilled in the field. In the following, compounds and compound groups according to the invention are described characterized by particular structural and functional features. Each of these compound groups exhibits also properties making them useful for particular applications, e.g. particular medical indications, which will be evident by normal experimentation available to the skilled person.
In one embodiment the invention relates to a triazolopyridine compound according to Formula I wherein
Ri is selected from a. hydrogen; b. Ci-Ce-alkyl; c. C2-C6-alkenyl optionally substituted with Ci-Cβ-alkyl; d. -NR6R7; e. C3-Cs-cycloalkoxy; f. C3-Cs-cycloalkyl sulfanyl; and g. 5 or 6-membered heteroaryl having at least one heteroatom selected from N, S and O optionally substituted with Ci-Cβ-alkyl;
R2 is selected from a. hydrogen; b. Cl or Br; c. aryl optionally substituted with Ri0, Rn and/or Ri2; and d. 5, 6 or 9-membered heteroaryl having at least one heteroatom selected from N, S and O and optionally substituted with Ci-C6 alkyl;
or Ri and R2 taken together form a -C=C-C=C- group-;
R3 is selected from a.hydrogen; b.chloro; bromo; c. methyl; and d.CF3; R4 is selected from a. hydrogen; and b. furanyl;
R5 is selected from a. Ci-Cβ-alkyl optionally substituted with at least one of the following groups i. alkoxycarbonyl, ii. Ci-Cβ-alkoxy, iii. -NHC(O)R' wherein R' is aryl optionally substituted with Ci-Cβ-alkyl, iv. benzyloxy; b. aiyl-Ci-Ce-alkyl; c. 5 or 6-membered heteroaryl-Ci-Cβ-alkyl having a heteroatom selected from N, S and O optionally substituted with Ci-Cβ-alkyl, halogen or Ci-Cβ-alkoxy; d. C3-C6 cycloalkyl optionally substituted with phenyl; e. 3 to 8-membered heterocycloalkyl having a heteroatom selected from N, S and O optionally substituted with an acyl group; f. aryl optionally substituted with at least one of the following groups i. Ci-Ce-alkyl, ii. perfluoro-Ci-C6-alkyl, iii. at least one Ci-Cβ-alkoxy optionally substituted with Ci-Cβ-alkoxy carbonyl, iv. phenyl, v. Ci-Cβ-alkyl sulfonyl, vi. -NC(O)Ci-C6-alkyl, vii. amino-Ci-Cβ-alkyl wherein amino is selected from -NH2, -NHCi-Cβ-alkyl,
-N(Ci-C6-alkyl)2, N(Ci-C6-alkyl)(Ci-C6-alkoxy-Ci-C6-alkyl), and the two substituents Ci-Cβ-alkyl can be the same or different, and wherein the two substituents may form a 3 to 8-membered heterocycloalkyl with the N to which they are attached to and wherein the heterocycloalkyl is optionally substituted with Ci-Cβ-alkyl or with hydroxy, viii. -N(Ci-C6-alkyl) (Ci-Ce-alkoxy-Ci-Ce-alkyl), ix. 5 to 6-membered heterocycloalkyl-Ci-Cβ-alkyl having a heteroatom selected from N and O, x. amido-Ci-Cβ-alkyl, xi. Ci-Cδ-alkoxy, xii. halogen; g. 5 to 10-membered heteroaryl having at least one heteroatom selected from N optionally substituted with halogen; and h. pyridinyl optionally substituted with at least one of the following groups i. halogen, ii. Ci-Cδ-alkyl optionally substituted with a 5 or 6-membered heterocycloalkyl having at least one heteroatom selected from O and N, iii. 5 or 6-membered heterocycloalkyl having at least one heteroatom selected from O and N, iv. -NH(hydroxy-Ci-C6-alkyl), v. -NH-(5-membered heteroaryl-Ci-C6-alkyl having as heteroatom O), vi. 5 or 6-membered heterocycloalkyl-Ci-Cδ-alkyl having at least one heteroatom selected from O and N; vii. 5 or 6-membered heterocycloalkyl having at least one heteroatom selected from O and N optionally substituted with hydroxy, -C(O)OR' wherein R' is
Ci-Ce-alkyl, halogen or Ci-C6-alkyl, viii. amino, ix. -NH(amino-Ci-C6-alkyl), x. -N(C1-C6-alkyl)2;
R6 is selected from a. Ci-Cδ-alkyl optionally substituted with one or two hydroxy groups, b. phenyl optionally substituted with at least one of the following groups i. halogen, ii. Ci-Cδ-alkyl, or iii. Ci-Cδ-alkoxy; c. 5 or 6-membered heterocycloalkyl having a heteroatom selected from O and N optionally substituted with is Ci-Cβ-alkyl; d. C3-C8-cycloalkyl optionally substituted with Rs; and e. -(CH2)nR9 wherein n equals 1, 2 or 3;
R7 is a. hydrogen or b. Ci-Ce-alkyl; or
or R6 and R7 can form a 3 to 8-membered heterocycloalkyl with the N to which they are attached to and wherein the heterocycloalkyl is optionally substituted with C1-C6- alkyl;
Rs is selected from a.hydrogen; b. hydroxy; c.unsubstituted or substituted Ci-Cδ-alkyl wherein the substituent is hydroxyl; d.C(O)O- Ci-Ce-alkyl; and e.-NH2;
R9 is selected from a. C3-Cs-cycloalkyl optionally substituted with an unsubstituted d-Cβ-alkyl; b. 5 or 6-membered heterocycloalkyl having a heteroatom selected from N and O optionally substituted with d-Cβ-alkyl; c.5 or 6-membered heteroaryl having a heteroatom selected from N and O optionally substituted with d-Cβ-alkyl; and d.phenyl.
Rio, Rn and R12 are each independently selected from a. hydrogen; b. fluoro, bromo; c. hydroxyl; d. Ci-Ce-alkyl; e. Ci-Cδ-alkoxy; f. cyano; g. -C(O)NH(C i-C6-alkyl)amino wherein the amino is -N(CH3)2); and L-NH2.
In another embodiment the invention relates to triazolopyridine compounds according to the following Formula 1-1
Figure imgf000021_0001
Formula 1-1 wherein R2 is hydrogen or bromo;
R3 is selected from a. hydrogen; b. halogen; and cCi-Cβ-alkyl optionally substituted with at least one fluoro;
R5 is selected from a. Ci-Cβ-alkyl optionally substituted with at least one of the following groups i. Ci-Cβ-alkoxycarbonyl, ii. Ci-Cβ-alkoxy, iii. -NHC(O)R' wherein R' is aryl optionally substituted with Ci-Cβ-alkyl, iv. benzyloxy; b. aryl-Ci-Ce-alkyl; c. 5 or 6-membered heteroaryl-Ci-Cβ-alkyl having a heteroatom selected from N, S and O optionally substituted with d-Cβ-alkyl, halogen or Ci-Cβ-alkoxy; d. C3-C6 cycloalkyl optionally substituted with phenyl; e. 3 to 8-membered heterocycloalkyl having a heteroatom selected from N, S and O optionally substituted with an acyl group; f. aryl optionally substituted with i. Ci-Cβ-alkyl optionally substituted with a γ-lactam or δ-lactam, ii. perfluoro-Ci-Cβ-alkyl, iii. at least one Ci-Cβ-alkoxy optionally substituted with Ci-Cβ-alkoxycarbonyl, iv. phenyl, v. Ci-Cβ-alkyl sulfonyl, vi. -NHC(O) Ci-Ce-alkyl, vii. amino-Ci-Cβ-alkyl wherein amino is selected from -NH2, -NHCi-Cβ-alkyl,
-N(Ci-C6-alkyl)2, N(Ci-C6-alkyl)(Ci-C6-alkoxy-Ci-C6-alkyl), and the two substituents Ci-Cδ-alkyl can be the same or different, and wherein the two substituents may form a 3 to 8-membered heterocycloalkyl with the N to which they are attached to and wherein the heterocycloalkyl is optionally substituted with Ci-C6-alkyl or with hydroxy, viii. -N(Ci-C6-alkyl) (Ci-C6-alkoxy-Ci-C6-alkyl), ix. 5 to 6-membered heterocycloalkyl-Ci-Cδ-alkyl having a heteroatom selected from N and O, x. amido-Ci-Cδ-alkyl, xi. Ci-Cδ-alkoxy, xii. halogen; g. 5 to 10-membered heteroaryl having at least one heteroatom selected from N optionally substituted with halogen; and h. pyridinyl optionally substituted with at least one of the following groups i. halogen, ii. Ci-Cδ-alkyl optionally substituted with a 5 or 6-membered heterocycloalkyl having at least one heteroatom selected from O and N, iii. 5 or 6-membered heterocycloalkyl having at least one heteroatom selected from O and N, iv. -NH(hydroxy-Ci-C6-alkyl), v. -NH-(5-membered heteroaryl-Ci-C6-alkyl having as heteroatom O), vi. 5 or 6-membered heterocycloalkyl-Ci-Cδ-alkyl having at least one heteroatom selected from O and N;
R6 is selected from a. Ci-Cδ-alkyl optionally substituted with one or two hydroxy groups, b. phenyl optionally substituted with at least one of the following groups i. halogen, ii. Ci-Ce-alkyl, iii. Ci-Cδ-alkoxy; c. 5 or 6-membered heterocycloalkyl having a heteroatom selected from O and N optionally substituted with is Ci-Cβ-alkyl; d. C3-Cs-cycloalkyl optionally substituted with R8; and e. -(CH2)nR9 wherein n equals 1, 2 or 3; R7 is a. hydrogen or b. Ci-Ce-alkyl.
In another embodiment the invention relates to triazolopyridine compounds according to the following Formula 1-2
Figure imgf000023_0001
Formula 1-2
wherein
R3 is selected from a. hydrogen; b. halogen; and c. Ci-Cβ-alkyl optionally substituted with at least one fluoro;
R5 is selected from a. Ci-Cβ-alkyl optionally substituted with at least one of the following groups i. Ci-Cβ-alkoxycarbonyl, ii. Ci-Cβ-alkoxy, iii. -NHC(O)R' wherein R' is aryl optionally substituted with Ci-Cβ-alkyl, iv. benzyloxy; b. aryl-Ci-Ce-alkyl; c. 5 or 6-membered heteroaryl-Ci-Cβ-alkyl having a heteroatom selected from N, S and O optionally substituted with Ci-Cβ-alkyl, halogen or Ci-Cβ-alkoxy; d. C3-C6 cycloalkyl optionally substituted with phenyl; e. 3 to 8-membered heterocycloalkyl having a heteroatom selected from N, S and O optionally substituted with an acyl group; f. aryl optionally substituted with i. Ci-Cβ-alkyl optionally substituted with a γ-lactam or δ-lactam, ii. perfluoro-Ci-Cβ-alkyl, iii. at least one Ci-Cβ-alkoxy optionally substituted with Ci-Cβ-alkoxycarbonyl, iv. phenyl, v. Ci-Cβ-alkyl sulfonyl, vi. -NHC(O) Ci-Ce-alkyl, vii. amino-Ci-Cβ-alkyl wherein amino is selected from -NH2, -NHCi-Cβ-alkyl,
-N(Ci-C6-alkyl)2, N(Ci-C6-alkyl)(Ci-C6-alkoxy-Ci-C6-alkyl), and the two substituents Ci-Cβ-alkyl can be the same or different, and wherein the two substituents may form a 3 to 8-membered heterocycloalkyl with the N to which they are attached to and wherein the heterocycloalkyl is optionally substituted with Ci-Cβ-alkyl or with hydroxy; viii. -N(Ci-C6-alkyl) (Ci-C6-alkoxy-Ci-C6-alkyl), ix. 5 to 6-membered heterocycloalkyl-Ci-Cβ-alkyl having a heteroatom selected from N and O; x. amido-Ci-Cβ-alkyl, xi. Ci-Cβ-alkoxy, xii. halogen; g. 5 to 10-membered heteroaryl having at least one heteroatom selected from N optionally substituted with halogen; and h. pyridinyl optionally substituted with at least one of the following groups i. halogen, ii. Ci-Cβ-alkyl optionally substituted with a 5 or 6-membered heterocycloalkyl having at least one heteroatom selected from O and N, iii. 5 or 6-membered heterocycloalkyl having at least one heteroatom selected from O and N, iv. -NHChydroxy-Ci-Ce-alkyl), v. -NH-(5-membered heteroaryl-Ci-Cβ-alkyl having as heteroatom O), vi. 5 or 6-membered heterocycloalkyl-Ci-Cβ-alkyl having at least one heteroatom selected from O and N;
Re is selected from a. Ci-Cβ-alkyl optionally substituted with one or two hydroxy groups, b. phenyl optionally substituted with at least one of the following groups i. halogen ii. Ci-Ce-alkyl, iii. Ci-Cδ-alkoxy; c. 5 or 6-membered heterocycloalkyl having a heteroatom selected from O and N optionally substituted with is Ci-Cδ-alkyl; d. C3-C8-cycloalkyl optionally substituted with Rs; and e. -(CH2)nR9 wherein n equals 1, 2 or 3.
Rs and R9 are as above defined.
Compounds according to Formula 1-2 as defined above exhibit an IC50 of 20μM or less, preferably 15 μM or less, more preferably 10 μM or less, even more preferably 5 μM or less and even more preferably 1 μM or less.
Preferred embodiments of the above Formula 1-2 are:
1. wherein R3 is Cl, Br, -CH3 or -CF3;
2. wherein R3 is Cl, Br, -CH3 or -CF3. R5 is selected from a. phenyl optionally substituted with at least one of the following groups i. Ci-Ce-alkyl, ii. at least one Ci-Cβ-alkoxy optionally substituted with Ci-Cβ-alkoxy carbonyl, iii. -NHC(O) Ci-Ce-alkyl, iv. -N(Ci-C6-alkyl)2, v. 5 to 6-membered heterocycloalkyl-Ci-Cδ-alkyl having a heteroatom selected from N and O optionally substituted with Ci-C6-alkyl, halogen or Ci-C6- alkoxy vi. Ci-Cδ-alkoxy, vii. halogen; and b. pyridinyl optionally substituted with at least one of the following groups i. Ci-Cδ-alkyl optionally substituted with a 5 or 6-membered heterocycloalkyl having at least one heteroatom selected from O and N, ii. 5 or 6-membered heterocycloalkyl having at least one heteroatom selected from O and N, iii. -NH-(5-membered heteroaryl-Ci-C6-alkyl having as heteroatom O), iv. 5 or 6-membered heterocycloalkyl-Ci-Cβ-alkyl having at least one heteroatom selected from O and N; Re is selected from a. unsubstituted Ci-Cβ-alkyl, b. phenyl optionally substituted with at least one of the following groups i. halogen, preferably F, Cl, ii. Ci-Ce-alkyl, iii. Ci-Cβ-alkoxy, c. 6-membered heterocycloalkyl having a heteroatom selected from O and N optionally substituted with Ci-Cβ-alkyl; d. C3-C8-cycloalkyl optionally substituted with Ci-Cβ-alkyl.
3. wherein R3 is Cl, Br, -CH3 or -CF3;
R5 is selected from a.phenyl optionally substituted with amino-Ci-Cβ-alkyl wherein amino is selected from i.-NH2, ii.-NHCi-Ce-alkyl, iii.-N(Ci-C6-alkyl)2, and iv. 5 or 6-membered heterocycloalkyl having as heteroatom N or O; b.pyridinyl; c. and pyridin-Ci-C6-alkyl;
R6 is selected from a. Ci-Cβ-alkyl optionally substituted with i. hydroxy, or ii.Ci-Cβ-alkoxy; b. C3-C8-cycloalkyl; c. -CH2R9 wherein R9 is C3-C6-cycloalkyl.
These preferred embodiments of the invention preferably exhibit an IC50 of 5 μM or less, preferably 1 μM or less, more preferably 0.9 μM or less, even more preferably 0.5 μM or less, even more preferably 0.3 μM or less and still preferably 0.1 μM or less. In another embodiment the invention relates to triazolopyridine compounds according to the following Formula 1-3
Figure imgf000027_0001
Formula 1-3 wherein Ri is selected from a. hydrogen; b. unsubstituted Ci-Cβ-alkyl; c. C2-C6-alkenyl optionally substituted with Ci-Cβ-alkyl; d. -NR6R7; e. unsubstituted Cs-Cs-cycloalkoxy; f. unsubstituted Cs-Cs-cycloalkyl sulfanyl; and g. 5 or 6 membered heteroaryl having at least one heteroatom selected from N, S and O optionally substituted with Ci-C6 alkyl;
R2 is hydrogen or bromo;
R5 is selected from a. Ci-Cβ-alkyl optionally substituted with at least one of the following groups i. Ci-Cβ-alkoxycarbonyl, ii. Ci-Cβ-alkoxy, iii. -NHC(O)R' wherein R' is aryl optionally substituted with Ci-Cβ-alkyl, iv. benzyloxy; b. aryl-Ci-Ce-alkyl; c. 5 or 6-membered heteroaryl-Ci-Cβ-alkyl having a heteroatom selected from N, S and O optionally substituted with Ci-Cβ-alkyl, halogen or Ci-Cβ-alkoxy; d. C3-C6 cycloalkyl optionally substituted with phenyl; e. 3 to 8-membered heterocycloalkyl having a heteroatom selected from N, S and O optionally substituted with an acyl group; f. aryl optionally substituted with i. Ci-Cδ-alkyl optionally substituted with a γ-lactam or δ-lactam, ii. perfluoro-Ci-C6-alkyl, iii. at least one Ci-Cβ-alkoxy optionally substituted with Ci-Cδ-alkoxycarbonyl, iv. phenyl, v. Ci-Cδ-alkyl sulfonyl, vi. -NHC(O) Ci-Ce-alkyl, vii. amino-Ci-C6-alkyl wherein amino is selected from -NH2, -NHCi-Cδ-alkyl,
-N(Ci-C6-alkyl)2, N(Ci-C6-alkyl)(Ci-C6-alkoxy-Ci-C6-alkyl), and the two substituents Ci-Cδ-alkyl can be the same or different, and wherein the two substituents may form a 3 to 8-membered heterocycloalkyl with the N to which they are attached to and wherein the heterocycloalkyl is optionally substituted with Ci-Cδ-alkyl or with hydroxy, viii. -N(Ci-C6-alkyl) (Ci-Ce-alkoxy-Ci-Ce-alkyl), ix. 5 to 6-membered heterocycloalkyl-Ci-Cδ-alkyl having a heteroatom selected from N and O, x. amido-Ci-Cδ-alkyl, xi. Ci-Cδ-alkoxy, xii. halogen; g. 5 to 10-membered heteroaryl having at least one heteroatom selected from N optionally substituted with halogen; and h. pyridinyl optionally substituted with at least one of the following groups i. halogen, ii. Ci-Cδ-alkyl optionally substituted with a 5 or 6-membered heterocycloalkyl having at least one heteroatom selected from O and N, iii. 5 or 6-membered heterocycloalkyl having at least one heteroatom selected from O and N, iv. -NH(hydroxy-Ci-C6-alkyl), v. -NH-(5-membered heteroaryl-Ci-C6-alkyl having as heteroatom O), vi. 5 or 6-membered heterocycloalkyl-Ci-Cδ-alkyl having at least one heteroatom selected from O and N.
In another embodiment the invention relates to triazolopyridine compounds according to the following Formula 1-4
Figure imgf000029_0001
Formula 1-4
wherein
Ri is selected from a. unsubstituted Ci-Cδ-alkyl; b. C2-C6-alkenyl optionally substituted with Ci-Cδ-alkyl; c. -NR6R7; d. unsubstituted C3-Cs-cycloalkoxy; e. unsubstituted Cs-Cs-cycloalkyl sulfanyl; and f. 5 or 6 membered heteroaryl having at least one heteroatom selected from N, S and O optionally substituted with Ci-C6 alkyl;
R5 is selected from a. Ci-Cδ-alkyl optionally substituted with at least one of the following groups i. Ci-Cδ-alkoxycarbonyl, ii. Ci-Cδ-alkoxy, iii. -NHC(O)R' wherein R' is aryl optionally substituted with Ci-Cβ-alkyl, iv. benzyloxy; b. aiyl-Ci-Ce-alkyl; c. 5 or 6-membered heteroaryl-Ci-Cδ-alkyl having a heteroatom selected from N, S and O optionally substituted with Ci-Cβ-alkyl, halogen or Ci-Cβ-alkoxy; d. C3-C6 cycloalkyl optionally substituted with phenyl; e. 3 to 8-membered heterocycloalkyl having a heteroatom selected from N, S and O optionally substituted with an acyl group; f. aryl optionally substituted with i. Ci-Cδ-alkyl optionally substituted with a γ-lactam or δ-lactam, ii. perfluoro-Ci-Cδ-alkyl, iii. at least one Ci-Cβ-alkoxy optionally substituted with Ci-Cδ-alkoxycarbonyl, iv. phenyl, v. Ci-Cδ-alkyl sulfonyl, vi. -NHC(O) Ci-Ce-alkyl, vii. amino-Ci-Cδ-alkyl wherein amino is selected from -NH2, -NHCi-Cδ-alkyl,
-N(Ci-C6-alkyl)2, N(Ci-C6-alkyl)(Ci-C6-alkoxy-Ci-C6-alkyl), and the two substituents Ci-Cδ-alkyl can be the same or different, and wherein the two substituents may form a 3 to 8-membered heterocycloalkyl with the N to which they are attached to and wherein the heterocycloalkyl is optionally substituted with Ci-Cδ-alkyl or with hydroxy, viii. -N(Ci-C6-alkyl) (Ci-Ce-alkoxy-Ci-Ce-alkyl), ix. 5 to 6-membered heterocycloalkyl-Ci-Cδ-alkyl having a heteroatom selected from N and O, x. amido-Ci-Cδ-alkyl, xi. Ci-Cδ-alkoxy, xii. halogen; g. 5 to 10-membered heteroaryl having at least one heteroatom selected from N optionally substituted with halogen; and h. pyridinyl optionally substituted with at least one of the following groups i. halogen, ii. Ci-Cδ-alkyl optionally substituted with a 5 or 6-membered heterocycloalkyl having at least one heteroatom selected from O and N, iii. 5 or 6-membered heterocycloalkyl having at least one heteroatom selected from O and N, iv. -NHChydroxy-Ci-Ce-alkyl), v. -NH-(5-membered heteroaryl-Ci-C6-alkyl having as heteroatom O), vi. 5 or 6-membered heterocycloalkyl-Ci-Cδ-alkyl having at least one heteroatom selected from O and N;
Preferably these compounds exhibit an IC50 of 20 μM or less, preferably 15 μM or less, more preferably 10 μM or less, even more preferably 5 μM or less.
A preferred embodiment of the above Formula 1-4 is where
Ri is an unsubstituted 5-membered heteroaryl having at least one heteroatom selected from O, S and N; Rs is selected from a. phenyl optionally substituted with at least one of the following groups i. Ci-Ce-alkyl, ii. perfluoro-Ci-C6-alkyl, iii. Ci-Cβ-alkoxy; iv. Ci-Cβ-alkoxy, v. halogen; and b. pyridinyl optionally substituted with at least one of the following groups i.Cl, ii.Br, iϋ.-NH(hydroxy-Ci-C6-alkyl).
Preferably these compounds exhibit an IC50 of 15 μM or less, more preferably 10 μM or less, even more preferably 5 μM or less, even more preferably 1 μM or less, and still more preferably 0,9 μM or less.
In another embodiment the invention relates to triazolopyridine compounds according to the following Formula 1-5
Figure imgf000031_0001
Formula 1-5
wherein
R2 is selected from a. phenyl optionally substituted with i. at least one unsubstituted d-Cβ-alkyl, ii. unsubstituted Ci-Cβ-alkoxy, iii. fluoro, iv. bromo, v. hydroxy, vi. cyano, or vii. -NH2; and b. 5 or 9-membered heteroaryl having a heteroatom selected from N, S and O;
R5 is selected from a. unsubstituted Ci-Cβ-alkyl; b. aryl optionally substituted with i.amino-Ci-C6-alkyl wherein amino is selected from -NH2, -NHCi-Cβalkyl or
-N(Ci-C6-alkyl)2, and the two substituents Ci-Cβ-alkyl may form a 3 to 8- membered heterocacloalkyl with the N to which they are attached to and wherein the heterocycloalkyl is optionally substituted with Ci-Cβ-alkyl, or ii.5 or 6-membered heterocycloalkyl- Ci-Cβ-alkyl; and c. pyridinyl optionally substituted with at least one of the following groups i. Ci-Cβ-alkyl optionally substituted with a 5 or 6-membered heterocycloalkyl having at least one heteroatom selected from O and N, ii. 5 or 6-membered heterocycloalkyl having at least one heteroatom selected from O and N, iii. -NH-(5-membered heteroaryl-Ci-Cβ-alkyl having as heteroatom O), iv. 5 or 6-membered heterocycloalkyl-Ci-Cβ-alkyl having at least one heteroatom selected from O and N.
Preferably these compounds exhibit an IC50 of 20 μM or less, more preferably 15 μM or less, even more preferably 10 μM or less, and even more preferably 5 μM or less.
A preferred embodiment of the above Formula 1-5 is where R2 is selected from a.phenyl optionally substituted with at least one of the following groups i.at least one unsubstituted Ci-Cβ-alkyl, ii.unsubstituted Ci-Cβ-alkoxy, iii.fluoro, iv. bromo, v. hydroxy, vi. cyano vii. -NH2; b.furanyl; and c.thienyl;
R5 is selected from a. unsubstituted Ci-Cβ-alkyl; b. phenyl optionally substituted with i.amino-Ci-C6-alkyl wherein amino is selected from -NH2, -NHCi-Cβ-alkyl or
-N(Ci-C6-alkyl)2, or ii.5 or 6-membered heterocycloalkyl-Ci-Cβ-alkyl; c. pyridinyl optionally substituted with at least one of the following groups i. Ci-Cβ-alkyl optionally substituted with a 5 or 6-membered heterocycloalkyl having at least one heteroatom selected from O and N, ii. 5 or 6-membered heterocycloalkyl having at least one heteroatom selected from O and N, iii. -NH-(5-membered heteroaryl-Ci-Cβ-alkyl having as heteroatom O), iv. 5 or 6-membered heterocycloalkyl-Ci-Cβ-alkyl having at least one heteroatom selected from O and N.
Preferably these compounds exhibit an IC50 of 20 μM or less, more preferably 15 μM or less, even more preferably 10 μM or less, even more preferably 5 μM or less, and even more preferably 1 μM or less.
In another embodiment the invention relates to triazolopyridine compounds according to the following Formula 1-6
Figure imgf000033_0001
Formula 1-6 wherein
R4 is furanyl;
R5 is selected from unsubstituted phenyl; and 5 or 6-membered heteroaryl having a heteroatom selected from N, S and O.
A preferred embodiment of the above Formula 1-6 is wherein R5 is selected from phenyl and 5-membered heteroaryl having a heteroatom selected from N, S and O.
In one embodiment Ri is hydrogen; furanyl, preferably furan-2-yl, more preferably furan-3-yl; or -NRsR7; R2 is hydrogen, or methoxy- hydroxy-phenyl, preferably IH pyrazol-4-yl; R3 is perfluoromethyl, Cl or Br; R4 is hydrogen; R5 is unsubstituted or substituted pyridine wherein the substituent is halogeno, preferably Cl or Br; dihydro-1, 4-benzodioxin-6-yl, 3, 5-bis (methoxy) phenyl; phenyl; or 4-(morpholoin-4-yl methyl) phenyl; Either of Re and R7 is hydrogen; cycloalkyl, preferably cyclopropyl, more preferably cyclohexyl; cyclohexyl C1-C6- alkyl; Ci-Cβ-alkyl, preferably methyl, more preferably isobutyl, even more preferably isopropyl. The remaining chemical groups are as earlier defined.
These compounds according to the invention are preferably characterized by an IC50 of 5μM or less, preferably of lμM or less.
The embodiments of Formulae 1-1, 1-2, 1-3, 1-4, 1-5 and 1-6 and the embodiments thereof described as preferred may bear in further preferred embodiments at each chemical moiety substituents as described in the definitions regarding substituents above.
It was found by the inventors that the combination of these specific chemical groups leads to triazolopyridine compounds exhibiting very good inhibition properties to its target, i.e. the ASK target, in particular to ASKl .
One structure of the compounds according to the invention is characterized by cycloalkyl, aryl or heteroaryl groups for Ri or R2 and R5 wherein the remaining chemical groups are as defined above. Yet another structure is a substituted cycloalkyl, a substituted aryl or a substituted heteroaryl group for Ri or R2 and a substituted aryl or heteroaryl group for R5 wherein the substituent is defined as above. These structures of the compounds according to the invention exhibit good inhibition of the target ASK, in particular ASKl, which is obvious from the advantageous IC50 values as exemplified in the experimental section below. Moreover, such compounds show positive results, i.e. inhibition, in in vivo assays as exemplified by the LPS-induced TNFα release assay.
In this assay it could be shown that compounds according to the invention as defined in this section characterized by the structural features as outlined above exhibit an in vivo inhibition of at least about 40%, preferably at least about 50%. Particularly good results could be achieved with compounds of the invention according to Formula 1-3 and Formula 1-4 that may achieve an in vivo inhibition of at least about 40%, preferably at least about 42%, more preferably at least about 45%, and even more preferably at least about 48%. A particular group of compounds is characterized by -NR6Ry with R6 and R7 as defined above or a 5 or 6 membered heteroaryl in position Ri and a pyridinyl in position R5 that exhibit an in vivo inhibition of at least about 43%, preferably at least about 48%.
The structural motif as described in the above section may even enhance the properties by additional groups such as -CF3 or a halogen in positions R2 or R3.
In particular advantageous is a perfluoromethyl group for R3 and/or a furanyl for Ri and/or a pyridine for R5. Such compounds are preferably characterized by positive IC50 values of e.g. lOμM ore less, preferably 5μM or less, preferably lμM or less, more preferably of 0.1 μM or less and even more preferably of 0.5 μM or less.
Advantageously, it was found by the inventors that the above characterized positions play a significant role in the positive inhibition effects of the inventive compounds to the target ASK
The invention is further exemplified by the following triazolopyridine compounds: N-[5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-2-phenylacetamide; N-[5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide; N-[5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-4-(trifluoromethyl)benzamide; ethyl 3-{[5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]amino}-3-oxopropanoate; N-[5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-2-methoxyacetamide; 6-chloro-N-[5-(3-flιryl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide; methyl 4-{[5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]amino}-4-oxobutanoate;
2-(benzyloxy)-N-[5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]acetamide;
3-methoxy-N-[5-(lH-pyrrol-2-yl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]benzamide;
N-[5-(lH-pyrrol-2-yl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]cyclopentanecarboxamide;
N-[5-(lH-pyrrol-2-yl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]benzamide;
N-[5-(lH-pyrazol-4-yl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]benzamide;
N-[5-(lH-pyrrol-2-yl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide;
N-[5-(2-furyl)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]benzamide;
N-[6-(3-fluorophenyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide;
N-(6-phenyl[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl)nicotinamide;
N-[6-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide;
N-[6-(3-thienyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide;
N-[5-(3-flιryl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-3-methoxybenzamide;
N-[5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-2-(2-thienyl)acetamide;
N-[5-(3-flιryl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]cyclopentanecarboxamide;
N-[5-(3-flιryl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-4-methoxybenzamide;
N-[5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]isonicotinamide;
N-[5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]quinoxaline-6-carboxamide;
N-[6-(3-methoxyphenyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide;
N-[6-(3-aminophenyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide;
N-[6-(3-cyanophenyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide;
N-[5-(3-flιryl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]isoxazole-5-carboxamide;
N-[5-(3-flιryl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-2,3-dihydro-l,4-benzodioxine-6- carboxamide;
N-[5-(cyclopropylamino)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide;
N-(5-pyrrolidin-l-yl[l,2,4]triazolo[l,5-a]pyridin-2-yl)nicotinamide;
N-[5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-3,5-dimethoxybenzamide;
N-[5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]biphenyl-4-carboxamide;
1 -(4-chlorophenyl)-N-[5-(3-furyl)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2- yl] cyclopentanecarboxamide;
N-[5-(3-flιryl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-2,3-dihydro-l-benzoflιran-5- carboxamide;
N-[5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-3-furamide; 1 -acetyl-N-[5-(3-furyl)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]piperidine-4-carboxamide;
2,2-difluoro-N-[5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-l,3-benzodioxole-4- carboxamide;
N-[5-(3-thienyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide;
N-[1 ,2,4]triazolo[ 1 ,5-a]quinolin-2-ylnicotinamide;
N-[5-(cyclopentylamino)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]benzamide;
N-[5-(3-flιryl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide 1-oxide;
N-{5-[(3-methoxypropyl)amino][l,2,4]triazolo[l,5-a]pyridin-2-yl}benzamide;
N-{5-[(2-furylmethyl)amino][l,2,4]triazolo[l,5-a]pyridin-2-yl}benzamide;
N-{5-[(tetrahydrofuran-2-ylmethyl)amino][l,2,4]triazolo[l,5-a]pyridin-2- yl}benzamide;
3-(acetylamino)-N-[5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]benzamide;
N-[5-(cyclohexylamino)[l,2,4]triazolo[l,5-a]pyridin-2-yl]benzamide;
N-[5-(3-flιryl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-3-(methylsulfonyl)benzamide;
3-(aminomethyl)-N-[5-(3-flιryl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]benzamide;
N-(5 - { [ 1 -(hydroxymethyl)propyl] amino } [ 1 ,2,4]triazolo [ 1 ,5 -a]pyridin-2-yl)benzamide;
N-[6-(3-hydroxyphenyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]benzamide; tert-butyl[4-({[5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2- yl] amino } carbonyl)benzyl] carbamate;
N-[5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-4-isobutylbenzamide; tert-butyl[4-({[5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2- yl]amino}carbonyl)phenoxy]acetate;
4-butyl-N-[5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]benzamide;
N-[6-(4-hydroxy-3-methoxyphenyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]benzamide hydrochloride;
N-{5-[(2-methoxyethyl)amino][l,2,4]triazolo[l,5-a]pyridin-2-yl}benzamide;
N-{5-[(2,3-dihydroxypropyl)amino][l,2,4]triazolo[l,5-a]pyridin-2-yl}benzamide;
N-[6-(2,3-dihydro- 1 -benzofuran-5-yl)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]benzamide;
N-[5-(benzylamino)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide;
N-[5-(cycloheptylamino)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]nicotinamide dihydrochloride;
N-[5-(cyclohexylamino)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide;
N-(5- {[(5-methyl-2-furyl)methyl]amino} [1 ,2,4]triazolo[l ,5-a]pyridin-2- yl)nicotinamide; N-{5-[(tetrahydrofuran-2-ylmethyl)amino][l,2,4]triazolo[l,5-a]pyridin-2- yl}nicotinamide;
N-[6-(4-hydroxyphenyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]benzamide;
N- [6-(4-hydroxy-3 -methoxyphenyl) [ 1 ,2 ,4]triazo Io [ 1 ,5 -a]pyridin-2-yl]nicotinamide hydrochloride;
N-[5-(cyclooctylamino)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]nicotinamide;
N-{5-[cyclohexyl(methyl)amino][l,2,4]triazolo[l,5-a]pyridin-2-yl}nicotinamide;
N-[5-(tetrahydro-2H-pyran-4-ylamino)[l ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]nicotinamide;
N-{5-[(l-methylpiperidin-4-yl)amino][l,2,4]triazolo[l,5-a]pyridin-2-yl}nicotinamide;
N-{5-[(3-aminocyclohexyl)amino][l,2,4]triazolo[l,5-a]pyridin-2-yl}benzamide;
N-{5-[(l-methylpiperidin-4-yl)amino][l,2,4]triazolo[l,5-a]pyridin-2-yl}benzamide;
N-[5-(cyclopropylamino)-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2- yl]nicotinamide;
N-[5-(cyclohexylamino)-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2- yl]nicotinamide;
N-[5-(cycloheptylamino)-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2- yl]nicotinamide;
N- [5 -(cyclopentylamino)-7-(trifluoromethyl) [ 1 ,2,4]triazo Io [ 1 ,5 -a]pyridin-2- yl]nicotinamide;
N-[5-[(cyclohexylmethyl)amino]-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2- yl]nicotinamide;
N-(6-bromo-5-methyl[l,2,4]triazolo[l,5-a]pyridin-2-yl)nicotinamide;
N- {5-[(3-hydroxycyclohexyl)amino][ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl}nicotinamide;
N- {5-[(4-tert-butylcyclohexyl)amino] [1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl}nicotinamide;
N-[5-(tetrahydro-2H-pyran-3-ylamino)[l,2,4]triazolo[l,5-a]pyridin-2-yl]benzamide;
N-[5-(cycloheptylamino)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]-4-(morpholin-4- ylmethyl)benzamide;
N-[5-(cyclohexylthio)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]nicotinamide;
N-{5-[(trans-4-hydroxycyclohexyl)amino][l,2,4]triazolo[l,5-a]pyridin-2- yl}nicotinamide;
N-[5-(cyclobutylamino)-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2- yl]nicotinamide;
N-[5-(cyclohexylamino)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-6-morpholin-4- ylnicotinamide; N-[5-(cyclohexylamino)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]-4-
[(dimethylamino)methyl]benzamide;
N-[5-(cyclohexylamino)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-3-(morpholin-4- ylmethyl)benzamide;
N-[5-[(cyclopropylmethyl)amino]-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2- yl]nicotinamide; methyltrans-4- { [2- [(pyridin-3 -ylcarbonyl)amino] -7-
(trifluoromethyl)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-5-yl]amino} cyclohexanecarboxylate;
N-[5-{[(lRS,2RS)-2-(hydroxymethyl)cyclohexyl]amino}-7-
(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide;
N-[6-bromo-5-(cyclohexylamino)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide;
N-[5-(cycloheptylamino)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]tetrahydro-2H-pyran-4- carboxamide;
N-[5-(2-methylprop- 1 -en- 1 -yl)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]nicotinamide dihydrochloride;
N-(3-oxo-3-{[5-(lH-pyrazol-l-yl)[l,2,4]triazolo[l,5-a]pyridin-2- yl] amino } propyl)benzamide;
N-(3- {[5-(3-furyl)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]amino} -3-oxopropyl)benzamide;
N-(3- {[5-(2-furyl)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]amino} -3-oxopropyl)benzamide;
N-(3-{[5-(cyclohexylamino)[l,2,4]triazolo[l,5-a]pyridin-2-yl]amino}-3- oxopropyl)benzamide;
N- [5 -(isopropylamino)-7-(trifluoromethyl) [ 1 ,2,4]triazo Io [ 1 ,5 -a]pyridin-2- yl]nicotinamide;
N-[5-(sec-butylamino)-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2- yl]nicotinamide;
N-[5-(methylamino)-7-(trifluoromethyl)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2- yl]nicotinamide;
N-[8-(3-furyl)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]benzamide;
N-[5-(cyclohexyloxy)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]-2-(3- methoxyphenyl)acetamide;
N-[5-(cyclohexyloxy)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]nicotinamide;
N-[5-(cyclohexylamino)[ 1 ,2,4]triazolo[l ,5-a]pyridin-2-yl]-6-(2-pyrrolidin- 1 - ylethyl)nicotinamide; N-[5-(cyclohexylamino)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-6-(morpholin-4- ylmethyl)nicotinamide;
N-[5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]cyclopropanecarboxamide; N-[5-(3-thienyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]benzamide; N-[5-(3-furyl)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]benzamide; N-[5-(3-flιryl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]benzamide; N-[6-(4-hydroxy-3-methoxyphenyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]acetamide; N- [6-(4-hydroxy-3 ,5 -dimethylphenyl) [ 1 ,2,4]triazo Io [ 1 ,5 -a]pyridin-2-yl]nicotinamide; 4-[2-(benzoylamino)[l,2,4]triazolo[l,5-a]pyridin-6-yl]-N-[2- (dimethylamino)ethyl]benzamide;
N-[6-(lH-pyrazol-4-yl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]benzamide; N-{5-[(cyclohexylmethyl)amino][l,2,4]triazolo[l,5-a]pyridin-2-yl}nicotinamide; N- {5-[(4-hydroxycyclohexyl)amino] [1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl} -3- methoxybenzamide;
N-[5-(cyclopentylamino)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]-2-furamide; N-[7-chloro-5-(cyclobutylamino)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide; N-[7-chloro-5-(cyclopentylamino)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]nicotinamide; N-[7-chloro-5-(cyclohexylamino)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide; N-[5-(sec-butylamino)-7-chloro[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide; N- [7-chloro-5 -(cyclopropylamino) [ 1 ,2 ,4]triazo Io [ 1 ,5 -a]pyridin-2-yl]nicotinamide; N- [5 - [(2-methoxyethyl)amino] -7-(trifluoromethyl) [ 1 ,2,4]triazo Io [ 1 ,5 -a]pyridin-2- yl]nicotinamide;
N-[5-[(3-hydroxypropyl)amino]-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2- yl]nicotinamide;
N- [5 - [(2-hydroxyethyl)amino] -7-(trifluoromethyl)[ 1 ,2,4]triazo Io [ 1 ,5 -a]pyridin-2- yl]nicotinamide;
N- [5 -(dimethylamino)-7-(trifluoromethyl) [ 1 ,2,4]triazolo [ 1 ,5 -a]pyridin-2- yl]nicotinamide;
N-[5-(cyclohexylamino)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-2-pyridin-3-ylacetamide; N-[5-(cyclohexylamino)[ 1 ,2,4]triazolo[l ,5-a]pyridin-2-yl]-4-(piperidin- 1 - ylmethyl)benzamide;
N-[5-(cyclohexylamino)[ 1 ,2,4]triazolo[l ,5-a]pyridin-2-yl]-4-(pyrrolidin- 1 - ylmethyl)benzamide; N-[5-(cyclohexylamino)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-4-{[(2- methoxyethyl)(methyl)amino]methyl}benzamide;
N-[5-(cyclohexylamino)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]-6-methylnicotinamide;
N-[5-(cyclohexylamino)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-6-[(3- hydroxypropyl)amino]nicotinamide;
N-[5-(cyclohexylamino)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-6-[(2- furylmethyl)amino]nicotinamide;
N-[5-(cyclohexylamino)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide 1 -oxide;
N- [5 -(isopropylamino)-7-(trifluoromethyl) [ 1 ,2,4]triazo Io [ 1 ,5 -a]pyridin-2-yl] -2- pyridin-3 -ylacetamide trihydrochloride;
N- [5 - [( 1 -ethylpropyl)amino] -7-(trifluoromethyl) [ 1 ,2,4]triazo Io [ 1 ,5 -a]pyridin-2- yl]nicotinamide;
N- [5 -(isopropylamino)-7-(trifluoromethyl) [ 1 ,2,4]triazo Io [ 1 ,5 -a]pyridin-2- yl]nicotinamide 1 -oxide;
N-[5-[(3-hydroxycyclohexyl)amino]-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-
2-yl]nicotinamide formic acid;
N-{7-chloro-5-[(3-hydroxycyclohexyl)amino][l,2,4]triazolo[l,5-a]pyridin-2- yl} nicotinamide formic acid;
N-[5-(cyclopropylamino)-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-4-
[(dimethylamino)methyl]benzamide;
N-[5-(cyclopropylamino)-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-4-[(2- oxopyrrolidin- 1 -yl)methyl]benzamide;
N-[5-(cyclopropylamino)-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-6- pyrrolidin- 1 -ylnicotinamide;
N-[5-(cyclopropylamino)-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-6- methylnicotinamide;
N-[6-(4-hydroxy-3-methoxyphenyl)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]-4-(piperidin- 1 - ylmethyl)benzamide;
N-[6-(4-hydroxy-3-methoxyphenyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-6- methylnicotinamide;
N-[6-(4-hydroxy-3-methoxyphenyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-4-[(2- oxopyrrolidin- 1 -yl)methyl]benzamide;
4-[(dimethylamino)methyl]-N-[6-(4-hydroxy-3-methoxyphenyl)[l,2,4]triazolo[l,5- a]pyridin-2-yl]benzamide; N- [5 - { [( 1 R,2S)-2-(hydroxymethyl)cyclohexyl] amino } -7-
(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide hydrochloride;
N-[5-(cyclopropylamino)-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-4-[(4- hydroxypiperidin- 1 -yl)methyl]benzamide;
N-[5-(cyclopropylamino)-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-4-
(pyrrolidin- 1 -ylmethyl)benzamide;
N-[5-(cyclopropylamino)-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-6-(4- hydroxypiperidin- 1 -yl)nicotinamide;
N-[5-(cyclopropylamino)-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-6- piperazin- 1 -ylnicotinamide;
N-[5-(cyclopropylamino)-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-6-
(dimethylamino)nicotinamide;
N-[6-bromo-5-(cyclopentylamino)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-6-morpholin-4- ylnicotinamide;
N-[5-(cyclopropylamino)-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-6- morpholin-4-ylnicotinamide;
N-[5-(cyclohexylamino)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-6-
(dimethylamino)nicotinamide; tert-butyl 4-[5-({[5-(cyclopropylamino)-7-(trifluoromethyl)[l,2,4]triazolo[l,5- a]pyridin-2-yl]amino} carbonyl)pyridin-2-yl]piperazine- 1 -carboxylate;
N-[5-(cyclohexylamino)[ 1 ,2,4]triazolo[l ,5-a]pyridin-2-yl]-4-[(4-hydroxypiperidin- 1 - yl)methyl]benzamide;
N-[5-(cyclohexylamino)[ 1 ,2,4]triazolo[l ,5-a]pyridin-2-yl]-6-(4-fluoropiperidin- 1 - yl)nicotinamide;
N-[5-(cyclohexylamino)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-6-(lH-pyrazol-l- yl)nicotinamide; tert-butyl 4-[5-( {[5-(cyclohexylamino)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2- yljamino} carbonyl)pyridin-2-yl]piperazine- 1 -carboxylate;
N-[5-(cyclopropylamino)-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-6-[(3- hydroxypropyl)amino]nicotinamide;
N-[5-(isopropylamino)-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-6-
(morpholin-4-ylmethyl)nicotinamide;
N- [5 - [(pyrro lidin-3 -ylmethyl)amino] -7-(trifluoromethyl)[ 1 ,2,4]triazo Io [ 1 ,5-a]pyridin-
2-yl]nicotinamide; N-[5-(cyclohexylamino)[ 1 ,2,4]triazolo[l ,5-a]pyridin-2-yl]-4-(piperazin- 1 - ylmethyl)benzamide;
N-[5-(cyclohexylamino)[ 1 ,2,4]triazolo[l ,5-a]pyridin-2-yl]-4-[(4-formylpiperazin- 1 - yl)methyl]benzamide;
N-[5-(piperidin-3-ylamino)-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2- yl]nicotinamide;
N-[5-(sec-butylamino)-7-chloro[l,2,4]triazolo[l,5-a]pyridin-2-yl]-6-[(2- methoxyethyl)(methyl)amino]nicotinamide;
N-[5-(sec-butylamino)-7-chloro[l,2,4]triazolo[l,5-a]pyridin-2-yl]-6-[(3- hydroxypropyl)amino]nicotinamide;
N-[5-(sec-butylamino)-7-chloro[l,2,4]triazolo[l,5-a]pyridin-2-yl]-6-morpholin-4- ylnicotinamide;
N-[5-(sec-butylamino)-7-chloro[l,2,4]triazolo[l,5-a]pyridin-2-yl]-4-{[(2- methoxyethyl)(methyl)amino]methyl}benzamide;
N-[5-(sec-butylamino)-7-chloro[l,2,4]triazolo[l,5-a]pyridin-2-yl]-6- methylnicotinamide;
N-[7-chloro-5-(isopropylamino)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide;
N- [5 - [(3 -isopropoxyphenyl)amino] -7-(trifluoromethyl) [ 1 ,2,4]triazolo [ 1 ,5 -a]pyridin-2- yl]nicotinamide;
N- [5 - [(3 -fluoro-4-methoxyphenyl)amino] -7-(trifluoromethyl)[ 1 ,2,4]triazo Io [ 1 ,5 - a]pyridin-2-yl]nicotinamide;
N-[5-{[3-(benzyloxy)phenyl]amino}-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-
2-yl]nicotinamide;
N-[5-(sec-butylamino)-7-chloro[l,2,4]triazolo[l,5-a]pyridin-2-yl]-4-(morpholin-4- ylmethyl)benzamide;
N- [5 -(isopropylamino)-7-(trifluoromethyl) [ 1 ,2,4]triazo Io [ 1 ,5 -a]pyridin-2-yl] -6- methylnicotinamide;
6-chloro-N-[5-(isopropylamino)-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2- yl]nicotinamide;
6-[(2-aminoethyl)amino]-N-[5-(isopropylamino)-7-
(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide;
N-[5-(sec-butylamino)-7-methyl[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide;
N-[5-(isopropylamino)-7-methyl[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide. In another aspect the invention relates to the following intermediate compounds: 5-(3-thienyl)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-amine;
5-(3-furyl)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-amine;
5-bromo[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-amine;
5-chloro[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-amine;
6-bromo[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-amine; tert-butyl 2-(2-amino[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-5-yl)- lH-pyrrole- 1 -carboxylate;
5-chloro-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2-amine;
6-bromo-5-methyl[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-amine;
N5-cyclohexyl[ 1 ,2,4]triazolo[ 1 ,5-a]pyridine-2,5-diamine;
N5-cycloheptyl[l,2,4]triazolo[l,5-a]pyridine-2,5-diamine;
5-(cyclohexyloxy)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-amine;
5-(lH-pyrazol-l-yl)[l,2,4]triazolo[l,5-a]pyridin-2-amine; [ 1 ,2,4]triazolo[ 1 ,5-a]quinolin-2-amine;
6-bromo-N5-cyclohexyl[l,2,4]triazolo[l,5-a]pyridine-2,5-diamine;
6-bromo-N5-cyclohexyl[l,2,4]triazolo[l,5-a]pyridine-2,5-diamine;
5-(2-furyl)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-amine;
N5-isopropyl-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridine-2,5-diamine;
N-(5-bromo[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl)benzamide;
N-(5-bromo[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl)nicotinamide;
N-(5-chloro[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl)benzamide;
N-(5-chloro[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl)nicotinamide;
N-(6-bromo[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl)benzamide;
N-(6-bromo[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl)nicotinamide hydrochloride;
N-[5-chloro-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide;
4-(chloromethyl)-N-[5-(cyclohexylamino)[l,2,4]triazolo[l,5-a]pyridin-2- yl]benzamide;
N-(8-bromo[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl)benzamide;
N-(5,7-dichloro[l,2,4]triazolo[l,5-a]pyridin-2-yl)nicotinamide;
6-chloro-N-[5-(cyclohexylamino)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide;
N--cyclopropyl-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridine-2,5-diamine;
5-chloro-7-methyl[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-amine;
N-(5-chloro-7-methyl[l,2,4]triazolo[l,5-a]pyridin-2-yl)nicotinamide. In another aspect the invention relates to the use of triazolopyridine compounds according to the invention for use as a medicament.
In another aspect the invention relates to a method for the prevention and/or treatment of autoimmune disorderes, inflammatory diseases, cardiovascular disceases and/or neurodegenerative diseases in a subject, comprising administering to the subject an effective amount of a compound according to the invention.
The compounds according to the invention may be used for the preparation of a medicament for modulating and/or inhibiting the activity or function of ASK, in particular ASK-I, in a subject and in particular for preventing and/or treating autoimmune disorderes, inflammatory diseases, cardiovascular disceases and/or neurodegenerative diseases
In another aspect the invention relates to a method for the prevention and/or treatment of autoimmune disorderes, inflammatory diseases, cardiovascular disceases and/or neurodegenerative diseases in a subject, comprising administering to the subject an effective amount of a compound according to the invention in combination with other active compounds useful in the same indication in order to achieve increased efficacy.
In another aspect the compounds according to the invention may advantageously be used in a method for modulating and/or inhibiting the activity or function of ASK, in particular ASK-I, in a subject, comprising administering to the subject an effective amount of one or more of said compounds.
Another aspect of the invention is a pharmaceutical composition containing at least one triazolopyridine compound according to the invention and a pharmaceutically acceptable carrier, diluent or excipient.
Another aspect of the invention is a process for the preparation of a triazolopyridine compound according to formula (I), comprising the step of reacting a compound of Formula (II) with an acylating agent of Formulas (Ilia or IHb) in a presence of a base or a coupling agent:
Figure imgf000046_0001
(Ilia) LG : OH (MIb) LG : Cl
wherein R1, R2, R3, R4 ,Rs are as defined in any of the above definitions, wherein the base is selected from tertiary amine bases such as DIEA, TEA, NMM or pyridine, and the coupling agent is selected from a peptide coupling agent such as DCC, HATU, EDC/HOBt, i- butylchloroformate, carbonyl diimidazole, Mukaiyama's reagent in a suitable solvent such as DCM or CH3CN; and optionally further purifying the obtained compound.
A further aspect is a process for the preparation of a triazolopyridine compound according to formula (Ia) or (Ic), comprising A) the step of reacting a compound of Formula (Ib) wherein R1, R2, R3, R4 are as above defined but at least one is a group X selected from a halogen such as F, Br, Cl, I or a sulfonate ester such as OTf, with a boronic agent of formula (IVa) or ester (IVb) wherein R'i is an optionally substituted aryl, heteroaryl or alkenyl group as above defined in the presence of a base such as K2CO3, K3PO4 and a catalytic amount of a palladium catalyst such as PdCl2(PPl^)2 or Pd(OAc)2 with a ligand such as DPPF in an appropriate solvent such as DMF, THF, dioxane or a combination of water with toluene, DMF, THF or dioxane to give a compound of formula (Ia) wherein at least one of Ri, R2, R3, R4 is R'ior B) the step of reacting a compound of Formula (Id) wherein Ri is a leaving group such as F, Cl, Br, I, OMs, OTf or SR13 where R13 is an alkyl group with a secondary amine NHR6R7 of formula (V) wherein R6 and R7 are as above defined in a polar solvent such as ethanol or butanol or the amine itself to give a compound of formula (Ic) wherein Ri is NRsR6, and optionally further purifying the obtained compound. Pd catalyst
is R'.,
Figure imgf000047_0001
(V)
Yet another aspect of the invention is a process for the preparation of a triazolopyridine compound according to formula (Ha) wherein R2, R3, R4, R5 and R6 are as above defined, comprising the step of reacting a triazolopyridine compound of Formula (lib) wherein Ri is a leaving group such as F, Cl, Br, I, OMs, OTf or SR13 where R13 is an alkyl group with a secondary amine NHR6Ry of formula (V) wherein R6 and R7 are as above defined in a polar solvent such as ethanol or butanol or the amine itself to give a compound of formula (Ic) wherein Ri is NR5R6 ; and optionally further purifying the obtained compound.
Figure imgf000047_0002
(lib) (V) (Ha)
Synthesis of compounds of the invention:
The following abbreviations refer respectively to the definitions below: aq (aqueous), h (hour), g (gram), L (liter), mg (milligram), MHz (Megahertz), min. (minute), mm (millimeter), mmol (millimole), mM (millimolar), m.p. (melting point), eq. (equivalent), mL (milliliter), μL (microliter), ACN (acetonitrile), BINAP (2,2'-bis(di phenylphosphino)- l,l'-binaphthalene), Boc (tert-Butoxycarbonyl), BuLi (Butyl Lithium), HATU (O-(7- azabenzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium hexafluoro-phosphate), c-Hex
(Cyclohexane), DCC (Dicycloexylcarbodiimide), DCM (Dichloromethane), DEA (diethylamine), DIEA (Diisopropylethylamine), DMF (Dimethylformamide), DMSO (Dimethyl sulfoxide), DMSO-(I6 (Deuterated dimethylsulfoxide), DPPF (1,1'- bis(diphenylphosphino)ferrocene), EDC (l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride ), EtOAc (Ethyl acetate), ESI (Electro-spray ionization), Et2O (Diethyl ether), EtOH (Ethanol), HOBT (1-hydroxybenzotriazole), HPLC (High Performance Liquid Chromatography), i-PrOH (2-propanol), MS (mass spectrometry), MTBE (Methyl tert-butyl ether), MW (micro-wave irradiation), NMM (N-methylmorpholine), NMR (Nuclear Magnetic Resonance), OTf (trifluoromethanesulfonate), rt (room temperature), SPE (solid phase extraction), TEA (Triethylamine), TFA (Trifluoroacetic acid), THF (Tetrahydrofuran), TLC (Thin Layer Chromatography).
Figure imgf000048_0001
(I)
The triazolopyridines compounds according to Formula (I) may be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred experimental conditions (i.e. reaction temperatures, time, moles of reagents, solvents, etc.) are given, other experimental conditions can also be used unless otherwise stated.
Generally, the triazolopyridines compounds according to the general Formula (I) may be obtained by several processes using both solution-phase and solid-phase chemistry protocols. Examples of synthetic pathways will be described. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by the person skilled in the art, using routine optimisation procedures.
Depending on the nature of R1, R2, R3, R4 and R5, different synthetic strategies may be selected for the synthesis of compounds of Formula (I). In the process illustrated in the following schemes R1, R2, R3, R4 and R5 are as above-defined in the description. In general, the synthesis pathways for any individual compound of Formula (I) will depend on the specific substitutents of each molecule and upon the ready availability of intermediates necessary; again such factors being appreciated by those of ordinary skill in the art. For all the protection and deprotection methods, see Philip J. Kocienski, in "Protecting Groups", Georg Thieme Verlag Stuttgart, New York, 1994 and, Theodora W. Greene and Peter G. M. Wuts in "Protective Groups in Organic Synthesis", Wiley Interscience, 3rd Edition 1999.
According to one process as of scheme 1, triazolopyridine compounds according to the general Formula (I) whereby R1, R2, R3, R4 and R5 are defined as in any of the above definitions, are prepared from the corresponding triazolopyridine amino compounds of formula (II) by reaction with an acylating agent of general Formula (III) whereby the substituent R5 is as in any of the above definitions, while LG could be any appropriate leaving group such as Cl, OH. Preferred acylating agents (III) are acid chlorides (Ilia) used in conjunction with a base such as tertiary amine bases (e.g. DIEA, TEA, NMM), pyridine, or carboxylic acids (HIb), used in conjunction with a peptide coupling agent (in solution or solid supported) such as DCC, HATU, EDC/HOBt, i-butylchloroformate, carbonyl diimidazole, Mukaiyama's reagent in the presence or the absence of a base such as DIEA, sodium tert- butytoxide.
Scheme 1
Figure imgf000049_0001
(MIa) LG : Cl (1Mb) LG : OH
A preferred condition for the preparation of a compound of Formula (I) whereby R1, R2, R3, R4 and R5 are as in any of the above definitions consists in the reaction of triazolopyridines amino derivatives of Formula (II) with an acid chloride (Ilia) wherein R5 is as defined above, in a suitable solvent such as DCM or CH3CN at a temperature between 00C and 1000C in the presence of pyridine. According to a further general process, compounds of Formula (I) can be converted to alternative compounds of Formula (I), employing suitable interconversion techniques well known by a person skilled in the art.
A preferred method as of scheme 2 to prepare the triazolopyridine compounds as of scheme 2 according to the general Formula (Ia) wherein R1, R2, R3, R4 are as above defined but at least one is an aryl, a heteroaryl or an alkenyl group R'i, consist in reacting triazolopyridine compounds according to the general Formula (Ib) wherein one of Ri, R2, R3 and R4 are as above defined, but at least one is a group X selected from a halogen atom such as Cl, Br, I or a sulfonate ester such as OTf with a boronic acid (IVa) or ester (IVb) wherein R'i is as above defined using well known Suzuki-Miyaura reaction conditions (Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457; Takahiro I. and Toshiaki M., Tetrahedron Lett. 2005, 46, 3573- 3577/ In a typical procedure, triazolopyridine compounds (Ib) and boronic acid (IVa) or ester (IVb) are heated at various temperature by traditional thermic methods or using microwave technology in presence of a base such as K2CO3, K3PO4 or CsF and a catalytic amount of palladium catalyst such as PdCl2(PPl^)2 or Pd(OAc)2 with a ligand such as DPPF in an appropriate solvent such as DMF or a combination of water with THF or dioxane such as those described hereinafter in the Examples.
Scheme 2
is R',
Figure imgf000050_0001
<l b> (,Vb) (la)
A preferred method as of scheme 3 to prepare the triazolopyridine compounds according to the general Formula (Ic) whereby R2, R3, R4 and NR6R7 are as defined above, consists in reacting triazolopyridine compounds according to the general Formula (Id) whereby R2, R3, R4 and R5 are as above defined and Ri is F, Cl, Br, I, OMs, OTf or SR13 where R13 is an alkyl group with an amine R6R7NH (V). In a typical procedure, triazolopyridine compounds according to the general Formula (Id) and amines R6R7NH (V) are heated at various temperature by traditional thermic methods or using microwave technology in an appropriate solvent such as ethanol, butanol or the amine itself such as those described hereafter in the examples.
Scheme 3
Figure imgf000051_0001
R1 is F, Cl, Br, I, OMs, OTf, SR8 R1 is NR6R7 (Id) (Ic)
Triazolopyridine amino compounds of formula (II), whereby the substituent R1, R2, R3, and R4 are as above defined, are prepared from 2-aminopyridine compounds of Formula (VI) by well known protocols such as shown in Scheme 4 below (Nettekoven M. et al, Synthesis 2003, 11, 1649-1652). In a typical procedure, 2-aminopyridine compounds of Formula (VI) whereby Ri, R2, R3, and R4 are as above defined are reacted with an alkyloxycarbonylisothiocyanate of Formula (IX) where R14 is an alkyl group such as methyl or ethyl in an appropriate solvent such as dioxane to give thiourea compounds (VII). Cyclisation of thiourea compounds (VII) to triazolopyridine amines of Formula (II) is then performed in presence of hydroxylamine or hydroxylamine hydrochloride in conjunction with an appropriate base such diisopropylethylamine and in an appropriate solvent such as methanol and ethanol.
Scheme 4
Figure imgf000051_0002
(Vl) (VII) (II)
According to a further general process, compounds of Formula (II) can be converted to alternative compounds of Formula (II), employing suitable interconversion techniques well known by a person skilled in the art.
A preferred method as of scheme 5 to prepare the triazolopyridine amine compounds of Formula (Ha) whereby R2, R3, R4 and NR6R7 are as above defined, consists in reacting triazolopyridine amine compounds according to the general Formula (lib) whereby R2, R3 and R4 are as above defined and R1 is F, Cl, Br, I, OMs, OTf or SR13 where R13 is an alkyl group with an amine R6R7NH (V). In a typical procedure, triazolopyridine amine compounds according to the general Formula (lib) and amines R6R7NH (V) are heated at various temperature by traditional thermic methods or using microwave technology in an appropriate solvent such as ethanol, butanol or the amine itself such as those described hereafter in the examples.
Scheme 5
R1 is
Figure imgf000052_0001
F, Cl, Br, I, OMs, OTf, SR13
(lib) (Na)
2-aminopyridine compounds of Formula (VI) whereby R1, R2, R3, and R4 are as above defined may be obtained either from commercial sources or they may be prepared from known compounds using procedures such as those described hereinafter in the examples, or conventional procedures, known by one skilled in the art.
A preferred method as of scheme 6 to prepare 2-amino pyridine compounds (Via) whereby one of R1, R2, R3 and R4, as above defined, is an aryl, a heteroaryl or an alkenyl group R'1, consist in reacting 2-aminopyridine compounds (VIb) whereby one of R1, R2, R3 and R4, as above defined, is a group X selected from a halogen atom such as Cl, Br, I or a sulfonate ester such as OTf with a boronic acid (IVa) or ester (IVb) whereby R'1 is as above defined using well known Suzuki-Miyaura reaction conditions (Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457; Takahiro I. and Toshiaki M., Tetrahedron Lett. 2005, 46, 3573-3577;. In a typical procedure, 2-aminopyridine compounds of Formula (VIb) and boronic acid (IVa) or ester (IVb) are heated at various temperature by traditional thermic methods or using microwave technology in presence of a base such as K2CO3, K3PO4 or CsF and a catalytic amount of palladium catalyst such as PdCl2(PPhS)2 or Pd(OAc)2 with DPPF in an appropriate solvent such as DMF or a combination of water with THF or dioxane such as those described hereinafter in the Examples.
Scheme 6 Is R'.,
Figure imgf000053_0001
If the above set of general synthetic methods is not applicable to obtain compounds according to Formula (I) and/or necessary intermediates for the synthesis of compounds of Formula (I), suitable methods of preparation known by a person skilled in the art should be used. Compounds of this invention can be isolated in association with solvent molecules by crystallization or from evaporation of an appropriate solvent. The pharmaceutically acceptable acid addition salts of the compounds of Formula (I), which contain a basic center, may be prepared in a conventional manner. For example, a solution of the free base may be treated with a suitable acid, either neat or in a suitable solution, and the resulting salt isolated either by filtration or by evaporation under vacuum of the reaction solvent.
The pharmaceutically acceptable cationic salts of compounds of the present invention are readily prepared by reacting the acid forms with an appropriate base, usually one equivalent, in a co-solvent. Typical bases are sodium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride, potassium hydroxide, potassium methoxide, magnesium hydroxide, calcium hydroxide, benzathine, choline, diethanolamine, ethylenediamine, meglumine, benethamine, diethylamine, piperazine and tromethamine. The salt is isolated by concentration to dryness or by addition of a non- solvent. In some cases, salts can be prepared by mixing a solution of the acid with a solution of the cation (sodium ethylhexanoate, magnesium oleate), employing a solvent in which the desired cationic salt precipitates, or can be otherwise isolated by concentration and addition of a non- solvent.
The compounds of invention have been named according the standards used in the program "ACD/Name Batch" from Advanced Chemistry Development Inc., ACD/Labs (7.00 Release). Product version: 7.10, build: 15 Sep 2003.
Examples
The novel compounds according to Formula (I) can be prepared from readily available starting materials by several synthetic approaches, using both solution-phase and solid-phase chemistry protocols or mixed solution and solid phase protocols. Examples of synthetic pathways for the will be described.
The commercially available starting materials used in the following experimental description were purchased from Aldrich, Fluka or Acros unless otherwise reported.
The HPLC, NMR and MS data provided in the examples described below are obtained as followed: HPLC: Waters Alliance 2695 equipped with Waters X-Bridge column C8 50 x 4.6 mm 3.5 μm, Conditions: MeCN (0.05% TFA)/H2O (0.1% TFA), 5 to 100% (8 min), max plot 230-400 nm; LC/MS spectra: waters ZMD (ES) equipped with Waters X-Bridge column C8 30 x 2.1 mm 3.5 μm; 1H-NMR: Bruker DPX-300MHz unless otherwise reported.
The preparative HPLC purifications are performed with a mass directed autopurification Fractionlynx from Waters equipped with a sunfϊre prep Cl 8 OBD column 19x100 mm 5 μm, unless otherwise reported. All HPLC purifications were performed with a gradient of ACN/H2O or ACN/H2O/HCOOH (0.1%).
The microwave chemistry is performed on a single mode microwave reactor Emrys™ Optimiser from Personal Chemistry.
INTERMEDIATES
Intermediate A
Figure imgf000054_0001
Intermediate Al : 5-( 3-thienyl) [1 ,2,41 triazolo [ 1 ,5-al pyridin-2-amine Step a) Formation of 6-(3-thienyl)pyridin-2-amine
Figure imgf000054_0002
To a mixture of 2-amino-6-bromopyridine (Lancaster, 5.0 g; 28.9 mmol; 1.0 eq.), 3- thienylboronic acid (4.44 g; 34.7 mmol; 1.2 eq.), potassium phosphate (12.27 g; 57.8 mmol; 2.0 eq.) in dry dioxane (150 rnL) was added l,r-bis(diphenylphosphino)ferrocenedichloro palladium (1.06 g; 1.44 mmol; 0.05 eq.) under inert atmosphere. The reaction mixture was heated at 800C overnight, cooled down to rt, filtered on a bed of celite and filtrates were evaporated under reduced pressure. Purification of the crude by flash chromatography on silica (gradient EtOAc/c-Hex, 5:95 to 50:50) gave the title compound as a beige solid (3.71 g, 73%). HPLC, Rt: 1.51 min. (purity 96.4%). LC/MS, M+(ESI): 177.4.
Step b) Formation of ethyl ({[6-(3-thienyl)pyridin-2-yl]amino}carbonothioyl)carbamate
A solution of 6-(3-thienyl)pyridin-2-amine (3.70 g; 21.0 mmol; 1.0 eq.) and ethoxycarbonyl isothiocyanate (2.73 mL; 24.1 mmol; 1.15 eq.) in dioxane (100 mL) was stirred at rt overnight. The precipitate formed was filtered and washed with c-Hex to give the title compound as a white solid (4.73 g; 73%). HPLC, Rt: 4.26 min. (purity 99.9%). LC/MS, M+(ESI): 308.3.
Step c) Formation of5-(3-thienyl)[l,2,4]triazolo[l,5-a]pyridin-2-amine
Figure imgf000055_0002
Intermediate Al
A suspension of ethyl ({[6-(3-thienyl)pyridin-2-yl]amino}carbonothioyl)carbamate (4.0 g; 13.01 mmol; 1.0 eq.), hydroxylamine hydrochloride (4.52 g; 65.1 mmol; 5.0 eq.) and DIEA (6.55 mL) in MeOH/EtOH (1 :1, 120 mL) was stirred at rt for 2 hours and then at 700C for 3 hours. Solvents were removed under reduced pressure, the residue was taken up in dioxane/water (1 :1) and filtered to give the title compound as a white powder (2.3 g; 82%). HPLC, Rt: 1.75 min. (purity 94.8%). LC/MS, M+(ESI): 217.3.
Intermediate A2 : 5-( 3-furyl) [ 1 ,2,41 triazolo \ 1 ,5-al pyridin-2-amine Step a) Formation of 6-(3-furyl)pyridin-2-amine
Figure imgf000056_0001
The title compound was prepared following procedure described for intermediate Al step a), but starting from 2-amino-6-chloropyridine (25.0 g; 194.5 mmol; 1.0 eq.) and furan-3-boronic acid (26.11 g; 233.4 mmol; 1.2 eq.). The crude was purified by flash chromatography (EtOAc/c-Hex, 50:50) to give the title compound as a brown oil (16.91 g; 54%). 1H NMR (DMSO-J6) δ 7.96 (s, IH), 7.42 (m, 2H), 6.82 (m, 2H), 6.37 (d, J = 7.2 Hz, IH), 4.54 (m, 2H). HPLC, Rt: 1.30 min. (purity 84.9%). LC/MS, M+(ESI): 161.4.
Step b) Formation of ethyl ({[6-(3-furyl)pyridin-2-yl]amino}carbonothioyl)carbamate
Figure imgf000056_0002
The title compound was prepared following procedure described for intermediate Al step b), but starting from 6-(3-furyl)pyridin-2-amine (16.0 g; 105.5 mmol; 1.0 eq.) as a white solid (28.2 g; 92%). HPLC, Rt: 3.98 min. (purity 99.7%). LC/MS, M+(ESI): 292.3, M (ESI): 290.2.
Step c) Formation of5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-amine
Figure imgf000056_0003
Intermediate A2 The title compound was prepared following procedure described for intermediate Al step c), but starting from ethyl ({[6-(3-furyl)pyridin-2-yl]amino}carbonothioyl)carbamate (28.1 g; 96.5 mmol; 1.0 eq.) as a clear beige powder (17.26 g; 89%). 1H NMR (DMSO-J6) δ 8.92 (s, IH), 7.88 (d, J = 1.7 Hz, IH), 7.50 (t, J = 8.1 Hz, IH), 7.29-7.37 (m, 3H), 6.11 (s, 2H). HPLC, Rt: 1.59 min. (purity 99.6%). LC/MS, M+(ESI): 201.3.
Intermediate A3: 5-bromo[l,2,41triazolo[l,5-alpyridin-2-amine
Step a) Formation of ethyl {[(6-bromopyridin-2-yl)amino]carbonothioyl}carbamate
Figure imgf000057_0001
The title compound was prepared following procedure described for intermediate Al step b), but starting from 2-amino-6-bromopyridine (20.0 g; 115.6 mmol; 1.0 eq.) as a white solid (36 g, quant, yield). HPLC, Rt: 4.17 min. (purity 99.8%). LC/MS, M+(ESI): 306.1.
Step b) Formation of5-bromo[l,2,4]triazolo[l,5-a]pyridin-2-amine
Figure imgf000057_0002
Intermediate A3
The title compound was prepared following procedure described for intermediate Al step c), but starting from ethyl {[(6-bromopyridin-2-yl)amino]carbonothioyl}carbamate (36.0 g; 118.4 mmol; 1.0 eq.) as a yellowish solid (20.65 g; 82%). HPLC, Rt: 1.03 min. (purity 97.6%). LC/MS, M+(ESI): 215.2.
Intermediate A4 : 5-chloro[l,2,41triazolo[l,5-alpyridin-2-amine
Step a) formation of ethyl {[(ό-chloropyridin^-yfyaminojcarbonothioyljcarbamate
Figure imgf000057_0003
The title compound was prepared following procedure described for intermediate Al step b), but starting from 2-amino-6-chloropyridine (49.38 g; 384.1 mmol; 1.0 eq.) as a yellow solid (107 g, quant, yield). HPLC, Rt: 3.93 min. (purity 94.5%). LC/MS, M+(ESI): 260.0.
Step b) formation of5-chloro[l,2,4]triazolo[l,5-a]pyridin-2-amine
Figure imgf000057_0004
Intermediate A4
The title compound was prepared following procedure described for intermediate Al step c), but starting from ethyl {[(6-chloropyridin-2-yl)amino]carbonothioyl} carbamate (99.76 g; 384.1 mmol; 1.0 eq.) as a greenish solid (51.19 g; 79.0 %). HPLC, Rt: 0.92 min. (purity 98.1%). LC/MS, M+(ESI): 169.0.
Intermediate A5: 6-bromo[l,2,41triazolo[l,5-alpyridin-2-amine
Step a) Formation of ethyl {[(5-bromopyridin-2-yl)amino]carbonothioyl}carbamate
Figure imgf000058_0001
The title compound was prepared following procedure described for intermediate Al step b), but starting from 2-amino-5-bromopyridine (35.0 g; 202.3 mmol; 1.0 eq.) as a yellowish solid (60 g; 97%). HPLC, Rt: 4.04 min. (purity 92.4%). LC/MS, M+(ESI): 305.9.
Step b) Formation of6-bromo[l,2,4]triazolo[l,5-a]pyridin-2-amine
Figure imgf000058_0002
Intermediate A5 The title compound was prepared following procedure described for intermediate Al step c), but starting from ethyl {[(5-bromopyridin-2-yl)amino]carbonothioyl}carbamate (61.0 g; 200.6 mmol; 1.0 eq.) as an off white powder (42.6 g; 99%). HPLC, Rt: 1.18 min. (purity 97.3%). LC/MS, M+(ESI): 214.9.
Intermediate A6 : tert-butyl 2-f2-amino[l,2,41triazolo[l,5-alpyridin-5-yl)-lH-pyrrole-l- carboxylate
Step a) Formation of tert-butyl 2-(6-aminopyridin-2-yl)-lH-pyrrole-l-carboxylate
Figure imgf000058_0003
The title compound was prepared following procedure described for intermediate Al step a), but starting from 2-amino-6-chloropyridine (2.05 g; 16.0 mmol; 1.0 eq.) and ethyl l-(t- butoxycarbonyl)pyrrole-2-boronic acid (5.06 g; 24.0 mmol; 1.5 eq.) as a beige powder (1.15 g, 27%). HPLC, Rt: 2.65 min. (purity 97.0%). LC/MS, M+(ESI): 204.3. Step b) Formation of tert-butyl 2-[6-
({[(ethoxycarbonyl)amino]carbonothioyl}amino)pyridin-2-yl]-lH-pyrrole-l-carboxylate
Figure imgf000059_0001
The title compound was prepared following procedure described for intermediate Al step b), but starting from tert-butyl 2-(6-aminopyridin-2-yl)-lH-pyrrole-l-carboxylate (1.15 g; 4.43 mmol; 1.0 eq.) as a beige solid (1.47 g, 85 %). HPLC, Rt: 4.99 min. (purity 94.0%). LC/MS, M+(ESI): 335.2.
Step c) Formation of tert-butyl 2-(2-amino[l,2,4]triazolo[l,5-a]pyridin-5-yl)-lH-pyrrole-l- carboxylate
Figure imgf000059_0002
Intermediate A6
The title compound was prepared following procedure described for intermediate Al step c), but starting from tert-butyl 2-[6-({[(ethoxycarbonyl)amino]carbonothioyl}amino)pyridin-2- yl]-lH-pyrrole-l-carboxylate (1.47 g; 3.76 mmol; 1.0 eq.) as a beige solid (870 mg, 77%). HPLC, Rt: 2.68 min. (purity 98.5%). LC/MS, M+(ESI): 244.3.
Intermediate A7: 5-chloro-7-( trifluoromethyl) [1 ,2,41 triazolo [ 1 ,5-al pyridin-2-amine Step a) Formation of6-chloro-4-(trifluoromethyl)pyridin-2-amine
Figure imgf000059_0003
A solution of 2,6-dichloro-4-(trifluoromethylpyridine) (Fluorochem, 10.0 g; 46.30 mmol; 1.0 eq.) in ammonium hydroxide (-25% in water) (40.0 mL; 4.0 V) was heated to 1800C for 3 h in a Parr apparatus and cooled down to rt. After this time, reaction mixture was filtered over a bed of celite, evaporated to dryness under reduced pressure, triturated with DCM and filtered. The mother liquors were concentrated under reduced pressure to give the title compound as a yellow oil that crystallized upon standing (4.83 g; 53%). HPLC, Rt: 3.58 min. (purity 96.9%). LC/MS, M+(ESI): 196.8, M (ESI): 194.8.
Step b) formation of ethyl ({[6-chloro-4-(trifluoromethyl)pyridin-2- yl]amino}carbonothioyl)carbamate
Figure imgf000060_0001
The title compound was prepared following procedure described for intermediate Al step b), but starting from 6-chloro-4-(trifluoromethyl)pyridin-2-amine (4.83 g; 24.57 mmol; 1.0 eq.) as a beige solid (6.90 g; 86%). HPLC, Rt: 5.00 min. (purity 96.0%). LC/MS, M+(ESI): 327.9.
Step c) Formation of5-chloro-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2-amine
Figure imgf000060_0002
Intermediate A7
The title compound was prepared following procedure described for intermediate Al step c), but starting from ethyl ({[6-chloro-4-(trifluoromethyl)pyridin-2- yl]amino}carbonothioyl)carbamate (6.90 g; 21.1 mmol; 1.0 eq.) as a white powder (3.6 g, 72%). HPLC, Rt: 2.45 min. (purity 98.9%). LC/MS, M+(ESI): 236.8, M (ESI): 234.8.
Intermediate A8 : 6-bromo-5-methyl [ 1 ,2,41 triazolo \ 1 i5-al pyridin-2-amine
Step a) Formation of ethyl {[(5-bromo-6-methylpyridin-2- yl)amino]carbonothioyl}carbamate
Figure imgf000060_0003
The title compound was prepared following procedure described for intermediate Al step b), but starting from 6-amino-3-bromo-2-methylpyridine (25.0 g; 133.7 mmol; 1.0 eq.) as a yellow powder (41.80 g; 98%). HPLC, Rt: 4.49 min. (purity 99.3%). LC/MS, M+(ESI): 319.9, M (ESI): 317.9. Step b) Formation of6-bromo-5-methyl[l,2,4]triazolo[l,5-a]pyridin-2-amine
Figure imgf000061_0001
Intermediate A8
The title compound was prepared following procedure described for intermediate Al step c), but starting from ethyl {[(5-bromo-6-methylpyridin-2-yl)amino]carbonothioyl}carbamate (41.8 g; 131.4 mmol; 1.0 eq.) as a white solid (23.90 g; 80%). HPLC, Rt: 1.55 min. (purity 99.9%). LC/MS, M+(ESI): 228.9.
Intermediate A9 : N5-cyclohexyl[l.,2,41triazolo[l,5-alpyridine-2,5-diamine
Figure imgf000061_0002
Intermediate A9
A suspension of 5-chloro[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A4), 10.0 g; 59.32 mmol; 1.0 eq.) in cyclohexylamine (60 mL) was heated to reflux for 52 h. Reaction mixture was taken up in MTBE and filtered. The resulting cake was washed with MTBE and filtrate was concentrated to dryness. Residue was purified by flash chromatography (Hept/EtOAc, 1 :1) to give the tilte compound as a beige powder (8.08 g, 59%). HPLC, Rt: 2.46 min. (purity 98.9%). LC/MS, M+(ESI): 231.9.
Intermediate AlO : N5-cvcloheptyl[l,2,41triazolo[l,5-alpyridine-2,5-diamine
Figure imgf000061_0003
Intermediate AlO
The title compound was prepared following procedure described for intermediate A9, but starting from 5-chloro[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A4), 2.88 g; 17.1 mmol; 1.0 eq.) and cycloheptylamine (14 mL) and heated at 1800C for 1 h under microwave radiation to give the title compound as a beige oil (2.48 g; 59%). HPLC, Rt: 2.90 min. (purity 97.2%). LC/MS, M+(ESI): 292.9.
Intermediate All : 5-fcyclohexyloxy)[l.,2,41triazolo[l,5-alpyri(iin-2-amine
Figure imgf000062_0001
Intermediate All
Cyclohexanol (1.68 rnL; 15.84 mmol; 5.0 eq.) was added to a suspension of NaH (152 mg; 3.80 mmol; 1.2 eq.) in THF (6.0 mL) and maintained under inert atmosphere at 00C. The reaction mixture was brought back to rt and stirred for 1 h before the addition of 5- chloro[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A4), 534 mg; 3.17 mmol; 1.0 eq.). Reaction mixture was then heated at reflux for 3 h after which time it was quenched by adition of water. It was then extracted with EtOAc, washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel (DCM/MeOH, 95:5 to 10:90) gave the title compound as a white solid (590 mg, 80%). HPLC, Rt: 2.18 min. (purity 90.1%). LC/MS, M+(ESI): 233.0.
Intermediate A12 : 5-flH-pyrazol-l-yl)[l,2,41triazolo[l,5-alpyridin-2-amine
Figure imgf000062_0002
Intermediate A12
5-bromo[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A3); 1,06 g; 5.0 mmol; 1.0 eq.), pyrazole (3.40 g; 50.0 mmol; 10 eq.) and potassium hydroxide (842 mg; 15.0 mmol; 3.0 eq.) were melted and stirred overnight at 110 0C. After this time, reaction mixture was cooled to rt poured into water and extracted with Et2O. The combined organic layers were washed with water, dried over magnesium sulfate, filtered and evaporated under reduced pressure to give the title compound as a white solid (650 mg, 65%). HPLC, Rt: 1.22 min. (purity 96.6%). LC/MS, M+(ESI): 201.0. Intermediate A13 : [l,2,41triazolo[l,5-alαuinolin-2-amine
Step a) Formation of ethyl [(quinolin-2-ylamino)carbonothioyl]carbamate
Figure imgf000063_0001
The title compound was prepared following procedure described for intermediate Al step b), but starting from quinolin-2-amine (1.06 g; 7.35 mmol; 1.0 eq.) as a yellow powder (1.68 g, 83%). HPLC, Rt: 3.66 min. (purity 97.8%). LC/MS, M (ESI): 274.3.
Step b) Formation of [l,2,4]triazolo[l,5-a]quinolin-2-amine
Figure imgf000063_0002
Intermediate A13
The title compound was prepared following procedure described for intermediate Al step c), but starting from ethyl [(quinolin-2-ylamino)carbonothioyl]carbamate (1.68 g; 6.10 mmol; 1.0 eq.) as a white powder (667 mg, 59%). 1H NMR (DMSO-J6) δ 8.26 (d, J = 8.3 Hz, IH), 7.81 (d, J = 7.9 Hz, IH), 7.74 (d, J = 9.4 Hz, IH), 7.70 (m, IH), 7.47 (m, IH), 7.45 (d, J = 9.0 Hz, IH). HPLC, Rt: 1.62 min. (purity 99.7%). LC/MS, M+(ESI): 185.4.
Intermediate A14 : 6-bromo-N5-cvclohexyl[l.,2,41triazolo[l,5-alpyridine-2,5-diamine Step a) Formation of5-bromo-6-chloropyridin-2-amine
Figure imgf000063_0003
N-bromosuccinimide (16.45 g; 92.41 mmol; 1.10 eq.) was added portionwise to a solution of 2-amino-6-chloropyridine (10.80 g; 84.01 mmol; 1.0 eq.) in DMF (200 mL) at rt. The reaction mixture was stirred at rt for 2 hours. Solvents were removed under reduced pressure and the residue was taken up in EtOAc and aqueous ammonia. The organic phase was washed again with aqueous ammonia and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The black solid obtained was washed with pentane and dried under vacuum to give the title compound as a beige powder (12.5 g, 72%). HPLC, Rt: 2.81 min. (purity 95.8%). Step b) Formation of ethyl {f(5-bromo-6-chloropyridin-2- yl)amino]carbonothioyl}carbamate
Figure imgf000064_0001
The title compound was prepared following procedure described for intermediate Al step b), but starting from 5-bromo-6-chloropyridin-2-amine (7.09 g; 34.2 mmol; 1.0 eq.) as an off- white solid (8.80 g; 76%). HPLC, Rt: 4.65 min. (purity 100.0%).
Step c) Formation of6-bromo-5-chloro[l,2,4]triazolo[l,5-a]pyridin-2-amine
Figure imgf000064_0002
The title compound was prepared following procedure described for intermediate Al step c), but starting from ethyl {[(5-bromo-6-chloropyridin-2-yl)amino]carbonothioyl}carbamate (8.80 g; 26.0 mmol; 1.0 eq.) as a beige powder (4.56 g; 70%). HPLC, Rt: 1.96 min. (purity 91.5%). LC/MS, M+(ESI): 248.8.
Step d) Formation of6-bromo- N5-cyclohexyl[l,2,4]triazolo[l,5-a]pyridine-2,5-diamine
Figure imgf000064_0003
Intermediate A14
The title compound was prepared following procedure described for intermediate A9 but starting from 6-bromo-5-chloro[l,2,4]triazolo[l,5-a]pyridin-2-amine (3.0 g; 12.1 mmol; 1.0 eq.) and cyclohexylamine (12.0 mL; 104.9 mmol; 8.65 eq.) to give the title compound as a dark foam (2.5 g, 66%). HPLC, Rt: 3.21 min. (purity 76.6%). LC/MS, M+(ESI): 310.0.
Intermediate A15 : 6-bromo-N5-cvclohexyl[l.,2,41triazolo[l,5-alpyridine-2,5-diamine Step a) Formation of ethyl {[(3-bromopyridin-2-yl)aminoJcarbonothioyl}carbamate
Figure imgf000064_0004
The title compound was prepared following procedure described for intermediate Al, step b) but starting from 2-amino-3-bromopyridine (4.18 g; 24.16 mmol; 1.0 eq.) to give the title compound as a light yellowish powder (7.4 g, quant, yield). HPLC, Rt: 2.72 min. (purity 99.7%). LC/MS, M+(ESI): 303.9.
Step b) Formation of8-bromo[l,2,4]triazolo[l,5-a]pyridin-2-amine
Figure imgf000065_0001
Intermediate Al 5
The title compound was prepared following procedure described for intermediate Al, step c) but starting from ethyl {[(3-bromopyridin-2-yl)amino]carbonothioyl}carbamate (7.40 g; 24.33 mmol; 1.0 eq.) to give the title compound as a white solid (4.4 g, 85%). HPLC, Rt: 1.16 min. (purity 99.8 %). LC/MS, M+(ESI): 212.9, 214.9.
Intermediate A16 : 5-f2-furyl)[l,2,41triazolo[l,5-alpyridin-2-amine Step a) Formation of 6-(2-furyl)pyridin-2-amine
Figure imgf000065_0002
The title compound was prepared following procedure described for intermediate Al step a), but starting from 2-amino-6-chloropyridine (925.64 mg; 7.20 mmol; 1.0 eq.) and 2- furanboronic acid (1.21 g; 10.8 mmol; 1.5 eq.). The crude was purified by flash chromatography (EtOAc/c-Hex, gradient from 25:75 to 40:60) to give the title compound (990 mg; 86%). HPLC, Rt: 1.33 min. (purity 99.9%). LC/MS, M+(ESI): 161.0.
Step b) Formation of of ethyl ({[6-(2-furyl)pyridin-2-yl]amino}carbonothioyl)carbamate
Figure imgf000065_0003
The title compound was prepared following procedure described for intermediate Al step b), but starting from 6-(2-furyl)pyridin-2-amine (970 mg; 6.06 mmol; 1.0 eq.) as a white solid (1.67 g; 94%). HPLC, Rt: 4.07 min. (purity 98.4%). LC/MS, M+(ESI): 292.0, M (ESI): 290.1. Step c) Formation of5-(2-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-amine
Figure imgf000066_0001
Intermediate Al 6
The title compound was prepared following procedure described for intermediate Al step c), but starting from ethyl ({[6-(2-furyl)pyridin-2-yl]amino}carbonothioyl)carbamate (1.65 g; 5.66 mmol; 1.0 eq.) as a white powder (1.13 g; 99%). HPLC, Rt:1.75 min. (purity 98.4%). LC/MS, M+(ESI): 201.1.
Intermediate Al 7: N5-isopropyl-7-( trifluoromethyl) [ 1 ,2,41 triazolo \ 1 ,5-al pyridine-2,5- diamine
Figure imgf000066_0002
Intermediate Al 7
A suspension of 5-chloro-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A7), 183.00 mg; 0.77 mmol; 1.00 eq.) and isopropylamine (664.58 μl; 7.74 mmol; 10.00 eq.) in n- butanol (1.50 mL) was heated at 1200C for lh30 under MW irradiation. The reaction mixture was then concentrated under vacuum till dryness. The solid obtained was triturated in water/MTBE and filtered. The solid which precipitated in mother liquor was finally filtered, washed with water and dried under vacuum at 400C to give the title compound as an off-white solid (122 mg, 61%). HPLC, Rt: 2.64 min. (purity 86.5%). LC/MS, M+(ESI): 259.9, M (ESI): 257.9.
Intermediate Al 8 : N--cyclopr opyl-7-(trifluoromethyl) [1 ,2,4] triazolo [ 1 ,5-a] pyridine-2,5- diamine
Figure imgf000067_0001
Intermediate Al 8
A suspension of 5-chloro-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A7), 3.60 g; 15.22 mmol; 1.0 eq.), cyclopropylamine (5.27 mL; 76.1 mmol; 5.0 eq.), and N- ethyldiisopropylamine (26.22 mL; 152.2 mmol; 10. 0 eq.) was heated at 800C in 1-butanol (36.0 mL) for 23 h., then 15 h. at 1000C. The reaction mixture was then concentrated under vacuum till dryness. Diethyl ether was added and the solid was filtered, washed with water and dried. The product was then purified by chromatography on silicagel (from 5% to 95% EtOAc in c-Hex), to give the title compound as a white solid (2.0 g; 51.1 %). HPLC, Rt: 2.54 min. (purity 100%). LC/MS, M+(ESI): 258.0, M (ESI): 256.0.
Intermediate Al 9 : 5-chloro-7-methyl[l,2,41triazolo[l,5-alpyridin-2-amine
Step a) Formation of6-Chloro-4-methylpyridin-2-amine
Figure imgf000067_0002
A solution of 2,6-Dichloro-4-methylpyridine (Chem. Mater., 2004, 16, 1564-1572, 30g, 0.185mol) in ammonium hydroxide (20OmL, 25% solution in water) was heated at 2000C in a pressure vessel for 1Oh. The reaction mixture was then concentrated under reduced pressure. The brown solid obtained was suspended in DCM for 30 min at 25-26°C and filtered. Filtrate was concentrated under reduced pressure. Purification of the crude thus obtained by flash chromatography (20% ethyl acetate in pet ether) afforded the title compound as off-white solid (13.5g, Yield 51%). LC/MS: M+(ESI): 142.7; 1H NMR (DMSO d6 : 400MHz) δ 6.34(1H, s), 6.23(2H, s), 6.15(1H, s), 2.1(3H, s).
Step b) Formation of ethyl {[(6-chloro-4-methylpyridin-2- yl)amino] carbonothioyl} carbamate
Figure imgf000068_0001
The title compound was prepared following procedure described for intermediate Al step b), but starting from 2-amino-4,6-dichloropyridine (2.5 g; 15.3 mmol; 1.0 eq.) as an off- white solid (5.0 g; 64%). HPLC, Rt: 4.36 min. (purity 98.3%). LC/MS, M+(ESI): 273.8, M (ESI): 271.8.
Step c) Formation of 5-chloro-7-methyl[ 1,2,4] triazolo[l,5-a]pyridin-2-amine
Figure imgf000068_0002
Intermediate Al 9
The title compound was prepared following procedure described for intermediate Al step c), but starting from ethyl {[(6-chloro-4-methylpyridin-2-yl)amino]carbonothioyl} carbamate (5.0 g; 18.4 mmol; 1.0 eq.) as a white solid (3.34 g; 99.5%). HPLC, Rt: 1.17 min. (purity 92.8%). LC/MS, M+(ESI): 282.8.
Intermediate B
Figure imgf000068_0003
Intermediate Bl : N-f5-bromo[l,2,41triazolo[l,5-alpyridin-2-yl)benzamide
Figure imgf000068_0004
Intermediate Bl
Benzoyl chloride (4.40 g; 31.4 mmol; 2.0 eq.) was added to a suspension of 5- bromo[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A3), 3.34 g; 15.7 mmol; 1.0 eq.) in pyridine (2.53 mL; 31.4 mmol; 2.0 eq.) and DCM (60 mL). The reaction mixture was then heated at reflux for 4 hours, after which it was cooled down to rt. Diethyl ether was added to the reaction mixture and the solid which precipitated was filtered off. The precipitate was resuspended in an aqueous mixture (pH 4/5), filtered and dried under vacuum to give the title compound as a white powder (4.97 g, quant, yield). HPLC, Rt: 2.40 min. (purity 93.4%), LC/MS, M+(ESI): 317.1, M (ESI): 315.1.
Intermediate B2 : N-(5-bromo[l, 2,41 triazolo[l,5-alpyridin-2-yl) nicotinamide
Figure imgf000069_0001
Intermediate B2
The title compound was prepared following procedure described for intermediate Bl, but starting from 5-bromo[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A3), 5.0 g; 23.5 mmol; 1.0 eq.) and nicotinoyl chloride hydrochloride (8.36 g; 47.0 mmol; 2.0 eq.) as a grey powder (5.86 g, 78%). HPLC, Rt: 1.24 min. (purity 97.4%). LC/MS, M+(ESI): 319.0, M (ESI): 318.3.
Intermediate B3 : N-f5-chloro[l,2,41triazolo[l,5-alpyridin-2-yl)benzamide
Figure imgf000069_0002
Intermediate B3
The title compound was prepared following procedure described for intermediate Bl, but starting from 5-chloro[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A4), 84.29 mg; 0.50 mmol; 1.0 eq.) and benzoyl chloride (70 mg; 0.50 mmol; 1.0 eq.) as a white powder (136 mg, quant, yield). HPLC, Rt: 2.30 min. (purity 99.0%). LC/MS, M+(ESI): 273.0.
Intermediate B4 : N-f5-chloro[l,2,41triazolo[l,5-alpyridin-2-yl)nicotinamide
Figure imgf000069_0003
Intermediate B4
The title compound was prepared following procedure described for intermediate Bl, but starting from 5-chloro[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A4), 14.60 g; 86.60 mmol; 1.0 eq.) and nicotinoyl chloride hydrochloride (18.5 g; 104 mmol; 1.2 eq.) as a greenish solid (20.61 g; 87%). HPLC, Rt: 1.19 min. (purity 99.4%). LC/MS, M+(ESI): 274.3, M+(ESI): 272.3.
Intermediate B5 : N-(6-bromor 1,2,41 triazolo ri,5-alpyridin-2-yl)benzamide
Figure imgf000070_0001
Intermediate B5
The title compound was prepared following procedure described for intermediate Bl, but starting from 6-bromo[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A5), 5.0 g; 23.47 mmol; 1.0 eq.) and benzoyl chloride (6.57 g; 46.9 mmol; 2.0 eq.) as a white powder (6.5 g, 87%). HPLC, Rt: 2.49 min. (purity 97.1%). LC/MS, M+(ESI): 317.0, M (ESI): 316.9.
Intermediate B6 N-( 6-bromo [ 1 ,2,41 triazolo [ 1 ,5-al pyridin-2-yl) nicotinamide hydrochloride
Figure imgf000070_0002
Intermediate B6
The title compound was prepared following procedure described for intermediate Bl, but starting from 6-bromo[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A5), 5.0 g; 23.5 mmol; 1.0 eq.) and nicotinoyl chloride hydrochloride (5.01 g; 28.2 mmol; 1.2 eq.) as a light yellow solid (6.30 g; 84%). HPLC, Rt: 1.32 min. (purity 99.6%). LC/MS, M+(ESI): 317.9. CHN analysis: [Ci2H8N5OBr -1.0 HCl -1.0 H2O] Corrected: C 38.68%, H 2.98%, N 18.80%; Found: C 38.76%, H 3.11%, N 18.66%.
Intermediate B7 N- r5-chloro-7-(trifluoromethyl) [ 1 ,2,41 triazolo [ 1 ,5-al pyridin-2- yll nicotinamide
Figure imgf000070_0003
Intermediate B7 The title compound was prepared following procedure described for intermediate Bl, but starting from 5-chloro-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A7), 2.72 g; 11.5 mmol; 1.0 eq.) and nicotinoyl chloride hydrochloride (2.46 g; 13.8 mmol; 1.2 eq.) as a greenish solid (1.42 g; 36%). HPLC, Rt: 2.16 min. (purity 100%). LC/MS, M+(ESI): 342.2, M"(ESI): 340.2.
Intermediate B8 : 4-(chloromethyl)-N-[5-(cyclohexylamino) [1,2,41 triazolo [1,5-al pyridin- 2-yllbenzamide
Figure imgf000071_0001
Intermediate B8
The title compound was prepared following procedure described for intermediate Bl, but starting from N5-cyclohexyl[l,2,4]triazolo[l,5-a]pyridine-2,5-diamine ((A9), 800 mg; 3.46 mmol; 1.0 eq.) and 4-(chloromethyl)benzoyl chloride (981 mg; 5.2 mmol; 1.5 eq.) as a brownish foam (1.32 g, 99%). LC/MS, M+(ESI): 384.0, M (ESI): 382.0.
Intermediate B9 : N-( 8-bromo [ 1 ,2,41 triazolo [ 1 ,5-al pyridin-2-yl)benzamide
Figure imgf000071_0002
Intermediate B9
The title compound was prepared following procedure described for intermediate Bl, but starting from 8-bromo[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A15), 4.40 g; 20.7 mmol; 1.0 eq.) and benzoyl chloride (5.81 g; 41.3 mmol; 2.0 eq.) as a white solid (4.9 g, 74%). HPLC, Rt: 2.45 min. (purity 90.1%). LC/MS, M+(ESI): 318.9, M (ESI): 316.9.
Intermediate BlO: N-( 5,7-dichloro [1,2,41 triazolo [ 1 ,5-al pyridin-2-yl) nicotinamide Step a) Formation of ethyl {[^rf-dichloropyridin^-yljaminojcarbonothioyljcarbamate
Figure imgf000072_0001
The title compound was prepared following procedure described for intermediate Al step b), but starting from 2-amino-4,6-dichloropyridine (J&W Pharma, 2.50 g; 15.34 mmol; 1.00 eq.) as a white solid (4.27 g; 94%). HPLC, Rt: 4.68 min. (purity 100%).
Step b) Formation of5,7-dichloro[l,2,4]triazolo[l,5-a]pyridin-2-amine
Figure imgf000072_0002
The title compound was prepared following procedure described for intermediate Al step c), but starting from ethyl {[(4,6-dichloropyridin-2-yl)amino]carbonothioyl} carbamate (4.27 g; 14.52 mmol; 1.00 eq.) as a white solid (2.61 g; 88%). HPLC, Rt: 1.78 min (purity 97.9%). LC/MS, M+(ESI): 202.8.
Step c) Formation ofN-(5,7-dichloro[l,2,4]triazolo[l,5-a]pyridin-2-yl)nicotinamide
Figure imgf000072_0003
Intermediate BlO
The title compound was prepared following procedure described for intermediate Bl, but starting from 5,7-dichloro[l,2,4]triazolo[l,5-a]pyridin-2-amine (1.00 g; 4.93 mmol; 1.00 eq.) and nicotinoyl chloride hydrochloride (1 052.16 mg; 5.91 mmol; 1.20 eq.) as a yellowish solid (1.06 g, 70 %). HPLC, Rt 1.61 min. (purity 92.4%). LC/MS, M+(ESI): 307.7, M (ESI): 305.8.
Intermediate BIl: 6-chloro-N- \5-( cyclohexylamino) [ 1 ,2,41 triazolo \ 1 i5-al pyridin-2- yll nicotinamide
Figure imgf000072_0004
Intermediate (BID
To a reaction vessel containing N-5-cyclohexyl-[l,2,4]triazolo[l,5-a]pyridine-2,5-diamine (500 mg, 2.16 mmol, 1 eq.) and triethylamine (0.75 rnL, 5.40 mmol, 2.5 eq.) in acetonitrile (8 rnL) was added 6-chloronicotinyl chloride (952 mg, 5.40 mmol, 2.5 eq.) in acetonitrile (2 mL), dropwise. The vessel was capped and stirred at room temperature for 16 hours. The solvent was removed in vacuo and the resulting solid dissolved in methanolic ammonia (15 mL, 7 N) and stirred at room temperature for a further 24 hours. The solvent was removed in vacuo and the solid dissolved in ethyl acetate (40 mL). The organic phase was washed with water (3 x 20 mL), dried (MgSO4) and concentrated. The resulting solid was triturated with dichloromethane and filtered to give the title compound as a white solid (250 mg, 31%). No further purification carried out.
Intermediate B12 : N-(5-chloro-7-methviri.,2.,41triazolori.,5-alpyridin-2-yr)nicotinamide
Figure imgf000073_0001
Intermediate B12
The title compound was prepared following procedure described for intermediate Bl, but starting from 5-chloro-7-methyl[l,2,4]triazolo[l,5-a]pyridin-2-amine (282 mg; 1.54 mmol; 1.0 eq.) and nicotinoyl chloride hydrochloride (330 mg; 1.85 mmol; 1.20eq.) as a off-white powder (244 mg, 55%). HPLC, Rt: 1.51 min. (purity 90.4%). LC/MS, M+(ESI): 288.1, M" (ESI): 286.2.
Example 1 : N-[5-f3-furyl)[l,2,41triazolo[l,5-alpyridin-2-yll-2-phenylacetamide
Figure imgf000074_0001
(1)
The title compound was prepared following procedure described for intermediate Bl, but starting from 5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A2), 41 mg; 0.20 mmol; 1.0 eq.) and phenylacetyl chloride (38 μl; 0.41 mmol; 2.0 eq). Purification of the compound by flash chromatography on silica (EtOAc/c-Hex, 50:50) gave the title compound as a white powder (21 mg, 29%). 1H NMR (DMSO-J6) δ 8.98 (brs, IH), 8.61 (brs, IH), 7.55 (m, 3H), 7.37 (m, 5H), 7.22 (m, IH), 6.91 (s, IH), 3.96 (brs, 2H), 1.99 (brs, 3H, water). HPLC, Rt: 3.27 min. (purity 94.5%). LC/MS, M+(ESI): 319.3, M (ESI): 317.3.
Example 2 : N- [5-f3-furyl)[l, 2,41 triazolo[l,5-alpyridin-2-yll nicotinamide
Figure imgf000074_0002
(2)
A solution of nicotinic acid (74 mg, 0.6 mmol, 1.2 eq.) and 1,1-carbonyldiimidazole (122 mg, 0.75 mmol, 1.5 eq.) in dry THF (1 mL) was stirred for 45 min. at rt. In parallel, a solution of 5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A2), 100 mg; 0.50 mmol; 1.0 eq.) and sodium tert-butoxide (96 mg, 1.0 mmol, 2.0 eq.) in dry THF (2 mL) was stirred for 45 min. at rt. The two solutions were then combined and the reaction mixture was stirred overnight at rt. Et2O was then added and the precipitate obtained was filtered, washed with Et2O, THF, a 5N solution of NaOH and water. It was resuspended in an acidic aqueous solution (pH 1) and filtered to give the tiltle compound as a white powder (52.4 mg, 31%). HPLC, Rt: 1.98 min. (purity 95.1%). LC/MS, M+(ESI): 306.1, M (ESI): 304.1.
Example 3 : N- r5-(3-furyl) \ 1 ,2,41 triazolo \ 1 ,5-al pyridin-2-yll -4-
(trifluoromethyl)benzamide
Figure imgf000075_0001
(3)
The title compound was prepared following procedure described for intermediate Bl, but starting from 5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A2), 660 mg; 0.30 mmol; 1.0 eq.) and 4-(trifluoromethyl)benzoyl chloride (125 mg, 0.60 mmol; 2.0 eq.) as a white powder (31.2 mg, 28%). HPLC, Rt: 4.02 min. (purity 99.4%). LC/MS, M+(ESI): 373.2, M (ESI): 373.1.
Example 4 : ethyl 3-{r5-(3-furyl)ri,2,41triazolori,5-alpyridin-2-yllamino}-3- oxopropanoate
Figure imgf000075_0002
(4)
The title compound was prepared following procedure described for intermediate Bl, but starting from 5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A2), 660 mg; 0.30 mmol; 1.0 eq.) and ethyl 3-chloro-3-oxopropionate (90 mg, 0.60 mmol; 2.0 eq.) as a white powder (42 mg, 45%). HPLC, Rt: 2.72 min. (purity 90.8%). LC/MS, M+(ESI): 315.3, M (ESI): 313.3.
Example 5 : N-[5-f3-furyl)[l,2,41triazolo[l,5-alpyridin-2-yll-2-methoxyacetamide
Figure imgf000075_0003
(5)
The title compound was prepared following procedure described for intermediate Bl, but starting from 5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A2), 660 mg; 0.30 mmol; 1.0 eq.) and methoxyacetyl chloride (65 mg, 0.60 mmol; 2.0 eq.) as a white powder (59 mg, 72%). HPLC, Rt: 2.21 min. (purity 98.2%). LC/MS, M+(ESI): 273.4, M (ESI): 271.4. Example 6 : 6-chloro-N-[5-(3-furyl)ri, 2,41 triazolori,5-alpyridin-2-yll nicotinamide
Figure imgf000076_0001
(6)
The title compound was prepared following procedure described for intermediate Bl, but starting from 5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A2), 660 mg; 0.30 mmol; 1.0 eq.) and 6-chloronicotinoyl chloride (65 mg, 0.60 mmol; 2.0 eq.) as a white powder (47.7 mg, 47%). HPLC, Rt: 3.00 min. (purity 98.6%). LC/MS, M+(ESI): 340.2, M (ESI): 338.2.
Example 7 methyl 4- { r5-(3-furyl) \ 1 ,2,41 triazolo \ 1 ,5-al pyridin-2-yll amino}-4- oxobutanoate
Figure imgf000076_0002
(7)
The title compound was prepared following procedure described for intermediate Bl, but starting from 5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A2), 660 mg; 0.30 mmol; 1.0 eq.) and 3-carbomethoxypropionyl chloride (65 mg, 0.60 mmol; 2.0 eq.) as a white powder (83.5 mg, 88%). HPLC, Rt: 2.40 min. (purity 95.4%). LC/MS, M (ESI): 313.2.
Example 8 : 2-fbenzyloxy)-N-[5-f3-furyl)[l,2,41triazolo[l,5-alpyridin-2-yllacetamide
Figure imgf000076_0003
(8)
The title compound was prepared following procedure described for intermediate Bl, but starting from 5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A2), 660 mg; 0.30 mmol; 1.0 eq.) and phenoxyacetyl chloride (65 mg, 0.60 mmol; 2.0 eq.) as a white powder (61.3 mg, 58%). HPLC, Rt: 3.59 min. (purity 96.1%). LC/MS, M+(ESI): 349.3, M (ESI): 347.3.
Example ! 3-methoxy-N- [5-f lH-pyrrol-2-yl) [1,2,41 triazolo [1,5-al pyridin-2- yllbenzamide
Figure imgf000077_0001
(9)
The title compound was prepared following procedure described for intermediate Bl, but starting from tert-butyl 2-(2-amino[l,2,4]triazolo[l,5-a]pyridin-5-yl)-lH-pyrrole-l- carboxylate ((A6), 50 mg; 0.17 mmol; 1.0 eq.) and m-anisoyl chloride (57 mg; 0.33 mmol; 2.0 eq.). Further treatement with a DCM/TFA solution (2:1) and purification by flash chromatography on silica (EtOAc/c-Hex, gradient from 50:60 to 80:20) gave the title compound as a white solid (23.1 mg, 41%). HPLC, Rt: 3.40 min. (purity 94.7%). LC/MS, M+(ESI): 334.3, M (ESI): 332.3.
Example 10 N- r5-qH-pyrrol-2-yl) n,2,41 triazolo [1,5-al pyridin-2- yll cyclopentanecarboxamide
Figure imgf000077_0002
(10)
The title compound was prepared following procedure and work up described for example 9, but starting from tert-butyl 2-(2-amino[l,2,4]triazolo[l,5-a]pyridin-5-yl)-lH-pyrrole-l- carboxylate ((A6), 50 mg; 0.17 mmol; 1.0 eq.) and cyclopentanecarbonyl chloride (44 mg; 0.33 mmol; 2.0 eq.) as a white solid (25.4 mg, 51%). HPLC, Rt: 3.17 min. (purity 99.7%). LC/MS, M+(ESI): 296.4, M (ESI): 294.3.
Example 11 : N-[5-flH-pyrrol-2-yl)[l,2,41triazolo[l,5-alpyridin-2-yllbenzamide
Figure imgf000078_0001
(H)
The title compound was prepared following procedure and work up described for example 9, but starting from tert-butyl 2-(2-amino[l,2,4]triazolo[l,5-a]pyridin-5-yl)-lH-pyrrole-l- carboxylate ((A6), 50 mg; 0.17 mmol; 1.0 eq.) and benzoyl chloride (47 mg; 0.33 mmol; 2.0 eq.) as a white solid (22.7 mg, 45%). HPLC, Rt: 3.23 min. (purity 91.6%). LC/MS, M+(ESI): 304.3, M-(ESI): 302.3.
Example 12 : N-[5-flH-pyrazol-4-yl)[l,2,41triazolo[l,5-alpyridin-2-yllbenzamide
Figure imgf000078_0002
(12)
The title compound was prepared following procedure described for intermediate Al step a), but starting from N-(5-bromo[l,2,4]triazolo[l,5-a]pyridin-2-yl)benzamide ((Bl), 75 mg; 0.24 mmol; 1.0 eq.) and 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-pyrazole-l-carboxylic acid tert-butyl ester (139 mg; 0.47 mmol; 2.0 eq.), at 1400C for 14h. Further treatement with a 1 N methanolic HCl solution (0.5 mL) and purification by flash chromatography on silica (EtOAc/c-Hex, 80:20) gave the title compound as a white powder (23 mg, 32%). HPLC, Rt: 2.07 min. (purity 96.9%). LC/MS, M+(ESI): 305.3, M (ESI): 303.3.
Example 13 : N-[5-flH-pyrrol-2-yl)[l,2,41triazolo[l,5-alpyridin-2-yllnicotinamide
Figure imgf000078_0003
(13)
The title compound was prepared following procedure described for example 9, but starting from tert-butyl 2-(2-amino[l,2,4]triazolo[l,5-a]pyridin-5-yl)-lH-pyrrole-l-carboxylate ((A6), 360 mg; 1.20 mmol; 1.0 eq.) and nicotinoyl chloride hydrochloride (428 mg; 2.41 mmol; 2.0 eq.) as a brown powder (245 mg, 67%). HPLC, Rt: 2.14 min. (purity 100.0%). LC/MS, M" (ESI): 303.3.
Example 14 : N-[5-f2-furyl)[l,2,41triazolo[l,5-alpyridin-2-yllbenzamide
Figure imgf000079_0001
(14)
The title compound was prepared following procedure described for intermediate Al step a), but starting from N-(5-bromo[l,2,4]triazolo[l,5-a]pyridin-2-yl)benzamide ((Bl), 75 mg; 0.24 mmol; 1.0 eq.) and 2-furanboronic acid (53 mg; 0.47 mmol; 2.0 eq.).
Purification by flash chromatography on silica (EtOAc/c-Hex, 45:55) gave the title compound as an off-white powder (19 mg, 26%). HPLC, Rt: 3.24 min. (purity 97.9%). LC/MS, M+(ESI): 305.3, M (ESI): 303.2.
Example 15 : N- [6-f3-fluorophenyl)[l ,2,41 triazolo[l,5-alpyridin-2-yll nicotinamide
Figure imgf000079_0002
(15)
The title compound was prepared following procedure described for intermediate Al step a), but starting from N-(6-bromo[l,2,4]triazolo[l,5-a]pyridin-2-yl)nicotinamide ((B6), 75 mg; 0.24 mmol; 1.0 eq.) and 3-fluorophenylboronic acid (66 mg; 0.47 mmol; 2.0 eq.). Purification by flash chromatography on silica (MeOH/EtOAc, 5:95) gave the title compound as a beige powder (42 mg, 53%). HPLC, Rt: 2.40 min. (purity 99.7%). LC/MS, M+(ESI): 334.3, M" (ESI): 332.3.
Example 16 : N-(6-phenyl[l, 2,41 triazolo[l,5-alpyridin-2-yl) nicotinamide
Figure imgf000080_0001
(16)
The title compound was prepared following procedure described for intermediate Al step a), but starting from N-(6-bromo[l,2,4]triazolo[l,5-a]pyridin-2-yl)nicotinamide ((B6), 75 mg; 0.24 mmol; 1.0 eq.) and phenylboronic acid (57 mg; 0.47 mmol; 2.0 eq.). Purification by flash chromatography on silica (MeOH/EtOAc, 5:95) gave the title compound as a beige powder (42 mg, 56%). HPLC, Rt: 2.26 min. (purity 98.7%).
Example 17 : N- [6-(3-furyl)[l, 2,41 triazolo[l,5-alpyridin-2-yll nicotinamide
Figure imgf000080_0002
(17) The title compound was prepared following procedure described for intermediate Al step a), but starting from N-(6-bromo[l,2,4]triazolo[l,5-a]pyridin-2-yl)nicotinamide ((B6), 75 mg; 0.24 mmol; 1.0 eq.) and furan-3-boronic acid (57 mg; 0.47 mmol; 2.0 eq.). Purification by flash chromatography on silica (MeOH/EtOAc, 5:95) gave the title compound as a beige powder (15.6 mg, 21%). HPLC, Rt: 1.82 min. (purity 92.2%). LC/MS, M+(ESI): 306.3, M" (ESI): 304.3.
Example 18 : N-[6-f3-thienyl)[l.,2,41triazolo[l,5-alpyridin-2-yllnicotinamide
Figure imgf000080_0003
(18)
The title compound was prepared following procedure described for intermediate Al step a), but starting from N-(6-bromo[l,2,4]triazolo[l,5-a]pyridin-2-yl)nicotinamide ((B6), 75 mg; 0.24 mmol; 1.0 eq.) and 3-thienylboronic acid (60 mg; 0.47 mmol; 2.0 eq.). Purification by flash chromatography on silica (MeOH/EtOAc, 5:95) gave the title compound as a beige powder (18.1 mg, 23%). HPLC, Rt: 2.13 min. (purity 94.3%). LC/MS, M+(ESI): 322.3, M" (ESI): 320.2. Example 19 : N-[5-f3-furyl)[l,2,41triazolo[l,5-alpyridin-2-yll-3-methoxybenzamide
Figure imgf000081_0001
(19)
The title compound was prepared following procedure described for intermediate Bl, but starting from 5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A2), 50 mg; 0.25 mmol; 1.0 eq.) and m-anisoyl chloride (85 mg; 0.50 mmol; 2.0 eq.). Crude was purified on SPE NH2 column and the title compound was isolated as a white powder (26.9 mg, 32%). HPLC, Rt: 3.32 min. (purity 89.0%). LC/MS, M+(ESI): 306.4.
Example 20 : N-r5-(3-furyl)ri,2,41triazolori,5-alpyridin-2-yll-2-q-thienyl)acetamide
Figure imgf000081_0002
(20)
The title compound was prepared following procedure and work up described for example 19, but starting from 5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A2), 50 mg; 0.25 mmol; 1.0 eq.) and 2-thiopheneacetyl chloride (80 mg; 0.50 mmol; 2.0 eq.) as a white powder (30.9 mg, 38%). HPLC, Rt: 3.28 min. (purity 96.6%). LC/MS, M+(ESI): 357.2, M (ESI): 355.2.
Example 21 : N-[5-(3-furyl)[l,2,41triazolo[l,5-alpyridin-2-yllcvclopentanecarboxamide
Figure imgf000081_0003
(21)
The title compound was prepared following procedure and work up described for example 19, but starting from 5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A2), 50 mg; 0.25 mmol; 1.0 eq.) and cyclopentanecarbonyl chloride (66 mg; 0.50 mmol; 2.0 eq.) as a white powder (64.1 mg, 86%). HPLC, Rt: 3.11 min. (purity 82.7%). LC/MS, M+(ESI): 297.4, M" (ESI): 295.3.
Example 22 : N-[5-f3-furyl)[l,2,41triazolo[l,5-alpyridin-2-yll-4-methoxybenzamide
Figure imgf000082_0001
(22)
The title compound was prepared following procedure and work up described for example 19, but starting from 5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A2), 50 mg; 0.25 mmol; 1.0 eq.) and p-anisoyl chloride (66 mg; 0.50 mmol; 2.0 eq.) as a white powder (58.2 mg, 69%). HPLC, Rt: 3.19 min. (purity 97.0%).
Example 23 : N-r5-(3-furyl)ri,2,41triazolori,5-alpyridin-2-yllisonicotinamide
Figure imgf000082_0002
(23)
The title compound was prepared following procedure and work up described for example 19, but starting from 5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A2), 50 mg; 0.25 mmol; 1.0 eq.) and isonicotinoyl chloride hydrochloride (89 mg; 0.50 mmol; 2.0 eq.) as a white powder (39.4 mg, 51%). HPLC, Rt: 1.90 min. (purity 97.2%). LC/MS, M+(ESI): 306.4, M (ESI): 304.4.
Example 24 : N-[5-f3-furyl)[l,2,41triazolo[l,5-alpyridin-2-yllαuinoxaline-6-carboxamide
Figure imgf000082_0003
(24) The title compound was prepared following procedure and work up described for example 19, but starting from 5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A2), 50 mg; 0.25 mmol; 1.0 eq.) and 6-quinoxalinecarbonyl chloride (96 mg; 0.50 mmol; 2.0 eq.) as a white powder (47.5 mg, 53%). HPLC, Rt: 2.73 min. (purity 62.3%). LC/MS, M+(ESI): 357.4, M" (ESI): 355.3.
Example 25 : N- [6-f3-methoxyphenyl)[l ,2,41 triazolo[l,5-alpyridin-2-yll nicotinamide
Figure imgf000083_0001
(25) The title compound was prepared following procedure described for intermediate Al step a), but starting from N-(6-bromo[l,2,4]triazolo[l,5-a]pyridin-2-yl)nicotinamide ((B6), 75 mg; 0.24 mmol; 1.0 eq.) and 3-methoxybenzeneboronic acid (71 mg; 0.47 mmol; 2.0 eq.). Purification by flash chromatography on silica (MeOH/DCM, gradient from 0:100 to 10:90) gave the title compound as a beige powder (43 mg, 53%). HPLC, Rt: 2.41 min. (purity 99.2%). LC/MS, M+(ESI): 346.4, M (ESI): 344.4.
Example 26 : N- [6-f3-aminophenyl)[l, 2,41 triazolo[l,5-alpyridin-2-yll nicotinamide
Figure imgf000083_0002
(26)
The title compound was prepared following procedure described for intermediate Al step a) but starting from N-(6-bromo[l,2,4]triazolo[l,5-a]pyridin-2-yl)nicotinamide ((B6), 75 mg; 0.24 mmol; 1.0 eq.) and 3-aminobenzeneboronic acid (64 mg; 0.47 mmol; 2.0 eq.). Purification by flash chromatography on silica (MeOH/DCM, gradient from 0:100 to 10:90) gave the title compound as a dark red solid (31 mg, 40%). HPLC, Rt: 1.07 min. (purity 96.3%). LC/MS, M+(ESI): 331.4, M (ESI): 329.4.
Example 27 : N-[6-f3-cyanophenyl)[l,2,41triazolo[l,5-alpyridin-2-yllnicotinamide
Figure imgf000084_0001
(27) The title compound was prepared following procedure described for intermediate Al step a), but starting from N-(6-bromo[l,2,4]triazolo[l,5-a]pyridin-2-yl)nicotinamide ((B6), 75 mg; 0.24 mmol; 1.0 eq.) and 3-cyanophenylboronic acid (69 mg; 0.47 mmol; 2.0 eq.). Purification by flash chromatography on silica (MeOH/DCM, gradient from 0:100 to 10:90) gave the title compound as a brown powder (6 mg, 7%). HPLC, Rt: 2.09 min. (purity 92.5%). LC/MS, M+(ESI): 341.4.
Example 28 : N-[5-(3-furyl)[l,2,41triazolo[l,5-alpyridin-2-yllisoxazole-5-carboxamide
Figure imgf000084_0002
(28)
The title compound was prepared following procedure described for example 19, but starting from 5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A2), 50 mg; 0.25 mmol; 1.0 eq.) and isoxazole-5-carbonyl chloride (49 mg; 0.37 mmol; 1.5 eq.) as a white powder (19.4 mg, 26%). HPLC, Rt: 2.62 min. (purity 95.3%). LC/MS, M+(ESI): 296.4, M (ESI): 294.3.
Example 29 : N-r5-(3-furyl)ri,2,41triazolori,5-alpyridin-2-yll-2,3-dihvdro-l,4- benzodioxine-6-carboxamide
Figure imgf000084_0003
(29)
The title compound was prepared following procedure and work up described for example 19, but starting from 5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A2), 50 mg; 0.25 mmol; 1.0 eq.) and 2,3-dihydro-l,4-benzodioxine-6-carbonyl chloride (74 mg; 0.37 mmol; 1.5 eq.) as a white powder (34 mg, 37 %). HPLC, Rt: 3.17 min. (purity 81.5%). LC/MS, M+(ESI): 363.0.
Example 30 : N- [5-fcyclopropylamino)[l, 2,41 triazolo[l,5-alpyridin-2-yll nicotinamide
Figure imgf000085_0001
(30)
N-(5-bromo[l,2,4]triazolo[l,5-a]pyridin-2-yl)nicotinamide ((B2), 50 mg; 0.16 mmol; 1.0 eq.) in cyclopropylamine (1 mL) was heated at 800C overnight. The reaction mixture was diluted with H2O and extracted with EtOAc. Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. The title compound was obtained by recrystalization in EtOAc/c-Hex as a white powder (16.60 mg; 35 %). HPLC, Rt: 1.77 min. (purity 98.3%). LC/MS, M+(ESI): 295.4, M (ESI): 293.4.
Example 31 : N-f5-pyrrolidin-l-yl[l.,2,41triazolo[l,5-alpyridin-2-yl)nicotinamide
Figure imgf000085_0002
(31)
The title compound was prepared following procedure and work up described for example 30, but starting from N-(5-bromo[l,2,4]triazolo[l,5-a]pyridin-2-yl)nicotinamide ((B2), 50 mg; 0.16 mmol; 1.0 eq.) and pyrrolidine (1 mL) as a white solid (1 mg, 2%). HPLC, Rt: 1.81 min. (purity 97.3%). LC/MS, M+(ESI): 309.4, M (ESI): 307.4.
Example 32 : N-[5-f3-furyl)[l,2,41triazolo[l,5-alpyridin-2-yll-3.,5-dimethoxybenzamide
Figure imgf000085_0003
(32)
The title compound was prepared following procedure described for intermediate Bl, but starting from 5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A2), 50 mg; 0.25 mmol; 1.0 eq.) and 3,5-dimethoxybenzoyl chloride (60 mg; 0.30 mmol; 1.2 eq.) as a white powder (42.9 mg; 47%). HPLC, Rt: 3.51 min. (purity 95.3%). LC/MS, M+(ESI): 365.3, M (ESI): 363.3.
Example 33 : N-r5-(3-furyl)ri,2,41triazolori,5-alpyridin-2-yllbiphenyl-4-carboxamide
Figure imgf000086_0001
(33)
The title compound was prepared following procedure described for intermediate Bl, but starting from 5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A2), 50 mg; 0.25 mmol; 1.0 eq.) and 4-biphenylcarbonyl chloride (87 mg; 0.37 mmol; 1.5 eq.) as a white powder (53.7 mg, 56%). HPLC, Rt: 4.25 min. (purity 95.2%). LC/MS, M+(ESI): 381.4, M (ESI): 379.4.
Example 34 : l-(4-chlorophenyl)-N-r5-(3-furvmi,2,41triazolori,5-alpyridin-2- yll cyclopentanecarboxamide
Figure imgf000086_0002
(34)
The title compound was prepared following procedure described for intermediate Bl, but starting from 5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A2), 50 mg; 0.25 mmol; 1.0 eq.) and l-(4-chlorophenyl)-l-cyclopentanecarbonyl chloride (Lancaster, 91 mg; 0.37 mmol; 1.5 eq.) as a white foam (61.1 mg, 60%). HPLC, Rt: 4.64 min. (purity 73.4%). LC/MS, M+(ESI): 407.4, M (ESI): 405.4.
Example 35 : N-r5-(3-furyl)ri,2,41triazolori,5-alpyridin-2-yll-2,3-dihvdro-l-benzofuran- 5-carboxamide
Figure imgf000087_0001
(35)
The title compound was prepared following procedure and work up described for example 19, but starting from 5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A2), 50 mg; 0.25 mmol; 1.0 eq.) and 2,3-dihydro-l-benzofuran-5-carbonyl chloride (68 mg; 0.37 mmol; 1.5 eq.) as a white solid (25.7 mg, 29%). HPLC, Rt: 3.14 min. (purity 78.8%). LC/MS, M+(ESI): 347.4, M-(ESI): 345.3.
Example 36 : N-r5-(3-furvmi,2,41triazolori,5-alpyridin-2-yll-3-furamide
Figure imgf000087_0002
(36)
The title compound was prepared following procedure and work up described for example 19, but starting from 5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A2), 50 mg; 0.25 mmol; 1.0 eq.) and 3-furoyl chloride (39 mg; 0.3 mmol; 1.2 eq.) as a white powder (45.3 mg, 61%). HPLC, Rt: 2.65 min. (purity 97.5%). LC/MS, M+(ESI): 295.4, M (ESI): 293.4.
Example 37 : l-acetyl-N-[5-f3-furyl)[l,2,41triazolo[l,5-alpyridin-2-yllpiperidine-4- carboxamide
Figure imgf000087_0003
(37)
The title compound was prepared following procedure and work up described for example 19, but starting from 5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A2), 50 mg; 0.25 mmol; 1.0 eq.) and l-acetylpiperidine-4-carbonyl chloride (57 mg; 0.3 mmol; 1.2 eq.) as a white powder (41.3 mg, 46%). HPLC, Rt: 2.15 min. (purity 93.3%). LC/MS, M+(ESI): 354.4, M"(ESI): 352.4.
Example 38 : 2,2-difluoro-N-r5-(3-furvmi,2,41triazolori,5-alpyridin-2-yll-l,3- benzodioxole-4-carboxamide
Figure imgf000088_0001
(38)
The title compound was prepared following procedure and work up described for example 19, but starting from 5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A2), 50 mg; 0.25 mmol; 1.0 eq.) and 2,2-difluoro-l,3-benzodioxole-4-carbonyl chloride (Alpha, 66 mg; 0.3 mmol; 1.2 eq.) as a white powder (75.2 mg, 78%). HPLC, Rt: 4.01 min. (purity 97.4%). LC/MS, M+(ESI): 385.3, M (ESI): 383.3.
Example 39 : N- [5-(3-thienyl)[l, 2,41 triazolori,5-alpyridin-2-yll nicotinamide
Figure imgf000088_0002
(39)
The title compound was prepared following procedure described for example 2, but starting from 5-(3-thienyl)[l,2,4]triazolo[l,5-a]pyridin-2-amine ((Al), 82 mg; 0.38 mmol; 1.5 eq.) and nicotinoyl chloride hydrochloride (55 mg; 0.3 mmol; 1.2 eq.) as a beige solid (21 mg, 26%). HPLC, Rt: 2.15 min. (purity 97.3%). LC/MS, M+(ESI): 322.0, M (ESI): 320.0.
Example 40 : N-[1 ,2,41 triazolo[l,5-alαuinolin-2-ylnicotinamide
Figure imgf000088_0003
(40) The title compound was prepared following procedure described for example 2, but starting from [l,2,4]triazolo[l,5-a]quinolin-2-amine ((A13), 67 mg; 0.37 mmol; 1.5 eq.) and nicotinoyl chloride hydrochloride (80 mg; 0.44 mmol; 1.2 eq.). Purification by flash chromatography on silica (DCM/MeOH, gradient from 98:2 to 95:5) gave the title compound as an orange oil (27 mg, 38%). HPLC, Rt: 1.83 min. (purity 97.9%). LC/MS, M+(ESI): 290.0, M-(ESI): 288.0.
Example 41 : N-[5-fcvclopentylamino)[l,2,41triazolo[l,5-alpyridin-2-yllbenzamide
Figure imgf000089_0001
(41)
The title compound was prepared following procedure described for example 30, but starting from N-(5-chloro[l,2,4]triazolo[l,5-a]pyridin-2-yl)benzamide ((B3), 44 mg; 0.16 mmol; 1.0 eq.) and cyclopentylamine (1.0 mL) as a white powder (23 mg, 44%). HPLC, Rt: 3.06 min. (purity 99.5%). LC/MS, M+(ESI): 322.1, M (ESI): 320.1.
Example 42 : N- [5-f3-furyl)[l, 2,41 triazolo[l,5-alpyridin-2-yll nicotinamide 1-oxide "
Figure imgf000089_0002
(42)
The title compound was prepared following procedure described for example 2, but starting from 5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A2), 100 mg; 0.50 mmol; 1.0 eq.) and nicotinic acid N-oxide (83 mg, 0.6 mmol, 1.2 eq.) as a light yellow solid (37.2 mg, 23%). HPLC, Rt: 1.98 min. (purity 98.8%). LC/MS, M+(ESI): 322.1, M (ESI): 320.1.
Example 43 : N-{5-[f3-methoxypropyl)aminol [l,2,41triazolo[l,5-alpyridin-2- yljbenzamide
Figure imgf000090_0001
(43)
The title compound was prepared following procedure described for example 30 but starting from N-(5-chloro[l,2,4]triazolo[l,5-a]pyridin-2-yl)benzamide ((B3), 50 mg; 0.18 mmol; 1.0 eq.) and 3-methoxypropylamine (195 μl; 1.91 mmol; 10.0 eq.) in THF (3.0 mL), 900C, 12 h, as white needles (35 mg; 56%). HPLC, Rt: 1.95 min. (purity 99.3%). LC/MS, M+(ESI): 326.2.
Example 44 : N-{5-[f2-furylmethyl)aminol [l,2,41triazolo[l,5-alpyridin-2-yl}benzamide
Figure imgf000090_0002
(44)
The title compound was prepared following procedure described for example 30 but starting from N-(5-chloro[l,2,4]triazolo[l,5-a]pyridin-2-yl)benzamide ((B3), 50 mg; 0.18 mmol; 1.0 eq.) and furfurylamine (1.0 mL) as a beige powder (31 mg, 51%). HPLC, Rt: 2.20 min. (purity 94.1%). LC/MS, M+(ESI): 334.1, M (ESI): 332.1.
Example 45 : N-{5-[ftetrahvdrofuran-2-ylmethyl)aminol [l,2,41triazolo[l,5-alpyridin-2- vUbenzamide
Figure imgf000090_0003
(45)
The title compound was prepared following procedure described for example 30 but starting from N-(5-chloro[l,2,4]triazolo[l,5-a]pyridin-2-yl)benzamide ((B3), 50 mg; 0.18 mmol; 1.0 eq.) and tetrahydrofurfurylamine (1.0 mL) as a white powder (32 mg, 52%). HPLC, Rt: 2.34 min. (purity 91.7%). LC/MS, M+(ESI): 339.0, M (ESI): 338.1.
Example 46 : 3-facetylamino)-N-[5-f3-furyl)[l,2,41triazolo[l,5-alpyridin-2-yllbenzamide
Figure imgf000091_0001
(46)
The title compound was prepared following procedure described for example 2, but starting from 5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A2), 100 mg; 0.50 mmol; 1.0 eq.) and isophthalamic acid (49 mg, 0.3 mmol, 1.2 eq.) as a beige powder (20 mg, 23%). HPLC, Rt: 2.64 min. (purity 90.7%). LC/MS, M+(ESI): 362.1, M (ESI): 360.1.
Example 47 : N-[5-fcvclohexylamino)[l,2,41triazolo[l,5-alpyridin-2-yllbenzamide
Figure imgf000091_0002
(47)
The title compound was prepared following procedure described for example 30 but starting from from N-(5-chloro[l,2,4]triazolo[l,5-a]pyridin-2-yl)benzamide ((B3), 50 mg; 0.18 mmol; 1.0 eq.) and cyclohexylamine (1.0 mL) as an off-white powder (50 mg, 81%). HPLC, Rt: 3.33 min. (purity 94.3%). LC/MS, M+(ESI): 336.2, M (ESI): 334.1.
Example 48 N- r5-(3-furyl) \ 1 ,2,41 triazolo \ 1 ,5-al pyridin-2-yll -3-
(methylsulfonyl)benzamide
Figure imgf000091_0003
(48)
The title compound was prepared following procedure described for example 2, but starting from 5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A2), 50 mg; 0.25 mmol; 1.0 eq.) and 3-methylsulphonylbenzoic acid (60 mg, 0.3 mmol, 1.2 eq.) as an off- white solid (9 mg, 9%). HPLC, Rt: 2.79 min. (purity 96.5%). LC/MS, M+(ESI): 383.0, M (ESI): 381.0. Example 49 : 3-faminomethyl)-N-[5-f3-furyl)[l,2,41triazolo[l,5-alpyridin-2- yllbenzamide
Step a) Formation of tert-butyl [3-({[5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2- yl]amino}carbonyl)benzyl] carbamate
Figure imgf000092_0001
The title compound was prepared following procedure and work up described for example 2, but starting from 5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A2), 50 mg; 0.25 mmol; 1.0 eq.) and boc-(3 -amino methyl)-benzoic acid (75 mg; 0.3 mmol; 1.2 eq.) as a white solid 20.0 mg, 18%). HPLC, Rt: 3.86 min. (purity 75.6%). LC/MS, M+(ESI): 434.1, M (ESI):
432.2.
Step b) Preparation of 3-(aminomethyl)-N-[5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2- yljbenzamide
Figure imgf000092_0002
(49)
Tert-butyl [4-({[5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2- yl]amino}carbonyl)benzyl]carbamate (20 mg, 0.05 mmol, 1.0 eq.) was suspended in DCM/TFA (50:1, ImL) and reaction mixture was stirred at rt for 1 h. The reaction mixture was then concentrated under vacuum, the residue slurried with diethyl ether and filtered to give the title compound as a white solid (11 mg, 54%). HPLC, Rt: 3.57 min. (purity 96.3%). LC/MS, M+(ESI): 334.1.
Example 50 : N-f5-{[l-fhvdroxymethyl)propyllamino}[l,2,41triazolo[l,5-alpyridin-2- vDbenzamide
Figure imgf000093_0001
(50)
The title compound was prepared following procedure described for example 30, but starting from N-(5-chloro[l,2,4]triazolo[l,5-a]pyridin-2-yl)benzamide ((B3), 52 mg; 0.19 mmol; 1.0 eq.) and 2-amino-l-butanol (0.2 mL) as a white powder (13 mg, 22%). HPLC, Rt: 2.25 min. (purity 90.7%). LC/MS, M+(ESI): 326.2.
Example 51 : N-[6-f3-hydroxyphenyl)[l.,2,41triazolo[l,5-alpyri(iin-2-yllbenzami(ie
Figure imgf000093_0002
(51)
The title compound was prepared following procedure described for intermediate Al, step a), but starting from N-(6-bromo[l,2,4]triazolo[l,5-a]pyridin-2-yl)benzamide ((B5), 75 mg; 0.24 mmol; 1.0 eq.) and 3-hydroxyphenylboronic acid (65 mg; 0.47 mmol; 2.0 eq.). Purification by flash chromatography on silica (EtOAc/c-Hex, gradient from 50:50 to 100:0) gave the title compound as a brown solid (9.5 mg, 12%). HPLC, Rt: 2.59 min. (purity 91.6%). LC/MS, M+(ESI): 331.1, M (ESI): 329.1.
Example 52 : tert-butyl r4-({r5-(3-furyl)ri,2,41triazolori,5-alpyridin-2- yll aminolcarbonvDbenzyll carbamate
Figure imgf000093_0003
(52)
The title compound was prepared following procedure and work up described for example 2, but starting from 5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A2), 75 mg; 0.37 mmol; 1.0 eq.) and boc-(4-aminomethyl)-benzoic acid (113 mg; 0.45 mmol; 1.2 eq.) as a white foam (35.4 mg, 22%). HPLC, Rt: 3.69 min. (purity 88.9%). LC/MS, M+(ESI): 434.1, M (ESI): 432.1.
Example 53 : N-[5-f3-furyl)[l,2,41triazolo[l,5-alpyridin-2-yll-4-isobutylbenzamide
Figure imgf000094_0001
(53)
The title compound was prepared following procedure and work up described for example 2, but starting from 5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A2), 75 mg; 0.37 mmol; 1.0 eq.) and 4-isobutylbenzoic acid (80 mg; 0.45 mmol; 1.2 eq.) as a yellow foam (25.5 mg, 19%). HPLC, Rt: 4.39 min. (purity 93.6%). LC/MS, M+(ESI): 361.1, M (ESI): 359.1.
Example 54 : tert-butyl r4-αr5-(3-furvmi,2,41triazolori,5-alpyridin-2- yll amino} carbonvDphenoxyl acetate
Figure imgf000094_0002
(54)
The title compound was prepared following procedure and work up described for example 2, but starting from 5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A2), 75 mg; 0.37 mmol; 1.0 eq.) and 4-(2-t-butoxy-2-oxoethoxy)benzoic acid (113 mg; 0.45 mmol; 1.2 eq.) as a white foam (21.6 mg, 13%). HPLC, Rt: 3.98 min. (purity 98.3%). LC/MS, M+(ESI): 435.1, M" (ESI): 433.1.
Example 55 : 4-butyl-N-[5-f3-furyl)[l,2,41triazolo[l,5-alpyridin-2-yllbenzamide
Figure imgf000095_0001
(55)
The title compound was prepared following procedure and work up described for example 2, but starting from 5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A2), 75 mg; 0.37 mmol; 1.0 eq.) and 4-butylbenzoic acid (80 mg; 0.45 mmol; 1.2 eq.) as a yellow foam (20 mg, 15%). HPLC, Rt: 4.45 min. (purity 82.6%). LC/MS, M+(ESI): 361.1, M (ESI): 359.1.
Example 56 : N- [6-(4-hvdroxy-3-methoxyphenyl)[ 1,2,41 triazolo[l,5-al pyridin-2- yllbenzamide hydrochloride
Figure imgf000095_0002
(56)
To N-(6-bromo[l,2,4]triazolo[l,5-a]pyridin-2-yl)benzamide ((B5), 400 mg; 1.26 mmol; 1.0 eq.), cesium fluoride (383 mg; 2.52 mmol; 2.0 eq.) dichlorobis(triphenylphosphine)palladium (89 mg; 0.13 mmol; 0.10 eq.) and 2-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenol (631 mg; 2.52 mmol; 2.0 eq.) in a sealed tube, under inert atmosphere, were added dioxane (3.2 mL) and water (1.6 mL). The mixture was heated at 1200C for 12 hours. The reaction mixture was cooled down to rt and filtered over a celite pad. The celite was carefully rinced with MeOH and a 0.1N solution of HCl was added to the filtrate. The desired product was precipitated by addition of EtOAc, filtered and dried under reduced pressure as a beige solid (373 mg, 74%). 1H NMR (DMSO-J6) δ 11.27 (s, IH), 9.24 (s, IH), 8.03-8.01 (m, 3H), 7.76 (d, J = 9 Hz, IH), 7.65-7.51 (m, 3H), 7.37 (d, J = 1.8 Hz, IH), 7.22 (dd, J = 1.8, 8.2 Hz, IH), 6.89 (d, J = 8.2 Hz, IH), 4.7-3.9 (bs, 7H), 3.89 (s, 3H). IH NMR (DMSO d6) δ . HPLC, Rt: 2.59 min. (purity 96.4%). LC/MS, M+(ESI): 361.03, M (ESI): 359.05. CHN analysis: [C20Hi6N4O3 -1.0 HCl -2.0 H2O] Corrected: C 55.50%, H 4.89%, N 12.94%; Found: C 55.83%, H 4.84%, N 13.14%.
Example 57 : N-{5-[f2-methoxyethyl)aminol [l,2,41triazolo[l,5-alpyridin-2-yl}benzamide
Figure imgf000096_0001
(57)
The title compound was prepared following procedure described for example 30 but starting from N-(5-chloro[l,2,4]triazolo[l,5-a]pyridin-2-yl)benzamide ((B3), 50 mg; 0.18 mmol; 1.0 eq.) and 2-methoxyethylamine (1.0 mL) as an off-white solid (52 mg, 91%). HPLC, Rt: 2.08 min. (purity 90.1%). LC/MS, M+(ESI): 312.1, M (ESI): 310.1.
Example 58 : N-{5-[(2,3-dihvdroxypropyl)aminol [l,2,41triazolo[l,5-alpyridin-2- yljbenzamide
Figure imgf000096_0002
(58)
The title compound was prepared following procedure described for example 30 but starting from N-(5-chloro[l,2,4]triazolo[l,5-a]pyridin-2-yl)benzamide ((B3), 50 mg; 0.18 mmol; 1.0 eq.) and 3-amino-l,2-propanediol (1.0 mL) as a white powder (6 mg, 7%). HPLC, Rt: 1.65 min. (purity 99.5%). LC/MS, M+(ESI): 328.1, M (ESI): 326.1.
Example 59 : N-r6-α,3-dihvdro-l-benzofuran-5-yl)ri,2,41triazolori,5-alpyridin-2- yllbenzamide
Figure imgf000096_0003
(59)
The title compound was prepared following procedure described for example 56 but starting from N-(6-bromo[l,2,4]triazolo[l,5-a]pyridin-2-yl)benzamide ((B5), 150 mg; 0.47 mmol; 1.0 eq.) and 2,3-dihydro-l-benzofuran-5-ylboronic acid (155 mg; 0.95 mmol; 2.0 eq.). Purification by flash chromatography on silica (EtOAc/c-Hex, gradient from 40:60 to 100:0) gave the title compound as a white solid (117.2 mg, 69%). HPLC, Rt: 3.18 min. (purity 84.6%). LC/MS, M+(ESI): 357.1, M (ESI): 355.1.
Example 60 : N- [5-(benzylamino)ri, 2,41 triazolori,5-alpyridin-2-yll nicotinamide
Figure imgf000097_0001
(60)
The title compound was prepared following procedure described for example 30 but starting from N-(5-bromo[l,2,4]triazolo[l,5-a]pyridin-2-yl)nicotinamide ((B2), 100 mg; 0.31 mmol; 1.0 eq.) and benzylamine (1.0 mL) as an oily solid (10 mg, 9%). HPLC, Rt: 2.46 min. (purity 85.8%). LC/MS, M+(ESI): 345.1, M (ESI): 343.1.
Example 61 : N- \5-( cycloheptylamino) [ 1 ,2,41 triazolo \ 1 ,5-al pyridin-2-yll nicotinamide dihydrochloride
Figure imgf000097_0002
(61)
The title compound was prepared following procedure described for example 30 but starting from N-(5-chloro[l,2,4]triazolo[l,5-a]pyridin-2-yl)nicotinamide ((B4), 296 mg; 1.08 mmol; 1.0 eq.) and cycloheptylamine (1.0 mL). The parent compound was dissolved in MeOH and Et2CVHCl was added. The precipitate obtained was filtered, washed with Et2O and dried under reduced pressure at 400C to give the title compound as a white powder (178 mg, 42%). HPLC, Rt: 2.98 min. (purity 99.7%). LC/MS, M+(ESI): 351.4, M (ESI): 349.4. CHN analysis: [Ci9H22N6O -2.0 HCl -1.5 H2O] Corrected: C 50.67%, H 6.04%, N 18.66%; Found: C 50.69%, H 5.97%, N 18.61%. Example 62 : N- [5-fcyclohexylamino)[l, 2,41 triazolo[l,5-alpyridin-2-yll nicotinamide
Figure imgf000098_0001
(62)
The title compound was prepared following procedure described for example 30 but starting from N-(5-bromo[l,2,4]triazolo[l,5-a]pyridin-2-yl)nicotinamide ((B2), 100 mg; 0.31 mmol; 1.0 eq.) and cyclohexylamine (1.0 mL) as a white powder (37 mg, 42%). HPLC, Rt: 2.60 min. (purity 99.6%). LC/MS, M+(ESI): 337.1, M (ESI): 335.2.
Example 63 : N-(5-{[(5-methyl-2-furyl)methyll amino} [1,2,41 triazolori,5-al pyridin-2- yDnicotinamide
Figure imgf000098_0002
(63)
The title compound was prepared following procedure described for example 30 but starting from N-(5-bromo[l,2,4]triazolo[l,5-a]pyridin-2-yl)nicotinamide ((B2), 100 mg; 0.31 mmol; 1.0 eq.) and 5-methylfurfurylamine (1.0 mL) as an off-white solid (40 mg, 37%). HPLC, 2.38 min. Rt: (purity 98.6%). LC/MS, M (ESI): 347.1.
Example 64 : N-{5-[(tetrahydrofuran-2-ylmethyl)aminol [l,2,41triazolo[l,5-alpyridin-2- yl} nicotinamide
Figure imgf000098_0003
(64)
The title compound was prepared following procedure described for example 30 but starting from N-(5-bromo[l,2,4]triazolo[l,5-a]pyridin-2-yl)nicotinamide ((B2), 100 mg; 0.31 mmol; 1.0 eq.) and tetrahydrofurfurylamine (1.0 mL) as a white powder (17 mg, 16%). HPLC, Rt: 1.73 min. (purity 95.5%). LC/MS, M+(ESI): 339.1, M"(ESI): 337.1. Example 65 : N-r6-(4-hydroxyphenyr)ri,2,41triazolori,5-alpyridin-2-yllbenzamide
Figure imgf000099_0001
(65)
The title compound was prepared following procedure described for example 56 but starting from N-(6-bromo[l,2,4]triazolo[l,5-a]pyridin-2-yl)benzamide ((B5), 150 mg; 0.47 mmol; 1.0 eq.) and 4-hydroxyphenylboronic acid (131 mg; 0.95 mmol; 2.0 eq.) as a white solid (15 mg, 9%). HPLC, Rt: 2.60 min. (purity 97.2%). LC/MS, M+(ESI): 331.1, M (ESI): 329.1.
Example 66 : N- [6-(4-hvdroxy-3-methoxyphenyl)[ 1,2,41 triazolo[l,5-al pyridin-2- yll nicotinamide hydrochloride
Figure imgf000099_0002
(66)
The title compound was prepared following procedure described for example 56 but starting from N-(6-bromo[l,2,4]triazolo[l,5-a]pyridin-2-yl)nicotinamide ((B6), 400 mg; 1.26 mmol; 1.0 eq.) and 2-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (629 mg; 2.51 mmol; 2.0 eq.) as a light yellow solid (249 mg, 55%). HPLC, Rt: 1.71 min. (purity 60.7%). LC/MS, M+(ESI): 362.0, M (ESI): 360.0. CHN analysis: [Ci9Hi5N5O3 1 HCl 0.4 CH3CN •0.6 H2O] Corrected: C 55.95%, H 4.36%, N 17.79%; Found: C 55.95%, H 4.76%, N 17.53%.
Example 67 : N- [5-(cyclooctylamino)[l, 2,41 triazolo[l,5-alpyridin-2-yll nicotinamide
Figure imgf000099_0003
(67) The title compound was prepared following procedure described for example 30 but starting from N-(5-chloro[l,2,4]triazolo[l,5-a]pyridin-2-yl)nicotinamide ((B4), 58 mg; 0.21 mmol; 1.0 eq.) and cyclooctylamine (440 μL) as a white powder (4 mg, 4%). HPLC, Rt: 3.25 min. (purity 97.9%). LC/MS, M+(ESI): 365.4, M (ESI): 363.4.
Example 68 : N-{5-rcvclohexyl(methyl)aminoi ri,2,41triazolori,5-alpyridin-2- yllnicotinamide
Figure imgf000100_0001
(68)
The title compound was prepared following procedure described for example 30 but starting from N-(5-chloro[l,2,4]triazolo[l,5-a]pyridin-2-yl)nicotinamide ((B4), 55 mg; 0.20 mmol; 1.0 eq.) and N-methylcyclohexylamine (1.0 mL) as an off white solid (30 mg, 43%). HPLC, Rt: 2.67 min. (purity 97.8%). LC/MS, M+(ESI): 351.4, M (ESI): 349.4.
Example 69 : N- [5-ftetrahvdro-2H-pyran-4-ylamino)[ 1,2,41 triazolo[l,5-al pyridin-2- yll nicotinamide
Figure imgf000100_0002
(69)
The title compound was prepared following procedure described for example 30 but starting from N-(5-bromo[l,2,4]triazolo[l,5-a]pyridin-2-yl)nicotinamide ((B2), 100 mg; 0.31 mmol; 1.0 eq.) and a»d 4-aminotetrahydropyran (Apollo), 1.0 mL) as a white powder (15 mg, 14%). 1H NMR (DMSO-J6) δ 11.27 (s, IH), 9.13 (d, J = 1.9 Hz, IH), 8.77 (d, J = 4.9, 1.5 Hz, IH), 8.33 (dd, J = 8.0, 1.9 Hz, IH), 7.58 (m, IH), 7.51 (t, J = 8.5 Hz, IH), 6.90 (d, J = 7.9 Hz, IH), 6.62 (d, J = 8.7 Hz, IH), 6.38 (d, J = 7.9 Hz, IH), 3.88 (m, 2H), 3.80 (m, IH), 3.45 (m, 2H), 1.89 (m, 2H), 1.72 (m, 2H). HPLC, Rt: 1.51 min. (purity 99.0%). LC/MS, M+(ESI): 339.4, M" (ESI): 337.4. Example 70 : N-{5-[fl-methylpiperidin-4-yl)aminol[l,2,41triazolo[l,5-alpyridin-2- yl| nicotinamide
Figure imgf000101_0001
(70)
The title compound was prepared following procedure described for example 30 but starting from N-(5-bromo[l,2,4]triazolo[l,5-a]pyridin-2-yl)nicotinamide ((B2), 100 mg; 0.31 mmol; 1.0 eq.) and 4-amino-l-methyl-piperidine (1.0 mL) as a white powder (30 mg, 27%). 1H NMR (DMSO-J6) δ 11.25 (brs, IH), 9.13 (d, J = 1.9 Hz, IH), 8.77 (dd, J = 4.7, 1.7 Hz, IH), 8.32 (dd, J = 8.0, 2.0 Hz, IH), 7.56 (dd, J = 8.1, 4.7 Hz, IH), 7.51 (t, J = 8.3 Hz, IH), 6.89 (d, J = 7.9 Hz, IH), 6.46 (d, J = 8.3 Hz, IH), 6.312 (d, J = 7.5 Hz, IH), 3.49 (m, IH), 2.77 (m, 2H), 2.17 (s, 3H), 2.05 (m, 2H), 1.89 (m, 2H), 1.70 (m, 2H). HPLC, Rt: 1.07 min. (purity 100.0%). LC/MS, M+(ESI): 352.4, M (ESI): 350.4.
Example 71 : N-{5-r(3-aminocvclohexyl)aminoi ri.,2.,41triazolori.,5-alpyridin-2- yljbenzamide
Figure imgf000101_0002
(71)
The title compound was prepared following procedure described for example 30 but starting from N-(5-chloro[l,2,4]triazolo[l,5-a]pyridin-2-yl)benzamide ((B3), 52 mg; 0.19 mmol; 1.0 eq) and 1,3-cyclohexanediamine (1.0 mL). The crude was directly purified by preparative HPLC (Starting with 45% ACN in water for 5 min, then up to 60% in 10 min.). The title compound was isolated after lyophilisation as a white powder (63 mg, 94%). HPLC, Rt: 1.84 min. (purity 98.2%). LC/MS, M+(ESI): 351.4, M (ESI): 349.4.
Example 72 : N-{5-[fl-methylpiperidin-4-yl)aminol [l,2,41triazolo[l,5-alpyridin-2- yljbenzamide
Figure imgf000102_0001
(72)
The title compound was prepared following procedure and work up described for example 71 but starting from N-(5-chloro[l,2,4]triazolo[l,5-a]pyridin-2-yl)benzamide ((B3), 100 mg; 0.37 mmol; 1.0 eq.) and 4-amino-l-methyl-piperidine (ABCR, 0.50 mL) as a white powder (59 mg, 46%). 1H NMR (DMSO-J6) δ 10.91 (brs, IH), 8.00 (d, J = 7.2 Hz, 2H), 7.57 (m, 4H), 6.87 (d, J = 8.3 Hz, IH), 6.49 (d, J = 8.3 Hz, IH), 6.29 (d, J = 7.9 Hz, IH), 3.84 (m, IH), 2.74 (m, 2H), 2.16 (s, 3H), 2.03 (m, 2H), 1.92 (m, 2H), 1.66 (m, 2H). HPLC, Rt: 1.70 min. (purity 99.4%). LC/MS, M+(ESI): 351.4, M (ESI). 349.4.
Example 73 : N- [5-(cyclopr opylamino)-7-(trifluoromethyl) [1,2,41 triazolo[l,5-al pyridin- 2-yll nicotinamide
Figure imgf000102_0002
(73)
The title compound was prepared following procedure described for example 71 but starting from N-[5-chloro-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide ((B7), 50 mg; 0.14 mmol; 1.0 eq.) and cyclopropylamine (1.0 mL) as a white powder (30 mg, 59%). HPLC, Rt: 2.98 min. (purity 99.6%). LC/MS, M+(ESI): 363.3, M (ESI): 361.3.
Example 74 : N-[5-fcvclohexylamino)-7-ftrifluoromethyl)[l,2,41triazolo[l,5-alpyridin-2- yll nicotinamide
Figure imgf000102_0003
(74)
The title compound was prepared following procedure described for example 71 at rt but starting from N-fS-chloro-y-^ifluoromethy^fl^^Jtriazolofl^-aJpyridin-l-ylJnicotinamide ((B7), 50 mg; 0.14 mmol; 1.0 eq.) and cyclohexylamine (1.0 mL) as a white powder (3 mg, 5%). HPLC, Rt: 3.78 min. (purity 100%). LC/MS, M+(ESI): 405.3, M (ESI): 403.2.
Example 75 : N-[5-(cvcloheptylamino)-7-(trifluoromethyl)[l,2,41triazolo[l,5-alpyridin-2- yll nicotinamide
Figure imgf000103_0001
(75)
The title compound was prepared following procedure described for example 71 at rt but starting from N-[5-chloro-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide ((B7), 50 mg; 0.14 mmol; 1.0 eq.) and cycloheptylamine (1.0 mL) as a white powder (8 mg, 13%). HPLC, Rt: 3.85 min. (purity 95.9%). LC/MS, M+(ESI): 419.3, M (ESI): 417.4.
Example 76 : N-[5-(cvclopentylamino)-7-(trifluoromethyl)[l,2,41triazolo[l,5-alpyridin-2- yll nicotinamide
Figure imgf000103_0002
(76)
N-[5-chloro-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide ((B7), 50 mg; 0.14 mmol; 1.0 eq.) in cyclopentylamine (1.0 mL) was stirred at rt overnight. The reaction mixture was diluted with a saturated solution of NaHCO3 (10 mL) and EtOAc (5 mL). The two phases were separated and the organic phase was washed four times with a saturated solution OfNaHCO3, after which the product precipitated in the organic phase. It was filtered, washed with a saturated solution OfNaHCO3 and EtOAc, dried under vacuum and isolated as a white solid (13 mg, 23%). HPLC, Rt: 3.54 min. (purity 100%). LC/MS, M+(ESI): 391.3, M" (ESI): 389.3.
Example 77 : N-rS-rfcvclohexylmethyDaminol-T-ftrifluoromethyDri^^ltriazolori^- al pyridin-2-yll nicotinamide
Figure imgf000104_0001
(77)
The title compound was prepared following procedure described for example 76 but starting from N-fS-chloro-y-^rifluoromethy^fl^^Jtriazolofl^-aJpyridin-l-ylJnicotinamide ((B7), 50 mg; 0.14 mmol; 1.0 eq.) and cyclohexanemethylamine (500 μl) as a white powder (27 mg; 44%). HPLC, Rt: 4.11 min. (purity 99.8%). LC/MS, M+(ESI): 419.4, M (ESI): 417.4.
Example 78 : N-f6-bromo-5-methyl[l,2,41triazolo[l,5-alpyridin-2-yl)nicotinamide
Figure imgf000104_0002
(78)
The title compound was prepared following procedure described for intermediate Bl, but starting from 6-bromo-5-methyl[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A8), 4.0 g; 17.62 mmol; 1.0 eq.) and nicotinoyl chloride hydrochloride (3.76 g; 21.1 mmol; 1.2 eq.) as a yellow solid (4.53 g; 77%). 1H NMR (DMSO-J6) δ 11.54 (s, IH), 9.13 (d, J = 2.3 Hz, IH), 9.78 (dd, J = 4.9, 1.5 Hz, IH), 8.34 (dt, J = 7.9, 1.8 Hz, IH), 7.85 (d, J = 8 Hz, IH), 7.63-7.54 (m, 2H), 2.8 (s, 3H). HPLC, Rt: 1.75 min. (purity 98.8%). LC/MS, M+(ESI): 334.2. CHN analysis: [Ci3Hi0N5OBr -1.0 H2O] Corrected: C 44.59%, H 3.45%, N 20.00%; Found: C 44.68%, H 3.41%, N 19.97%.
Example 79 : N-IS-rO-hydroxycyclohexyDaminoin^^ltriazolon^-alpyridin-l- yl} nicotinamide
Figure imgf000105_0001
(79)
3-amino-cyclohexanol (Betapharma, 67.33 mg; 0.58 mmol; 2.0 eq.) was added to a mixture of N-(5-chloro[l,2,4]triazolo[l,5-a]pyridin-2-yl)nicotinamide ((B4), 80 mg; 0.29 mmol; 1.0 eq.), DIEA (76 mg; 0.58 mmol; 2.0 eq.) and activated Charcoal (8 mg) in tBuOH (0.8 mL). The reaction mixture was heated at 2000C for 2 x 30 min under microwave irradiation. After this time, it was filtered on a celite pad and the cake was washed with ACN. The filtrate was directly purified by RP-HPLC (Starting with 15% ACN in water for 5 min, then up to 30% in 10 min.). The title compound was isolated after lyophilisation as a white powder (51 mg, 49%). HPLC, Rt: 2.14 min. (purity 98.0%). LC/MS, M+(ESI): 353.0, M (ESI): 351.0.
Figure imgf000105_0002
yl} nicotinamide
Figure imgf000105_0003
(80)
The title compound was prepared following procedure and work up described for example 79 but starting from N-(5-chloro[l,2,4]triazolo[l,5-a]pyridin-2-yl)nicotinamide ((B4), 80 mg; 0.29 mmol; 1.0 eq.) and 4-tert-butylcyclohexylamine (91 mg; 0.58 mmol; 2.0 eq.) as a white powder (32 mg, 27%). HPLC, Rt: 4.63 min. (purity 99.3%). LC/MS, M+(ESI): 393.1, M" (ESI): 391.1.
Example 81 : N- [5-ftetrahydro-2H-pyran-3-ylamino)[ 1,2,41 triazolo[l,5-al pyridin-2- yllbenzamide
Figure imgf000106_0001
(81)
The title compound was prepared following procedure and work up described for example 30 but starting from N-(5-chloro[l,2,4]triazolo[l,5-a]pyridin-2-yl)benzamide ((B3), 100 mg; 0.37 mmol; 1.0 eq.) and tetrahydro-pyran-3-ylamine hydrochloride (CBI, 257 mg; 1.87 mmol; 5 eq.) in DMA (1 mL) as a white powder (32 mg, 26%). 1H NMR (DMSO-J6) δ 11.05 (s, IH), 8.00 (d, J = 6.8 Hz, 2H), 7.48-7.63 (m, 4H), 6.91 (d, J = 8.3 Hz, IH), 6.46 (d, J = 9.0 Hz, IH), 6.36 (d, J = 7.9 Hz, IH), 3.86 (m, IH), 3.71 (m, 2H), 3.50 (m, 2H), 2.06 (m, IH), 1.22-1.97 (m, 3H). HPLC, Rt: 2.27 min. (purity 99.6%). LC/MS, M+(ESI): 338.1, M (ESI): 336.0.
Example 82 : N- [5-fcycloheptylamino) [1,2,41 triazolo[l,5-al pyridin-2-yll-4-(morpholin-4- ylmethvDbenzamide
Figure imgf000106_0002
(82)
The title compound was prepared following procedure described for intermediate Bl, but starting from N5-cycloheptyl[l,2,4]triazolo[l,5-a]pyridine-2,5-diamine ((AlO), 123 mg; 0.50 mmol; 1.0 eq.) and 4-(chloromethyl)benzoyl chloride (142 mg; 0.75 mmol; 1.5 eq.). Solvents were removed under reduced pressure to yield a gummy solid that was resuspended in morpholine (1.74 g; 20.0 mmol; 10.0 eq.) and the mixture was stirred at 600C for 2 h. After this time, reaction mixture was cooled down to rt, solvents were evaporated under reduced pressure and the residue washed with Et2O (4 x 5 mL). A solid crystallized in the Et2O phase which, after filtration, gave the title compound as a white solid (90 mg, 40%). HPLC, Rt: 3.99 min. (purity 98.9%). LC/MS, M+(ESI): 423.1, M (ESI): 421.1.
Example 83 : N-[5-fcvclohexylthio)[l,2,41triazolo[l,5-alpyridin-2-yllnicotinamide
Figure imgf000107_0001
(83)
To a solution of N-(5-chloro[l,2,4]triazolo[l,5-a]pyridin-2-yl)nicotinamide ((B4), 136 mg; 0.5 mmol; 1.0 eq.) in dry THF (10 rnL) was added in one pot cyclohexyl mercaptan (58 mg; 0.5 mmol; 1.0 eq.). The reaction mixture was stirred at rt for 14 h. The product precipitated upon addition of water after which filtration and washing with MeOH and Et2O gave the title compound as a white solid (78 mg, 44%). HPLC, Rt: 2.94 min. (purity 94.6%). LC/MS, M+(ESI): 354.1, M (ESI): 352.0.
Example 84 : N-{5-[ftrans-4-hvdroxycvclohexyl)aminol [l,2,41triazolo[l,5-alpyridin-2- yl| nicotinamide
Figure imgf000107_0002
(84)
A solution of N-(5-chloro[l,2,4]triazolo[l,5-a]pyridin-2-yl)nicotinamide ((B4), 100 mg; 0.37 mmol; 1.0 eq.), trans-4-aminocyclohexanol hydrochloride (ABCR), 277 mg; 1.83 mmol; 5.0 eq.), DIEA (472 mg; 3.65 mmol; 10.0 eq.) in n-butanol (1.0 mL) was heated at 2200C for 20 min under microwave irradiation. The reaction mixture was directly purified by reverse phase chromatography (Starting with water then up to 60% ACN in water in 40 min.). The title compound was isolated after lyophilisation as a white powder (31 mg, 24%). HPLC, Rt: 1.77 min. (purity 80.2%). LC/MS, M+(ESI): 353.1, M (ESI): 351.1.
Example 85 : N-[5-fcvclobutylamino)-7-ftrifluoromethyl)[l,2,41triazolo[l,5-alpyridin-2- yll nicotinamide
Figure imgf000108_0001
(85)
The title compound was prepared following procedure described for example 84, but starting from N-fS-chloro-y-^rifluoromethy^fl^^Jtriazolofl^-aJpyridin-l-ylJnicotinamide ((B7), 100 mg; 0.3 mmol; 1.0 eq.) and cyclobutylamine (125 μl; 0.150 mmol; 5.0 eq.) at 1200C for 30 min. under microwave irradiations. Solvents were removed under vacuum to dryness after which the residue was triturated with water, filtered and washed with EtOAc to give the title compound as a white powder (59 mg; 53%). 1H NMR (DMSO-J6) δ 11.4 (s, IH), 9.15 (d, J = 2.2 Hz, IH), 8.79 (dd, J = 1.5, 4.5 Hz, IH), 8.35 (dt, J = 1.8, 7.9 Hz, IH), 7.63-7.56 (m, 2H), 7.32 (bs, IH), 6.36 (d, J = 1.5 Hz, IH), 4.32-4.24 (m, IH), 2.43-2.34 (m, 2H), 2.25-2.18 (m, 2H), 1.79-1.70 (m, 2H). HPLC, Rt: 3.20 min. (purity 94.8%). LC/MS, M+(ESI): 377.0, M" (ESI): 375.0.
Example 86 : N-[5-fcvclohexylamino)[l,2,41triazolo[l,5-alpyridin-2-yll-6-morpholin-4- ylnicotinamide
Figure imgf000108_0002
(86)
The title compound was prepared following procedure described for intermediate Bl, but starting from N5-cyclohexyl[l,2,4]triazolo[l,5-a]pyridine-2,5-diamine ((A9), 174 mg; 0.75 mmol; 1.0 eq.) and 6-morpholinonicotinoyl chloride (255 mg; 1.12 mmol; 1.5 eq.) as a white solid (15 mg, 5%). HPLC, Rt: 2.83 min. (purity 99.0%). LC/MS, M+(ESI): 422.2, M (ESI): 420.1.
Example 87 : N-[5-fcvclohexylamino)[l,2,41triazolo[l,5-alpyridin-2-yll-4- r(dimethylamino)methyllbenzamide
Figure imgf000109_0001
(87)
The title compound was prepared following procedure described for example 82, but starting from N5-cyclohexyl[l,2,4]triazolo[l,5-a]pyridine-2,5-diamine ((B8), 288 mg; 0.75 mmol; 1.0 eq.) and dimethylamine (2 rnL, 2M solution in THF) as a yellow powder (91 mg, 31%). HPLC, Rt: 2.65 min. (purity 97.4%). LC/MS, M+(ESI): 393.1, M (ESI): 391.1.
Example 88 : N-[5-(cvclohexylamino)[l,2,41triazolo[l,5-alpyridin-2-yll-3-(morpholin-4- ylmethvDbenzamide
Figure imgf000109_0002
(88)
The title compound was prepared following procedure described for example 82, but starting from N5-cyclohexyl[l,2,4]triazolo[l,5-a]pyridine-2,5-diamine ((B8), 173 mg; 0.75 mmol; 1.0 eq.) and morpholine (653 mg, 7.5 mmol, 10 eq.) as an off white powder (120 mg, 37%). HPLC, Rt: 2.69 min. (purity 99.3%). LC/MS, M+(ESI): 435.2, M (ESI): 433.1.
Example 89 : N-[5-[(cvclopropylmethyl)aminol-7-(trifluoromethyl)[l,2,41triazolo[l,5- al pyridin-2-yll nicotinamide
Figure imgf000109_0003
(89)
The title compound was prepared following procedure described for example 85, but starting from N-[5-chloro-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide ((B7), 50 mg; 0.15 mmol; 1.0 eq.) and (aminomethyl)cyclopropane (52 μl; 0.73 mmol; 5.0 eq.) as a white solid (43 mg, 78%). HPLC, Rt: 3.19 min. (purity 78.6%). LC/MS, M+(ESI): 420.0, M" (ESI): 418.0.
Example 90 : methyl tr ans-4- { [2- \( pyridin-3-ylcarbonyl)aminol -7-
( trifluoromethyl) [1 ,2,41 triazolo [ 1 ,5-al pyridin-5-yll aminojcyclohexanecarboxylate
Figure imgf000110_0001
(90)
The title compound was prepared following procedure described for example 85, but starting from N-[5-chloro-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide ((B7), 50 mg; 0.15 mmol; 1.0 eq.) and trans-4-amino-cyclohexylcarboxylic acid methyl ester hydrochloride (IRIS), 52 μl; 0.73 mmol; 5.0 eq.) as a white powder (23 mg, 34%). HPLC, Rt: 3.33 min. (purity 96.4%). LC/MS, M+(ESI): 463.1, M (ESI): 461.1.
Example 91 : N-[5-{rαRS,2RS)-2-(hydroxymethyl)cvclohexyllaminol-7-
( trifluoromethyl) [1 ,2,41 triazolo [ 1 ,5-al pyridin-2-yll nicotinamide
Figure imgf000110_0002
(91)
The title compound was prepared following procedure described for example 85, but starting from N-[5-chloro-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide ((B7), 50 mg; 0.15 mmol; 1.0 eq.) and trans-2-hydroxymethyl-l-cyclohexylamine hydrochloride (121 mg; 0.73 mmol; 5.0 eq.) as a white solid (32 mg, 50%). HPLC, Rt: 3.00 min. (purity 89.6%). LC/MS, M+(ESI): 435.1, M (ESI): 433.0. Example 92 : N-[6-bromo-5-fcvclohexylamino)[l,2,41triazolo[l,5-alpyridin-2- yll nicotinamide
Figure imgf000111_0001
(92)
The title compound was prepared following procedure described for intermediate Bl, but starting from 6-bromo-N5-cyclohexyl[l,2,4]triazolo[l,5-a]pyridine-2,5-diamine ((A14), 616 mg; 1.99 mmol; 1.0 eq.) and nicotinoyl chloride hydrochloride (424 mg; 2.38 mmol; 1.2 eq.) as a beige powder (99 mg, 12%). HPLC, Rt: 3.41 min. (purity 94.6%). LC/MS, M+(ESI): 416.9.
Example 93 : N-[5-fcvcloheptylamino)[l,2,41triazolo[l,5-alpyridin-2-ylltetrahvdro-2H- pyran-4-carboxamide
Figure imgf000111_0002
(93)
The title compound was prepared following procedure described for intermediate Bl, but starting from N5-cycloheptyl[l,2,4]triazolo[l,5-a]pyridine-2,5-diamine ((AlO), 50 mg; 0.20 mmol; 1.0 eq.) and tetrahydro-2H-pyran-4-carbonyl chloride (45 mg; 0.30 mmol; 1.5 eq.) as a white solid (33 mg, 46%). HPLC, Rt: 3.02 min. (purity 96.9%). LC/MS, M+(ESI): 358.0, M" (ESI): 356.0.
Example 94 : N-[5-(2-methylprop-l-en-l-yl)[l.,2,41triazolo[l,5-alpyridin-2- yll nicotinamide dihydrochloride
Figure imgf000111_0003
(94)
N-(5-chloro[l,2,4]triazolo[l,5-a]pyridin-2-yl)nicotinamide ((B4), 141.00 mg; 0.52 mmol; 1.00 eq.), 2,2-dimethylethenylboronic acid (Synthonix, 102.96 mg; 1.03 mmol; 2.00 eq.), cesium fluoride (156.53 mg; 1.03 mmol; 2.00 eq.) and bis(triphenylphosphine)palladium(II) chloride (36.16 mg; 0.05 mmol; 0.10 eq.) were flushed with nitrogen in a sealed vial. THF (degassed with nitrogen, 1.50 mL) and water (1 mL) were then added and the mixture was heated at 1200C O/N in an oil bath. A solution of saturated NH4Cl was added and the reaction mixture was extracted with EtOAc (twice). Combined Organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated to give 186 mg of a yellow foam. Hydrochloride salt was then obtained by addition of Et2OZHCl (1 M solution) to a solution of this crude in DCM. The precipitate obtained was filtered and dried under vacuum at 400C to give the title compound as a beige solid (181 mg, 96%). HPLC, Rt: 2.05 min. (purity 92.3%). LC/MS, M+(ESI): 293.9, M (ESI): 291.9.
Example 95 : N-(3-oxo-3-{r5-αH-pyrazol-l-vmi,2,41triazolori,5-alpyridin-2- yll aminolpropyDbenzamide
Figure imgf000112_0001
(95)
The title compound was prepared following procedure and work up described for example 94 but starting from 5-(lH-pyrazol-l-yl)[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A12), 43 mg; 0.27 mmol; 1.0 eq.) as a white solid (13 mg, 13%). HPLC, Rt: 2.41 min. (purity 87.3%). LC/MS, M+(ESI): 376.0, M (ESI): 374.0.
Example 96 : N-(3-{r5-(3-furyl)ri,2,41triazolori,5-alpyridin-2-yllamino}-3- oxopropyDbenzamide
Figure imgf000112_0002
(96) The title compound was prepared following procedure and work up described for example 94 but starting from 5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A2), 43 mg; 0.27 mmol; 1.0 eq.) as a white solid (52 mg, 51%). HPLC, Rt: 2.72 min. (purity 84.8%). LC/MS, M+(ESI): 376.0, M (ESI): 374.0.
Example 97 : N-(3-{r5-α-furyl)ri,2,41triazolori,5-alpyridin-2-yllamino}-3- oxopropyDbenzamide
Figure imgf000113_0001
(97)
The title compound was prepared following procedure and work up described for example 94 but starting from 5-(2-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A16), 43 mg; 0.27 mmol; 1.0 eq.) as a white solid (51 mg, 42%). HPLC, Rt: 2.85 min. (purity 92.7%). LC/MS, M+(ESI): 447.0, M (ESI): 445.0.
Example 98 : N-f3-{[5-fcvclohexylamino)[l,2,41triazolo[l,5-alpyridin-2-yllamino}-3- oxopropyDbenzamide
Figure imgf000113_0002
(98)
The title compound was prepared following procedure and work up described for example 94 but starting from N5-cyclohexyl[l,2,4]triazolo[l,5-a]pyridine-2,5-diamine ((A9), 49 mg; 0.27 mmol; 1.0 eq.) as a white solid (28 mg, 25%). HPLC, Rt: 3.22 min. (purity 87.4%). LC/MS, M+(ESI): 407.1, M (ESI): 405.0.
Example 99 : N-[5-fisopropylamino)-7-ftrifluoromethyl)[l,2,41triazolo[l,5-alpyridin-2- yll nicotinamide
Figure imgf000114_0001
(99)
The title compound was prepared following procedure and work up described for example 85 but starting from from N-[5-chloro-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2- yl]nicotinamide ((B7), 50 mg; 0.15 mmol; 1.0 eq.) and isopropylamine (43 mg, 0.73 mmol; 5.0 eq.) as a white solid (8 mg, 15%). HPLC, Rt: 3.09 min. (purity 87.7%). LC/MS, M+(ESI): 365.0, M (ESI): 363.0.
Example 100 : N-[5-(sec-butylamino)-7-(trifluoromethyl)[l,2,41triazolo[l,5-alpyridin-2- yll nicotinamide
Figure imgf000114_0002
(100)
The title compound was prepared following procedure and work up described for example 85 but starting from from N-[5-chloro-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2- yl]nicotinamide ((B7), 50 mg; 0.15 mmol; 1.0 eq.) and sec-butylamine (53.50 mg; 0.73 mmol; 5.0 eq.) as a white solid (4 mg, 7%). HPLC, Rt: 3.44 min. (purity 89.4%). LC/MS, M+(ESI): 379.1, M-(ESI): 377.0.
Example 101 : N-[5-fmethylamino)-7-ftrifluoromethyl)[l,2,41triazolo[l,5-alpyridin-2- yll nicotinamide
Figure imgf000114_0003
(101) The title compound was prepared following procedure and work up described for example 85 but starting from N-[5-chloro-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2- yl]nicotinamide ((B7), 50 mg; 0.15 mmol; 1.0 eq.) and methylamine (1.46 mL of a 2M solution in MeOH; 0.73 mmol; 5.0 eq.) as a white solid (15 mg, 30%). HPLC, Rt: 2.47 min. (purity 96.6%). LC/MS, M+(ESI): 337.0, M (ESI): 335.0.
Example 102 : N-r8-(3-furvmi,2,41triazolori,5-alpyridin-2-yllbenzamide
Figure imgf000115_0001
(102)
The title compound was prepared following procedure and work up described for example 56 but starting from N-(8-bromo[l,2,4]triazolo[l,5-a]pyridin-2-yl)benzamide ((B9), 159 mg; 0.50 mmol; 1.0 eq.) and furan-3-boronic acid (112 mg; 1.0 mmol; 2.0 eq.) as a white powder (80 mg, 52 %). HPLC, Rt: 3.26 min. (purity 99.6%). LC/MS, M+(ESI): 305.0, M (ESI): 303.1.
Example 103 : N- r5-(cvclohexyloxy)r 1,2,41 triazolon,5-al pyridin-2-yll-2-(3- methoxyphenvDacetamide
Figure imgf000115_0002
(103)
The title compound was prepared following procedure and work up described for intermediate Bl but starting from 5-(cyclohexyloxy)[l,2,4]triazolo[l,5-a]pyridin-2-amine ((All), 80 mg; 0.34 mmol; 1.0 eq.) and 3-methoxyphenylacetyl chloride (64 μl; 0.41 mmol; 1.2 eq.) as a white powder (11 mg, 8%). HPLC, Rt: 3.60 min. (purity 88.2%). LC/MS, M+(ESI): 381.1, M (ESI): 379.1.
Example 104 : N- [5-fcyclohexyloxy)[l, 2,41 triazolo[l,5-alpyridin-2-yll nicotinamide
Figure imgf000116_0001
(104)
The title compound was prepared following procedure and work up described for intermediate Bl but starting from 5-(cyclohexyloxy)[l,2,4]triazolo[l,5-a]pyridin-2-amine ((All), 268 mg; 1.15 mmol; 1.0 eq.) and nicotinoyl chloride hydrochloride (247 mg; 1.38 mmol; 1.2 eq.) as an off-white foam (230 mg, 59%). HPLC, Rt: 2.36 min. (purity 94.7%). LC/MS, M (ESI): 336.1.
Example 105 : N- [5-(cyclohexylamino)[ 1,2,41 triazolo[l,5-al pyridin-2-yll-6-(2-pyrrolidin- l-ylethyl)nicotinamide
Figure imgf000116_0002
(105)
The title compound was prepared following procedure described for intermediate Bl but starting from N5-cyclohexyl[l,2,4]triazolo[l,5-a]pyridine-2,5-diamine ((A9), 116 mg; 0.5 mmol; 1.0 eq.) and 6-(2-pyrrolidin-l-ylethyl)nicotinoyl chloride (239 mg, 1.0 mmol; 2.0 eq.) as a white powder (130 mg, 60%). HPLC, Rt: 2.67 min. (purity 99.9%). LC/MS, M+(ESI): 434.1, M-(ESI): 432.1.
Example 106 : N- [5-fcyclohexylamino)[ 1,2,41 triazolo[l,5-al pyridin-2-yll-6-(morpholin-4- ylmethyDnicotinamide
Step a) Formation of potassium 6-(hydroxymethyl)pyridine-3-carboxylate.
Figure imgf000116_0003
An aqueous solution of potassium hydroxide (40.4 mmol, 8 mL, 5 N, 2.0 eq.) was added to a solution of ethyl 6-(hydroxymethyl)pyridine-3-carboxylate (3.7 g; 20.4 mmol; 1.0 eq.) (J. Med. Chem. 2004, 47, 5230-5234) in THF (80 mL). The resulting reaction mixture was stirred at rt for 3 h. The precipitate was collected by filtration and dried on under vacuum to give the title compound as a white powder (3.6 g, 92%).
Step b) Formation of6-(chloromethyl)pyridine-3-carbonyl chloride hydrochloride.
Cl, N-Λ. p W' y^ .HCI X=/ Cl
To a suspention of potassium 6-(hydroxymethyl)pyridine-3-carboxylate (96 mg; 0.50 mmol; 1.0 eq.) in DCM (1 mL) was added DMF (0.07 mg; 0.02 eq., 0.01 mmol). The mixture was chilled at 00C. Then oxalyl chloride (317 mg; 2.5 mmol; 5.0 eq.) was added dropwise and the resulting mixture was stirred 4 h at rt. Evaporation of the solvent gave a black fine powder without further purification in the next step.
Step c) Formation of N-[5-(cyclohexylamino)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-6- (morpholin-4-ylmethyl)nicotinamide
Figure imgf000117_0001
(106)
Pyridine (198 mg; 2.5 mmol; 5.0 eq.) was added to a solution of N5- cyclohexyl[l,2,4]triazolo[l,5-a]pyridine-2,5-diamine ((A9), 116 mg; 0.50 mmol; 1.0 eq.) in DCM (2.0 mL). 6-(chloromethyl)pyridine-3-carbonyl chloride hydrochloride (190 mg; 1.0 mmol; 2.0 eq.) was added and the resulting black solution was stirred under reflux for 14 h. The solvents were evaporated to yield a black oil. Morpholine (218 mg; 2.5 mmol; 5.0 eq.) and THF (0.5 mL) were added to this residue, and the mixture was then stirred and heated at 600C for 12 h. Purification by RP-HPLC (Waters Sunfire™ Prep C18 OBD™ 5μM, 100x49 mm) following a gradient starting with 20/80 (0.1% formic acid in CH3CN / 0.1% formic acid in H2O) up to 95/5 in 12 min. The fractions were collected and lyophilized to give the title compound as a white powder (20 mg, 9%). HPLC, Rt: 2.11 min. (purity 100%). LC/MS, M+(ESI): 436.3. Example 107: N- [5-( 3-furyl) [ 1 ,2,41 triazolo \ 1 ,5-al pyridin-2-yll cyclopropanecarboxamide
The title compound was aquired from Bio focus DPI (UK) cat. number: 320 4252 0343.
Figure imgf000118_0001
(107)
Example 108: N- \5-( 3-thienyl) [1,2,41 triazolo [ 1 ,5-al pyridin-2-yll benzamide
The title compound was aquired from Bio focus DPI (UK) cat. Number: 320 4251 0074.
Figure imgf000118_0002
(108) Example 109: N- \5-( 3-furyl) [1 ,2,41 triazolo [ 1 ,5-al pyridin-2-yll benzamide
The title compound was aquired from Bio focus DPI (UK) cat. number: 320 4251 0343.
Figure imgf000118_0003
(109) Example 110: N- [5-(3-furyl) [ 1 ,2,41 triazolo [ 1 ,5-al pyridin-2-yll benzamide
The title compound was aquired from Bio focus DPI (UK), cat. number: 320 4262 0343.
Figure imgf000118_0004
(110)
Example 111: N- \6-( 4-hydroxy-3-methoxyphenyl) [ 1 ,2,41 triazolo [ 1 ,5-al pyridin-2- yllacetamide
The title compound was aquired from Bio focus DPI (UK), cat. number: 395 2182 0314.
Figure imgf000119_0001
(111)
Example 112: N- [6-( 4-hydroxy-3,5-dimethylphenyl) [ 1 ,2,41 triazolo \ 1 ,5-al pyridin-2- yll nicotinamide
(112)
The title compound was prepared following procedure described for example 113 but using the N-(6-bromo-[l,2,4]triazolo[l,5-a]pyridin-2-yl)-benzamide ((B5), 95 mg, 0.3 mmol, 1 mol eq.) and the 2,6-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (89 mg, 0.36 mmol, 1.2 mol eq.) as a white solid (8.1 mg, 8 %). HPLC, Rt: 1.75 min (purity: 98 %). LC/MS M+(ESI): 360.3.
Example 113: 4- [2-(benzoylamino) [1 ,2,41 triazolo [1 ,5-al pyridin-6-yll -N- [2-
(dimethylamino)ethyll benzamide
Figure imgf000119_0003
(113)
To a reaction vessel containing N-(6-bromo-[l,2,4]triazolo[l,5-a]pyridin-2-yl)-benzamide ((B5), 95 mg, 0.3 mmol, 1 mol eq.), N-(2-dimethylamino-ethyl)-4-boronic acid-benzamide (85 mg, 0.36 mmol, 1.2 mol eq.) and cesium fluoride (135 mg, 0.9 mmol, 3 mol eq.) in DMF (0.75 mL) and H2O (0.5 mL) was added δώ-triphenylphosphine palladium dichloride (0.009 mmol, 3 mol %) in DMF (0.25 mL). The vessel was purged with nitrogen, capped and heated at 95 0C for approximately 18 hours. The reaction mixture was cooled to room temperature, filtered and the residue dissolved in DMSO (1.5 mL) and purified by reverse phase preparatory HPLC to give the title compound as a white solid (30.4 mg, 24%). HPLC, Rt: 1.74 min (purity: 99 %). LC/MS M+(ESI): 429.3, M"(ESI) 427.4.
Example 114 : N-[6-flH-pyrazol-4-yl)[l,2,41triazolo[l,5-alpyridin-2-yllbenzamide
Figure imgf000120_0001
(114)
The title compound was prepared following procedure described for example 112 but strating from N-(6-bromo-[l,2,4]triazolo[l,5-a]pyridin-2-yl)-benzamide ((B5), 95 mg, 0.3 mmol, 1 eq.) and 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lh-pyrazole_(Boron-Mol, 85 mg, 0.36 mmol, 1.2 mol eq.) as a white solid (6.2 mg, 7 %). HPLC, Rt: 2.26 min (purity: 99 %). LC/MS M+(ESI): 305.2.
Example 115 : N-{5-[fcvclohexylmethyl)aminol [l,2,41triazolo[l,5-alpyridin-2- yl| nicotinamide
Figure imgf000120_0002
(115)
To a microwave vial (0.5-2 mL) was added N-(5-bromo[l,2,4]triazolo[l,5-a]pyridin-2- yl)nicotinamide
(Intermediate B2, 60 mg, 0.19 mmol, 1 equivalent), diisopropylethylamine (0.05 mL, 0.30 mmol, 1.5 equivalent), cyclohexyl-methylamine (34 mg, 0.3 mmol, 1.5 equivalent) in butanol (0.6 mL). The mixture was heated in a Biotage initiator 60 microwave at 220 0C for 30 minutes. The reaction mixture was cooled and the solvent removed in vacuo. The residue dissolved in DMSO (1.5 mL) and purified by reverse phase preparatory HPLC to give the title compound as a white solid (4.0 mg, 6%). HPLC, Rt: 2.56 min (purity: 99 %). LC/MS M+(ESI): 351.2, M (ESI) 349.2. Example 116: N-IS-f^-hydroxycyclohexyDaminol [l,2,41triazolo[l,5-alpyridin-2-yl}-3- methoxybenzamide
Figure imgf000121_0001
A sealed vessel containing N-(5-bromo-[l,2,4]triazolo[l,5-a]pyridin-2-yl)-3-methoxy- benzamide (69 mg, 0.20 mmol, 1 mol eq.), trans-aminocyclohexanol (35 mg, 0.30 mmol, 1.5 mol eq.), di-ώo-propylethylamine (60 μL, 0.32 mmol, 1.6 mol eq.) and n-butanol (0.75 mL) was irradiated at 220 0C, with stirring, for 20 minutes. The solvent was removed in vacuo and the residue dissolved in DMSO (1.5 mL) and purified by reverse phase preparatory HPLC to give the title compound as a beige solid (27.5 mg, 36 %). HPLC, Rt: 1.86 min (purity: 100 %). LC/MS M+(ESI): 382.3, M (ESI) 380.3.
Example 117: N- \5-( cyclopentylamino) [ 1 ,2,41 triazolo \ 1 ,5-al pyridin-2-yll -2-furamide
Figure imgf000121_0002
(117)
A sealed vessel containing furan-2-carboxylic acid (5-bromo-[l,2,4]triazolo[l,5-a]pyridin-2- yl)-amide (61 mg, 0.20 mmol, 1 mol eq.), cyclopentylamine (26 mg, 0.30 mmol, 1.5 mol eq.), di-ώo-propylethylamine (60 μL, 0.32 mmol, 1.6 mol eq.) and n-butanol (0.75 ml) was irradiated at 220 0C, with stirring, for 20 minutes. The solvent was removed in vacuo and the residue dissolved in DMSO (1.5 mL) and purified by reverse phase preparatory HPLC to give the title compound as a white solid (28.4 mg, 46 %). HPLC, Rt: 2.32 min (purity: 97 %). LC/MS M+(ESI): 312.3.
Example 118: N- [7-chloro-5-( cyclobutylamino) [ 1 ,2,41 triazolo \ 1 ,5-al pyridin-2- yll nicotinamide
Figure imgf000122_0001
(118)
The title compound was prepared following procedure described for example 84, but starting from N-(5,7-dichloro[l,2,4]triazolo[l,5-a]pyridin-2-yl)nicotinamide ((BlO), lOOmg; 0.32 mmol; 1.0 eq) and cyclobutylamine (139 μL; 1.62 mmol; 5.0 eq) heated at 1800C for 1800s after which solvents were evaporated under vacuum, then resuspended in water, filtered and washed with EtOAc to give the title compound as a white solid (23 mg, 21%). HPLC, Rt: 2.95 min. (purity 96.7%). LC/MS, M+(ESI): 342.8, M (ESI): 340.9.
Example 119 : N-[7-chloro-5-(cvclopentylamino)[l,2,41triazolo[l,5-alpyridin-2- yll nicotinamide
Figure imgf000122_0002
(119)
The title compound was prepared following procedure and work up described for example 118, but starting from N-(5,7-dichloro[l,2,4]triazolo[l,5-a]pyridin-2-yl)nicotinamide ((BlO), 100 mg; 0.32 mmol; 1.0 eq) and cyclopentylamine (161 μL; 1.62 mmol; 5.0 eq) to give the title compound as a white solid (5 mg, 4%). HPLC, Rt: 3.20 min. (purity 92.3%). LC/MS, M+(ESI): 356.9, M (ESI): 354.9.
Example 120 : N-[7-chloro-5-(cvclohexylamino)[l,2,41triazolo[l,5-alpyridin-2- yll nicotinamide
Figure imgf000123_0001
(120)
The title compound was prepared following procedure and work up described for example 118, but starting from N-(5,7-dichloro[l,2,4]triazolo[l,5-a]pyridin-2-yl)nicotinamide ((BlO), 100 mg; 0.32 mmol; 1.0 eq) and cyclohexylamine (187 μL; 1.62 mmol; 5.0 eq) to give the title compound as a white solid (26 mg, 22%). HPLC, Rt: 3.48 min. (purity 98.5%). LC/MS, M+(ESI): 370.9, M (ESI): 368.9.
Example 121 : N-[5-(sec-butylamino)-7-chloro[l,2,41triazolo[l,5-alpyridin-2- yll nicotinamide
Figure imgf000123_0002
(121)
The title compound was prepared following procedure and work up described for example 118, but starting from N-(5,7-dichloro[l,2,4]triazolo[l,5-a]pyridin-2-yl)nicotinamide ((BlO), 100 mg; 0.32 mmol; 1.0 eq) and sec-butylamine (118 mg; 1.62 mmol; 5.0 eq) to give the title compound as a white solid (15 mg, 13%). HPLC, Rt: 3.07 min. (purity 96.3%). LC/MS, M+(ESI): 344.8, M (ESI): 342.9.
Example 122 : N-[7-chloro-5-(cvclopropylamino)[l,2,41triazolo[l,5-alpyridin-2- yll nicotinamide
Figure imgf000123_0003
(122) The title compound was prepared following procedure and work up described for example 118, but starting from N-(5,7-dichloro[l,2,4]triazolo[l,5-a]pyridin-2-yl)nicotinamide ((BlO), 100 mg; 0.32 mmol; 1.0 eq) and cyclopropylamine (113 μL; 1.62 mmol; 5.00 eq) to give the title compound as a white solid (50 mg, 43%). HPLC, Rt: 2.59 min. (purity 92.6%). LC/MS, M+(ESI): 328.8, M (ESI): 326.9.
Example 123 : N-[5-[f2-methoxyethyl)aminol-7-ftrifluoromethyl)[l,2,41triazolo[l,5- al pyridin-2-yll nicotinamide
Figure imgf000124_0001
(123)
The title compound was prepared following procedure and work up described for example 118, but starting from N-[5-chloro-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2- yl]nicotinamide ((B7), 50 mg; 0.14 mmol; 1.0 eq) and 2-methoxyethylamine (55.0 mg; 0.73 mmol; 5.0 eq), heated at 1200C, to give the title compound as a white solid (23 mg, 40%). HPLC, Rt: 2.70 min. (purity 98.1%). LC/MS, M+(ESI): 380.8, M (ESI): 378.9.
Example 124 : N-[5-[f3-hvdroxypropyl)aminol-7-ftrifluoromethyl)[l,2,41triazolo[l,5- al pyridin-2-yll nicotinamide
Figure imgf000124_0002
(124)
The title compound was prepared following procedure and work up described for example 118, but starting from N-[5-chloro-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2- yl]nicotinamide ((B7), 50 mg; 0.14 mmol; 1.0 eq) and 3-amino-l-propanol (56 μL; 0.73 mmol; 5.0 eq), heated at 1200C, to give the title compound as an off-white solid (22 mg, 40%). HPLC, Rt: 2.05 min. (purity 96.2%). LC/MS, M+(ESI): 380.8, M (ESI): 378.9.
Example 125 : N-[5-[f2-hvdroxyethyl)aminol-7-ftrifluoromethyl)[l,2,41triazolo[l,5- al pyridin-2-yll nicotinamide
(125)
The title compound was prepared following procedure and work up described for example 118, but starting from N-[5-chloro-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2- yl]nicotinamide ((B7), 50 mg; 0.14 mmol; 1.0 eq) and ethanolamine (44 μL; 0.73 mmol; 5.0 eq), heated at 1200C, to give the title compound as a white solid (15 mg, 28%). HPLC, Rt: 1.91 min. (purity 97.9%). LC/MS, M+(ESI): 366.8, M (ESI): 364.9.
Example 126 : N-[5-fdimethylamino)-7-ftrifluoromethyl)[l,2,41triazolo[l,5-alpyridin-2- yll nicotinamide
Figure imgf000125_0002
(126)
The title compound was prepared following procedure and work up described for example 118, but starting from N-[5-chloro-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2- yl]nicotinamide ((B7), 50 mg; 0.14 mmol; 1.0 eq) and dimethylamine (43.0 μL; 0.73 mmol; 5.0 eq), heated at 1200C, to give the title compound as a white solid (20 mg, 39%). HPLC, Rt: 2.52 min. (purity 99.7%). LC/MS, M+(ESI): 350.8, M (ESI): 348.9.
Example 127: N- \5-( cyclohexylamino) [ 1 ,2,41 triazolo \ 1 i5-al pyridin-2-yll -2-pyridin-3- ylacetamide Step a) Formation of pyridin-3-ylacetyl chloride
Figure imgf000126_0001
Oxalyl chloride (211. μl; 2.23 mmol; 1.2 eq.) was added to a suspension of 3-pyridineacetic acid (255 mg; 1.86 mmol; 1.0 eq.) in DCM/DMF (5 mL:3 μL) maintained at 00C under nitrogen atmosphere. The reaction mixture was then stirred at rt for Ih. It was then concentrated under reduced pressure. The solid obtained was used as such in amidation reactions.
Step b) Formation ofN-[5-(cyclohexylamino)[l,2,4]triazolo[l, 5-a]pyridin-2-yl]-2-pyridin-3- ylacetamide
Figure imgf000126_0002
(127)
A mixture of pyridin-3-ylacetyl chloride (120.07 mg; 0.77 mmol; 1.50 eq.) and N5- cyclohexyl[l,2,4]triazolo[l,5-a]pyridine-2,5-diamine ((A9); 119 mg; 0.51 mmol; 1.0 eq.) in DCM (ImL) in presence of pyridine (124 μL; 1.54 mmol; 3 eq.) was heated in a sealed tube at 55°C for 3h. Et2O and Water were then added to the mixture, the precipitate obtained was filtered, washed with water, Et2O, Acetonitrile and dried under vacuum at 400C to give the title compound as an off-white powder (74 mg, 41%). HPLC, Rt: 2.49 min. (purity 98.0%). LC/MS, M+(ESI): 350.9, M (ESI): 348.9.
Example 128: N- \5-( cyclohexylamino) [ 1 ,2,41 triazolo \ 1 ,5-al pyridin-2-yll -4-( piperidin- 1- ylmethyDbenzamide
Figure imgf000126_0003
(128)
To a reaction vessel containing N-5-cyclohexyl-[l,2,4]triazolo[l,5-a]pyridine-2,5-diamine (69 mg, 0.3 mmol, 1 eq.) and triethylamine (104 μL, 0.75 mmol, 2.5 eq.) in acetonitrile (1 rnL) was added 4-piperidin-l-ylmethyl-benzoyl chloride (178 mg, 0.75 mmol, 2.5 eq) as a solution in acetonitrile (2 mL), dropwise. The vessel was capped and stirred at room temperature for approximately 16 hours. The solvent was removed in vacuo and the resulting solid dissolved in methanolic ammonia (4 mL, 7 N) and stirred at room temperature for a further 16 hours. The solvent was removed in vacuo and the residue dissolved in DMSO (1.5 mL) and purified by reverse phase preparatory HPLC to give the title compound as a beige solid (15.3 mg, 12%). Rt: 3.86 min (purity: 97 %). LC/MS M+(ESI): 433.2, M (ESI) 431.2 .
Example 129: N- \5-( cyclohexylamino) [ 1 ,2,41 triazolo \ 1 i5-al pyridin-2-yll -4-( pyrrolidin- 1- ylmethyDbenzamide
Figure imgf000127_0001
(129)
To a reaction vessel containing N-5-cyclohexyl-[l,2,4]triazolo[l,5-a]pyridine-2,5-diamine (69 mg, 0.3 mmol, 1 eq.) and pyridine (63 μL, 1.2 mmol, 4 eq.) in dichloromethane (1 mL) was added 4-(pyrrolidin-l-ylmethyl)benzoyl chloride hydrochloride (142 mg, 0.6 mmol, 2 eq., prepared from 4-pyrrolidin-l-ylmethyl-benzoic acid, catalytic DMF and oxalyl chloride in DCM) as a solution in dichloromethane (2 mL), dropwise. The vessel was capped and heated to reflux for approximately 16 hours. The reaction mixture was cooled and the solvent removed in vacuo. The residue dissolved in DMSO (1.5 mL) and purified by reverse phase preparatory HPLC to give the title compound as a beige solid (12.4 mg, 10%). HPLC, Rt: 3.50 min (purity: 100 %). LC/MS M+(ESI): 419.2, M"(ESI) 417.2 .
Example 130: N- [S-fcvclohexylamino) [ 1 ,2,41 triazolo [ 1 ,5-al pyridin-2-yll -4- { \(2- methoxyethyl)(methyl)aminolmethyl}benzamide
Figure imgf000128_0001
(130)
To a reaction vessel containing 4-chloromethyl-N-(5-cyclohexylamino-[l,2,4]triazolo[l,5- a]pyridin-2-yl)-benzamide ((B8), 90 mg, 0.23 mmol, 1 eq.) and N, N- diiospropylethylamine (0.35 mmol, 61 μL, 1.5 eq.) in dioxane (3 mL) was added N-(2-methoxyethyl)methylamine (0.28 mmol, 25 μL, 1.2 eq.) dropwise. The vessel was capped and the reaction stirred at room temperature for 1 hour and heated to 80 0C for a further 15 hours. The solvent was removed in vacuo and the residue dissolved in DMSO (1.5 mL) and purified by reverse phase preparatory HPLC to give the title compound as a light yellow solid (3.9 mg, 4%). HPLC, Rt: 3.46 min (purity: 93 %). LC/MS M+(ESI): 437.2, M (ESI) 435.2 .
Example 131: N- \5-( cyclohexylamino) [1 ,2,41 triazolo [ 1 ,5-al pyridin-2-yll -6- methylnicotinamide
Figure imgf000128_0002
(131)
This was prepared using the same method as that described for N-(5-cyclohexylamino- [l,2,4]triazolo[l,5-a]pyridin-2-yl)-4-(2-oxo-pyrrolidin-l-ylmethyl)-benzamide to give N-(5- cyclohexylamino-[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl)-6-methyl-nicotinamide as a brown/yellow solid (36.5 mg, 35%). HPLC, Rt: 3.21 min (purity: 95 %). LC/MS M+(ESI): 351.1, M-(ESI) 349.1 .
Example 132: N- \5-( cyclohexylamino) [ 1 ,2,41 triazolo \ 1 ,5-al pyridin-2-yll -6-f(3- hydroxypropyl)aminol nicotinamide
Figure imgf000129_0001
(132)
To a biotage initiator microvave vial (0.2-0.5 mL) containing 6-chloro-N-(5- cyclohexylamino-fl^^jtriazolofl^-ajpyridin^-y^-nicotinamide ( (BIl), 0.27 mmol, 100 mg, 1 eq.), 3-aminopropan-l-ol (0.54 mmol, 0.028 mL, 2 eq.) and N, JV-diiospropylethylamine (0.54 mmol, 0.094 mL, 2 eq.) in butanol (2 mL), was capped and heated in a biotage initiator 60 microwave for 30 minutes at 180 0C, and a further 10 minutes at 210 0C. The solvent was removed in vacuo and the residue dissolved in DMSO (1.5 mL) and purified by reverse phase preparatory HPLC to give the title compound as a white solid (33.4 mg, 30%). HPLC, Rt: 2.37 min (purity: 92 %). LC/MS M+(ESI): 410.2, M"(ESI) 408.2 .
Example 133 : N- [S-fcyclohexylamino) [ 1 ,2,41 triazolo \ 1 ,5-al pyridin-2-yll -6- \(2- furylmethvDaminol nicotinamide
Figure imgf000129_0002
(133)
The title compound was prepared following the procedure described for the example 132 but starting from 2-aminomethylfuran as a brown solid (17.5 mg, 15%). HPLC, Rt: 3.50 min (purity: 91 %). LC/MS M+(ESI): 432.2, M (ESI) 430.2 .
Example 134 : N- [5-fcyclohexylamino)[ 1,2,41 triazolo [l,5-alpyridin-2-yll nicotinamide 1- oxide
Step a) Formation nicotinoyl chloride 1-oxide
Figure imgf000130_0001
The title compound was prepared following procedure described for example 127, step a), but starting from nicotinic acid N-oxide (255 mg; 1.83 mmol; 1.0 eq.). The solid obtained was used as such in amidation reactions.
Step b) Formation ofN-[5-(cyclohexylamino)[l,2,4]triazolo[l,5-a]pyridin-2- yl] nicotinamide 1-oxide
Figure imgf000130_0002
(134)
A mixture of N5-cyclohexyl[l,2,4]triazolo[l,5-a]pyridine-2,5-diamine ((A9), 108.00 mg; 0.47 mmol; 1.00 eq.) and nicotinoyl chloride 1-oxide (125 mg; 0.79 mmol; 1.7 eq.) in DCM (1 mL) in the presence of pyridine (113 μL; 1.40 mmol; 3 eq.) was heated in a sealed tube at 55°C for 3h. Water was then added and the reaction mixture was extracted with DCM (three times). Combined organic phases were then washed with brine, dried over magnesium sulfate, filtrated and con concentrated. The crude was purified by Mass Directed AutoPrep. The title compound was obtained after lyophilisation as a white powder (36 mg, 22%). HPLC, Rt: 2.64 min. (purity 99.4%). LC/MS, M+(ESI): 353.0, M (ESI): 351.0.
Example 135 : N-[5-fisopropylamino)-7-ftrifluoromethyl)[l,2,41triazolo[l,5-alpyridin-2- yll -2-pyridin-3-ylacetamide trihydrochloride
Figure imgf000130_0003
(135)
A mixture of N5-isopropyl-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridine-2,5-diamine ((A17), 73 mg; 0.28 mmol; 1.0 eq.), pyridin-3-ylacetyl chloride (90 mg; 0.58 mmol; 2.05 eq.) and Pyridine (67.98 μL) in DCM (1.00 mL) was heated at 55°C for 3h in a sealed tube. Water was added and the reaction mixture was extracted with DCM/MeOH (3:1, three times). Combined organic phases were then washed with brine, dried over magnesium sulfate, filtered and concentrated to give 105 mg of a yellowish powder. This crude was dissolved in MeOH (5 mL) and Et2O/HCl (9 mL of a 1 M solution) was added. The solution was concentrated under reduced pressure. A precipitate was then obtained by addition of DCMZEt2O (1 :1). It was filtered and dried under reduced pressure at 400C to give the title compound as an off- white solid (73 mg, 2%).
HPLC, Rt: 2.94 min. (purity 95.6%). LC/MS, M+(ESI): 379.0, M (ESI): 377.0. CHN analysis: [Ci7Hi7N6OF3-3.0 HCl- H2O] Corrected: C 40.37%, H 4.38%, N 16.62%; Found: C 40.52%, H 4.28%, N 16.71%.
Example 136 : N-[5-[fl-ethylpropyl)aminol-7-ftrifluoromethyl)[l,2,41triazolo[l,5- al pyridin-2-yll nicotinamide
Figure imgf000131_0001
(136)
The title compound was prepared following procedure and work up described for example 118, but starting from N-[5-chloro-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2- yl]nicotinamide ((B7), 50 mg; 0.14 mmol; 1.0 eq) and 3-aminopentane (86 μL; 0.73 mmol; 5.0 eq), heated at 1200C, to give the title compound as a white solid (23 mg, 40%). HPLC, Rt: 3.66 min. (purity 96%). LC/MS, M+(ESI): 392.9, M (ESI): 391.0.
Example 137 : N-[5-fisopropylamino)-7-ftrifluoromethyl)[l,2,41triazolo[l,5-alpyridin-2- yll nicotinamide 1-oxide
Figure imgf000131_0002
(137)
A mixture of nicotinoyl chloride 1-oxide (180.0 mg; 1.12 mmol; 3.4 eq.) and N5-isopropyl-7- (trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridine-2,5-diamine ((A17), 86.0 mg; 0.33 mmol; 1.0 eq.) in DCM (1 mL) in presence of pyridine (80 μL; 1.0 mmol; 3 eq.) was heated in a sealed tube at 55°C for 3h. Water was then added to the mixture and the precipitate obtained was filtered, washed with water and DCM and purified by Mass Directed AutoPrep. The title compound was obtained after lyophilisation as a white powder (19 mg, 15%). HPLC, Rt: 3.13 min. (purity 99.4%). LC/MS, M+(ESI): 380.9, M (ESI): 379.0.
Example 138 : N-[5-[f3-hvdroxycvclohexyl)aminol-7-ftrifluoromethyl)[l,2,41triazolo[l,5- alpyridin-2-yll nicotinamide formic acid
Figure imgf000132_0001
(138)
The title compound was prepared following procedure and work up described for example 118, but starting from N-[5-chloro-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2- yl]nicotinamide ((B7), 50.0 mg; 0.14 mmol; 1.00 eq) and 3-aminocyclohexanol (Betapharma, 84 mg; 0.73 mmol; 5.00 eq), heated at 1200C. HCl (1.5 M) in MeOH (2 mL) was added to the solid residue and the salt was precipitated by addition of Et2O, filtered and dried under vacuum, purified by Mass Directed AutoPrep and lyophilized to give the title compound as a mixture of cis:trans isomers as a white solid (11 mg, 18%). HPLC, Rt : 1.72 min. (purity 48.9%, isomer A), 1.87 min. (purity 46.6%, isomer B). LC/MS, M+(ESI): 420.9, M (ESI): 418.9.
Example 139 : N-{7-chloro-5-[f3-hvdroxycvclohexyl)aminol [l,2,41triazolo[l,5-alpyridin- 2-yl}nicotinamide formic acid
Figure imgf000133_0001
(139)
The title compound was prepared following procedure and work up described for example 118, but starting from N-(5,7-dichloro[l,2,4]triazolo[l,5-a]pyridin-2-yl)nicotinamide ((BlO), 100 mg; 0.32 mmol; 1.0 eq) and 3-aminocyclohexanol (Betapharma, 187 mg; 1.62 mmol; 5.0 eq), heated at 1200C, filtered and dried under vacuum, purified by Mass Directed AutoPrep and lyophilized to give the title compound as a mixture of cis:trans isomers as a beige powder (9 mg, 7%). HPLC, Rt : 2.15 min. (purity 57.4%, isomer A), 2.28 min. (purity 34.7%, isomer B). LC/MS, M+(ESI): 386.9, M (ESI): 384.9.
Example 140 : N- [5-(cvclopropylamino)-7-(trifluoromethyl)[ 1,2,41 triazolo[l,5-al pyridin- 2-yll -4- [(dimethylamino)methyll benzamide
Figure imgf000133_0002
(140)
To a reaction vessel containing N5-cyclopropyl-7-(trifluoromethyl)[l,2,4]triazolo[l,5- a]pyridine-2,5-diamine ((A18), 77 mg, 0.3 mmol, 1 eq.) and pyridine (0.063 mL, 1.2 mmol, 4 eq.) in dichloromethane (1 mL) was added 4-dimethylaminomethyl-benzoyl chloride (118 mg, 0.6 mmol, 2 eq.) as a solution in dichloromethane (2 mL), dropwise. The vessel was capped and heated to reflux for approximately 16 hours. The reaction mixture was cooled and the solvent removed in vacuo. The residue dissolved in DMSO (1.5 mL) and purified by reverse phase preparatory HPLC to give the title compound as a white solid (65.1 mg, 52%). HPLC, Rt: 2.59 min (purity: 100 %). LC/MS M+(ESI): 419.2, M (ESI) 417.2.
Example 141 : N- [5-(cyclopr opylamino)-7-(trifluoromethyl) [ 1 ,2,41 triazolo \ 1 ,5-al pyridin- 2-yll -4- [(2-oxopyrrolidin- l-yl)methyll benzamide
Figure imgf000134_0001
(141)
The title compound was prepared following procedure and work up described for example 140 but starting from 4-[(2-oxopyrrolidin-l-yl)methyl]benzoyl chloride (prepared in DCM from 4-[(2-oxopyrrolidin-l-yl)methyl]benzoic acid (Enamine), oxalyl chloride and catalytic amount of DMF following the procedure described for example 127, step a)). The title compound was obtained_as an off- white solid (73.6 mg, 27%). HPLC, Rt: 2.43 min (purity: 94 %). LC/MS M+(ESI): 459.2, M (ESI) 457.2.
Example 142: N- [5-(cyclopr opylamino)-7-(trifluoromethyl) [ 1 ,2,41 triazolo \ 1 i5-al pyridin- 2-yll-6-pyrrolidin-l-ylnicotinamide
Figure imgf000134_0002
(142)
The title compound was prepared following procedure and work up described for example 140 but starting from 6-pyrrolidin-l-ylpyridine-3-carbonyl chloride (prepared in DCM from 6-(l-pyrrolidinyl)nicotinic acid (ABCR), oxalyl chloride and catalytic amount of DMF following the procedure described for example 127, step a)). The title compound was obtained as a beige solid (18.5 mg, 14%). HPLC, Rt: 2.70 min (purity: 97 %). LC/MS M+(ESI): 432.2, M (ESI) 430.2.
Example 143 : N- \5-( cyclopr opylamino)-7-( trifluoromethyl) [ 1 ,2,41 triazolo \ 1 ,5-al pyridin- 2-yll -6-methylnicotinamide
Figure imgf000135_0001
(143)
The title compound was prepared following procedure and work up described for example 140 but starting from 6-methylpyridine-3-carbonyl chloride (prepared in DCM from 6- methylnicotinic acid, oxalyl chloride and catalytic amount of DMF following the procedure described for example 127, step a)). The title compound was obtained as a cream solid (14.6 mg, 13%). HPLC, Rt: 2.35 min (purity: 97 %). LC/MS M+(ESI): 377.2, M (ESI) 375.2.
Example 144: N- [6-( 4-hydroxy-3-methoxyphenyl) [ 1 ,2,41 triazolo [1 ,5-al pyridin-2-yll -4- (piperidin-l-ylmethyl)benzamide
Figure imgf000135_0002
(144)
Step a) Formation of 6-{3-(methyloxy)-4-[(phenylmethyl)oxy] phenyl} [1,2, 4] triazolo [1,5- aJpyridin-2-amine
Figure imgf000135_0003
To a reaction vessel containing 6-bromo[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A5), 3.44 g, 16.1 mmol, 1 eq.), 4-benzyloxy-3-methoxy boronic acid (5.0 g, 19.3 mmol, 1.2 eq., Synthonix) and cesium fluoride (7.34 g, 48.3 mmol, 3 eq.) in dimethylformamide (60 mL) and water (24 mL) was added δώ-triphenylphosphine palladium dichloride (0.3 g, 0.4 mmol, 3%). The vessel was purged with nitrogen, capped and heated at 80 0C for approximately 18 hours. After this time, the crude mixture was filtered through celite washing the celite with ethyl acetate and water. The resulting filtrate was extracted with ethyl acetate (3 x 150 mL) and the combined organic layers dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by flash column chromatography (ethyl acetate: petroleum ether; 1 :1) to give the title compound as a brown solid (4.82 g, 86%). HPLC, Rt: 2.55 min (purity 96%). LC/MS M+(ESI): 347, M (ESI) 345.
Step b) Formation of N-(6-{3-(methyloxy)-4-[(phenylmethyl)oxy]phenyl} [1,2,4] triazolo[ 1,5- a]pyridin-2-yl)-4-(piperidin-l-ylmethyl)benzamide
Figure imgf000136_0001
To a reaction vessel containing the 6-{3-(methyloxy)-4-
[(phenylmethyl)oxy]phenyl}[l,2,4]triazolo[l,5-a]pyridin-2-amine (104 mg, 0.3 mmol, 1 equivalent) and pyridine (0.063 mL, 1.2 mmol, 4 eq.) in dichloromethane (1 mL) was added 4-piperidin-l-ylmethyl-benzoyl chloride (142 mg, 0.6 mmol, 2 eq.) as a solution in dichloromethane (2 mL), dropwise. The vessel was capped and heated to reflux for approximately 16 hours. The reaction mixture was cooled and the solvent removed in vacuo. The residue dissolved in DMSO (1.5 mL) and purified by reverse phase preparatory HPLC to give N-[6-(4-benzyloxy-3-methoxy-phenyl)-[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]-4-piperidin- 1 - ylmethyl-benzamide as a white solid (14.9 mg, 9%).
Step c) Formation ofN-[6-(4-hydroxy-3-methoxyphenyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-4- (piperidin-l-ylmethyl)benzamide
N-(6- {3-(methyloxy)-4-[(phenylmethyl)oxy]phenyl} [ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl)-4- (piperidin-l-ylmethyl)benzamide (14.9 mg, 0.027 mmol) was treated with trifluoroacetic acid (2 mL) and the reaction mixture was stirred for 1 hour at 75 0C. The reaction mixture was cooled and the solvent removed in vacuo. The residue dissolved in DMSO (1.5 mL) and purified by reverse phase preparatory HPLC to give the title compound as a white solid (1.4 mg, 11%). HPLC, Rt: 2.23 min (purity: 99 %). LC/MS M+(ESI): 458.2, M (ESI) 456.2. Example 145: N- \6-( 4-hvdroxy-3-methoxyphenyl) [ 1 ,2,41 triazolo [1 ,5-al pyridin-2-yll -6- methylnicotinamide
Figure imgf000137_0001
(145)
The title compound was prepared following procedure and work up described for example 145 but starting from 6-methylpyridine-3-carbonyl chloride (prepared in DCM from 6- methylnicotinic acid, oxalyl chloride and catalytic amount of DMF following the procedure described for example 127, step a)). The title compound was obtained as a cream solid (5.2 mg, 24%). HPLC, Rt: 1.52 min (purity: 98 %). LC/MS M+(ESI): 376.1, M (ESI) 374.1.
Example 146: N- [6-(4-hydroxy-3-methoxyphenyl) [ 1 ,2,41 triazolo [1 ,5-al pyridin-2-yll -4- r(2-oxopyrrolidin-l-yl)methyllbenzamide
Figure imgf000137_0002
(146)
The title compound was prepared following procedure and work up described for example 144 but starting from 4-[(2-oxopyrrolidin-l-yl)methyl]benzoyl chloride (prepared in DCM from 4-[(2-oxopyrrolidin-l-yl)methyl]benzoic acid (Enamine), oxalyl chloride and catalytic amount of DMF following the procedure described for example 127, step a)). The title compound was obtained as a white solid (4.1 mg, 28%). HPLC, Rt: 1.68 min (purity: 98 %). LC/MS M+(ESI): 458.2, M (ESI) 456.2.
Example 147: 4-[(dimethylamino)methyll-N-[6-(4-hydroxy-3- methoxyphenyl) [ 1 ,2,41 triazolo \ 1 ,5-al pyridin-2-yll benzamide
Figure imgf000138_0001
(147)
The title compound was prepared following procedure and work up described for example 144 but starting from 4-dimethylaminomethyl-benzoyl chloride (prepared in DCM from 4- [(dimethylamino)methyl]benzoic acid (Enamine), oxalyl chloride and catalytic amount of DMF following the procedure described for example 127, step a)). The title compound was obtained as a white solid (13.7 mg, 45%). HPLC, Rt: 1.81 min (purity: 97 %). LC/MS M+(ESI): 418.2, M (ESI) 416.2
The following additional compounds (Examples 148-182) of Table 1 have been prepared following the above protocols.
Table 1: Examples of additional Triazolopyridine compounds
Figure imgf000139_0001
Table 1: Examples of additional Triazolopyridine compounds (contd.)
Figure imgf000140_0001
Table 1: Examples of additional Triazolopyridine compounds (contd.)
Figure imgf000141_0001
Table 1: Examples of additional Triazolopyridine compounds (contd.)
Figure imgf000142_0001
Assays
Example 183: Enzyme Inhibition Assays (in vitro ASKl assays)
Assays were performed in a 384 well plate (Corning, #3654) format, using the human recombinant ASKl as an enzyme and MBP (myelin basic protein, Upstate/Millipore, #13- 104) with ATP as substrates. Assay read out was the measurement of the amount of ATP remaining after stopping the reaction, using a luciferase-based kit from Cambrex.
Materials and Methods
Compounds to be tested were dissolved in 100% DMSO at a concentration of 10 mM. Subsequent dilutions were performed in 100% DMSO using a Biomek FX Workstation. 5 μL of diluted compound or vehicle (6% DMSO) was distributed to a 384 well plate. 5 μL of substrates (ATP 7.5 μM, MBP 450 ng/μL) diluted in ASKl buffer (20 mM Tris HCl pH 7.4, 0.001% Brij35, 0.01% BSA, 5mM MgCl2, 1 mM DL-Dithiothreitol) were added, followed by 5 μL of human recombinant ASKl enzyme (22.5 ng/mL) diluted in ASKl buffer in order to start the reaction. The reaction ran for 180 minutes at 300C before the addition of 5 μL of stop solution (Cambrex, #LT23-231). 10 μL of Pklight ATP detection reagent (Cambrex #LT23- 233) were added. After 120 min of incubation, luminescence was measured on a Perkin-Elmer Victor 2 spectrofluorimeter. The percentage of inhibition relative to the fluorescence observed in the presence of solvent (1% DMSO) alone was determined. The IC50 values for inhibition were determined in triplicates on at least 2 separate occasions.
The results are expressed in terms of IC50 (the concentration of compound required to give a 50% decrease in enzyme activity) and are presented in Table 2 below for compounds of Formula (I).
Table 2: IC50 on ASKl in nM
Figure imgf000143_0001
Figure imgf000143_0002
Figure imgf000144_0001
Figure imgf000144_0002
Example 184: Lipopolysaccharide (LPS)-induced TNFα release assay in mice
Rationale
The administration of LPS induces the release of TNFα from white blood cells (monocytes, macrophages, Kupffer cells, etc) and endothelial cells into the blood. This is a model for cytokine release that occurs during inflammation. Free radical scavengers (Edaravone, N-Acetylcystein, etc) were shown to reduce LPS-induced TNFα release in mice. ASKl mediates free radical pathways. Based on this mechanism, the blockade of ASKl by specific inhibitors should reduce LPS-induced TNFα release in mice.
Method
Female C3H mice (Elevage Janvier) (8 week old), received E. Coli's LPS (O111 :B4, Sigma, 0.3 mg/kg, ip) after the administration of the test articles. Ninety min later, the animals were sacrificed and the blood was sampled. Plasma levels of TNFa were determined in serum using an ELISA kit (R&D). LPS was solubilized in sterile saline. Protocol
The test articles were suspended in 0.5% CMC/0.25% Tween 20 and administered 15 min prior the challenge of LPS by oral route at the doses of 3 to 30 mg/kg. Control animals received the vehicle. In time course experiments, the test articles were administered 15 min to 4 hrs prior the challenge of LPS. Dexamethasone (0.1 mg/kg, po) was used as reference.
Summary of the experimental design
The animals were divided into 5 groups (6 mice each group):
Group 1 : (control LPS) received 0.5% CMC/0.25% tween-20 and injection of LPS;
Group 2: Experimental group (Compound of the invention Dose 1 is 3mg/kg) received a compound of the invention and injection of LPS;
Group 3: Experimental group (Compound of the invention Dose 2 is 10mg/kg) received a compound of the invention and injection of LPS;
Group 4: Experimental group (Compound of the invention Dose 3 is 30mg/kg) received a compound of the invention and injection of LPS;
Group 5: Reference group received the reference compound (dexamethasone) and injection of
LPS.
Calculation
Inhibition of TNF α release was calculated as follows:
% inhibition = 100 * (1 - (TNFα X) / TNFα I))
Where TNFα 1= TNFα concentration in group 1 (pg/ml), TNFα X= TNFα concentration in group X (pg/ml).
Table 3: Percentage of inhibition of LPS-induced TNFα release in mice by compounds of the invention:
Figure imgf000145_0001
Formulations
Preparation of a pharmaceutical formulation
Formulation 1 - Tablets
A compound of Formula (I) is admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 240-270 mg tablets (80-90 mg of active compound according to the invention per tablet) in a tablet press.
Formulation 2 - Capsules
A compound of Formula (I) is admixed as a dry powder with a starch diluent in an approximate 1 :1 weight ratio. The mixture is filled into 250 mg capsules (125 mg of active compound according to the invention per capsule).
Formulation 3 - Liquid
A compound of Formula (I) (1250 mg), sucrose (1.75 g) and xanthan gum (4 mg) are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously prepared solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11 :89, 50 mg) in water. Sodium benzoate (10 mg), flavor, and color are diluted with water and added with stirring. Sufficient water is then added to produce a total volume of 5 ml.
Formulation 4 - Tablets
A compound of Formula (I) is admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 450-900 mg tablets (150-300 mg of active compound according to the invention) in a tablet press.
Formulation 5 - Injection
A compound of Formula (I) is dissolved in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg/ml.

Claims

Claims
1. A triazolopyridine compound of formula I:
Figure imgf000147_0001
Formula (I) wherein Ri is selected from a. hydrogen; b. Ci-Ce-alkyl; c. C2-C6-alkenyl optionally substituted with Ci-C6-alkyl; d. -NR6R7; e. C3-C8-cycloalkoxy, Ci-C6-alkoxy; f. C3-Cs-cycloalkyl sulfanyl, Ci-C6-alkyl sulfanyl; and g. 5 or 6-membered heteroaryl having at least one heteroatom selected from N, S and O, said heteroaryl being optionally substituted with Ci-C6 alkyl, halogen, or Ci-C6 alkoxy;
R2 is selected from a. hydrogen; b. halogen; c. aryl optionally substituted with Ri0, Rn and/or Ri2; and d. 5 to 10-membered heteroaryl having at least one heteroatom selected from N, S and O and optionally substituted with Ci-C6 alkyl;
or Ri and R2 taken together form a -C=C-C=C- group-; R-3 is selected from a. hydrogen; b. halogen; and c. Ci-Cβ-alkyl optionally substituted with at least one fluoro;
R4 is selected from a.hydrogen; and b.5 or 6-membered heteroaryl having at least one heteroatom selected from N, S and
O;
R5 is selected from a. Ci-Cβ-alkyl optionally substituted with at least one of the following groups i. alkoxycarbonyl, ii. Ci-Cβ-alkoxy, iii. -NC(O)R' wherein R' is aryl optionally substituted with Ci-Cβ-alkyl, iv. benzyloxy; b. aryl-Ci-Ce-alkyl; c. 5 or 6-membered heteroaryl-Ci-Cβ-alkyl having a heteroatom selected from N, S and O optionally substituted with Ci-Cβ-alkyl, halogen or Ci-Cβ-alkoxy; d. C3-C6-cycloalkyl optionally substituted with phenyl; e. 3 to 8-membered heterocycloalkyl having a heteroatom selected from N, S and O optionally substituted with an acyl group; f. aryl optionally substituted with at least one of the following groups i. Ci-Ce-alkyl, ii. halogen, iii. Ci-Cβ-alkoxy, iv. perfluoro-Ci-C6-alkyl, v. at least one Ci-Cβ-alkoxy optionally substituted with Ci.Cβ-alkoxy carbonyl, vi. phenyl, vii. Ci-Cβ-alkyl sulfonyl,
Viii. -NHC(O) Ci-Ce-alkyl, ix. amino-Ci-Cβ-alkyl wherein amino is selected from -NH2, -NHCi-Cβ-alkyl, -
N(Ci-C6-alkyl)2, N(Ci-C6-alkyl)(Ci-C6-alkoxy-Ci-C6-alkyl), and the two substituents Ci-Cδ-alkyl can be the same or different, and wherein the two substituents may form a 3 to 8-membered heterocycloalkyl with the N to which they are attached to and wherein the heterocycloalkyl is optionally substituted with Ci-C6-alkyl or with hydroxy, x. -N(Ci-C6-alkyl) (Ci-C6-alkoxy-Ci-C6-alkyl), xi. 5 to 6-membered heterocycloalkyl-Ci-Cδ-alkyl having a heteroatom selected from N and O, xii. amido-Ci-Cδ-alkyl; g. 5 to 10-memberedheteroaryl having at least one heteroatom selected from N, O or S optionally substituted with halogen; and h. pyridinyl optionally substituted with at least one of the following groups i. halogen, ii. Ci-Ce-alkyl, iii. amino-Ci-C6-alkyl wherein amino is selected from -NH2, -NHCi-Cδ-alkyl or -N(Ci-C6-alkyl)2, wherein the two substituents Ci-Cβ-alkyl can be the same or different, and wherein the two substituents may form a 3 to 8-membered heterocycloalkyl with the N to which they are attached to and wherein the heterocycloalkyl is optionally substituted with Ci-C6-alkyl or hydroxy, iv. -NH(hydroxy-Ci-C6-alkyl), v. -NH-(5-membered heteroaryl-Ci-C6-alkyl having as heteroatom O), vi. 5 or 6-membered heterocycloalkyl-Ci-Cδ-alkyl having at least one heteroatom selected from O and N, vii. 5 or 6-membered heterocycloalkyl having at least one heteroatom selected from O and N optionally substituted with hydroxy, -C(O)OR' wherein R' is
Ci-Ce-alkyl, halogen or Ci-C6-alkyl, viii. amino, ix. -NH(amino-Ci-C6-alkyl), x. -N(Ci-C6-alkyl)2;
R6 is selected from a. Ci-Cδ-alkyl optionally substituted with one or two hydroxy groups, b. phenyl optionally substituted with at least one of the following groups i. halogen ii. Ci-C6-alkyl,or iii. Ci-Cδ-alkoxy; c. 5 or 6-membered heterocycloalkyl having a heteroatom selected from O and N optionally substituted with Ci-C6-alkyl; d. C3-C8-cycloalkyl optionally substituted with Rs; and e. -(CH2)nR9 wherein n equals 1, 2 or 3;
R7 is a. hydrogen or b. Ci-Ce-alkyl;
or R6 and R7 can form a 3 to 8-membered heterocycloalkyl with the N to which they are attached to and wherein the heterocycloalkyl is optionally substituted with C1-C6- alkyl;
Rs is selected from a.hydrogen; b. hydroxy; c. Ci-Cδ-alkyl optionally substituted with hydroxy; d.C(O)O-Ci-C6-alkyl; and e.-NH2;
R9 is selected from a. C3-Cs-cycloalkyl optionally substituted with an unsubstituted Ci-Cβ-alkyl; b. 5 or 6-membered heterocycloalkyl having a heteroatom selected from N and O optionally substituted with Ci-Cβ-alkyl; c.5 or 6-membered heteroaryl having a heteroatom selected from N and O optionally substituted with Ci-C6-alkyl; d. phenyl;
Rio, Rn and R12 are each independently selected from a. hydrogen; b. halogen; c. hydroxy; d. Ci-Ce-alkyl; e. Ci-Cδ-alkoxy; f. cyano; g. -C(O)NH(C i-C6-alkyl)amino wherein the amino is -N(CH3)2); and L-NH2.
2. A triazolopyridine compound according to claim 1 wherein
Ri is selected from a. hydrogen; b. Ci-Ce-alkyl; c. C2-C6-alkenyl optionally substituted with Ci-C6-alkyl; d. -NR6R7; e. C3-C8-cycloalkoxy; f. C3-Cs-cycloalkyl sulfanyl; and g. 5 or 6-membered heteroaryl having at least one heteroatom selected from N, S and O optionally substituted with Ci-Cβ-alkyl;
R2 is selected from a. hydrogen; b. Cl or Br; c. aryl optionally substituted with Rio, Rn and/or Ri2; and d. 5, 6 or 9-membered heteroaryl having at least one heteroatom selected from N, S and O and optionally substituted with Ci-C6 alkyl;
or Ri and R2 taken together form a -C=C-C=C- group-;
R3 is selected from a.hydrogen; b.chloro; bromo; c. methyl; and d.CF3;
R4 is selected from a. hydrogen; and b. fliranyl;
R5 is selected from a. Ci-Cβ-alkyl optionally substituted with at least one of the following groups i. alkoxycarbonyl, ii. Ci-Cβ-alkoxy, iii. -NHC(O)R' wherein R' is aryl optionally substituted with Ci-Cβ-alkyl, iv. benzyloxy; b. aiyl-Ci-Ce-alkyl; c. 5 or 6-membered heteroaryl-Ci-Cβ-alkyl having a heteroatom selected from N, S and O optionally substituted with Ci-Cβ-alkyl, halogen or Ci-Cβ-alkoxy; d. C3-C6 cycloalkyl optionally substituted with phenyl; e. 3 to 8-membered heterocycloalkyl having a heteroatom selected from N, S and O optionally substituted with an acyl group; f. aryl optionally substituted with at least one of the following groups iCi-Ce-alkyl, ii. halogen, iii. Ci-Cβ-alkoxy, iv. perfluoro-Ci-C6-alkyl, v. at least one Ci-Cβ-alkoxy optionally substituted with Ci-Cβ-alkoxy carbonyl, vi. phenyl, vii. Ci-Cβ-alkyl sulfonyl, viii. -NC(O)Ci-C6-alkyl, ix. amino-Ci-Cβ-alkyl wherein amino is selected from -NH2, -NHCi-Cβ-alkyl, -
N(Ci-C6-alkyl)2, N(Ci-C6-alkyl)(Ci-C6-alkoxy-Ci-C6-alkyl), and the two substituents Ci-Cβ-alkyl can be the same or different, and wherein the two substituents may form a 3 to 8-membered heterocycloalkyl with the N to which they are attached to and wherein the heterocycloalkyl is optionally substituted with Ci-Cβ-alkyl or with hydroxy, x. -N(Ci-C6-alkyl) (Ci-C6-alkoxy-Ci-C6-alkyl), xi. 5 to 6-membered heterocycloalkyl-Ci-Cβ-alkyl having a heteroatom selected from N and O, xii. amido-Ci-Cβ-alkyl; g. 5 to 10-membered heteroaryl having at least one heteroatom selected from N optionally substituted with halogen; and h. pyridinyl optionally substituted with at least one of the following groups i. halogen, ii. Ci-Cβ-alkyl optionally substituted with a 5 or 6-membered heterocycloalkyl having at least one heteroatom selected from O and N, iii. 5 or 6-membered heterocycloalkyl having at least one heteroatom selected from O and N, iv. -NHChydroxy-Ci-Ce-alkyl), v. -NH-(5-membered heteroaryl-Ci-Cβ-alkyl having as heteroatom O), vi. 5 or 6-membered heterocycloalkyl-Ci-Cβ-alkyl having at least one heteroatom selected from O and N, vii. 5 or 6-membered heterocycloalkyl having at least one heteroatom selected from O and N optionally substituted with hydroxy, -C(O)OR' wherein R' is
Ci-Ce-alkyl, halogen or Ci-C6-alkyl, viii. amino, ix. -NHtamino-Ci-Ce-alkyl), x. -N(Ci-C6-alkyl)2;
R6 is selected from a. Ci-Cβ-alkyl optionally substituted with one or two hydroxy groups, b. phenyl optionally substituted with at least one of the following groups i. halogen, ii. Ci-Cβ-alkyl, or iii. Ci-Cβ-alkoxy; c. 5 or 6-membered heterocycloalkyl having a heteroatom selected from O and N optionally substituted with is Ci-Cβ-alkyl; d. C3-C8-cycloalkyl optionally substituted with Rs; and e. -(CH2)nR9 wherein n equals 1, 2 or 3;
R7 is a. hydrogen or b. Ci-Ce-alkyl; or or R6 and R7 can form a 3 to 8-membered heterocycloalkyl with the N to which they are attached to and wherein the heterocycloalkyl is optionally substituted with C1-C6- alkyl;
Rs is selected from a.hydrogen; b. hydroxy; c.unsubstituted or substituted Ci-Cδ-alkyl wherein the substituent is hydroxyl; d.C(O)O- Ci-Ce-alkyl; and e.-NH2;
R9 is selected from a. C3-C8-cycloalkyl optionally substituted with an unsubstituted d-Cβ-alkyl; b. 5 or 6-membered heterocycloalkyl having a heteroatom selected from N and O optionally substituted with d-Cβ-alkyl; c.5 or 6-membered heteroaryl having a heteroatom selected from N and O optionally substituted with d-Cβ-alkyl; and d.phenyl.
Rio, Rn and R12 are each independently selected from a. hydrogen; b. fluoro, bromo; c. hydroxyl; d. Ci-Ce-alkyl; e. Ci-Cδ-alkoxy; f. cyano; g. -C(O)NH(C i-C6-alkyl)amino wherein the amino is -N(CH3)2); and L-NH2. A triazolopyridine compound according to claim 1 of the following Formula 1-1
Figure imgf000155_0001
Formula 1-1
wherein
R2 is hydrogen or bromo;
R3 is selected from a. hydrogen; b. halogen; and cCi-Cβ-alkyl optionally substituted with at least one fluoro;
R5 is selected from a. Ci-Cβ-alkyl optionally substituted with at least one of the following groups i. Ci-Cβ-alkoxycarbonyl, ii. Ci-Cβ-alkoxy, iii. -NHC(O)R' wherein R' is aryl optionally substituted with Ci-Cβ-alkyl, iv. benzyloxy; b. aryl-Ci-Ce-alkyl; c. 5 or 6-membered heteroaryl-Ci-Cβ-alkyl having a heteroatom selected from N, S and O optionally substituted with Ci-Cβ-alkyl, halogen or Ci-Cβ-alkoxy; d. C3-C6 cycloalkyl optionally substituted with phenyl; e. 3 to 8-membered heterocycloalkyl having a heteroatom selected from N, S and O optionally substituted with an acyl group; f. aryl optionally substituted with i. Ci-Cβ-alkyl optionally substituted with a γ-lactam or δ-lactam, ii. halogen, iii. Ci-Cβ-alkoxy, iv. perfluoro-Ci-C6-alkyl, v. at least one Ci-Cβ-alkoxy optionally substituted with Ci-Cδ-alkoxycarbonyl, vi. phenyl, vii. Ci-Cδ-alkyl sulfonyl, viii. -NHC(O) Ci-C6-alkyl, ix. amino-Ci-Cδ-alkyl wherein amino is selected from -NH2, -NHCi-Cδ-alkyl, -
N(Ci-C6-alkyl)2, N(Ci-C6-alkyl)(Ci-C6-alkoxy-Ci-C6-alkyl), and the two substituents Ci-Cδ-alkyl can be the same or different, and wherein the two substituents may form a 3 to 8-membered heterocycloalkyl with the N to which they are attached to and wherein the heterocycloalkyl is optionally substituted with Ci-Cδ-alkyl or with hydroxy, x. -N(Ci-C6-alkyl) (Ci-Ce-alkoxy-Ci-Ce-alkyl), xi. 5 to 6-membered heterocycloalkyl-Ci-Cδ-alkyl having a heteroatom selected from N and O, xii. amido-Ci-Cδ-alkyl; g. 5 to 10-membered heteroaryl having at least one heteroatom selected from N optionally substituted with halogen; and h. pyridinyl optionally substituted with at least one of the following groups i. halogen, ii. Ci-Cδ-alkyl optionally substituted with a 5 or 6-membered heterocycloalkyl having at least one heteroatom selected from O and N, iii. 5 or 6-membered heterocycloalkyl having at least one heteroatom selected from O and N, iv. -NHChydroxy-Ci-Ce-alkyl), v. -NH-(5-membered heteroaryl-Ci-C6-alkyl having as heteroatom O), vi. 5 or 6-membered heterocycloalkyl-Ci-Cδ-alkyl having at least one heteroatom selected from O and N;
Re is selected from a. Ci-Cδ-alkyl optionally substituted with one or two hydroxy groups, b. phenyl optionally substituted with at least one of the following groups i. halogen, ii. Ci-Ce-alkyl, iii. Ci-Cδ-alkoxy; c. 5 or 6-membered heterocycloalkyl having a heteroatom selected from O and N optionally substituted with is Ci-Cβ-alkyl; d. C3-C8-cycloalkyl optionally substituted with Rs; and e. -(CH2)nR9 wherein n equals 1, 2 or 3;
R7 is a. hydrogen or b. Ci-Ce-alkyl.
4. A triazolopyridine compound according to claim 3 of the following Formula 1-2
Figure imgf000157_0001
Formula 1-2
wherein
R3 is selected from a. hydrogen; b. halogen; and c. Ci-Cβ-alkyl optionally substituted with at least one fluoro;
R5 is selected from a. Ci-Cβ-alkyl optionally substituted with at least one of the following groups i. Ci-Cβ-alkoxycarbonyl, ii. Ci-Cβ-alkoxy, iii. -NHC(O)R' wherein R' is aryl optionally substituted with d-Cβ-alkyl, iv. benzyloxy; b. aryl-Ci-Ce-alkyl; c. 5 or 6-membered heteroaryl-Ci-Cβ-alkyl having a heteroatom selected from N, S and O optionally substituted with d-Cβ-alkyl, halogen or Ci-Cβ-alkoxy; d. C3-C6 cycloalkyl optionally substituted with phenyl; e. 3 to 8-membered heterocycloalkyl having a heteroatom selected from N, S and O optionally substituted with an acyl group; f. aryl optionally substituted with i. Ci-Cβ-alkyl optionally substituted with a γ-lactam or δ-lactam, ii. halogen, iii. Ci-Cβ-alkoxy, iv. perfluoro-Ci-Cβ-alkyl, v. at least one Ci-Cβ-alkoxy optionally substituted with Ci-Cβ-alkoxycarbonyl, vi. phenyl, vii. Ci-Cβ-alkyl sulfonyl, viii. -NHC(O) Ci-C6-alkyl, ix. amino-Ci-C6-alkyl wherein amino is selected from -NH2, -NHCi-Cβ-alkyl, -
N(Ci-C6-alkyl)2, N(Ci-C6-alkyl)(Ci-C6-alkoxy-Ci-C6-alkyl), and the two substituents Ci-Cβ-alkyl can be the same or different, and wherein the two substituents may form a 3 to 8-membered heterocycloalkyl with the N to which they are attached to and wherein the heterocycloalkyl is optionally substituted with Ci-Cβ-alkyl or with hydroxy; x. -N(Ci-C6-alkyl) (Ci-C6-alkoxy-Ci-C6-alkyl), xi. 5 to 6-membered heterocycloalkyl-Ci-Cβ-alkyl having a heteroatom selected from N and O; xii. amido-Ci-Cβ-alkyl; g. 5 to 10-membered heteroaryl having at least one heteroatom selected from N optionally substituted with halogen; and h. pyridinyl optionally substituted with at least one of the following groups i. halogen, ii. Ci-Cβ-alkyl optionally substituted with a 5 or 6-membered heterocycloalkyl having at least one heteroatom selected from O and N, iii. 5 or 6-membered heterocycloalkyl having at least one heteroatom selected from O and N, iv. -NH(hydroxy-Ci-C6-alkyl), v. -NH-(5-membered heteroaryl-Ci-Cβ-alkyl having as heteroatom O), vi. 5 or 6-membered heterocycloalkyl-Ci-Cβ-alkyl having at least one heteroatom selected from O and N; R6 is selected from a. Ci-Cδ-alkyl optionally substituted with one or two hydroxy groups, b. phenyl optionally substituted with at least one of the following groups i. halogen ii. Ci-Ce-alkyl, iii. Ci-Cδ-alkoxy; c. 5 or 6-membered heterocycloalkyl having a heteroatom selected from O and N optionally substituted with is Ci-Cδ-alkyl; d. C3-Cs-cycloalkyl optionally substituted with R8; and e. -(CH2)nR9 wherein n equals 1, 2 or 3.
5. A triazolopyridine compound according to claim 3 wherein R3 is Cl, Br, -CH3 or -CF3.
6. A triazolopyridine compound according to claim 3 wherein R3 is Cl, Br, -CH3 Or -CF3.
R5 is selected from a. phenyl optionally substituted with at least one of the following groups i. Ci-Ce-alkyl, ii. halogen, iii. Ci-Cδ-alkoxy, iv. at least one Ci-Cβ-alkoxy optionally substituted with Ci-Cβ-alkoxy carbonyl, v. -NHC(O) Ci-Ce-alkyl, vi. -N(Ci-C6-alkyl)2, vii. amino-Ci-C6-alkyl wherein amino is selected from -NH2, -NHCi-Cδ-alkyl,
-N(Ci-C6-alkyl)2, N(Ci-C6-alkyl)(Ci-C6-alkoxy-Ci-C6-alkyl), and the two substituents Ci-Cδ-alkyl can be the same or different, and wherein the two substituents may form a 3 to 8-membered heterocycloalkyl with the N to which they are attached to and wherein the heterocycloalkyl is optionally substituted with Ci-Cδ-alkyl or with hydroxy; viii. -N(Ci-C6-alkyl) (Ci-Ce-alkoxy-Ci-Ce-alkyl), ix. 5 to 6-membered heterocycloalkyl-Ci-Cβ-alkyl having a heteroatom selected from N and O optionally substituted with Ci-Cβ-alkyl, halogen or Ci- Cβ-alkoxy; x. amido-Ci-Cβ-alkyl; and b. pyridinyl optionally substituted with at least one of the following groups i. Ci-Cβ-alkyl optionally substituted with a 5 or 6-membered heterocycloalkyl having at least one heteroatom selected from O and N, ii. 5 or 6-membered heterocycloalkyl having at least one heteroatom selected from O and N, iii. -NH-(5-membered heteroaryl-Ci-Cβ-alkyl having as heteroatom O), iv. 5 or 6-membered heterocycloalkyl-Ci-Cβ-alkyl having at least one heteroatom selected from O and N;
R6 is selected from a.unsubstituted d-Cβ-alkyl, b. phenyl optionally substituted with at least one of the following groups i. halogen, ii.Ci-Ce-alkyl, iii. Ci-Cβ-alkoxy; c.6-membered heterocycloalkyl having a heteroatom selected from O and N optionally substituted with Ci-Cβ-alkyl; d.C3-C8-cycloalkyl optionally substituted with Ci-Cβ-alkyl.
7. A triazolopyridine compound according to claim 3 wherein R3 is Cl, Br, -CH3 Or -CF3;
R5 is selected from a.phenyl optionally substituted with amino-Ci-Cβ-alkyl wherein amino is selected from i. -NH2, ii. -N(C1.C6-alkyl)2, iii. -NHCi.Ce-alkyl, and iv. 5 or 6-membered heterocycloalkyl having as heteroatom N or O; b. pyridinyl optionally substituted with at least one of the following groups i. Ci-Cδ-alkyl optionally substituted with a 5 or 6-membered heterocycloalkyl having at least one heteroatom selected from O and N, ii. 5 or 6-membered heterocycloalkyl having at least one heteroatom selected from O and N, iii. -NH-(5-membered heteroaryl-Ci-C6-alkyl having as heteroatom O), iv. 5 or 6-membered heterocycloalkyl-Ci-C6-alkyl having at least one heteroatom selected from O and N; c. pyridin-Ci-C6-alkyl;
R6 is selected from a. Ci-Cδ-alkyl optionally substituted with at least one of the following groups i. hydroxy, ii. Ci-Cδ-alkoxy; b. C3-C8-cycloalkyl; c. -CH2R9 wherein R9 is C3-C6-cycloalkyl.
8. A triazolopyridine compound according to claim 1 of the following Formula 1-3
Figure imgf000161_0001
Formula 1-3 wherein Ri is selected from a. hydrogen; b. unsubstituted Ci-C6-alkyl; c. C2-C6-alkenyl optionally substituted with Ci-C6-alkyl; d. -NR6R7; e. unsubstituted C3-Cs-cycloalkoxy; f. unsubstituted Cs-Cs-cycloalkyl sulfanyl; and g. 5 or 6 membered heteroaryl having at least one heteroatom selected from N, S and O optionally substituted with Ci-C6 alkyl;
R2 is hydrogen or bromo; Rs is selected from a. Ci-Cδ-alkyl optionally substituted with at least one of the following groups i. Ci-Cδ-alkoxycarbonyl, ii. Ci-Cδ-alkoxy, iii. -NHC(O)R' wherein R' is aryl optionally substituted with Ci-C6-alkyl, iv. benzyloxy; b. aiyl-Ci-Ce-alkyl; c. 5 or 6-membered heteroaryl-Ci-Cδ-alkyl having a heteroatom selected from N, S and O optionally substituted with Ci-C6-alkyl, halogen or Ci-Cβ-alkoxy; d. C3-C6 cycloalkyl optionally substituted with phenyl; e. 3 to 8-membered heterocycloalkyl having a heteroatom selected from N, S and O optionally substituted with an acyl group; f. aryl optionally substituted with i. Ci-Cδ-alkyl optionally substituted with a γ-lactam or δ-lactam, ii. halogen, iii. Ci-Cδ-alkoxy, iv. perfluoro-Ci-C6-alkyl, v. at least one Ci-Cβ-alkoxy optionally substituted with Ci-Cδ-alkoxycarbonyl, vi. phenyl, vii. Ci-Cδ-alkyl sulfonyl, viii. -NHC(O) Ci-C6-alkyl, ix. amino-Ci-Cδ-alkyl wherein amino is selected from -NH2, -NHCi-Cδ-alkyl, -
N(Ci-C6-alkyl)2, N(Ci-C6-alkyl)(Ci-C6-alkoxy-Ci-C6-alkyl), and the two substituents Ci-Cδ-alkyl can be the same or different, and wherein the two substituents may form a 3 to 8-membered heterocycloalkyl with the N to which they are attached to and wherein the heterocycloalkyl is optionally substituted with Ci-C6-alkyl or with hydroxy, x. -N(Ci-C6-alkyl) (Ci-C6-alkoxy-Ci-C6-alkyl), xi. 5 to 6-membered heterocycloalkyl-Ci-Cδ-alkyl having a heteroatom selected from N and O, xii. amido-Ci-C6-alkyl; g. 5 to 10-membered heteroaryl having at least one heteroatom selected from N optionally substituted with halogen; and h. pyridinyl optionally substituted with at least one of the following groups i. halogen, ii. Ci-Cβ-alkyl optionally substituted with a 5 or 6-membered heterocycloalkyl having at least one heteroatom selected from O and N, iii. 5 or 6-membered heterocycloalkyl having at least one heteroatom selected from O and N, iv. -NHChydroxy-Ci-Ce-alkyl), v. -NH-(5-membered heteroaryl-Ci-Cβ-alkyl having as heteroatom O), vi. 5 or 6-membered heterocycloalkyl-Ci-Cβ-alkyl having at least one heteroatom selected from O and N.
9. A triazolopyridine compound according to claim 8 of the following Formula 1-4
Figure imgf000163_0001
Formula 1-4 wherein Ri is selected from a. unsubstituted Ci-Cβ-alkyl; b. C2-C6-alkenyl optionally substituted with Ci-Cβ-alkyl; c. -NR6R7; d. unsubstituted C3-Cs-cycloalkoxy; e. unsubstituted Cs-Cs-cycloalkyl sulfanyl; and f. 5 or 6 membered heteroaryl having at least one heteroatom selected from N, S and O optionally substituted with Ci-C6 alkyl;
R5 is selected from a. Ci-Cβ-alkyl optionally substituted with at least one of the following groups i. Ci-Cβ-alkoxycarbonyl, ii. Ci-Cβ-alkoxy, iii. -NHC(O)R' wherein R' is aryl optionally substituted with Ci-Cβ-alkyl, iv. benzyloxy; b. aryl-Ci-Ce-alkyl; c. 5 or 6-membered heteroaryl-Ci-Cβ-alkyl having a heteroatom selected from N, S and O optionally substituted with Ci-Cβ-alkyl, halogen or Ci-Cβ-alkoxy; d. C3-C6 cycloalkyl optionally substituted with phenyl; e. 3 to 8-membered heterocycloalkyl having a heteroatom selected from N, S and O optionally substituted with an acyl group; f. aryl optionally substituted with i. Ci-Cβ-alkyl optionally substituted with a γ-lactam or δ-lactam, ii. halogen, iii. Ci-Cβ-alkoxy, iv. perfluoro-Ci-C6-alkyl, v. at least one Ci-Cβ-alkoxy optionally substituted with Ci-Cβ-alkoxycarbonyl, vi. phenyl, vii. Ci-Cβ-alkyl sulfonyl, viii. -NHC(O) Ci-C6-alkyl, ix. amino-Ci-Cβ-alkyl wherein amino is selected from -NH2, -NHCi-Cβ-alkyl, -
N(Ci-C6-alkyl)2, N(Ci-C6-alkyl)(Ci-C6-alkoxy-Ci-C6-alkyl), and the two substituents Ci-Cβ-alkyl can be the same or different, and wherein the two substituents may form a 3 to 8-membered heterocycloalkyl with the N to which they are attached to and wherein the heterocycloalkyl is optionally substituted with Ci-Cβ-alkyl or with hydroxy, x. -N(Ci-C6-alkyl) (Ci-C6-alkoxy-Ci-C6-alkyl), xi. 5 to 6-membered heterocycloalkyl-Ci-Cβ-alkyl having a heteroatom selected from N and O, xii. amido-Ci-Cβ-alkyl; g. 5 to 10-membered heteroaryl having at least one heteroatom selected from N optionally substituted with halogen; and h. pyridinyl optionally substituted with at least one of the following groups i. halogen, ii. Ci-Cβ-alkyl optionally substituted with a 5 or 6-membered heterocycloalkyl having at least one heteroatom selected from O and N, iii. 5 or 6-membered heterocycloalkyl having at least one heteroatom selected from O and N, iv. -NHChydroxy-Ci-Ce-alkyl), v. -NH-(5-membered heteroaryl-Ci-Cβ-alkyl having as heteroatom O), vi. 5 or 6-membered heterocycloalkyl-Ci-Cβ-alkyl having at least one heteroatom selected from O and N;
10. A triazolopyridine compound according to claim 8 wherein
Ri is an unsubstituted 5-membered heteroaryl having at least one heteroatom selected from O, S and N;
R5 is selected from a. phenyl optionally substituted with i. Ci-Ce-alkyl, ii. perfluoro-Ci-C6-alkyl, or iii. Ci-Cβ-alkoxy; and b. pyridinyl optionally substituted with i. Cl, ii. Br, or iii. -NH(hydroxy-Ci-C6-alkyl).
11. A triazolopyridine compound according to claim 1 of the following Formula 1-5
Figure imgf000165_0001
Formula 1-5
wherein
R2 is selected from a. phenyl optionally substituted with i. at least one unsubstituted Ci-Cβ-alkyl, ii. unsubstituted Ci-Cβ-alkoxy, iii. fluoro, iv. bromo, v. hydroxy, vi. cyano, or vii. -NH2; and b. 5 or 9-membered heteroaryl having a heteroatom selected from N, S and O;
R5 is selected from a. unsubstituted Ci-Cβ-alkyl; b. aryl optionally substituted with i.amino-Ci-C6-alkyl wherein amino is selected from -NH2, -NHCi-Cβalkyl or
-N(Ci-C6-alkyl)2, and the two substituents Ci-Cβ-alkyl may form a 3 to 8- membered heterocacloalkyl with the N to which they are attached to and wherein the heterocycloalkyl is optionally substituted with Ci-Cβ-alkyl, or ii.5 or 6-membered heterocycloalkyl- Ci-Cβ-alkyl; and c. pyridinyl optionally substituted with at least one of the following groups i. Ci-Cβ-alkyl optionally substituted with a 5 or 6-membered heterocycloalkyl having at least one heteroatom selected from O and N, ii. 5 or 6-membered heterocycloalkyl having at least one heteroatom selected from O and N, iii. -NH-(5-membered heteroaryl-Ci-Cβ-alkyl having as heteroatom O), iv. 5 or 6-membered heterocycloalkyl-Ci-Cβ-alkyl having at least one heteroatom selected from O and N.
12. A triazolopyridine compound according to claim 11 wherein R2 is selected from a. phenyl optionally substituted with i.at least one unsubstituted d-Cβ-alkyl, ii.unsubstituted Ci-Cβ-alkoxy, iii.fluoro, iv. bromo, v. hydroxy, vi. cyano or vii. -NH2; b.furanyl; and c.thienyl;
R5 is selected from a. unsubstituted Ci-Cδ-alkyl; b. phenyl optionally substituted with i.amino-Ci-C6-alkyl wherein amino is selected from -NH2, or
-N(Ci-C6-alkyl)2, or ii. 5 or 6-membered heterocycloalkyl- Ci-Cδ-alkyl; c. pyridinyl optionally substituted with at least one of the following groups i. Ci-Cδ-alkyl optionally substituted with a 5 or 6-membered heterocycloalkyl having at least one heteroatom selected from O and N, ii. 5 or 6-membered heterocycloalkyl having at least one heteroatom selected from O and N, iii. -NH-(5-membered heteroaryl-Ci-Cδ-alkyl having as heteroatom O), iv. 5 or 6-membered heterocycloalkyl-Ci-Cδ-alkyl having at least one heteroatom selected from O and N..
13. A triazolopyridine compound according to claim 1 of the following Formula 1-6
Figure imgf000167_0001
Formula 1-6
wherein
R4 is furanyl;
R5 is selected from unsubstituted phenyl; and 5 or 6-membered heteroaryl having a heteroatom selected from N, S and O.
14. A triazolopyridine compound according to claim 13 wherein
R5 is selected from unsubstituted phenyl and 5-membered heteroaryl having a heteroatom selected from N, S and O.
5. The triazolopyridine compounds according to any of the preceding claims, selected from the following group:
N-[5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-2-phenylacetamide; N-[5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide; N-[5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-4-(trifluoromethyl)benzamide; ethyl 3-{[5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]amino}-3-oxopropanoate; N-[5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-2-methoxyacetamide; 6-chloro-N-[5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide; methyl 4- {[5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]amino}-4-oxobutanoate; 2-(benzyloxy)-N-[5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]acetamide; 3-methoxy-N-[5-(lH-pyrrol-2-yl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]benzamide; N-[5-(lH-pyrrol-2-yl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]cyclopentanecarboxamide; N-[5-(lH-pyrrol-2-yl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]benzamide; N-[5-(lH-pyrazol-4-yl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]benzamide; N-[5-(lH-pyrrol-2-yl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide; N-[5-(2-furyl)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]benzamide; N-[6-(3-fluorophenyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide; N-(6-phenyl[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl)nicotinamide; N-[6-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide; N-[6-(3-thienyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide; N-[5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-3-methoxybenzamide; N-[5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-2-(2-thienyl)acetamide; N-[5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]cyclopentanecarboxamide; N-[5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-4-methoxybenzamide; N-[5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]isonicotinamide; N-[5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]quinoxaline-6-carboxamide; N-[6-(3-methoxyphenyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide; N-[6-(3-aminophenyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide; N-[6-(3-cyanophenyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide; N-[5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]isoxazole-5-carboxamide; N-[5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-2,3-dihydro-l,4-benzodioxine-6- carboxamide; N- [5 -(cyclopropylamino) [ 1 ,2 ,4]triazo Io [ 1 ,5 -a]pyridin-2-yl]nicotinamide; N-(5-pyrrolidin-l-yl[l,2,4]triazolo[l,5-a]pyridin-2-yl)nicotinamide;
N-[5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-3,5-dimethoxybenzamide;
N-[5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]biphenyl-4-carboxamide;
1 -(4-chlorophenyl)-N-[5-(3-furyl)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2- yl] cyclopentanecarboxamide;
N-[5-(3-flιryl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-2,3-dihydro-l-benzoflιran-5- carboxamide;
N-[5-(3-mryl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-3-furamide;
1 -acetyl-N-[5-(3-flιryl)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]piperidine-4-carboxamide;
2,2-difluoro-N-[5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-l,3-benzodioxole-4- carboxamide;
N-[5-(3-thienyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide;
N-[1 ,2,4]triazolo[ 1 ,5-a]quinolin-2-ylnicotinamide;
N-[5-(cyclopentylamino)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]benzamide;
N-[5-(3-flιryl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide 1-oxide;
N-{5-[(3-methoxypropyl)amino][l,2,4]triazolo[l,5-a]pyridin-2-yl}benzamide;
N-{5-[(2-furylmethyl)amino][l,2,4]triazolo[l,5-a]pyridin-2-yl}benzamide;
N-{5-[(tetrahydrofuran-2-ylmethyl)amino][l,2,4]triazolo[l,5-a]pyridin-2- yl}benzamide;
3-(acetylamino)-N-[5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]benzamide;
N-[5-(cyclohexylamino)[l,2,4]triazolo[l,5-a]pyridin-2-yl]benzamide;
N-[5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-3-(methylsulfonyl)benzamide;
3-(aminomethyl)-N-[5-(3-flιryl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]benzamide;
N-(5 - { [ 1 -(hydroxymethyl)propyl] amino } [ 1 ,2,4]triazolo [ 1 ,5 -a]pyridin-2-yl)benzamide;
N-[6-(3-hydroxyphenyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]benzamide; tert-butyl[4-({[5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2- yl] amino } carbonyl)benzyl] carbamate;
N-[5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-4-isobutylbenzamide; tert-butyl[4-({[5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2- yl] amino } carbonyl)phenoxy] acetate;
4-butyl-N-[5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]benzamide;
N-[6-(4-hydroxy-3-methoxyphenyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]benzamide hydrochloride;
N-{5-[(2-methoxyethyl)amino][l,2,4]triazolo[l,5-a]pyridin-2-yl}benzamide; N-{5-[(2,3-dihydroxypropyl)amino][l,2,4]triazolo[l,5-a]pyridin-2-yl}benzamide;
N-[6-(2,3-dihydro- 1 -benzofuran-5-yl)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]benzamide;
N-[5-(benzylamino)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide;
N-[5-(cycloheptylamino)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]nicotinamide dihydrochloride;
N-[5-(cyclohexylamino)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide;
N-(5- {[(5-methyl-2-furyl)methyl]amino} [1 ,2,4]triazolo[l ,5-a]pyridin-2- yl)nicotinamide;
N-{5-[(tetrahydrofuran-2-ylmethyl)amino][l,2,4]triazolo[l,5-a]pyridin-2- yl}nicotinamide;
N-[6-(4-hydroxyphenyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]benzamide;
N-[6-(4-hydroxy-3-methoxyphenyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide hydrochloride;
N-[5-(cyclooctylamino)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]nicotinamide;
N-{5-[cyclohexyl(methyl)amino][l,2,4]triazolo[l,5-a]pyridin-2-yl}nicotinamide;
N-[5-(tetrahydro-2H-pyran-4-ylamino)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide;
N-{5-[(l-methylpiperidin-4-yl)amino][l,2,4]triazolo[l,5-a]pyridin-2-yl}nicotinamide;
N-{5-[(3-aminocyclohexyl)amino][l,2,4]triazolo[l,5-a]pyridin-2-yl}benzamide;
N-{5-[(l-methylpiperidin-4-yl)amino][l,2,4]triazolo[l,5-a]pyridin-2-yl}benzamide;
N-[5-(cyclopropylamino)-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2- yl]nicotinamide;
N-[5-(cyclohexylamino)-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2- yl]nicotinamide;
N-[5-(cycloheptylamino)-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2- yl]nicotinamide;
N- [5 -(cyclopentylamino)-7-(trifluoromethyl) [ 1 ,2,4]triazo Io [ 1 ,5 -a]pyridin-2- yl]nicotinamide;
N-[5-[(cyclohexylmethyl)amino]-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2- yl]nicotinamide;
N-(6-bromo-5-methyl[l,2,4]triazolo[l,5-a]pyridin-2-yl)nicotinamide;
N- {5-[(3-hydroxycyclohexyl)amino] [1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl}nicotinamide;
N- {5-[(4-tert-butylcyclohexyl)amino] [1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl}nicotinamide;
N-[5-(tetrahydro-2H-pyran-3-ylamino)[l,2,4]triazolo[l,5-a]pyridin-2-yl]benzamide; N-[5-(cycloheptylamino)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]-4-(morpholin-4- ylmethyl)benzamide;
N-[5-(cyclohexylthio)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]nicotinamide;
N-{5-[(trans-4-hydroxycyclohexyl)amino][l,2,4]triazolo[l,5-a]pyridin-2- yl}nicotinamide;
N-[5-(cyclobutylamino)-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2- yl]nicotinamide;
N-[5-(cyclohexylamino)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-6-morpholin-4- ylnicotinamide;
N-[5-(cyclohexylamino)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-4-
[(dimethylamino)methyl]benzamide;
N-[5-(cyclohexylamino)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-3-(morpholin-4- ylmethyl)benzamide;
N-[5-[(cyclopropylmethyl)amino]-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2- yl]nicotinamide; methyltrans-4- { [2- [(pyridin-3 -ylcarbonyl)amino] -7-
(trifluoromethyl)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-5-yl]amino} cyclohexanecarboxylate;
N-[5-{[(lRS,2RS)-2-(hydroxymethyl)cyclohexyl]amino}-7-
(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide;
N-[6-bromo-5-(cyclohexylamino)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide;
N-[5-(cycloheptylamino)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]tetrahydro-2H-pyran-4- carboxamide;
N-[5-(2-methylprop- 1 -en- 1 -yl)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]nicotinamide dihydrochloride;
N-(3-oxo-3-{[5-(lH-pyrazol-l-yl)[l,2,4]triazolo[l,5-a]pyridin-2- yl] amino } propyl)benzamide;
N-(3- {[5-(3-furyl)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]amino} -3-oxopropyl)benzamide;
N-(3- {[5-(2-furyl)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]amino} -3-oxopropyl)benzamide;
N-(3-{[5-(cyclohexylamino)[l,2,4]triazolo[l,5-a]pyridin-2-yl]amino}-3- oxopropyl)benzamide;
N- [5 -(isopropylamino)-7-(trifluoromethyl) [ 1 ,2,4]triazo Io [ 1 ,5 -a]pyridin-2- yl]nicotinamide;
N- [5 -(sec-butylamino)-7-(trifluoromethyl) [ 1 ,2,4]triazo Io [ 1 ,5 -a]pyridin-2- yl]nicotinamide; N-[5-(methylamino)-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2- yl]nicotinamide;
N-[8-(3-furyl)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]benzamide; N-[5-(cyclohexyloxy)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]-2-(3- methoxyphenyl)acetamide;
N-[5-(cyclohexyloxy)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]nicotinamide; N-[5-(cyclohexylamino)[ 1 ,2,4]triazolo[l ,5-a]pyridin-2-yl]-6-(2-pyrrolidin- 1 - ylethyl)nicotinamide;
N-[5-(cyclohexylamino)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-6-(morpholin-4- ylmethyl)nicotinamide;
N-[5-(3-furyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]cyclopropanecarboxamide; N-[5-(3-thienyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]benzamide; N-[5-(3-furyl)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]benzamide; N-[5-(3-furyl)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]benzamide; N-[6-(4-hydroxy-3-methoxyphenyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]acetamide; N- [6-(4-hydroxy-3 ,5 -dimethylphenyl) [ 1 ,2,4]triazo Io [ 1 ,5 -a]pyridin-2-yl]nicotinamide; 4-[2-(benzoylamino)[l,2,4]triazolo[l,5-a]pyridin-6-yl]-N-[2- (dimethylamino)ethyl]benzamide;
N-[6-(lH-pyrazol-4-yl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]benzamide; N-{5-[(cyclohexylmethyl)amino][l,2,4]triazolo[l,5-a]pyridin-2-yl}nicotinamide; N- {5-[(4-hydroxycyclohexyl)amino] [1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl} -3- methoxybenzamide;
N-[5-(cyclopentylamino)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]-2-furamide; N-[7-chloro-5-(cyclobutylamino)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide; N-[7-chloro-5-(cyclopentylamino)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]nicotinamide; N-[7-chloro-5-(cyclohexylamino)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide; N-[5-(sec-butylamino)-7-chloro[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]nicotinamide; N- [7-chloro-5 -(cyclopropylamino) [ 1 ,2 ,4]triazo Io [ 1 ,5 -a]pyridin-2-yl]nicotinamide; N- [5 - [(2-methoxyethyl)amino] -7-(trifluoromethyl) [ 1 ,2,4]triazo Io [ 1 ,5 -a]pyridin-2- yl]nicotinamide;
N-[5-[(3-hydroxypropyl)amino]-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2- yl]nicotinamide;
N- [5 - [(2-hydroxyethyl)amino] -7-(trifluoromethyl)[ 1 ,2,4]triazo Io [ 1 ,5 -a]pyridin-2- yl]nicotinamide; N- [5 -(dimethylamino)-7-(trifluoromethyl) [ 1 ,2,4]triazolo [ 1 ,5 -a]pyridin-2- yl]nicotinamide;
N-[5-(cyclohexylamino)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-2-pyridin-3-ylacetamide;
N-[5-(cyclohexylamino)[ 1 ,2,4]triazolo[l ,5-a]pyridin-2-yl]-4-(piperidin- 1 - ylmethyl)benzamide;
N-[5-(cyclohexylamino)[ 1 ,2,4]triazolo[l ,5-a]pyridin-2-yl]-4-(pyrrolidin- 1 - ylmethyl)benzamide;
N-[5-(cyclohexylamino)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-4-{[(2- methoxyethyl)(methyl)amino]methyl}benzamide;
N-[5-(cyclohexylamino)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-6-methylnicotinamide;
N-[5-(cyclohexylamino)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-6-[(3- hydroxypropyl)amino]nicotinamide;
N-[5-(cyclohexylamino)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-6-[(2- furylmethyl)amino]nicotinamide;
N-[5-(cyclohexylamino)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide 1 -oxide;
N- [5 -(isopropylamino)-7-(trifluoromethyl) [ 1 ,2,4]triazo Io [ 1 ,5 -a]pyridin-2-yl] -2- pyridin-3 -ylacetamide trihydrochloride;
N- [5 - [( 1 -ethylpropyl)amino] -7-(trifluoromethyl) [ 1 ,2,4]triazo Io [ 1 ,5 -a]pyridin-2- yl]nicotinamide;
N- [5 -(isopropylamino)-7-(trifluoromethyl) [ 1 ,2,4]triazo Io [ 1 ,5 -a]pyridin-2- yl]nicotinamide 1 -oxide;
N-[5-[(3-hydroxycyclohexyl)amino]-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-
2-yl]nicotinamide formic acid;
N-{7-chloro-5-[(3-hydroxycyclohexyl)amino][l,2,4]triazolo[l,5-a]pyridin-2- yl} nicotinamide formic acid;
N-[5-(cyclopropylamino)-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-4-
[(dimethylamino)methyl]benzamide;
N-[5-(cyclopropylamino)-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-4-[(2- oxopyrrolidin- 1 -yl)methyl]benzamide;
N-[5-(cyclopropylamino)-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-6- pyrrolidin- 1 -ylnicotinamide;
N-[5-(cyclopropylamino)-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-6- methylnicotinamide; N-[6-(4-hydroxy-3-methoxyphenyl)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]-4-(piperidin- 1 - ylmethyl)benzamide;
N-[6-(4-hydroxy-3-methoxyphenyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-6- methylnicotinamide;
N-[6-(4-hydroxy-3-methoxyphenyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-4-[(2- oxopyrrolidin- 1 -yl)methyl]benzamide;
4-[(dimethylamino)methyl]-N-[6-(4-hydroxy-3-methoxyphenyl)[l,2,4]triazolo[l,5- a]pyridin-2-yl]benzamide;
N- [5 - { [( 1 R,2S)-2-(hydroxymethyl)cyclohexyl] amino } -7-
(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide hydrochloride;
N-[5-(cyclopropylamino)-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-4-[(4- hydroxypiperidin- 1 -yl)methyl]benzamide;
N-[5-(cyclopropylamino)-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-4-
(pyrrolidin- 1 -ylmethyl)benzamide;
N-[5-(cyclopropylamino)-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-6-(4- hydroxypiperidin- 1 -yl)nicotinamide;
N-[5-(cyclopropylamino)-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-6- piperazin- 1 -ylnicotinamide;
N-[5-(cyclopropylamino)-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-6-
(dimethylamino)nicotinamide;
N-[6-bromo-5-(cyclopentylamino)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-6-morpholin-4- ylnicotinamide;
N-[5-(cyclopropylamino)-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-6- morpholin-4-ylnicotinamide;
N-[5-(cyclohexylamino)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]-6-
(dimethylamino)nicotinamide; tert-butyl 4-[5-({[5-(cyclopropylamino)-7-(trifluoromethyl)[l,2,4]triazolo[l,5- a]pyridin-2-yl]amino} carbonyl)pyridin-2-yl]piperazine- 1 -carboxylate;
N-[5-(cyclohexylamino)[ 1 ,2,4]triazolo[l ,5-a]pyridin-2-yl]-4-[(4-hydroxypiperidin- 1 - yl)methyl]benzamide;
N-[5-(cyclohexylamino)[ 1 ,2,4]triazolo[l ,5-a]pyridin-2-yl]-6-(4-fluoropiperidin- 1 - yl)nicotinamide;
N-[5-(cyclohexylamino)[l,2,4]triazolo[l,5-a]pyridin-2-yl]-6-(lH-pyrazol-l- yl)nicotinamide; tert-butyl 4-[5-( {[5-(cyclohexylamino)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2- yljamino} carbonyl)pyridin-2-yl]piperazine- 1 -carboxylate;
N- [5 -(cyclopropylamino)-7-(trifluoromethyl)[ 1 ,2,4]triazo Io [ 1 ,5 -a]pyridin-2-yl] -6- [(3 - hydroxypropyl)amino]nicotinamide;
N- [5 -(isopropylamino)-7-(trifluoromethyl) [ 1 ,2,4]triazo Io [ 1 ,5 -a]pyridin-2-yl] -6-
(morpholin-4-ylmethyl)nicotinamide;
N- [5 - [(pyrro lidin-3 -ylmethyl)amino] -7-(trifluoromethyl)[ 1 ,2,4]triazo Io [ 1 ,5-a]pyridin-
2-yl]nicotinamide;
N-[5-(cyclohexylamino)[ 1 ,2,4]triazolo[l ,5-a]pyridin-2-yl]-4-(piperazin- 1 - ylmethyl)benzamide;
N-[5-(cyclohexylamino)[ 1 ,2,4]triazolo[l ,5-a]pyridin-2-yl]-4-[(4-formylpiperazin- 1 - yl)methyl]benzamide;
N-[5-(piperidin-3-ylamino)-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2- yl]nicotinamide;
N-[5-(sec-butylamino)-7-chloro[l,2,4]triazolo[l,5-a]pyridin-2-yl]-6-[(2- methoxyethyl)(methyl)amino]nicotinamide;
N-[5-(sec-butylamino)-7-chloro[l,2,4]triazolo[l,5-a]pyridin-2-yl]-6-[(3- hydroxypropyl)amino]nicotinamide;
N-[5-(sec-butylamino)-7-chloro[l,2,4]triazolo[l,5-a]pyridin-2-yl]-6-morpholin-4- ylnicotinamide;
N-[5-(sec-butylamino)-7-chloro[l,2,4]triazolo[l,5-a]pyridin-2-yl]-4-{[(2- methoxyethyl)(methyl)amino]methyl}benzamide;
N-[5-(sec-butylamino)-7-chloro[l,2,4]triazolo[l,5-a]pyridin-2-yl]-6- methylnicotinamide;
N-[7-chloro-5-(isopropylamino)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide;
N- [5 - [(3 -isopropoxyphenyl)amino] -7-(trifluoromethyl) [ 1 ,2,4]triazolo [ 1 ,5 -a]pyridin-2- yl]nicotinamide;
N- [5 - [(3 -fluoro-4-methoxyphenyl)amino] -7-(trifluoromethyl)[ 1 ,2,4]triazo Io [ 1 ,5 - a]pyridin-2-yl]nicotinamide;
N-[5-{[3-(benzyloxy)phenyl]amino}-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-
2-yl]nicotinamide;
N-[5-(sec-butylamino)-7-chloro[l,2,4]triazolo[l,5-a]pyridin-2-yl]-4-(morpholin-4- ylmethyl)benzamide; N-[5-(isopropylamino)-7-(trifluoromethyl)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]-6- methylnicotinamide;
6-chloro-N-[5-(isopropylamino)-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2- yl]nicotinamide;
6- [(2-aminoethyl)amino] -N- [5 -(isopropylamino)-7-
(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide;
N-[5-(sec-butylamino)-7-methyl[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide;
N-[5-(isopropylamino)-7-methyl[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide.
16. A triazolopyridine intermediate compound selected from 5-(3-thienyl)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-amine; 5-(3-furyl)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-amine; 5-bromo[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-amine; 5-chloro[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-amine; 6-bromo[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-amine; tert-butyl 2-(2-amino[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-5-yl)- lH-pyrrole- 1 -carboxylate; 5-chloro-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2-amine; 6-bromo-5-methyl[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-amine; N5-cyclohexyl[ 1 ,2,4]triazolo[ 1 ,5-a]pyridine-2,5-diamine; N5-cycloheptyl[ 1 ,2,4]triazolo[ 1 ,5-a]pyridine-2,5-diamine; 5-(cyclohexyloxy)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-amine; 5-(lH-pyrazol-l-yl)[l,2,4]triazolo[l,5-a]pyridin-2-amine; [ 1 ,2,4]triazolo[ 1 ,5-a]quinolin-2-amine;
6-bromo-N5-cyclohexyl[l,2,4]triazolo[l,5-a]pyridine-2,5-diamine; 6-bromo-N5-cyclohexyl[l,2,4]triazolo[l,5-a]pyridine-2,5-diamine; 5-(2-furyl)[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-amine;
N5-isopropyl-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridine-2,5-diamine; N-(5-bromo[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl)benzamide; N-(5-bromo[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl)nicotinamide; N-(5-chloro[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl)benzamide; N-(5-chloro[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl)nicotinamide; N-(6-bromo[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl)benzamide; N-(6-bromo [ 1 ,2,4]triazolo [ 1 ,5-a]pyridin-2-yl)nicotinamide hydrochloride; N-[5-chloro-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide; 4-(chloromethyl)-N-[5-(cyclohexylamino)[l,2,4]triazolo[l,5-a]pyridin-2- yljbenzamide;
N-(8-bromo[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl)benzamide;
N-(5,7-dichloro[l,2,4]triazolo[l,5-a]pyridin-2-yl)nicotinamide;
6-chloro-N-[5-(cyclohexylamino)[l,2,4]triazolo[l,5-a]pyridin-2-yl]nicotinamide;
N--cyclopropyl-7-(trifluoromethyl)[l,2,4]triazolo[l,5-a]pyridine-2,5-diamine;
5-chloro-7-methyl[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-amine;
N-(5-chloro-7-methyl[l,2,4]triazolo[l,5-a]pyridin-2-yl)nicotinamide.
17. The triazolopyridine compounds according to any one of claims 1 - 15 for use as a medicament.
18. A method for the prevention and/or treatment of autoimmune diseases, inflammatory diseases, cardiovascular diseases and/or neurodegenerative diseases in a subject, comprising administering to the subject an effective amount of a compound according to any of claims 1 - 15.
19. A pharmaceutical composition containing at least one triazolopyridine amide compound according to any of claims 1 - 15 and a pharmaceutically acceptable carrier, diluent or excipient thereof.
20. A process for the preparation of a triazolopyridine compound according to formula (I), comprising the step of reacting a compound of Formula (II) with an (acylating) agent of Formulas (Ilia or IHb) in a presence of a base and/or a coupling agent:
Figure imgf000177_0001
(II) (i)
(MIa) LG : OH (MIb) LG : Cl wherein R1, R2, R3, R4 ,Rs are as defined in any of the preceding claims, wherein the base is selected from tertiary amine bases such as DIEA, TEA, NMM or pyridine, and the coupling agent is selected from a peptide coupling agent such as DCC, HATU, EDC/HOBt, i-butylchloro formate, carbonyl diimidazole, Mukaiyama's reagent in a suitable solvent such as DCM or CH3CN; and optionally further purifying the obtained compound.
21. A process for the preparation of a triazolopyridine compound according to formula (I), comprising
A) reacting a compound of Formula (Ib) wherein least one of Ri, R2, R3, R4 is a group X selected from halogen such as Br, Cl, I or a sulfonate ester such as OTf, with a boronic agent of formula (IVa) or ester (IVb) wherein R'i is an aryl or heteroaryl as above defined in the presence of a base such as K2CO3, K3PO4 and a catalytic amount of a palladium catalyst such as PdCl2(PPhS)2 or Pd(OAc)2 with a ligand such as DPPF in an appropriate solvent such as DMF or a combination of water with THF or dioxane
or
B) the step of reacting a compound of Formula (Id) wherein Ri is selected from Cl, Br, I, OMs, OTf with a secondary amine NHR6R7 of formula (V) wherein Ri in formula (Id) and the solvent is the secondary amine itself or a polar solvent such as ethanol or butanol
Pd catalyst
Figure imgf000179_0001
(V)
and optionally further purifying the obtained compound.
22. A process for the preparation of a triazolopyridine compound according to formula (Ha) wherein Ri is a group NR6Ry, comprising the step of reacting a triazolopyridine compound of Formula (lib) wherein Rl is a group selected from F, Cl, Br, OMs, OTf with a secondary amine NHR6R7 of formula (V) in an appropriate solvent which is a secondary amine itself or a polar solvent such as ethanol or butanol and optionally further purifying the obtained compound
Figure imgf000179_0002
(lib) (V) (Ha)
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