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HK1207078B - Inhibition of enzymes - Google Patents

Inhibition of enzymes Download PDF

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Publication number
HK1207078B
HK1207078B HK15107783.9A HK15107783A HK1207078B HK 1207078 B HK1207078 B HK 1207078B HK 15107783 A HK15107783 A HK 15107783A HK 1207078 B HK1207078 B HK 1207078B
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HK
Hong Kong
Prior art keywords
phenyl
methyl
trifluoromethyl
pyridin
triazolo
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HK15107783.9A
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Chinese (zh)
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HK1207078A1 (en
Inventor
C‧卡帕蒂
R‧A‧希尔德
N‧C‧瑞
J‧M‧萨顿
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奇斯药制品公司
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Priority claimed from PCT/EP2013/064603 external-priority patent/WO2014009425A1/en
Publication of HK1207078A1 publication Critical patent/HK1207078A1/en
Publication of HK1207078B publication Critical patent/HK1207078B/en

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Description

inhibition of enzymes
Technical Field
The present invention relates to heterocyclic compounds which are pyridine derivatives having human neutrophil elastase (human neutrophil elastase) inhibitory properties and their use in therapy.
Background
Human Neutrophil Elastase (HNE) is a 32kDa serine proteolytic enzyme found in the azurophilic granules of neutrophils. It plays a role in the degradation of a variety of extracellular Matrix proteins including fibronectin, laminin, proteoglycans, collagen types III and IV and elastin (Bieth, G. see Regulation of Matrix administration, Mecham, R.P (Eds.), Academic Press, NY, USA1986, 217-. HNE has long been thought to play an important role in homeostasis, which is achieved by degrading tissue structural proteins, thereby repairing and treating damaged tissues. By degrading the bacterial body, it also plays a role in defense against bacterial infection. In addition to its effect on stromal tissue, HNE has been implicated in the upregulation of IL-8 gene expression and also induces the release of IL-8 by lung epithelial cells. Small molecule inhibitors and protein inhibitors of HNE inhibit inflammatory responses and the development of emphysema (emphysema) in animal models of tobacco smoke exposure-induced chronic obstructive pulmonary disease (Wright, J.L. et al, am.J.Respir.crit.Care Med.2002,166, 954-960; Churg, A. et al, am.J.Respir.crit.Cared.2003, 168, 199-207). Thus, HNE may play a role in matrix destruction and in amplifying the inflammatory response of chronic respiratory diseases (where neutrophil influx is a characteristic feature). Indeed, HNE is thought to play a role in severe lung diseases including Chronic Obstructive Pulmonary Disease (COPD), Cystic Fibrosis (CF), Acute Respiratory Distress Syndrome (ARDS), pulmonary emphysema, pneumonia and pulmonary fibrosis. It is also implicated in several cardiovascular diseases in which tissue remodeling is involved, e.g., heart failure and the development of ischemic tissue injury following acute myocardial infarction.
COPD is a comprehensive (umbrella) term that includes 3 different pathological states that all contribute to airflow limitation, chronic bronchitis, emphysema and small airway disease, in general, all 3 will be present to varying degrees in patients presenting with COPD, all 3 likely due to neutrophil-mediated inflammation, supported by the increased number of neutrophils observed in bronchoalveolar leakage (BAL) fluid of COPD patients (Thompson, A.B.; Daughton, D.; et al am. Rev. Respir. Dis.1989,140, 1527-1537.) it has long been recognized that the primary pathogenic determinant of COPD is the protease-anti-protease balance (also known as the "elastase: anti-elastase hypothesis"), where HNE and endogenous anti-proteases (such as α 1-antitrypsin (α)1Individuals with genetic defects in the protease inhibitor α 1-antitrypsin develop emphysema, whose severity increases over time (Laurrell, c.b.; Erikkson, sscard.j. clin.invest.196315, 132-140.) thus, excessive HNE is destructive, leading to destruction of lung morphology, loss of elasticity and destruction of alveolar attachment of airways in the lung (anchorage) (emphysema), while increasing microvascular permeability and mucus hypersecretion (chronic bronchitis).
Disclosure of Invention
The present invention provides novel compounds that are inhibitors of HNE and are useful in the treatment of diseases or conditions in which HNE activity plays a role.
Detailed Description
In one embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof:
wherein
R1Selected from the group consisting of halogen, -CN, -OH and the group (C)1-C4) An alkyl group;
R2selected from halogen, (C)1-C4) Alkyl, (C)1-C4) Haloalkyl, -CN, (C)1-C4) Alkoxy group, (C)1-C4) Haloalkoxy, nitro and the group-OH;
w is (i) a 5,6 membered heteroaryl ring, optionally substituted with one or two groups independently selected from: halogen, -OH, (C)1-C4) Alkyl, (C)1-C4) Haloalkyl, -CN, (C)1-C4) Alkoxy, nitro, radicals-NHR18A group-COOR28group-COR29And the group-CONHR19；(ii)(C5-C6) A heterocycloalkyl ring which is partially unsaturated and optionally substituted with one or two groups independently selected from: halogen, (C)1-C4) Alkyl, (C)1-C4) Haloalkyl, -CN, -OH, (C)1-C4) Alkoxy, nitro, carbonyl, a group-NHR18And the group-CONHR19(ii) a Or (iii) phenyl, optionally substituted with one or two groups independently selected from: halogen, (C)1-C4) Alkyl, (C)1-C4) Haloalkyl, -CN, nitro, group-NHR18group-CONHR19And a group-OR20；
R18Is hydrogen, (C)1-C4) Alkyl, radical-SO2R21Or a group (C)1-C4) An alkylcarbonyl group;
R21is (C)1-C4) An alkyl group;
R19is hydrogen or (C)1-C4) An alkyl group;
R20is hydrogen, (C)1-C4) Alkyl or a radical- (C)1-C4) alkylene-OR22；
R22Is hydrogen or (C)1-C4) An alkyl group;
R3is a group-CH2-R23；
R23Is a group selected from: hydrogen, (C)1-C4) Alkyl, (C)1-C4) Haloalkyl, -CN, (C)1-C4) Alkoxy and halogen;
R5is a group selected from: hydrogen, (C)1-C4) Alkyl, (C)1-C4) Haloalkyl, -CN, (C)1-C4) Alkoxy and halogen;
R6selected from hydrogen, halogen, (C)1-C4) Alkyl and CN;
A1is a group-CR7Or a group-N ═ or;
A2is a radical ═ CR8-or a group ═ N-;
R7selected from hydrogen, halogen, (C)1-C4) Alkyl, (C)1-C4) Haloalkyl and (C)1-C4) An alkoxy group;
R8selected from hydrogen, halogen, (C)1-C4) Alkyl, (C)1-C4) Haloalkyl, (C)1-C4) Alkoxy, radical-S (C)1-C4) Alkyl and group-SO2(C1-C4) An alkyl group;
wherein A is1And A2May not be simultaneously a group-N ═ N;
A3--A4is a moiety selected from: group-CR4-N-group-CR4＝CR9And the group-NR17-CO-；
R9Is hydrogen or (C)1-C4) An alkyl group;
R4is a group selected from: hydrogen, (C)1-C4) Alkyl, -NR10R11、-NHCOR12、-NHCOO-R13、-NHCONR27-R14、(C1-C4) Alkoxy, -NH (CH)2)n-SO2(C1-C4) Alkyl, - (NH)q(CH2)n-(C6H6)-SO2(C1-C4) Alkyl, -NHSO2(C1-C4) Alkyl and- (NH)r(CH2)nCONR15R16；
R17Is a group selected from: hydrogen, (C)1-C4) Alkyl, - (CH)2)n-(C6H6)-SO2(C1-C4) Alkyl, - (CH)2)n-SO2(C1-C4) Alkyl and- (CH)2)nCONR15R16；
n is 0 or an integer in the range of 1 to 5;
q is 0 or 1;
r is 0 or 1;
R10is hydrogen, a radical (C)1-C6) Alkyl, radical (C)1-C6) Hydroxyalkyl radical, radical (C)1-C4) alkylene-NH- (C ═ N)H)-NH2Group (C)1-C6) Alkylene radical NRaRbGroup (C)1-C6) Alkylene radical NRaRdOr a group (C)1-C6) Alkylene radical N+RaRbRc；
R11Is hydrogen, a radical (C)1-C6) Alkyl, radical (C)1-C6) Hydroxyalkyl radical, radical (C)1-C4) alkylene-NH- (C ═ NH) -NH2Group (C)1-C6) Alkylene radical NRaRbOr a group (C)1-C6) Alkylene radical N+RaRbRc；
Or R10And R11Together with the nitrogen atom to which they are attached may form (C)5-C7) A heterocycloalkyl group;
Raand RbIndependently at each occurrence, is hydrogen, (C)1-C4) Alkyl group of (C)1-C4) The alkyl group may optionally be substituted by a group-COOR30Substituted or by radicals (C)5-C7) Heterocycloalkyl, radical (C)5-C7) Heterocycloalkyl, radical (C)1-C6) Alkylene radical NReRfOr a group (C)1-C6) Alkylene radical N+ReRfRgSubstitution; alternatively, RaAnd RbTogether with the nitrogen atom to which they are attached may form a group C optionally substituted by one or more groups1-C6Alkyl substituted (C)5-C7) A heterocycloalkyl ring system, and said (C)5-C7) Heterocycloalkyl optionally containing the group-S (O) -or-S (O)2Or a further heteroatom being oxygen, sulfur or nitrogen, said nitrogen atom being optionally substituted by (C)1-C6) Alkyl substitution;
or RaAs defined above, and RbAttached to a radical (C)1-C6) One carbon atom of an alkylene moiety, said groups and their useLinked nitrogen to form saturated (C)5-C6) A heterocycloalkyl ring;
Ra、Rband RcIf present at the same time, (C) is independently present at each occurrence1-C4) Alkyl group of (C)1-C4) The alkyl group may optionally be substituted by a group-COOR30Substituted or by radicals (C)5-C7) Heterocycloalkyl, radical (C)5-C7) Heterocycloalkyl, radical (C)1-C6) Alkylene radical NReRfOr a group (C)1-C6) Alkylene radical N+ReRfRgSubstitution; alternatively, RaAnd RbOr RaAnd RcTogether with the nitrogen atom to which they are attached may form a group C optionally substituted by one or more groups1-C6Alkyl or-NHR24Substituted (C)5-C7) A heterocycloalkyl ring system, and said (C)5-C7) The heterocycloalkyl ring optionally containing the group-S (O) -or-S (O)2Or a further heteroatom being oxygen, sulfur or nitrogen, said nitrogen atom being optionally substituted by (C)1-C6) Alkyl substitution; or RaAnd RbAs defined above, and Rc(C) attached to said group1-C6) One carbon atom of the alkylene moiety, said group being linked to the nitrogen to which they are attached to form saturated (C)5-C6) A heterocycloalkyl ring;
Rdis (C)5-C7) A heterocycloalkyl group;
Reand RfIndependently at each occurrence is hydrogen or (C)1-C4) An alkyl group;
or Re、RfAnd RgIf present at the same time, is independently at each occurrence (C)1-C4) An alkyl group;
R12is selected from- (C)6H6)-SO2(C1-C4) Alkyl, (C)1-C6) Alkyl, (C)1-C4) Haloalkyl, (C)5-C7) Heterocycloalkyl, radical- (CH)2)n-S(O)t(C1-C4) Alkyl, radical- (CH)2)n-S(O)t(C1-C4) Alkyl radical NRaRbGroup- (CH)2)n-S(O)t(C1-C4) Alkyl radical N+RaRbRcGroup (C)1-C4) alkylene-NH- (C ═ NH) -NH2Group (C)1-C4) alkylene-CO2H. Group- (C)1-C4) alkylene-CO2NR25R26Group- (C)1-C4) alkylene-CO2NR25(C1-C6) Alkylene radical NRaRbGroup- (C)1-C4) alkylene-CO2NR25(C1-C6) Alkylene radical N+RaRbRcGroup- (C)1-C6) Alkylene radical NRaRbGroup- (C)1-C6) Alkylene radical N+RaRbRcAnd (C)1-C4) Alkyl radical (C)5-C7) Heterocycloalkyl, wherein such groups may be optionally substituted with one or two substituents selected from: (C)1-C4) Alkyl, hydroxy, halogen, -SO2(C1-C4) Alkyl, amino or (C)1-C4) An alkylamino group;
t may be 0,1 or 2;
R13is selected from the group consisting of6H6)-SO2Alkyl, (C)1-C6) Alkyl, (C)1-C4) Haloalkyl, (C)5-C7) Heterocycloalkyl, radical (C)1-C4) alkylene-NH- (C ═ NH) -NH2、(C1-C6) Alkylene radical NRaRb、-(C1-C6) AAlkyl radical N+RaRbRcAnd (C)1-C4) Alkylene (C)5-C7) Heterocycloalkyl, wherein such groups may be optionally substituted with one or two substituents selected from: (C)1-C4) Alkyl, (C)1-C4) Alkoxy, hydroxy, halogen, -SO2(C1-C4) Alkyl, amino or (C)1-C4) An alkylamino group;
R14is selected from (C)1-C4) Alkyl, - (C)6H6)-SO2Alkyl, (C)1-C4) Haloalkyl, (C)5-C7) Heterocycloalkyl, radical (C)1-C4) alkylene-NH- (C ═ NH) -NH2、(C1-C6) Alkylene radical NRaRb、-(C1-C6) Alkylene radical N+RaRbRcAnd (C)1-C4) Alkyl radical (C)5-C7) Heterocycloalkyl, wherein such groups may be optionally substituted with one or two substituents selected from: (C)1-C4) Alkyl, hydroxy, halogen, -SO2(C1-C4) Alkyl, amino, (C)1-C4) Alkylcarbonyl and (C)1-C4) An alkylamino group;
R15is hydrogen, a radical (C)1-C6) Alkyl, radical (C)1-C4) alkylene-NH- (C ═ NH) -NH2Group (C)1-C6) Alkylene radical NRaRbOr a group- (C)1-C6) Alkylene radical N+RaRbRc；
R16Is hydrogen, a radical (C)1-C6) Alkyl radical, radical (C)1-C4) alkylene-NH- (C ═ NH) -NH2Group (C)1-C6) Alkylene radical NRaRbOr a group- (C)1-C6) Alkylene radical N+RaRbRc；
Or R15And R16Together with the nitrogen atom to which they are attached may form (C)5-C7) A heterocycloalkyl group;
R24is hydrogen or (C)1-C4) An alkyl group;
R25is hydrogen or (C)1-C4) An alkyl group;
R26is hydrogen or (C)1-C4) An alkyl group;
R27is hydrogen or (C)1-C4) An alkyl group;
R28is hydrogen or (C)1-C4) An alkyl group;
R29is hydrogen or (C)1-C4) An alkyl group;
R30is hydrogen or (C)1-C4) An alkyl group;
wherein if one or more radicals- (C)1-C6) Alkylene radical N+RaRbRcWhen present, they form quaternary salts with pharmaceutically acceptable counterions;
and wherein the radical R18、R19、R20、R21、R22、R24、R25、R26、R27、R28、R29、R30、Ra、Rb、Rc、Rd、Re、Rf、RgAnd n, if present in more than one group, may have the same or different meaning at each occurrence.
The compounds of formula (I) above may be prepared in the form of their salts, in particular their pharmaceutically acceptable salts, N-oxides, hydrates and solvates. Any reference to a compound herein, or to "a compound of the invention", "a compound to which the invention relates", "a compound of formula (I)" and the like, includes such compounds (salt or non-salt forms), N-oxides, hydrates or solvate forms.
The compounds of the present invention may be used for the treatment or prevention of diseases in which HNE is implicated, such as Chronic Obstructive Pulmonary Disease (COPD), chronic bronchitis, pulmonary fibrosis, pneumonia, Acute Respiratory Distress Syndrome (ARDS), emphysema, smoking-induced emphysema, bronchiectasis, and cystic fibrosis.
Thus, other aspects of the invention are: (i) a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier or excipient; and (ii) the use of a compound of the invention for the manufacture of a medicament for the treatment or prevention of a disease or condition in which HNE is involved.
Term(s) for
The term "halogen atom" as used herein includes fluorine, chlorine, bromine and iodine, preferably chlorine.
The term "(C) as used herein1-Cx) Alkyl ", in case x is an integer greater than 1, denotes straight-chain and branched alkyl groups, wherein the number of constituent carbon atoms is in the range of 1 to x. Specific alkyl groups are methyl, ethyl, n-propyl, isopropyl and tert-butyl.
By analogy, the term "(C)1-Cx) Alkylene "represents divalent (C)1-Cx) Alkyl residue of which (C)1-Cx) Alkyl is as defined above.
Term "(C)1-Cx) Alkoxy ", in case x is an integer greater than 1, denotes straight and branched chain alkoxy groups, wherein the number of component carbon atoms is in the range of 1 to x. Specific alkoxy groups (alkyl) are methoxy, ethoxy, n-propoxy, isopropoxy and tert-butoxy.
Expression "(C)1-Cx) Haloalkyl "means as defined above" (C)1-Cx) An alkyl "group in which one or more hydrogen atoms are replaced by one or more halogen atoms, which may be the same or different from each other.
Thus, the (C)1-C6) Examples of the haloalkyl group may include a halogenated alkyl group, a polyhalogenated alkyl group and a perhalogenated alkyl group in which all hydrogen atoms are replaced with halogen atoms, such as a trifluoromethyl group or a difluoromethyl group.
Expression "(C)1-Cx) Haloalkoxy "represents the above-defined" (C)1-Cx) Alkoxy "groups in which one or more hydrogen atoms are replaced by one or more halogen atoms, which may be the same or different from each other.
Thus, the (C)1-C6) Examples of haloalkoxy groups may include halogenated, polyhalogenated and perhalogenated alkoxy groups in which all hydrogen atoms are replaced by halogen atoms, such as trifluoromethoxy groups.
Expression "(C)1-Cx) Hydroxyalkyl "represents the above-defined" (C)1-Cx) An alkyl "group in which one or more hydrogen atoms are replaced by one or more groups-OH.
Expression "(C)1-Cx) Alkylamino "denotes the radical" (C) defined above1-Cx) Alkyl "radicals in which one or more hydrogen atoms are replaced by one or more radicals-NH2And (4) replacing.
Term "(C)3-Cy) Cycloalkyl ", in the case where y is an integer greater than or equal to 3, denotes a saturated cyclic hydrocarbon group containing from 3 to y ring carbon atoms. Examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
Derived expression "(C)3-Cy) Heterocycloalkyl "denotes a saturated monocyclic ring (C)3-Cy) Cycloalkyl in which at least one ring carbon atom is replaced by a heteroatom such as N, NH, S or O. (C)3-Cy) Non-limiting examples of heterocycloalkyl groups are represented by pyrrolidinyl, thiazolidinyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, azetidinyl.
By analogy, the term "(C)3-Cy) Heterocyclylene-ene represents a divalent radical (C)3-Cy) A heterocycloalkyl residue of which (C)3-Cy) Heterocycloalkyl is as defined above.
Expression "(C)1-Cx) Alkylcarbonyl "denotes (C)1-Cx) Alkyl CO-group, wherein the group "(C)1-Cx) Alkyl "has the meaning defined above.
Expression "(C)3-Cy) Cycloalkylcarbonyl "represents (C)3-Cy) Cycloalkyl CO-group, wherein the group "(C)3-Cy) Cycloalkyl "has the meaning defined above.
Term "(C)2-C6) Alkenyl "means a straight or branched chain, conjugated or unconjugated carbon chain having one or more double bonds in the cis or trans configuration, wherein the numbered atoms are in the range of 2-6.
Term "(C)5-Cz) Cycloalkenyl ", in the case where z is an integer greater than or equal to 5, denotes a cyclic hydrocarbon radical containing from 5 to z ring carbon atoms and one or more double bonds.
Term "(C)2-C6) Alkynyl "means a straight or branched carbon chain having one or more triple bonds wherein the numbered atoms are in the range of 2 to 6.
Term "(C)3-Cy) Heterocycloalkyl (C)1-Cx) Alkyl "represents the above" (C)1-Cx) Alkyl "groups in which one or more hydrogen atoms are replaced by one or more" (C)3-Cy) Heterocycloalkyl "group substitution.
The expression "ring system" denotes a compound havingMonocyclic or bicyclic ring systems of 5 to 11 ring atoms, which may be saturated, partially unsaturated or unsaturated, such as aryl, (C)3-C8) Cycloalkyl group, (C)3-C7) Heterocycloalkyl or heteroaryl, in which at least one ring atom is a heteroatom (e.g., N, S or O).
The expression "aryl" denotes a monocyclic or bicyclic ring system having 6 to 10 ring atoms, wherein at least one ring is aromatic.
The expression "heteroaryl" denotes a monocyclic or bicyclic ring system having 5 to 11 ring atoms, wherein at least one ring is aromatic and wherein at least one ring atom is a heteroatom (e.g. N, NH, S or O).
Examples of suitable aryl or 5, 6-membered heteroaryl monocyclic systems include, for example, phenyl, thiophene, benzene, pyrrole, pyrazole, imidazole, iso-arylAzole,Oxazole, isothiazole, thiazole, pyridine, imidazolidine, furan residues, and the like.
Examples of suitable aryl or heteroaryl bicyclic ring systems include naphthalene, biphenylene, purine, pteridine, benzotriazole, quinoline, isoquinoline, indole, isoindole, benzothiophene, dihydrobenzodioxine, dihydrobenzodioxepine, benzoOxazine residues and the like.
Symbol "-C6H6- "denotes a divalent phenylene ring residue.
The term "salt" includes base addition salts and acid addition salts. The acidic compounds of the present invention may form salts (including pharmaceutically acceptable salts) with: bases, such as alkali metal hydroxides, e.g., sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide, barium hydroxide and magnesium hydroxide; organic bases such as N-methyl-D-glucamine (glucamine), choline tris (hydroxymethyl) amino-methane, L-arginine, L-lysine, N-ethylpiperidine, dibenzylamine and the like. Those compounds (I) which are basic may form salts (including pharmaceutically acceptable salts) with: inorganic acids, for example, hydrohalic acids such as hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid, and the like; organic acids such as acetic acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malic acid, salicylic acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, benzoic acid, benzenesulfonic acid, glutamic acid, lactic acid, mandelic acid and the like. Those compounds (I) having quaternary nitrogen may also form quaternary ammonium salts with pharmaceutically acceptable counter ions such as chloride, bromide, acetate, formate, p-toluenesulfonate, succinate, hemisuccinate, naphthalene-disulfonate, methanesulfonate, xinafoate (xinafoate), and the like.
Compounds of the present invention that contain one or more actual or potential stereocenters due to the presence of asymmetric carbon atoms may exist as a number of optical isomers (enantiomers, diastereomers, etc.) in which the R or S stereochemistry is located at each stereocenter. The present invention includes all such optical isomers (enantiomers, diastereomers, etc.) and mixtures thereof.
In one embodiment, the present invention provides a compound of formula (I)' or a pharmaceutically acceptable salt or solvate thereof:
wherein
R1Selected from the group consisting of halogen, -CN, -OH and the group (C)1-C4) An alkyl group;
R2selected from halogen, (C)1-C4) Alkyl, (C)1-C4) Haloalkyl, -CN, (C)1-C4) Alkoxy group, (C)1-C4) Haloalkoxy, nitro and the group-OH;
w is (i) a 5, 6-membered heteroaryl ring, optionally substituted with one or two groups independently selected from: halogen, -OH, (C)1-C4) Alkyl, (C)1-C4) Haloalkyl, -CN, (C)1-C4) Alkoxy, nitro, radicals-NHR18And the group-CONHR19；(ii)(C5-C6) A heterocycloalkyl ring which is partially unsaturated and optionally substituted with one or two groups independently selected from: halogen, (C)1-C4) Alkyl, (C)1-C4) Haloalkyl, -CN, -OH, (C)1-C4) Alkoxy, nitro, carbonyl, a group-NHR18And the group-CONHR19(ii) a Or (iii) phenyl, optionally substituted with one or two groups independently selected from: halogen, (C)1-C4) Alkyl, (C)1-C4) Haloalkyl, -CN, nitro, group-NHR18group-CONHR19And a group-OR20；
R18Is hydrogen, (C)1-C4) Alkyl, radical-SO2R21；
R21Is (C)1-C4) An alkyl group;
R19is hydrogen or (C)1-C4) An alkyl group;
R20is hydrogen, (C)1-C4) Alkyl or a radical- (C)1-C4) alkylene-OR22；
R22Is hydrogen or (C)1-C4) An alkyl group;
R3is a group-CH2-R23；
R23Is a group selected from: hydrogen, (C)1-C4) Alkyl, (C)1-C4) Haloalkyl, -CN, (C)1-C4) Alkoxy and halogen;
R5is a group selected from: hydrogen, (C)1-C4) Alkyl, (C)1-C4) Haloalkyl, -CN, (C)1-C4) Alkoxy and halogen;
R6selected from hydrogen, halogen, (C)1-C4) Alkyl and CN;
A1is a group-CR7Or a group-N ═ or;
A2is a radical ═ CR8-or a group ═ N-;
R7selected from hydrogen, halogen, (C)1-C4) Alkyl, (C)1-C4) Haloalkyl and (C)1-C4) An alkoxy group;
R8selected from hydrogen, halogen, (C)1-C4) Alkyl, (C)1-C4) Haloalkyl, (C)1-C4) Alkoxy, radical-S (C)1-C4) Alkyl and group-SO2(C1-C4) An alkyl group;
wherein A is1And A2May not be simultaneously a group-N ═ N;
A3--A4is a moiety selected from: group-CR4-N-group-CR4＝CR9And the group-NR17-CO-；
R9Is hydrogen or (C)1-C4) An alkyl group;
R4is a group selected from: hydrogen, (C)1-C4) Alkyl, -NR10R11、-NHCOR12、-NHCOO-R13、-NHCONH-R14、(C1-C4) Alkoxy, -NH (CH)2)n-SO2(C1-C4) Alkyl, - (NH)q(CH2)n-(C6H6)-SO2(C1-C4) Alkyl, -NHSO2(C1-C4) Alkyl and- (NH)r(CH2)nCONR15R16；
R17Is a group selected from: hydrogen, (C)1-C4) Alkyl, - (CH)2)n-(C6H6)-SO2(C1-C4) Alkyl, - (CH)2)n-SO2(C1-C4) Alkyl and- (CH)2)nCONR15R16；
n is 0 or an integer in the range of 1 to 5;
q is 0 or 1;
r is 0 or 1;
R10is hydrogen, a radical (C)1-C6) Alkyl, radical (C)1-C6) Hydroxyalkyl radical, radical (C)1-C4) alkylene-NH- (C ═ NH) -NH2Group (C)1-C6) Alkylene radical NRaRbOr a group (C)1-C6) Alkylene radical N+RaRbRc；
R11Is hydrogen, a radical (C)1-C6) Alkyl, radical (C)1-C6) Hydroxyalkyl radical, radical (C)1-C4) alkylene-NH- (C ═ NH) -NH2Group (C)1-C6) Alkylene radical NRaRbOr a group (C)1-C6) Alkylene radical N+RaRbRc；
Or R10And R11Together with the nitrogen atom to which they are attached may form (C)5-C7) A heterocycloalkyl group;
Raand RbIndependently at each occurrence is hydrogen or (C)1-C4) Alkane (I) and its preparation methodA group; alternatively, RaAnd RbTogether with the nitrogen atom to which they are attached may form a group C optionally substituted by one or more groups1-C6Alkyl substituted (C)5-C7) A heterocycloalkyl ring system, and said (C)5-C7) Heterocycloalkyl optionally containing the group-S (O) -or-S (O)2Or a further heteroatom being oxygen, sulfur or nitrogen, said nitrogen atom being optionally substituted by (C)1-C6) Alkyl substitution;
or RaAs defined above, and RbAttached to a radical (C)1-C6) One carbon atom of the alkylene moiety, said group being linked to the nitrogen to which they are attached to form saturated (C)5-C6) A heterocycloalkyl ring;
Ra、Rband RcIndependently at each occurrence is (C)1-C4) An alkyl group; alternatively, RaAnd RbOr RaAnd RcTogether with the nitrogen atom to which they are attached may form a group C optionally substituted by one or more groups1-C6Alkyl substituted (C)5-C7) A heterocycloalkyl ring system, and said (C)5-C7) The heterocycloalkyl ring optionally containing the group-S (O) -or-S (O)2Or a further heteroatom being oxygen, sulfur or nitrogen, said nitrogen atom being optionally substituted by (C)1-C6) Alkyl substitution; or RaAnd RbAs defined above, and Rc(C) attached to said group1-C6) One carbon atom of the alkylene moiety, said group being linked to the nitrogen to which they are attached to form saturated (C)5-C6) A heterocycloalkyl ring;
R12is selected from- (C)6H6)-SO2(C1-C4) Alkyl, (C)1-C6) Alkyl, (C)1-C4) Haloalkyl, (C)5-C7) Heterocycloalkyl, radical- (CH)2)n-S(O)t(C1-C4) Alkyl, radical (C)1-C4) alkylene-NH- (C ═ NH) -NH2Group (C)1-C4) alkylene-CO2H. Group- (C)1-C6) Alkylene radical NRaRbGroup- (C)1-C6) Alkylene radical N+RaRbRcAnd (C)1-C4) Alkyl radical (C)5-C7) Heterocycloalkyl, wherein such groups may be optionally substituted with one or two substituents selected from: (C)1-C4) Alkyl, hydroxy, halogen, -SO2(C1-C4) Alkyl, amino or (C)1-C4) An alkylamino group;
t may be 0,1 or 2;
R13is selected from the group consisting of6H6)-SO2Alkyl, (C)1-C6) Alkyl, (C)1-C4) Haloalkyl, (C)5-C7) Heterocycloalkyl, radical (C)1-C4) alkylene-NH- (C ═ NH) -NH2、(C1-C6) Alkylene radical NRaRb、-(C1-C6) Alkylene radical N+RaRbRcAnd (C)1-C4) Alkylene (C)5-C7) Heterocycloalkyl, wherein such groups may be optionally substituted with one or two substituents selected from: (C)1-C4) Alkyl, (C)1-C4) Alkoxy, hydroxy, halogen, -SO2(C1-C4) Alkyl, amino or (C)1-C4) An alkylamino group;
R14is selected from- (C)6H6)-SO2Alkyl, (C)1-C4) Haloalkyl, (C)5-C7) Heterocycloalkyl, radical (C)1-C4) alkylene-NH- (C ═ NH) -NH2、(C1-C6) Alkylene radical NRaRb、-(C1-C6) Alkylene radical N+RaRbRcAnd (C)1-C4) Alkyl radical (C)5-C7) Heterocycloalkyl, wherein such groups may be optionally substituted with one or two substituents selected from: (C)1-C4) Alkyl, hydroxy, halogen, -SO2(C1-C4) Alkyl, amino, (C)1-C4) Alkylcarbonyl and (C)1-C4) An alkylamino group;
R15is hydrogen, a radical (C)1-C6) Alkyl, radical (C)1-C4) alkylene-NH- (C ═ NH) -NH2Group (C)1-C6) Alkylene radical NRaRbOr a group- (C)1-C6) Alkylene radical N+RaRbRc；
R16Is hydrogen, a radical (C)1-C6) Alkyl radical, radical (C)1-C4) alkylene-NH- (C ═ NH) -NH2Group (C)1-C6) Alkylene radical NRaRbOr a group- (C)1-C6) Alkylene radical N+RaRbRc；
Or R15And R16Together with the nitrogen atom to which they are attached may form (C)5-C7) A heterocycloalkyl group;
wherein if one or more radicals- (C)1-C6) Alkylene radical N+RaRbRcWhen present, they form quaternary salts with pharmaceutically acceptable counterions;
and wherein the radical R18、R19、R20、R21、R22、Ra、Rb、RcAnd n, if present in more than one group, may have the same or different meaning at each occurrence.
It is to be understood that all preferred sets or embodiments described hereinafter and above in relation to the compounds of the formula (I) can be combined with one another and, mutatis mutandis, also apply to the compounds of the formulae (I)', (IA) and (IB).
In a preferred embodiment, R1is-CN.
In a preferred embodiment, R2Is (C)1-C4) A haloalkyl group; in another preferred embodiment, R2Is 3-trifluoromethyl.
In a preferred embodiment, W is an optionally substituted 5,6 membered heteroaryl ring.
In a preferred embodiment, R3Is a group-CH2-R23. In another preferred embodiment, R3Is a group-CH2-R23And R is23Is hydrogen, e.g. R3Is methyl.
In a preferred embodiment, R5Is hydrogen.
In a preferred embodiment, R6Is hydrogen.
In a preferred embodiment, A1Is a group-CR7Is as follows. In a preferred embodiment, R7Is hydrogen.
In a preferred embodiment, A2Is a group-CR8Is as follows. In a preferred embodiment, R8Is hydrogen or a radical-SO2(C1-C4) An alkyl group.
In a preferred embodiment, A3--A4Is part-CR4＝N-。
In a preferred embodiment, R4Is a group selected from: -NR10R11、-NHCOR12、-NHCOO-R13、-NHCONH-R14、-NH(CH2)n-SO2(C1-C4) Alkyl, - (NH)q(CH2)n-(C6H6)-SO2(C1-C4) Alkyl, -NHSO2(C1-C4) Alkyl and- (NH)r(CH2)nCONR15R16。
In a preferred embodiment, the present invention provides a compound of formula (IA) or a pharmaceutically acceptable salt thereof:
wherein A is3---A4Is part-CR4is-N-, and R1、R2、R3、R4、R6、A1And A2As defined for the compounds of formula (I).
In another preferred embodiment, the present invention provides a compound of formula (IB):
wherein R is2Is 3-trifluoromethyl, and R1、R3、R4、R6、A3---A4、A1And A2As defined for the compounds of formula (I).
In a preferred embodiment, the compound of formula (I) is selected from:
4- {5- [ 2-amino-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -2,2, 2-trifluoro-acetamide;
4- {5- [ 7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
4- {5- [2, 7-dimethyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
4- {5- [2, 7-dimethyl-8- (3-trifluoromethyl-phenyl) -imidazo [1,2-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
4- {5- [ 7-methyl-8- (3-trifluoromethyl-phenyl) -imidazo [1,2-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
4- {5- [2- (4-methanesulfonyl-phenylamino) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
4- {5- [2- (4-methanesulfonyl-benzyl) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
4- {5- [ 7-methyl-3-oxo-8- (3-trifluoromethyl-phenyl) -2, 3-dihydro- [1,2,4] triazolo [4,3-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
4- {5- [2- (4-methanesulfonyl-benzyl) -7-methyl-3-oxo-8- (3-trifluoromethyl-phenyl) -2, 3-dihydro- [1,2,4] triazolo [4,3-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
2- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-3-oxo-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [4,3-a ] pyridin-2-yl ] -N, N-dimethyl-acetamide;
2- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-3-oxo-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [4,3-a ] pyridin-2-yl ] -N-methyl-acetamide;
4- {5- [2- (3-methanesulfonyl-propyl) -7-methyl-3-oxo-8- (3-trifluoromethyl-phenyl) -2, 3-dihydro- [1,2,4] triazolo [4,3-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -2-dimethylamino-acetamide;
{ [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-ylcarbamoyl ] -methyl } -trimethyl-ammonium bromide;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -4-dimethylamino-butyramide;
{3- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-ylcarbamoyl ] -propyl } -trimethyl-ammonium bromide;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -2- (4-methyl-piperazin-1-yl) -acetamide;
4- { [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-ylcarbamoyl ] -methyl } -1, 1-dimethyl-piperazin-1-ium (ium) iodide;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -2-morpholin-4-yl-acetamide;
4- { [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-ylcarbamoyl ] -methyl } -1, 1-dimethyl-piperazin-1-ium iodide;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -2-morpholin-4-yl-acetamide;
n- [6- [1- (4-cyano-phenyl) -1H-pyrazol-5-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -2- (1, 1-dioxothiomorpholin-4-yl) -acetamide;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -4-methanesulfonyl-benzamide;
4- {5- [2- (4-methanesulfonyl-benzylamino) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
2- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-ylamino ] -N, N-dimethyl-acetamide;
1- { [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-ylcarbamoyl ] -methyl } -1, 4-dimethyl-piperazin-1-ium chloride;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -acetamide;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -methanesulfonamide;
4- {5- [2- (3-dimethylamino-propylamino) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
4- {5- [2- (2-dimethylamino-ethylamino) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
4- {5- [2- (4-dimethylamino-butylamino) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
4- {5- [ 2-methoxy-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
{3- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-ylamino ] -propyl } -trimethyl-benzenesulfonate ammonium;
{3- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-ylamino ] -ethyl } -trimethyl-benzenesulfonate ammonium;
{4- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-ylamino ] -butyl } -trimethyl-ammonium formate;
ethyl [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -carbamate;
2-methoxyethyl [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -carbamate;
{3- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-ylcarbamoyloxy ] -propyl } -trimethyl-ammonium formate;
(3- {3- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -ureido } -propyl) -trimethyl-ammonium formate;
n- [6- [2- (4-cyano-phenyl) -2H- [1,2,4] triazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -acetamide;
4- {5- [ 2-amino-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -3-methanesulfonyl-benzonitrile;
n- [6- [2- (4-cyano-2-fluoro-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -acetamide;
n- [6- [2- (4-cyano-phenyl) -4-methyl-2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -acetamide;
n- [6- (4' -cyano-biphenyl-2-yl) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -acetamide;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethoxy-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -acetamide;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -3-methanesulfinyl-propionamide;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -3-methanesulfonyl-propionamide;
4- {5- [2- (3-methanesulfonyl-propylamino) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
4- {5- [2- (2-hydroxy-ethylamino) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
4- {5- [2- (2-hydroxy-propylamino) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
1- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -3-piperidin-4-yl-urea;
(1-methyl-4-piperidinyl) [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -urea;
1- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -3-ethyl-urea;
4- {5- [2- (3-hydroxy-propylamino) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
4- {5- [2- (4-hydroxy-butylamino) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -succinamic acid;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -4-methylamino-butyramide;
1- (1-acetyl-piperidin-4-yl) -3- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -urea;
1- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -3- (1-methanesulfonyl-piperidin-4-yl) -urea;
4- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-ylamino ] -N-methyl-butyramide;
4- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-ylamino ] -N- (2-dimethylamino-ethyl) -N-methyl-butyramide;
4- { 3-amino-5- [ 2-amino-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] - [1,2,4] triazol-1-yl } -benzonitrile;
and pharmaceutically acceptable salts thereof.
In another preferred embodiment, the compound of formula (I) is selected from:
4- {5- [ 2-amino-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -2,2, 2-trifluoro-acetamide;
4- {5- [ 7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
4- {5- [2, 7-dimethyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
4- {5- [2, 7-dimethyl-8- (3-trifluoromethyl-phenyl) -imidazo [1,2-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
4- {5- [ 7-methyl-8- (3-trifluoromethyl-phenyl) -imidazo [1,2-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
4- {5- [2- (4-methanesulfonyl-phenylamino) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
4- {5- [2- (4-methanesulfonyl-benzyl) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
4- {5- [ 7-methyl-3-oxo-8- (3-trifluoromethyl-phenyl) -2, 3-dihydro- [1,2,4] triazolo [4,3-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
4- {5- [2- (4-methanesulfonyl-benzyl) -7-methyl-3-oxo-8- (3-trifluoromethyl-phenyl) -2, 3-dihydro- [1,2,4] triazolo [4,3-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
2- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-3-oxo-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [4,3-a ] pyridin-2-yl ] -N, N-dimethyl-acetamide;
2- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-3-oxo-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [4,3-a ] pyridin-2-yl ] -N-methyl-acetamide;
4- {5- [2- (3-methanesulfonyl-propyl) -7-methyl-3-oxo-8- (3-trifluoromethyl-phenyl) -2, 3-dihydro- [1,2,4] triazolo [4,3-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -2-dimethylamino-acetamide;
{ [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-ylcarbamoyl ] -methyl } -trimethyl-ammonium bromide;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -4-dimethylamino-butyramide;
{3- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-ylcarbamoyl ] -propyl } -trimethyl-ammonium bromide;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -2- (4-methyl-piperazin-1-yl) -acetamide;
4- { [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-ylcarbamoyl ] -methyl } -1, 1-dimethyl-piperazin-1-ium iodide;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -2-morpholin-4-yl-acetamide;
4- { [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-ylcarbamoyl ] -methyl } -1, 1-dimethyl-piperazin-1-ium iodide;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -2-morpholin-4-yl-acetamide;
n- [6- [1- (4-cyano-phenyl) -1H-pyrazol-5-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -2- (1, 1-dioxothiomorpholin-4-yl) -acetamide;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -4-methanesulfonyl-benzamide;
4- {5- [2- (4-methanesulfonyl-benzylamino) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
2- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-ylamino ] -N, N-dimethyl-acetamide;
1- { [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-ylcarbamoyl ] -methyl } -1, 4-dimethyl-piperazin-1-ium chloride;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -acetamide;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -methanesulfonamide;
4- {5- [2- (3-dimethylamino-propylamino) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
4- {5- [2- (2-dimethylamino-ethylamino) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
4- {5- [2- (4-dimethylamino-butylamino) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
4- {5- [ 2-methoxy-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
{3- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-ylamino ] -propyl } -trimethyl-benzenesulfonate ammonium;
{3- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-ylamino ] -ethyl } -trimethyl-benzenesulfonate ammonium;
{4- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-ylamino ] -butyl } -trimethyl-ammonium formate;
ethyl [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -carbamate;
2-methoxyethyl [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -carbamate;
{3- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-ylcarbamoyloxy ] -propyl } -trimethyl-ammonium formate;
(3- {3- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -ureido } -propyl) -trimethyl-ammonium formate;
n- [6- [2- (4-cyano-phenyl) -2H- [1,2,4] triazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -acetamide;
4- {5- [ 2-amino-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -3-methanesulfonyl-benzonitrile;
n- [6- [2- (4-cyano-2-fluoro-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -acetamide;
n- [6- [2- (4-cyano-phenyl) -4-methyl-2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -acetamide;
n- [6- (4' -cyano-biphenyl-2-yl) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -acetamide;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethoxy-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -acetamide;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -3-methanesulfinyl-propionamide;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -3-methanesulfonyl-propionamide;
4- {5- [2- (3-methanesulfonyl-propylamino) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
4- {5- [2- (2-hydroxy-ethylamino) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
4- {5- [2- (2-hydroxy-propylamino) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
1- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -3-piperidin-4-yl-urea;
(1-methyl-4-piperidinyl) [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -urea;
1- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -3-ethyl-urea;
4- {5- [2- (3-hydroxy-propylamino) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
4- {5- [2- (4-hydroxy-butylamino) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -succinamic acid;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -4-methylamino-butyramide;
1- (1-acetyl-piperidin-4-yl) -3- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -urea;
1- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -3- (1-methanesulfonyl-piperidin-4-yl) -urea;
4- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-ylamino ] -N-methyl-butyramide;
4- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-ylamino ] -N- (2-dimethylamino-ethyl) -N-methyl-butyramide;
4- { 3-amino-5- [ 2-amino-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] - [1,2,4] triazol-1-yl } -benzonitrile;
1- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -3- [3- (piperidin-4-ylamino) -propyl ] -urea;
4- {5- [2- {3- [ (azetidin-3-ylmethyl) -amino ] -propylamino } -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
4- {5- [ 7-methyl-2- [3- (piperidin-4-ylamino) -propylamino ] -8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
1- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -3- {3- [ (3-dimethylamino-propyl) -methyl-amino ] -propyl } -urea;
4- {5- [2- {3- [ (3-dimethylamino-propyl) -methyl-amino ] -propylamino } -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
4- {5- [ 7-methyl-2- [3- (4-methylamino-piperidin-1-yl) -propylamino ] -8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
1- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -3- [2- (4-methylamino-piperidin-1-yl) -ethyl ] -urea;
n- [6- [4- (4-cyano-phenyl) -5-oxo-4, 5-dihydro-1H- [1,2,4] triazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -acetamide;
4- {5- [ 7-methyl-2- [2- (piperidin-4-ylamino) -ethylamino ] -8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
4- {3- [ 2-amino-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -5-oxo-1, 5-dihydro- [1,2,4] triazol-4-yl } -benzonitrile;
1- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -3- (R) -piperidin-3-yl-urea;
{3- [6- [2- (4-cyano-phenyl) -5-methoxycarbonyl-2H- [1,2,4] triazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5a ] pyridin-2-ylcarbamoyl ] -propyl } -ammonium trimethyl formate;
(3- {2- [6- [2- (4-cyano-phenyl) -2H- [1,2,4] triazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-ylcarbamoyl ] -ethanesulfonyl } -propyl) -trimethyl-ammonium formate;
n- [6- [2- (4-cyano-phenyl) -2H- [1,2,4] triazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -3-dimethylamino-propionamide;
n- [6- [2- (4-cyano-phenyl) -2H- [1,2,4] triazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -3- (3-dimethylamino-propane-1-sulfonyl) -propionamide;
3- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -1- (3-dimethylamino-propyl) -1-methyl-urea;
1- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -3- (S) -piperidin-3-yl-urea;
{3- [6- [ 5-carboxy-2- (4-cyano-phenyl) -2H- [1,2,4] triazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-ylcarbamoyl ] -propyl } -trimethyl-ammonium formate;
{3- [6- [2- (4-cyano-phenyl) -5-methoxycarbonyl-2H- [1,2,4] triazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-ylcarbamoyl ] -propyl } -trimethyl-ammonium bromide;
carboxymethyl- (3- {3- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -ureido } -propyl) -dimethyl-ammonium formate;
1- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -3- (3-methylamino-propyl) -urea;
1- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -3- (3-dimethylamino-propyl) -urea;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -3-guanidino-propionamide;
{3- [6- [2- (4-cyano-phenyl) -2H- [1,2,4] triazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-ylcarbamoyl ] -propyl } -trimethyl-ammonium bromide;
n- [6- [1- (4-cyano-phenyl) -1H-imidazol-2-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -acetamide;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -4-hydroxy-butyramide;
n- [6- [2- (4-cyano-phenyl) -2H- [1,2,4] triazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -4-dimethylamino-butyramide;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -3-hydroxy-propionamide;
n- [6- [2- (5-cyano-pyridin-2-yl) -2H- [1,2,4] triazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -acetamide;
n- [6- [3- (4-cyano-phenyl) -3H-imidazol-4-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -acetamide;
n- [6- [ 5-amino-2- (4-cyano-phenyl) -2H- [1,2,4] triazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -acetamide;
5- [ 2-acetylamino-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -1- (4-cyano-phenyl) -1H- [1,2,4] triazole-3-carboxylic acid methyl ester;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -succinamide;
n- [6- [ 5-acetylamino-2- (4-cyano-phenyl) -2H- [1,2,4] triazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -acetamide;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -N '- (2-dimethylamino-ethyl) -N' -methylsuccinamide;
and pharmaceutically acceptable salts thereof.
The therapeutic utility of the compounds of the present invention relates to any disease known to be mediated at least in part by the action of human neutrophil elastase. For example, the compounds of the invention may be beneficial for the treatment of Chronic Obstructive Pulmonary Disease (COPD), Cystic Fibrosis (CF), Acute Respiratory Distress Syndrome (ARDS), emphysema, pneumonia, bronchiectasis, and pulmonary fibrosis.
The invention also relates to pharmaceutical preparations comprising the compounds of the invention as active ingredients. Other compounds may be used in combination with the compounds of the present invention for the prevention and treatment of inflammatory diseases of the lung. Accordingly, the present invention also relates to pharmaceutical compositions for the prevention and treatment of inflammatory diseases of the lung comprising a therapeutically effective amount of a compound of the present invention and one or more other therapeutic agents.
Therapeutic agents suitable for use in combination therapy with the compounds of the present invention include: (1) corticosteroids, such as fluticasone or budesonide; (2) a beta 2-adrenergic receptor agonist, such as salmeterol or formoterol; (3) leukotriene modulators, such as montelukast or pranlukast; (4) anticholinergic agents, for example selective muscarinic-3 (M3) receptor antagonists such as tiotropium bromide; (5) phosphodiesterase-IV (PDE-IV) inhibitors, such as roflumilast or cilomilast; (6) antitussives such as codeine or dextromethorphan; and (7) non-steroidal anti-inflammatory agents (NSAIDs), such as ibuprofen or ketoprofen.
The weight ratio of the first and second active ingredients may vary and depends upon the effective dosage of each ingredient. Generally, an effective dose of each will be used.
The magnitude of the prophylactic or therapeutic dose of a compound of the invention will, of course, vary with the nature of the severity of the condition to be treated and the particular compound and its route of administration and will generally be determined by clinical trials required in the pharmaceutical arts. It will also vary according to the age, weight and response of the individual patient. In general, the daily dosage range will be within the following ranges: from about 0.001mg to about 100mg per kilogram of body weight of the mammal, preferably from 0.01mg to about 50mg per kilogram, and most preferably from 0.1 to 10mg per kilogram, in single or divided doses. On the other hand, in some cases, it may be desirable to use dosages outside these limits.
Another aspect of the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier. The term "composition" in pharmaceutical compositions is intended to encompass a product comprising the active ingredient and the inert ingredient(s) (pharmaceutically acceptable excipients) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from decomposition of one or more of the ingredients, or from direct or indirect formation of other types of reactive or interactive ingredients with one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention include any composition made by admixing a compound of the present invention, other active ingredients, and pharmaceutically acceptable excipients.
The pharmaceutical compositions of the invention comprise a compound of the invention as an active ingredient or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids as well as organic bases or acids.
Any suitable route of administration may be employed to provide an effective dose of a compound of the invention to a mammal, especially a human. In therapeutic use, the active compound may be administered by any convenient, suitable or effective route. Suitable routes of administration are known to those skilled in the art and include oral, intravenous, rectal, parenteral, topical, ocular, nasal, buccal and pulmonary (by inhalation).
Compositions suitable for administration by inhalation are known and may include carriers and/or diluents known for use in such compositions. The compositions may contain from 0.01 to 99% by weight of active compound. Preferably, the unit dose contains an amount of active compound of 1. mu.g to 10 mg.
The most suitable dosage level may be determined by any suitable method known to those skilled in the art. It will be understood, however, that the specific amount for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, diet, general health and sex of the patient, the time of administration, the route of administration, the rate of excretion, the use of any other drug, and the severity of the disease undergoing therapy.
For inhalation delivery, the active compound is preferably in particulate form. These microparticles can be prepared by a variety of techniques including spray drying, freeze drying and micronization.
For example, the compositions of the present invention may be prepared as a suspension for delivery from a nebulizer, or prepared as a suspension inAerosols in liquid propellants are used, for example, in Pressurized Metered Dose Inhalers (PMDI). Propellants suitable for use in PMDI are known to those skilled in the art and include CFC-12, HFA-134a, HFA-227, HCFC-22 (CCl)2F2) And HFA-152 (CH)4F2And isobutane).
In a preferred embodiment, the composition of the invention is in the form of a dry powder for delivery using a Dry Powder Inhaler (DPI). Many types of DPIs are known.
Microparticles for administration delivery may be formulated with excipients that aid in delivery and release. For example, in a dry powder formulation, the microparticles may be formulated with large carrier particles that facilitate flow from the DPI into the lung. Suitable carrier particles are known and include lactose particles; they may have a mass median diameter of greater than 90 μm.
In the case of aerosol-based formulations, preferred compositions are:
the compounds of the present invention may be used in combination with other drugs for the treatment/prevention/inhibition or amelioration of the diseases or conditions for which the compounds of the present invention are useful. Such other agents may be administered by their usual routes and amounts, either simultaneously or sequentially with the compounds of the present invention. When the compound of the present invention is used simultaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the present invention is preferable. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients in addition to the compounds of the present invention.
The agents of the invention may be administered in inhaled form. Aerosols can be generated using, for example, pneumatically driven jet nebulizers or ultrasonic nebulizers, preferably propellant driven metered dose aerosols, or propellant-free administration of micronized active compounds, e.g., inhalation capsules or other "dry powder" delivery systems.
The active compound may be administered as previously described, depending on the inhaler system used. In addition to the active compounds, the administration forms may additionally contain excipients, for example propellants (for example Freon for metered-dose aerosols), surface-active substances, emulsifiers, stabilizers, preservatives, flavorings, fillers (for example lactose for powder inhalers) or, if appropriate, further active compounds.
For inhalation purposes, a wide variety of systems are available that generate and administer aerosols having the most appropriate particle size, using inhalation techniques appropriate to the patient. Except for the use of adapter (spacer), spreader) and pear-shaped containers (e.g. for example) And automatic means for emitting a blowing spray (puffsspray) (() Besides, for metered dose aerosols, in particular in the case of powder inhalers, a wide variety of solutions are available (e.g. for exampleOr an inhaler such as described in EP- ｃA-0505321).
Synthesis method
The present invention further provides a process for the preparation of a compound of formula (I) as defined above or a pharmaceutically acceptable salt or quaternary salt thereof.
The compounds of the present invention may be prepared according to the routes explained in schemes 1-18 below.
The skilled person may, where appropriate, introduce suitable variations to the conditions specifically described in the experimental section in order to adapt the synthetic route to the provision of the other compounds of the invention. Such variations include, but are not limited to: the use of appropriate starting materials for the preparation of the different compounds, the variation of the solvents and temperatures of the reaction, the substitution of reactants with similar chemical action, the introduction or removal of the protection/deprotection stage of the functional groups sensitive to the reaction conditions and reagents.
Also, the introduction or removal of specific synthetic steps aimed at further functionalization of the chemical backbone can be foreseen and included within the scope of the present invention.
Methods that may be used and that are described and depicted in the examples and schemes should not be taken as limiting the scope of synthetic methods that may be used to prepare the compounds of the present invention.
The compounds used as starting materials or intermediates can be commercially available, their preparation can be described specifically in the literature, or they can be prepared according to methods available in the literature and well known to the skilled person. In some cases, procedures for preparing intermediates or starting materials may also be provided in the experimental section.
The described method is particularly advantageous since it is easily adjusted appropriately by any appropriate variant known to the skilled person to give any desired compound of the invention. Such variations are included within the scope of the present invention.
From all the above, it is obvious to the skilled person that any of the groups described may be present as such or in any suitably protected form.
In particular, functional groups present in intermediates and compounds and which can generate undesirable side reactions and by-products need to be properly protected prior to alkylation, acylation, coupling or sulfonylation. Likewise, subsequent deprotection of those same protected groups may occur after the reaction is complete.
In the present invention, unless otherwise specified, the term "protecting group" means a protecting group that is engineered to retain the function of the group to which it is bound. Typically, protecting groups are used to retain amino, hydroxyl or carboxyl functionality. Thus, suitable protecting groups may include, for example, benzyl, benzyloxycarbonyl, tert-butoxycarbonyl, alkyl or benzyl esters and the like as are well known to those skilled in the art [ see, for general reference, t.w. green; protective Groups in Organic Synthesis (Wiley, N.Y.1981) ].
Likewise, selective protection and deprotection of any of the groups (including, for example, carbonyl, hydroxyl or amino groups) can be accomplished according to well known methods commonly used in organic synthetic chemistry.
The optional salification of the compounds of formula (I) can be achieved by appropriate conversion of any free acidic group or amino group to the corresponding pharmaceutically acceptable salt. Also in this case, the working conditions for the optional salification of the compounds of the invention are within the ordinary knowledge of the skilled person.
From all the above it is clear that the above process, widely any variant thereof for the preparation of suitable compounds of the invention, can be easily adapted to suit the specific needs, e.g. by selecting appropriate condensing agents, solvents and protecting groups, as the case may be.
In the following schemes, for compounds of formulae (I) to (Iz), unless otherwise indicated, the group A1、A2、A3、A4、W、R1To R6Have the same meanings as described above for the compounds of formula (I).
Scheme 1
According to scheme 1, compounds of formula (I) can be prepared, wherein A3--A4is-CR4or-CR4＝CR9-, and R4＝-NR10R11、-NHCOR12、-NHCOO-R13、-NR27CONH-R14、-NSO2Alkyl or- (NH) r (CH)2)CONR15R16。
The compound of formula (In) (i.e., the compound of formula (I) wherein A is3--A4is-CR4either-N-or-CR4＝CR9-, and R4＝NH2) Preparation of the Compound of formula (Ia), i.e. the Compound of formula (I), wherein A3--A4is-R4or-CR4＝CR9-, and R4＝NHCOR12. Typical reaction conditions include: an acid chloride such as acetyl chloride is used in a solvent such as pyridine or THF containing a base such as pyridine, triethylamine or DIPEA at a temperature between room temperature and 120 ℃. Alternatively, the compound of formula (In) may be reacted with a carboxylic acid In the presence of a solvent such as DMF with HATU together with a base such as triethylamine at a temperature between room temperature and 80 ℃.
The compounds of formula (Ib), i.e. the compounds of formula (I) wherein a is prepared from the compound of formula (In) by reaction with an appropriately substituted chloroformate or isocyanate In a solvent such as pyridine or THF containing a base such as pyridine, triethylamine or DIPEA at a temperature between room temperature and 120 ℃3--A4is-CR4or-CR4＝CR9-, and R4＝NHCOO-R13or-NHCONR27-R14。
According to scheme 1, by preparing the intermediate tosylurea, wherein R4＝-NHCONR27-Ts followed by reaction with NH of formula2-R14Can also be prepared by reacting an amine of formula (Ib) as defined above, wherein R is R (see WO2006/38116 for a representative protocol)4＝-NHCONR27-R14. Typical reaction conditions consist of the following conditions: at a temperature of from 0 ℃ to room temperature in a suitable solvent such as DMFThe compound of formula (In) is reacted with tosylisocyanate to give the intermediate tosylurea. R4＝-HCONR27-Ts to R4＝-NHCONR27-R14The transformation of (a) can be achieved as follows: heating the intermediate tosylurea solution with the appropriately substituted primary amine NH at a temperature between 100-160 ℃ under microwave irradiation2-R14A mixture of (a).
Compounds of formula (Ic), i.e. compounds of formula (I), can be prepared from compounds of formula (In) using reductive amination, wherein A3--A4is-CR4or-CR4＝CR9-, and R4＝-NR10R11. Typical conditions include: suitably substituted benzaldehydes are used in the presence of titanium isopropoxide and triethylamine in a solvent such as DCM at a temperature up to 65 ℃, followed by treatment with a reducing agent such as sodium borohydride in a solvent such as ethanol. Alternatively, the conversion may be effected by alkylation. The compound of formula (In) may be reacted with an appropriately substituted alkyl halide In the presence of a base such as cesium carbonate or potassium carbonate In a solvent such as DMF at room temperature.
By preparing intermediate aryl halides (III), according to scheme 1, e.g. with compounds of formula (Ic) (wherein R is4Ci), the compounds of formula (Ic) as defined above may also be prepared. Typical reaction conditions consist of the following conditions: the compound of formula (In) is reacted with tert-butyl nitrite and copper (II) chloride In a solvent such as MeCN at 65 ℃ to give the compound of formula (III) as defined above. R4From Cl to R4＝-NR10R11or-NH (CH)2)n-SO2(C1-C4) Alkyl, or- (NH)r(CH2)nCONR15R16(where n ═ 2-5 ") the conversion can be achieved as follows: a mixture of a suitably substituted primary amine in a solvent such as N-methylpyrrolidine containing a base such as triethylamine is heated under microwave radiation at a temperature between 150 and 220 ℃.
Using appropriately substitutedSulfonyl chlorides, such as methanesulfonyl chloride, may be prepared from compounds of formula (In), i.e., compounds of formula (I), wherein A is a compound of formula (Id), In a solvent, such as pyridine, at a temperature In the range of room temperature to 60 deg.C3--A4is-CR4or-CR4＝CR9-, and R4is-NSO2An alkyl group.
The compound of formula (Ie), i.e. the compound of formula (I), can be prepared from the compound of formula (III) by reaction with an alkoxide (such as sodium methoxide) in a solvent (such as methanol) at a temperature of from room temperature to 100 ℃ under microwave radiation, wherein a3--A4is-CR4or-CR4＝CR9-, and R4Is (C)1-C4) An alkoxy group.
Scheme 2
According to scheme 2, compounds of formula (If), i.e. compounds of formula (I), can be prepared from compounds of formula (IV) wherein A3--A4is-NR17-CO-. Typical reaction conditions include: treatment with a base (such as cesium carbonate) with a suitable alkylating agent (such as 1-bromomethyl-4-methanesulfonyl-benzene) in a solvent (such as DMF) at ambient temperature.
Scheme 3
Compounds of formula (Ig), i.e. compounds of formula (I) wherein A is a suitable leaving group such as bromo, iodo or trifluoromethylsulfonate, can be prepared from compounds of formula (V) wherein X is a suitable leaving group such as bromo, iodo or trifluoromethylsulfonate, using known C-C and C-N crosslinking methods described in the literature, using appropriately functionalized linking groups "W" such as aryl, heteroaryl, cycloalkyl or heterocycloalkylboronic/boronic acid esters, stannane or zincate3--A4is-CR4or-CR4＝CR9-. Typical reaction conditions consist of the following conditions: using microwave radiation, at a temperature between 50 ℃ and reflux or higher, using an organometallic reactant such as 4- (5-tributylstannyl-pyrazol-1-yl) -benzonitrile and a palladium source such as bis (triphenylphosphine) palladium (II) dichloride and a solvent such as bis (triphenylphosphine) palladium (II) dichlorideAn alkane.
Scheme 4
According to scheme 4, by dissolving in a solvent (such as bis)Alkyl) with a reagent such as ethoxycarbonyl isothiocyanate, followed by treatment with hydroxylamine hydrochloride in a solvent such as ethanol or methanol together with a base such as diisopropylethylamine at elevated temperature (. gtoreq.60 ℃) may be prepared from compounds of formula (VI) i.e. compounds of formula (V) as defined above, wherein R is4＝NH2And A is4＝N。
According to scheme 4, compounds of formula (Vb), i.e. compounds of formula (V) as defined above, wherein R is prepared from compounds of formula (VI)4＝NHCOCF3And A is4CH. Typical reaction conditions include: treatment with p-toluenesulfonyl chloride in a solvent such as pyridine at a temperature from room temperature to, for example, (example)80 ℃. The intermediate p-toluenesulfonylamide thus obtained may be treated with a base such as sodium hydride in a solvent such as DMF and then reacted with 2-iodoacetamide and an acylating agent such as trifluoroacetic anhydride under reflux in a solvent such as DCM.
According to scheme 4, compounds of formula (Vc), i.e. compounds of formula (V) as defined above, may be prepared from compounds of formula (VI)In which R is4Is methyl or hydrogen. Typical conditions consist of the following conditions: treatment of (VI) with an appropriate chloroacetone or chloroacetaldehyde in a solvent such as ethanol or MeCN at reflux for a period of up to 2 days gives the compound of formula (Vc). Alternatively, compounds of formula (VI) may be treated with the appropriate dimethylformamide dimethyl acetal or dimethylacetamide dimethyl acetal at temperatures up to 130 ℃ in a solvent such as DMF or IPA followed by reaction with a reagent such as hydroxylamine hydrochloride or hydroxylamine-O-sulfonic acid in a solvent such as ethanol or methanol and pyridine at temperatures in the range of 0 ℃ to 50 ℃ to give compounds of formula (Vc).
Scheme 5
According to scheme 5, compounds of formula (VIa), i.e. compounds of formula (VI) as defined above, wherein X is bromine, can be obtained from compounds of formula (VII) using coupling partners (e.g. aryl boronic acids) using known metal-catalyzed C-C cross-linking methods or other methods described in the literature. Typical reaction conditions consist of the following conditions: organometallic reactants such as 3- (trifluoromethyl) benzeneboronic acid and a palladium source such as 1,1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride dichloromethane are used at reflux temperature along with a base such as aqueous sodium carbonate and a solvent such as toluene and ethanol. The compounds of formula (VII) can be prepared using other methods described in the literature.
Scheme 6
According to scheme 6, the compound of formula (Ih), i.e. the compound of formula (I), can be obtained from the compound of formula (VIII) using the methods described in scheme 3 for the conversion of the compound of formula (V) to the compound of formula (Ig), wherein a3--A4is-NR17CO-。
Scheme 7
According to scheme 7, by dissolving in a solvent (such as diAlkane) with hydrazine hydrate at temperatures up to 100 ℃ followed by reaction with an acylating agent (such as carbonyldiimidazole) in a solvent (such as THF) can give compounds of formula (VIIIa) from compounds of formula (IX), i.e. compounds of formula (VIII) as defined above, wherein X is bromine.
Scheme 8
The compound of formula (IX) may be prepared from the compound of formula (VIa) by typical reaction conditions consisting of: a diazotizing agent, such as tert-butyl nitrite, is used in a solvent, such as MeCN, at a temperature of room temperature to 70 ℃, and quenched with a chloride source, such as aqueous hydrogen chloride solution.
Scheme 9
According to scheme 9, compounds of formula (XI) (wherein A3--A4is-CR4or-CR4＝CR9-) preparation of the Compound of formula (Ij), i.e. the Compound of formula (I), wherein A3--A4is-CR4or-CR4＝CR9-and wherein the linker (linkage) "W" is a1, 5-disubstituted pyrazole. Can be used forTo react a compound of formula (XI) with an appropriately substituted hydrazine. Typical conditions include: the compound of formula (XI) is heated under acidic conditions (such as HCl or acetic acid) in a high boiling alcohol solvent (such as n-butanol) with an aryl/heteroaryl hydrazine.
Scheme 10
The compound of formula (XII) (wherein A is prepared from dimethylformamide dimethyl acetal) by reaction with dimethylformamide dimethyl acetal in a high boiling solvent (such as toluene) under reflux conditions3--A4is-CR4or-CR4＝CR9-) preparation of the compound of formula (XI) as defined above.
Scheme 11
According to scheme 11, using the C-C crosslinking method described in the literature, it is possible to obtain compounds of formula (Ve) (i.e.compounds of formula (V) as defined above, in which A is3--A4is-CR4or-CR4＝CR9And X is bromo) to give a compound of formula (XII). Typical reaction conditions include: the intermediate enol ether is subsequently hydrolyzed with aqueous acid (such as HCl) using microwave radiation in a solvent (such as DMF) using an organometallic reagent such as tributyl (1-ethoxyvinyl) tin and a palladium source such as bis (triphenylphosphine) palladium (II) dichloride at temperatures from 50 ℃ to reflux or higher. Alternatively, the intermediate enols can be obtained from the compounds of formula (Ve) using a Heck reaction with 1-vinyloxy-butane. Typical reaction conditions include: a palladium source such as palladium (II) acetate is used in a solvent such as MeCN at a temperature of 50 ℃ to reflux.
Scheme 12
According to scheme 12, compounds of formula (Vf), i.e. compounds of formula (V), wherein a is prepared from compounds of formula (VIa) as defined above3--A4is-CR4or-CR4＝CR9X is bromine and R4＝CH2PhSO2Me. Typical reaction conditions consist of the following conditions: reaction of (VIa) with 4- (methylsulfonyl) phenylacetyl chloride in a solvent such as DCM at a temperature of 0 ℃ to room temperature affords compounds of formula (XIIIa), wherein X ═ O. Compounds of formula (XIIIa), wherein X ═ O, can be converted to the corresponding thioamide compounds of formula (XIIIb), wherein X ═ S, by using a thiolating reagent, such as a lawson' S reagent, in a solvent, such as toluene, at reflux. Compounds of formula (XIIIc) (where X ═ NOH) can be prepared from compounds of formula (XIIIb) by treatment with hydroxylamine hydrochloride and a base such as triethylamine in a solvent such as ethanol at room temperature. The compound of formula (Vf) can be obtained from the compound of formula (XIIIc) by suspending it in a solvent such as toluene together with a base such as pyridine and treating it with p-toluenesulfonyl chloride at a temperature in the range of 0 ℃ to room temperature.
Scheme 13
According to scheme 13, compounds of formula (Im) or (Ik) can be prepared, i.e. incorporating the group (C), respectively1-C6) Alkylene radical NRaRbOr a group (C)1-C6) Alkylene radical N+RaRbRc as a substituent.
By means of appropriate tertiary amines RaRbRcAlkylation of N, such as trimethylamine or dimethylpiperazine, with a compound of formula (XIV) can directly give a compound of formula (Ik), where X is suitableAnd a leaving group of (X ═ Cl, Br, I, tosylate, etc.), and a group-CH2R represents an unsubstituted group (C) of a compound of formula (Ik)1-C4) Alkylene radical N+RaRbThe remainder of the Rc substitution. Typical conditions may include: the tertiary amine is heated at an elevated temperature of 60 ℃ to 150 ℃ using microwave radiation in a solvent such as ethanol or THF.
Alternatively, the conversion of the compound of formula (XIV) to the compound of formula (Ik) can be achieved by the formation of a tertiary amine (Im) wherein Ra and Rb ≠ H. By reaction with a secondary amine RaRbReaction of NH, a tertiary amine compound of formula (Im) can be prepared from the compound of formula (XIV). Typical reaction conditions include: a base (such as cesium carbonate or potassium carbonate) is used at room temperature in a solvent (such as DMF). Compounds of formula (Im) (where R is methyl bromide, methyl iodide or methyl benzenesulfonate) may be achieved using methylating agents such as methyl bromide, methyl iodide or methyl benzenesulfonateaAnd RbNot equal to H) to the compound of formula (Ik). Typical reaction conditions consist of the following conditions: using a solvent such as MeCN or acetone at a temperature of room temperature to 60 ℃, under conventional heating or microwave heating.
Furthermore, by reaction with ammonia or a suitable primary amine, respectively, RaNH2The primary and secondary amine compounds of formula (Im) can also be prepared from compounds of formula (XIV).
The following compounds, shown in schemes 14-17, can also be prepared by one skilled in the art.
Scheme 14
According to scheme 14, compounds of formula (Iq), (Io) and (Ip), i.e. compounds of formula (I) as described above, wherein a is prepared3--A4is-CR4or-CR4＝CR9And R is4Is NH2Or NHCOR12A group. Compounds of formula (Io) may also be prepared according to scheme 4.A compound of formula (XII) (wherein A is prepared from3--A4is-CR4or-CR4＝CR9And R is4Is NH2Or NHCOR12Group) preparation of a compound of formula (XV) wherein A3--A4is-CR4or-CR4＝CR9And R is4Is NH2Or NHCOR12A group. Typical conditions include: (XII) is stirred with NBS in a suitable solvent such as THF at ambient temperature. The compounds of formula (XVII) can be formed from compounds of formula (XV) by nucleophilic displacement of cyanide to bromide, wherein A3--A4is-CR4or-CR4＝CR9And R is4Is NH2Or NHCOR12A group. Typical conditions include: compound (XV) is stirred with a metal cyanide such as sodium cyanide or potassium cyanide in a suitable solvent such as water or DMF at ambient temperature. The compound of formula (Iq) may be prepared from the compound of formula (XVII). Typical conditions include: (XVII) is stirred with the desired arylhydrazine in a high boiling solvent such as n-butanol at reflux temperature.
The compound of formula (Vd) (i.e. the compound of formula (V) as defined above, wherein A is3--A4is-CR4or-CR4＝CR9And R is4Is NH2Or NHCOR12Group) preparation of a compound of formula (XVIII) wherein A3--A4is-CR4or-CR4＝CR9And R is4Is NH2Or NHCOR12A group. Typical conditions include: in the presence of a palladium catalyst such as Pd2(PPh3)2Cl2Aryl bromide is heated with sodium formate and carbon monoxide gas (at atmospheric pressure or pressures up to 150 psi) in the presence of a high boiling point solvent such as DMF at a temperature between 100 ℃ and 150 ℃. Compounds of formula (XIX) can be prepared from compounds of formula (XVIII) wherein A3--A4is-R4or-CR4＝CR9And R is4Is NH2Or NHCOR12A group; typical conditions include: compound (XVIII) is stirred with the desired aniline (e.g., para-cyanoaniline) in the presence of a strong acid (such as para-toluenesulfonic acid) in a high boiling solvent (such as toluene) under azeotropic removal of water (such as in a Dean-Stark apparatus). Compounds of formula (Io) can be prepared from compounds of formula (XIX) by reaction with Tosylmethylisocyanate (TOSMIC) (for a representative procedure, see EP 1424329). Typical reaction conditions include: stirred in a solvent such as dimethoxyethane at ambient temperature.
The compounds of formula (Ip) may be prepared from compounds of formula (XVIII). Typical conditions include: the desired aniline (e.g. para-cyanoaniline) is stirred with glyoxal in a suitable solvent (such as methanol) at ambient temperature, followed by addition of compound (XVIII) and ammonium chloride and stirring at reflux in the presence of a strong acid (such as phosphoric acid) (for a representative protocol, see WO 2008/54584).
According to scheme 15, compounds of formula (Iu), (Ir), (Is) and (It), i.e. compounds of formula (I) as described above, wherein a Is, can be synthesized from compounds of formula (Vd) as defined above3--A4is-CR4or-CR4＝CR9And R is4Is NH2Or NHCOR12A group. The compounds of formula (XX) may be prepared from compounds of formula (Vd) by palladium catalysed carbonylation, wherein A3--A4is-CR4or-CR4＝CR9And R is4Is NH2Or NHCOR12A group. Typical conditions include: in the presence of a suitable metal carbonyl compound (such as molybdenum hexacarbonyl), a suitable palladium catalyst/ligand system such as trans-bis (acetoxy) bis [ o- (di-o-tolylphosphino) benzyl]Dipalladium (II)/tri-tert-butylphosphine (Herrmann-Beller catalyst) and a suitable base (such as DBU) in the presence of a suitable solvent (such as dipalladium (II)/tri-tert-butylphosphineAlkane), microwave heating the mixture of (XX) and hydroxylamine hydrochloride at a temperature of 120 ℃ to 150 ℃. A compound of formula (XXI) may be prepared from a compound of formula (XX) by reaction with a carbon electrophile such as dimethylformamide dimethyl acetal (DMF-DMA), wherein A3--A4is-CR4or-CR4＝CR9And R is4Is NH2Or NHCOR12A group. Typical conditions include: (XX) is heated with DMF-DMA using microwave radiation in a suitable solvent such as THF at a temperature of 80-100 ℃. Compounds of formula (Iu) may be prepared from compounds of formula (XXI) by heating with a suitable aryl hydrazine, such as para-cyanophenylhydrazine, using microwave radiation in a suitable solvent, such as acetic acid, at a temperature between 80-100 ℃ (for representative procedures, see US 4259504).
Compounds of formula (XXIIa) can be prepared from compounds of formula (Vd) by palladium catalysed carbonylation, wherein A3--A4is-CR4or-CR4＝CR9And R is4Is NH2Or NHCOR12A group. Typical conditions include: in the presence of a suitable metal carbonyl compound (such as molybdenum hexacarbonyl), a suitable palladium catalyst/ligand system such as trans-bis (acetoxy) bis [ o- (di-o-tolylphosphino) benzyl]Dipalladium (II)/tri-tert-butylphosphine and a suitable base (such as DBU) in the presence of a suitable solvent (such as diAlkane), microwave heating (Vd) and a suitable aniline, such as para-cyanoaniline, at a temperature between 120 ℃ and 150 ℃. Compounds of formula (XXIIb) may be prepared from compounds of formula (XXIIa) by treatment with Lawson's reagent in a suitable solvent such as THF at a temperature between 80-100 deg.C, wherein A3--A4is-CR4or-CR4＝CR9And R is4Is NH2Or NHCOR12A group. Alternatively, by making appropriateThe compound of formula (XXIIb) can be prepared from the compound of formula (Vd) by treatment with a suitable organolithium reagent (such as n-butyllithium) in a solvent (such as THF) at a temperature between-78 ℃ and 0 ℃ and treatment of the resulting anion with a suitable isothiocyanate (such as p-cyanobenzene isothiocyanate) at a temperature between-78 ℃ and 0 ℃. Compounds of formula (Ir) can be prepared from compounds of formula (XXIIb) by reaction with an appropriately substituted hydrazine. Typical conditions include: (XXIIb) is heated with the formyl hydrazine in a suitable solvent (such as DMF) at reflux temperature (150-. Compounds of formula (Is) may be prepared from compounds of formula (XXIIb) by reaction with hydrazine hydrate in a suitable solvent (such as ethanol) at a temperature of 50-70 ℃ followed by cyclisation with cyanogen bromide in a suitable solvent (such as methanol) at ambient temperature (for a representative protocol see biorg. med. chem. letters 1998,8(22), 3153). The compound of formula (It) can be prepared from the compound of formula (XXIIb) by reaction with an appropriately substituted hydrazine. Typical conditions include: in the presence of mercuric (II) chloride and a suitable base (such as pyridine) in a suitable solvent (such as diethyl ether)Alkane), at reflux temperature, (XXIIb) is heated with methyl carbazate (see US2008/125587 for representative procedures). Alternatively, compounds of formula (It) may be prepared from compounds of formula (XXIIa) by treatment with a suitable chlorinating agent, such as thionyl chloride, at temperatures between room temperature and reflux. The resulting imidate can be converted to the compound of formula (It) by treatment with a suitable hydrazide such as ethyl hydrazinoformate followed by cyclization with a suitable base such as sodium methoxide.
Scheme 16
According to scheme 16, compounds of formula (Iw), i.e. formula (Iw) as described above, may be prepared from compounds of formula (Vd)(I) A compound of (1), wherein A3--A4is-CR4or-CR4＝CR9And R is4Is NH2Or NHCOR12A group. Compounds of formula (XXIII) can be prepared from compounds of formula (Vd) by Sonogashira coupling, wherein A3--A4is-R4or-CR4＝CR9And R is4Is NH2Or NHCOR12A group. Typical reaction conditions include: (Vd) is stirred with an appropriately substituted alkyne (such as p-cyanophenylacetylene) in the presence of copper (I) iodide and a suitable base (such as triethylamine) in a suitable solvent (such as THF) at a temperature from ambient temperature to 60 ℃. The compounds of the formula (XXIV) can be prepared from the compounds of the formula (XXIII) by hydrolysis, in which A3--A4is-CR4or-CR4＝CR9And R is4Is NH2Or NHCOR12A group. Typical conditions include: heating (XXIII) in a suitable solvent, such as formic acid, using microwave radiation at a temperature between 100 ℃ and 120 ℃. A compound of formula (XXV) may be synthesized from a compound of formula (XXIV) by treatment with a carbon electrophile such as dimethylformamide dimethyl acetal (DMF-DMA), wherein A3--A4is-CR4or-CR4＝CR9And R is4Is NH2Or NHCOR12A group. Typical conditions include: (XXIV) is heated with DMF-DMA using microwave radiation in a suitable solvent such as THF at a temperature between 80-100 ℃. The compound of formula (Iw) may be prepared from the compound of formula (XXV) by treatment with hydroxylamine (wherein X ═ O) or hydrazine (wherein X ═ NH). Typical conditions include: (XXV) is heated together with the relevant nucleophile using microwave radiation in a suitable solvent such as ethanol at a temperature between 80-100 ℃ (for a representative protocol see eur.j.med.chem.2010,45(11), 4887; for X ═ NH, see WO 2009/137538).
Scheme 17
According to scheme 17, compounds of formula (Iy) and (Iv), i.e. compounds of formula (I) as described above, can be prepared from compounds of formula (XXIV) as defined above, wherein a3--A4is-CR4or-CR4＝CR9And R is4Is NH2Or NHCOR12A group. Compounds of formula (XXVI) may be prepared from compounds of formula (XXIV) by treatment with a suitable brominating agent, such as N-bromosuccinimide (NBS) or bromine, wherein A3--A4is-CR4or-CR4＝CR9And R is4Is NH2Or NHCOR12A group. Typical conditions include: (XXIV) is stirred with bromine in the presence of acetic acid in a suitable solvent such as THF at ambient temperature. Compounds of formula (Iy) may be prepared from (XXVI) by treatment with formamide, wherein X ═ NH. Typical conditions include: (XXVI) is stirred with formamide in a suitable solvent such as water at reflux temperature. Compounds of formula (Iy) can be prepared from (XXVI) by treatment with formic acid, wherein X ═ O. Typical conditions include: (XXVI) is heated together with formic acid in the presence of ammonium formate at reflux temperature. By using phosphorus pentasulfide (P)2S5) And formamide treatment, a compound of formula (Iy) can be prepared from (XXVI), wherein X ═ S. Typical conditions include: (XXVI) is reacted with P in a suitable solvent such as toluene at reflux temperature2S5And formamide (for a representative protocol, see j.med. chem.2005,48(6),1849 for X ═ O; US4576958 for X ═ S; US4451471 for X ═ S).
Compounds of formula (Iv) may be prepared from (XXVI) by treatment with N-acylguanidine, where X ═ NH. Typical conditions include: (XXVI) is stirred with N-acylguanidine in a suitable solvent such as DMF at ambient temperature and the product obtained is subsequently deacetylated in a suitable solvent (usually methanol/water) at reflux temperature with a strong acid (usually sulphuric acid). Compounds of formula (Iv) can be prepared from (XXVI) by treatment with urea, where X ═ O. Typical conditions include: (XXVI) is stirred with urea in a suitable solvent such as DMF at reflux temperature. Compounds of formula (Iv) can be prepared from (XXVI) by treatment with thiourea. Typical conditions include: (XXVI) is stirred with thiourea in a suitable solvent (such as ethanol) and heated to 100-.
According to scheme 18, compounds of formula (Iz), i.e. compounds of formula (I) as described above, wherein a is synthesized from compounds of formula (Vd) wherein3--A4is-CR4or-CR4＝CR9And R is4Is NH2Or NHCOR12A group. Compounds of formula (XXVII) may be prepared from compounds of formula (Vd) by palladium catalysed carbonylation, wherein A3--A4is-R4or-CR4＝CR9And R is4Is NH2Or NHCOR12A group. Typical conditions include: in the presence of a suitable metal carbonyl compound (such as molybdenum hexacarbonyl), a suitable palladium catalyst/ligand system such as trans-bis (acetoxy) bis [ o- (di-o-tolylphosphino) benzyl]Dipalladium (II)/tri-tert-butylphosphine (Herrmann-Beller catalyst) and a suitable base (such as DBU) in a suitable solvent (such as MeCN/methanol) at a temperature of 120 ℃ to 150 ℃ with microwave heating (Vd). A compound of formula (XXVIII) can be prepared from a compound of formula (XXVII) by hydrolysis, for example with lithium hydroxide, in a solvent such as THF and water, wherein A3--A4is-CR4or-CR4＝CR9And R is4Is NH2Or NHCOR12A group. The compounds of formula (XXVIII) can be synthesized from compounds of formula (XXVIII) by amide formation using appropriately substituted thioureas and coupling agents such as HATU in solvents such as THF and bases such as triethylamine at temperatures between room temperature and 80 ℃(XXIX) compound wherein A3--A4is-CR4or-CR4＝CR9And R is4Is NH2Or NHCOR12A group. Compounds of formula (XXX) may be prepared from compounds of formula (XXIX) by reaction with an appropriately substituted hydrazine, wherein A3--A4is-CR4or-CR4＝CR9And R is4Is NH2Or NHCOR12A group. Typical conditions include: (XXIX) is heated with the arylhydrazine in the presence of a suitable base such as DIPEA in a suitable solvent such as DMF at 80 ℃. Compounds of formula (Iz) may be prepared from compounds of formula (XXX) by acetylation with acetyl chloride in a solvent containing a base such as triethylamine, such as THF, followed by deprotection with an acid such as TFA in a solvent such as DCM at room temperature, or by direct deprotection of (XXX) without an acetylation step.
According to scheme 18, compounds of formula (Iz'), i.e., compounds of formula (I) as described above, wherein a is may also be synthesized from compounds of formula (Vd) wherein3--A4is-CR4or-CR4＝CR9And R is4Is NH2Or NHCOR12A group. Compounds of formula (XXXI) may be prepared from compounds of formula (XXVIII) by reaction with an appropriately substituted amidine such as amino-imino-acetic acid methyl ester. Typical conditions include: treatment of (XXVIII) with amidine in the presence of a suitable coupling agent such as HATU using a base such as DIPEA in a suitable solvent such as DMF at room temperature. Compounds of formula (Iz') may be prepared from compounds of formula (XXXI) by reaction with an appropriately substituted aryl hydrazine, such as 4-hydrazino-benzonitrile, in a solvent such as acetic acid at a temperature between room temperature and reflux.
Finally, corresponding compounds of formulae (Iq), (Io), (Ip), (Iu), (Ir), (Is), (It), (Iw), (Iv), (Iy), (Iz) and (Iz') (wherein R Is R) can be isolated from the corresponding compounds by hydrolysis under suitable acid or base conditions4Aroyl (or other suitable protecting group)) to prepare formula (Iq), (Io), (Ip), (Iu), (Ir), (Is), (It), (Iw), (Iv), (I), (ii), and (Iv))y), (Iz) and (Iz') (wherein R4＝NH2). Typical alkaline conditions include: compounds of formula (Iq), (Io), (Ip), (Iu), (Ir), (Is), (It), (Iw), (Iv), (Iy), (Iz) and (Iz') (wherein R Is R) are reacted in a suitable solvent such as methanol4Acetyl) with a base such as potassium carbonate at ambient temperature. According to scheme 1, compounds of formula (Iq), (Io), (Ip), (Iu), (Ir), (Is), (It), (Iw), (Iv), (Iy), (Iz) and (Iz') can be achieved (wherein R Is4＝NH2) To wherein R4＝-NR10R11、-NHCOR12、-NHCOO-R13、-NHCONH-R14、-NSO2Alkyl and- (NH) r (CH)2)CONR15R16Further details of the compounds of (1). According to scheme 13, a detailed description of these compounds with suitable leaving groups (X ═ Cl, Br, I, tosylate, etc.) to amino or quaternary amino compounds can be obtained.
The following compounds may be prepared according to appropriate modifications of the synthetic schemes/methods or experimental protocols reported herein, as would be known to one skilled in the art:
1- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -3- [3- (piperidin-4-ylamino) -propyl ] -urea;
4- {5- [2- {3- [ (azetidin-3-ylmethyl) -amino ] -propylamino } -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
4- {5- [ 7-methyl-2- [3- (piperidin-4-ylamino) -propylamino ] -8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
1- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -3- {3- [ (3-dimethylamino-propyl) -methyl-amino ] -propyl } -urea;
4- {5- [2- {3- [ (3-dimethylamino-propyl) -methyl-amino ] -propylamino } -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
4- {5- [ 7-methyl-2- [3- (4-methylamino-piperidin-1-yl) -propylamino ] -8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
1- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -3- [2- (4-methylamino-piperidin-1-yl) -ethyl ] -urea;
n- [6- [4- (4-cyano-phenyl) -5-oxo-4, 5-dihydro-1H- [1,2,4] triazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -acetamide;
4- {5- [ 7-methyl-2- [2- (piperidin-4-ylamino) -ethylamino ] -8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
4- {3- [ 2-amino-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -5-oxo-1, 5-dihydro- [1,2,4] triazol-4-yl } -benzonitrile;
1- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -3- (R) -piperidin-3-yl-urea;
{3- [6- [2- (4-cyano-phenyl) -5-methoxycarbonyl-2H- [1,2,4] triazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5a ] pyridin-2-ylcarbamoyl ] -propyl } -ammonium trimethyl formate;
(3- {2- [6- [2- (4-cyano-phenyl) -2H- [1,2,4] triazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-ylcarbamoyl ] -ethanesulfonyl } -propyl) -trimethyl-ammonium formate;
n- [6- [2- (4-cyano-phenyl) -2H- [1,2,4] triazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -3-dimethylamino-propionamide;
n- [6- [2- (4-cyano-phenyl) -2H- [1,2,4] triazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -3- (3-dimethylamino-propane-1-sulfonyl) -propionamide;
3- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -1- (3-dimethylamino-propyl) -1-methyl-urea;
1- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -3- (S) -piperidin-3-yl-urea;
{3- [6- [ 5-carboxy-2- (4-cyano-phenyl) -2H- [1,2,4] triazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-ylcarbamoyl ] -propyl } -trimethyl-ammonium formate;
{3- [6- [2- (4-cyano-phenyl) -5-methoxycarbonyl-2H- [1,2,4] triazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-ylcarbamoyl ] -propyl } -trimethyl-ammonium bromide;
carboxymethyl- (3- {3- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -ureido } -propyl) -dimethyl-ammonium formate;
1- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -3- (3-methylamino-propyl) -urea;
1- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -3- (3-dimethylamino-propyl) -urea;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -3-guanidino-propionamide;
{3- [6- [2- (4-cyano-phenyl) -2H- [1,2,4] triazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-ylcarbamoyl ] -propyl } -trimethyl-ammonium bromide;
n- [6- [1- (4-cyano-phenyl) -1H-imidazol-2-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -acetamide;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -4-hydroxy-butyramide;
n- [6- [2- (4-cyano-phenyl) -2H- [1,2,4] triazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -4-dimethylamino-butyramide;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -3-hydroxy-propionamide;
n- [6- [2- (5-cyano-pyridin-2-yl) -2H- [1,2,4] triazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -acetamide;
n- [6- [3- (4-cyano-phenyl) -3H-imidazol-4-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -acetamide;
n- [6- [ 5-amino-2- (4-cyano-phenyl) -2H- [1,2,4] triazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -acetamide;
5- [ 2-acetylamino-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -1- (4-cyano-phenyl) -1H- [1,2,4] triazole-3-carboxylic acid methyl ester;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -succinamide;
n- [6- [ 5-acetylamino-2- (4-cyano-phenyl) -2H- [1,2,4] triazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -acetamide; and
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -N '- (2-dimethylamino-ethyl) -N' -methylsuccinamide.
General experimental details
NMR spectra were obtained on a Varian Unity Inova 400 spectrometer (with a 5mm inverted detection triple resonance probe operating at 400 MHz), or on a Bruker Avance DRX 400 spectrometer (with a 5mm inverted detection triple resonance TXI probe operating at 400 MHz), or on a Bruker Avance DPX 300 spectrometer (with a standard 5mm dual frequency probe operating at 300 MHz). Migration is given in ppm relative to tetramethylsilane. The following abbreviations have been used: br is broad signal, s is singlet, d is doublet, dd is doublet, t is triplet, td is triplet of doublet, q is quartet, and m is multiplet. NMR analysis of the compound purified by HPLC showed different amounts of formic acid equivalents (not depicted).
Purification by chromatography indicates the usePurification of the purification system or the biotage sp1 purification system. In useIn the case of column purification of the product, the ` Isolute SPE Si column ` represents a pre-packed polypropylene column containing irregular particles of unbound active silica having an average size of 50 μm and a nominal sizePorosity of the porous material. For alternative purification, in useIn the case of a column,'Column' represents a pre-packed polypropylene column containing an uncapped propyl sulfonic acid functionalized silica strong cation exchange adsorbent. Similarly, in through'In the case of column' purification of the product, this means a pre-packed polypropylene column containing a silica-based adsorbent having chemically bonded quaternary ammonium functional groups.
Where Thin Layer Chromatography (TLC) has been used, it represents a silica gel TLC using flat plates (typically 3X 6cm silica gel with a fluorescent indicator (254nm) on aluminium foil plates), e.g.Fluka 60778. All solvents and commercial reagents were used as received.
Compounds purified by preparative HPLC were purified as follows: use of C18-reverse phase column (100 × 22.5.5 mm inner diameter Genesis column with 7 μm particle size, or 250 × 21.2.2 mm inner diameter Gemini column with 5 μm particle size) or Phenyl-cohexyl column (250 × 21.2.2 mm inner diameter Gemini column with 5 μm particle size), with uv detection at 220, 230 or 254nm, flow rate of 10-20mL/min, eluting with 95-5% to 5-95% water/acetonitrile or water/MeOH gradient containing 0.1% TFA or 0.1% formic acid.
Biotage Initiator 60 was usedTMPerforming a microwave experiment, wherein the Biotage Initiator 60TMSingle mode resonators and dynamic zone tuning are used. Temperatures of 40-250 ℃ can be reached, and pressures of up to 30 bar can be reached.
In MDL ISISTMThe Autonom 2000 part was used in the/Draw 2.5SP2 software to generate compound names.
Analysis of LC-MS conditions
Method 1
Method 2
Method 3
Method 4
Method 5
Abbreviations
aq is aqueous; app is apparent; bs (nmr) broad singlet; the temperature is equal to the centigrade temperature; CDCl3Deuterated chloroform; DCM ═ dichloromethane/dichloromethane; d (nmr) bimodal; dd (nmr) doublet; DAD ═ diode array detection (LCMS); DIPEA ═ diisopropylethylamine; DMF ═ N, N-dimethylformamide; DMSO ═ dimethyl sulfoxide; DMSO-d6Deuterated dimethyl sulfoxide; et ═ ethyl; EtOAc ═ ethyl acetate; EtOH ═ ethanol; ex — example; g is gram; NMR ═ nuclear magnetic resonance; HATU ═ O- (7-azabenzotriazol-1-yl) -N, N' -tetramethylUronium hexafluorophosphate; HCl ═ hydrochloric acid; HPLC ═ high pressure liquid chromatography; hr-hour; hz is hertz; IMS ═ industrial methanolated alcohol (3-5% methanol in ethanol solution); int ═ intermediate; IPA ═ isopropyl alcohol; iPr ═ isopropyl; k2CO3Potassium carbonate; lawson reagent ═ 2, 4-bis (4-methoxyphenyl) -1,3,2, 4-dithiadiphosphetane (dithiadiphosphetane) -2, 4-disulfide; LC-MS is combined with liquid chromatography and mass spectrometry; m (nmr) ═ multiplet; m-molarity (concentration); MeBr ═ bromomethane; MeCN ═ acetonitrile; MeOH ═ methanol; mg ═ mg; MgSO (MgSO)4Magnesium sulfate; MHz-megahertz; min(s) minutes; mmol to millimole; mol is mol; n-standard (concentration); na (Na)2SO4Sodium ═ sulfate; NaOMe ═ sodium methoxide; NH (NH)3＝Ammonia; NMP ═ N-methyl 2-pyrrolidone; pr is n-propyl; q (nmr) quartet; qn (nmr) quintet; rf ═ retention factor (TLC); RT — room (ambient) temperature; rt ═ retention time (LCMS or HPLC); s (nmr) singlet; SCX-2 ═ strong cation exchange resin; t (nmr) triplet; TFA ═ trifluoroacetic acid; THF ═ tetrahydrofuran; TLC ═ thin layer chromatography; chemical shift values in parts per million relative to tetramethylsilane.
Detailed synthetic routes and protocols for specific examples are described in examples 1-61.
Examples 62-97 were prepared according to the protocol described above. And reported them1H NMR and LCMS data.
In the following procedures, following each starting material, a reference to the compound number is sometimes provided. This is provided merely to assist the skilled chemist. The starting materials are not necessarily already prepared from the mentioned batches.
When referring to the use of "similar" or "analogous" procedures, one skilled in the art will appreciate that such procedures may involve minor variations, such as reaction temperature, reagent/solvent amounts, reaction times, work-up conditions, or chromatographic purification conditions.
Example 1
4- {5- [ 2-amino-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]]Triazolo [1,5-a]Pyridine-6- Base of]-pyrazol-1-yl } -benzonitrile
Step 1
5-bromo-4-methyl-3- (3-trifluoromethyl-phenyl) -pyridin-2-ylamine(intermediate 1)
5-bromo-3-iodo-4-methyl-pyridin-2-ylamine (20.0g,63.9mmol) and 3- (trifluoromethyl) phenylboronic acid (12.73g,67.0mmol) were combined with sodium carbonate (2M,160mL,320mmol), toluene (570mL) and IMS (190mL) and degassed. 1,1' -bis (diphenylphosphino) ferrocene dichloropalladium (II) dichloromethane (3.13g,36.83mmol) was added and the reaction mixture was degassed again and then heated to reflux for 2 h. The second reaction was carried out on a 1.08-fold scale. The two batches were combined and the solvent was removed in vacuo and the resulting mixture was partitioned between DCM and water. The organic phase was separated, washed with water and dried (Na)2SO4) And concentrated in vacuo. The resulting residue was purified by flash chromatography through a pad of silica gel (silica) eluting with a gradient of 5-30% EtOAc in cyclohexane to give the title compound as a beige solid (34.6 g).
LC-MS (method 1) Rt 3.30min, M/z 331/333[ M + H]+
Step 2
6-bromo-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-ylamines(intermediate 2)
5-bromo-4-methyl-3- (3-trifluoromethyl-phenyl) -pyridin-2-ylamine (intermediate 1,12.0g,36.25mmol) was added to diAlkyl (250mL) was stirred at room temperature and ethoxycarbonyl isothiocyanate (4.27mL,36.25mmol) was added dropwise. The reaction mixture was stirred for 18h, then the solvent was evaporated in vacuo. The resulting residue was dissolved in MeOH/IMS (1:1,460mL) and hydroxylamine hydrochloride (12.58g,181mmol) was added and the reaction mixture was heated to 60 ℃. DIPEA (18.6mL,109mmol) was added and the reaction mixture was heated for an additional 4.5h, then cooled. The resulting precipitate was collected by filtration, washed with MeOH and dried to give the title compound as a white solid (11.49 g).
LC-MS (method 2) Rt 3.45min, M/z 371/373[ M + H]+
Step 3
4- (5-Tributylstannanyl-pyrazol-1-yl) -benzonitrile (intermediate 3)
Hexyllithium (2.3M in hexanes) (16.96mL,39.01mmol) was added to a stirred solution of 2,2,6, 6-tetramethyl-piperidine (6.85mL,40.63mmol) in anhydrous THF (15mL) at-30 deg.C, and the resulting suspension was stirred for 20 minutes. The suspension was warmed to 10 ℃ to aid dissolution and 4-pyrazol-1-yl-benzonitrile (5.50g,32.51mmol, according to Bioorganic) was added via cannula at-78 ℃&Medicinal Chemistry Letters,2006,16(11),2955-2959 preparation) in THF (85mL) while maintaining the internal reaction temperature<-50 ℃. The resulting reaction mixture was stirred at-75 ℃ for 4h, and tributyltin (IV) chloride (9.08mL,33.49mmol) was added, which was maintained during the additionInternal reaction temperature<The reaction mixture was stirred at-60 ℃ for 1.5h, then allowed to warm to room temperature the resulting solution was quenched by addition of EtOAc (100mL), then washed with water (2 × 50mL), followed by saturated brine (50mL)2SO4) Filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography, eluting with a gradient of 0-5% EtOAc in pentane to give the title compound (10.11g) as an amber oil which solidified upon standing.
LC-MS (method 1) with Rt 5.36min, M/z 459[ M + H ]]+
Step 4
4- {5- [ 2-amino-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]]Triazolo [1,5-a]Pyridine-6- Base of]-pyrazol-1-yl } -benzonitrile(example 1)
Reacting 6-bromo-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]]Triazolo [1,5-a]Pyridin-2-ylamine (intermediate 2,100mg,0.27mmol) and 4- (5-tributylstannyl) -pyrazol-1-yl) -benzonitrile (intermediate 3,115mg,0.25mmol) were dissolved in THF (5mL) and degassed, then bis (triphenylphosphine) palladium (II) dichloride (18mg,0.025mmol) was added, the reaction mixture was stirred at reflux temperature for 21h, then cooled, then washed with cesium fluoride (saturated aqueous solution) and extracted with EtOAc (2 × 30mL), the combined organic extracts were filtered and the filtrate concentrated in vacuo, the resulting residue was subjected to preparative C18HPLC, eluting with a gradient of 40-90% MeCN in water (+ 0.1% formic acid) gave 51mg of impure title compound (containing 25% starting material) dissolved and degassed in THF (3mL) together with 4- (5-tributylstannyl-pyrazol-1-yl) -benzonitrile (intermediate 3,4.72g,0.103mmol) and then bis (triphenylphosphine) palladium (II) dichloride (10mg,0.014mmol) was added. The reaction mixture was heated at 75 ℃ for 6.5h, then a SCX-2 column (loaded in MeOH/with 2N NH) was used3Solution in MeOH) was eluted. The resulting residue was dissolved in MeOH (5mL) and washed with 3-mercaptopropylethylsulfide silica gel (silica) (Phosphonic SPM 32,0.5 weight equivalents)) Treated and stirred at 50 ℃ for 1h, then filtered and evaporated. The resulting residue was dissolved in DCM, then filtered and evaporated in vacuo, then passed through preparative C18HPLC further purification, eluting with a gradient of 40-90% MeCN in water (+ 0.1% formic acid) gave the title compound (25mg) as a white solid.
LC-MS (method 3) Rt 4.63min, M/z 460.0[ M + H [, et al]+
1H NMR(400MHz,DMSO-d6)8.67(1H,s),7.95(1H,d J＝1.8Hz),7.92-7.87(2H,m),7.77(1H,d J＝7.6Hz),7.72(1H,t J＝8Hz),7.66(1H,s),7.63(1H,d J＝7.6Hz),7.59-7.54(2H,m),6.76(1H,d J＝1.8Hz),6.14(2H,s),1.69(3H,s)。
Example 2
N- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2, 4]triazolo [1,5-a]Pyridin-2-yl]-2,2, 2-trifluoro-acetamide
Step 1
N- [ 5-bromo-4-methyl-3- (3-trifluoromethyl-phenyl) -pyridin-2-yl]-4-methyl-benzenesulfonamide(intermediate 4)
To a solution of 5-bromo-4-methyl-3- (3-trifluoromethyl-phenyl) -pyridin-2-ylamine (intermediate 1,1.91g,5.77mmol) in pyridine (25mL) was added p-toluenesulfonyl chloride (1.75g,9.18mmol), and the reaction mixture was heated at 80 ℃ for 23 h. The solvent was removed by evaporation in vacuo, then the residue was purified by flash chromatography, eluting with a gradient of 0-30% EtOAc in cyclohexane to give the title compound as an off-white solid (2.41 g).
LC-MS (method 2) Rt 3.65min, M/z 485/487[ M []+
Step 2
N- [ 6-bromo-7-methyl-8- (3-trifluoromethyl-phenyl) -imidazo [1,2-a]Pyridin-2-yl]-2,2, 2-tris Fluoro-acetamides(intermediate 5)
To N- [ 5-bromo-4-methyl-3- (3-trifluoromethyl-phenyl) -pyridin-2-yl]-4-methyl-benzenesulfonamide (intermediate 4,800mg,1.65mmol) in DMF (10mL) added sodium hydride (79mg,1.98 mmol.) the reaction mixture was stirred at room temperature for 30 minutes then 2-iodoacetamide (366mg,1.98 mmol.) the reaction mixture was stirred at room temperature for 2h then at 60 ℃ for 21h then partitioned between EtOAc (20mL) and water (20 mL.) the aqueous phase was extracted with EtOAc (3 × 20mL) and the combined organic extracts were dried (Na)2SO4) Filtered and concentrated in vacuo. The resulting residue was dissolved in DCM (15mL) and treated with trifluoroacetic anhydride (15mL), then the mixture was heated at reflux for 1.5 h. The reaction mixture was evaporated in vacuo and then partitioned between DCM and water. The organic phase was separated and concentrated in vacuo. The residue was triturated with MeOH to give a yellow precipitate, which was collected by filtration to give the title compound (118 mg).
LC-MS (method 1) Rt 3.61min, M/z 465.8/468[ M ]]+
Step 3
N- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) -imidazo [1,2-a]Pyridin-2-yl]-2,2, 2-trifluoro-acetamide(example 2)
The title compound (6mg) was prepared from N- [ 6-bromo-7-methyl-8- (3-trifluoromethyl-phenyl) -imidazo [1,2-a ] pyridin-2-yl ] -2,2, 2-trifluoro-acetamide (intermediate 5,35mg,0.075mmol) and 4- (5-tributylstannyl-pyrazol-1-yl) -benzonitrile (intermediate 3,52mg,0.113mmol) using a method analogous to that used in example 1 (step 4).
LC-MS (method 3) Rt 4.70min, M/z 555.0[ M + H]+
1H NMR(400MHz,DMSO-d6)8.50(1H,s),7.99(1H,d J＝1.7Hz),7.91-7.86(2H,m),7.83(1H,d J＝7.7Hz),7.79-7.72(1H,m),7.71-7.63(3H,m),7.61-7.56(2H,m),6.81(1H,s),1.65(3H,s)。
Example 3
4- {5- [ 7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]]Triazolo [1,5-a]Pyridin-6-yl]-pyrazole- 1-yl } -benzonitrile
Step 1
6-bromo-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]Triazolo [1,5-a]Pyridine compound(intermediate 6)
A suspension of 5-bromo-4-methyl-3- (3-trifluoromethyl-phenyl) -pyridin-2-ylamine (intermediate 1,1.0g,3.02mmol) in IPA (3mL) was treated with dimethylformamide dimethyl acetal (522 uL, 3.93mmol) and then heated at reflux for 3 h. The reaction mixture was cooled to 50 ℃ and hydroxylamine hydrochloride (273mg,3.93mmol) was added. The reaction mixture was stirred at 50 ℃ for 1.5h, then cooled and the resulting precipitate was collected by filtration and washed with IMS. The solid thus obtained was dissolved in THF (10mL) and cooled to0 deg.C, trifluoroacetic anhydride (481. mu.L, 3.46mmol) was then added dropwise, keeping the internal temperature below 10 deg.C after the end of the addition, the reaction mixture was stirred at room temperature for 18h, sodium bicarbonate (5% solution, 25mL) was added, and the mixture was extracted with EtOAc (2 × 25mL), the combined organic extracts were washed with 5% sodium bicarbonate solution (15mL) and then dried (Na)2SO4) Filtration and concentration in vacuo gave the title compound (1.05g) as a white solid.
LC-MS (method 2) Rt 3.74min, M/z 355.9[ M []+
Step 2
4- {5- [ 7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]]Triazolo [1,5-a]Pyridin-6-yl]-pyrazole- 1-yl } -benzonitrile(example 3)
The title compound (91mg) was prepared from 6-bromo-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridine (intermediate 6,100mg,0.281mmol) and 4- (5-tributylstannyl-pyrazol-1-yl) -benzonitrile (intermediate 3,193mg,0.421mmol) using a method similar to that used in example 1 (step 4).
LC-MS (method 3) Rt 4.94min, M/z 444.9[ M + H]+
1H NMR(400MHz,DMSO-d6)9.15(1H,s),8.49(1H,s),8.00(1H,d J＝1.9Hz),7.91-7.86(2H,m),7.84(1H,d J＝8Hz),7.78-7.73(2H,m),7.70(1H,d J＝8Hz),7.62-7.57(2H,m),6.84(1H,d J＝1.8Hz),1.80(3H,s)。
Example 4
4- {5- [2, 7-dimethyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]]Triazolo [1,5-a]Pyridin-6-yl]- Pyrazol-1-yl } -benzonitriles
Step 1
6-bromo-2, 7-dimethyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]Triazolo [1,5-a]Pyridine compound(intermediate 7)
To a stirred solution of 5-bromo-4-methyl-3- (3-trifluoromethyl-phenyl) -pyridin-2-ylamine (intermediate 1,1.0g,3.02mmol) in DMF (5mL) was added dimethylacetamide dimethyl acetal (1.33mL,9.06mmol) and the reaction mixture was heated at 130 ℃ for 3 h. The reaction mixture was cooled and then concentrated in vacuo. The resulting residue was dissolved in MeOH (10mL) and pyridine (486. mu.L, 6.04mmol) was added, then the mixture was cooled to 0 deg.C and hydroxylamine-O-sulfonic acid (512mg,4.53mmol) was added. The reaction mixture was warmed to room temperature and stirred at this temperature for 20 h. The resulting precipitate was collected by filtration and then washed with MeOH to give the title compound (323mg) as a grey solid.
LC-MS (method 1) Rt 3.92min, M/z 370/372[ M []+
Step 2
4- {5- [2, 7-dimethyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]]Triazolo [1,5-a]Pyridin-6-yl]- Pyrazol-1-yl } -benzonitriles(example 4)
The title compound (91mg) was prepared from 6-bromo-2, 7-dimethyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridine (intermediate 7,100mg,0.27mmol) and 4- (5-tributylstannyl-pyrazol-1-yl) -benzonitrile (intermediate 3,186mg,0.405mmol) using a method similar to that used in example 1 (step 4).
LC-MS (method 3) with Rt 5.03min, M/z 458.9[ M + H ]]+
1H NMR(400MHz,DMSO-d6)9.00(1H,s),7.99(1H,d J＝1.8Hz),7.91-7.86(2H,m),7.83(1H,d J＝7.9Hz),7.76(1H,d t＝7.8Hz),7.70(1H,s),7.67(1H,d J＝7.8Hz),7.60-7.55(2H,m),6.82(1H,d J＝1.8Hz),2.42(3H,s),1.77(3H,s)。
Example 5
4- {5- [2, 7-dimethyl-8- (3-trifluoromethyl-phenyl) -imidazo [1,2-a [ ]]Pyridin-6-yl]-pyrazole-1- -benzonitrile
Step 1
6-bromo-2, 7-dimethyl-8- (3-trifluoromethyl-phenyl) -imidazo [1,2-a]Pyridine compound(intermediate 8)
5-bromo-4-methyl-3- (3-trifluoromethyl-phenyl) -pyridin-2-ylamine (intermediate 1,500mg,1.51mmol) and 1-chloropropan-2-one (144. mu.L, 1.81mmol) were heated at reflux in IMS (3mL) for 18h, then an additional amount of 1-chloropropan-2-one (144. mu.L) was added. Heating was continued for 24h, then the solvent was evaporated in vacuo and the residue was purified by flash chromatography with a gradient of 0-50% EtOAc in cyclohexane followed by 0-10% (2N NH)3In MeOH) in DCM to give the title compound (455mg) as a beige solid.
LC-MS (method 2) Rt 2.31 and 2.36min, M/z 368.9,370.9[ M + H ═ M]+
Step 2
4- {5- [2, 7-dimethyl-8- (3-trifluoromethyl-phenyl) -imidazo [1,2-a [ ]]Pyridin-6-yl]-pyrazole-1- -benzonitrile(example 5)
The title compound (61mg) was prepared from 6-bromo-2, 7-dimethyl-8- (3-trifluoromethyl-phenyl) -imidazo [1,2-a ] pyridine (intermediate 8,50mg,0.136mmol) and 4- (5-tributylstannyl-pyrazol-1-yl) -benzonitrile (intermediate 3,125mg,0.270mmol) using a method analogous to that used in example 1 (step 4).
LC-MS (method 3) with Rt 3.68min, M/z 458[ M + H ]]+
1H NMR(400MHz,DMSO)8.61(1H,s),7.96(1H,d J＝1.8Hz),7.92-7.87(2H,m),7.79(1H,d J＝8Hz),7.73(1H,t J＝8Hz),7.69(1H,d J＝0.8Hz),7.63(2H,d J＝6.5Hz),7.58-7.54(2H,m),6.76(1H,d J＝1.8Hz),2.26(3H,s),1.64(3H,s)。
Example 6
4- {5- [ 7-methyl-8- (3-trifluoromethyl-phenyl) -imidazo [1,2-a [ ]]Pyridin-6-yl]-pyrazol-1-yl- Benzonitrile
Step 1
6-bromo-7-methyl-8- (3-trifluoromethyl-phenyl) -imidazo [1,2-a]Pyridine compound(intermediate 9)
The title compound (233mg) was prepared from 5-bromo-4-methyl-3- (3-trifluoromethyl-phenyl) -pyridin-2-ylamine (intermediate 1,237mg,0.716mmol) using a method analogous to that used in example 5 (step 1) and substituting 2-chloroacetaldehyde (185 μ L,1.43mmol) for 1-chloropropan-2-one.
LC-MS (method 2) Rt 2.34min, M/z 354.9[ M []+
Step 2
4- {5- [ 7-methyl-8- (3-trifluoromethyl-phenyl) -imidazo [1,2-a]Pyridin-6-yl]-pyrazol-1-yl- Benzonitrile(example 6)
The title compound (28mg) was prepared from 6-bromo-7-methyl-8- (3-trifluoromethyl-phenyl) -imidazo [1,2-a ] pyridine (intermediate 9,30mg,0.085mmol) and 4- (5-tributylstannyl-pyrazol-1-yl) -benzonitrile (intermediate 3,62mg,0.135mmol) using a method analogous to that used in example 1 (step 4).
LC-MS (method 3) Rt 3.56min, M/z 443.9[ M + H]+
1H NMR(400MHz,DMSO-d6)8.72(1H,s),7.98(1H,d J＝1.8Hz),7.96(1H,d J＝1.3Hz),7.93-7.88(2H,m),7.79(1H,d J＝7.9Hz),7.73(1H,t J＝7.8Hz),7.68(1H,s),7.64(1H,d J＝7.8Hz),7.61-7.57(2H,m),7.54(1H,d J＝1.3Hz),6.78(1H,d J＝1.8Hz),1.68(3H,s)。
Example 7
4- {5- [2- (4-methanesulfonyl-phenylamino) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]]Triazole compounds And [1,5-a ]]Pyridin-6-yl]-pyrazol-1-yl } -benzonitrile
Mixing 4- {5- [ 2-amino-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]]Triazolo [1,5-a]Pyridin-6-yl]A mixture of-pyrazol-1-yl } -benzonitrile (example 1,20mg,0.0435mmol), 4-bromophenyl methyl sulfone (20mg,0.087mmol), tris (dibenzylideneacetone) dipalladium (0) (8mg,0.0087mmol), 2 '-bis (diphenylphosphino) -1, 1' -dinaphthalene (16mg,0.026mmol) and sodium tert-butoxide (10mg,0.109mmol) in THF (0.5mL) was degassed and then heated using microwave radiation at 130 ℃ for 1 h. The volatiles were removed in vacuo and the resulting residue was purified by flash chromatography using 0-10% (2N NH)3In MeOH) in DCM, then eluted by preparative HPLC using 40-90% MeCN in water (+0.1% formic acid) to give the title compound (10mg) as a white solid.
LC-MS (method 3) Rt 5.22min, M/z 614.1[ M + H]+
1H NMR(400MHz,DMSO-d6)10.36(1H,s),9.02(1H,s),7.99(1H,d J＝1.8Hz),7.92-7.87(2H,m),7.85-7.74(7H,m),7.70(1H,d J＝7.2Hz),7.64-7.59(2H,m),6.82(1H,dJ＝1.8Hz),3.13(3H,s),1.76(3H,s)。
Example 8
4- {5- [2- (4-methanesulfonyl-benzyl) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2, 4%]A triazolo [1 ] group, a triazolo [1 ], 5-a]pyridin-6-yl]-pyrazol-1-yl } -benzonitrile
Step 1
N- [ 5-bromo-4-methyl-3- (3-trifluoromethyl-phenyl) -pyridin-2-yl]-2- (4-methanesulfonyl-phenyl) -ethanone Amides of carboxylic acids(intermediate 10)
To a suspension of 4- (methylsulfonyl) phenylacetic acid (388mg,1.8mmol) in dry DCM (5mL) was added oxalyl chloride (320. mu.L, 3.6mmol) followed by DMF (2 drops). The reaction mixture was stirred at room temperature for 3h, then the solvent was removed in vacuo. The resulting residue was dissolved in DCM (2mL) at 0-5 ℃ and a stirred solution of 5-bromo-4-methyl-3- (3-trifluoromethyl-phenyl) -pyridin-2-ylamine (intermediate 1,500mg,1.51mmol) and triethylamine (420 μ L,36.02mmol) in DCM (2mL) was added dropwise. The reaction mixture was stirred at 0-5 ℃ for 3h and then gradually warmed to room temperature over 5 h. The reaction mixture was partitioned between saturated sodium bicarbonate solution and DCM. The organic phase was concentrated in vacuo and purified by flash chromatography, eluting with a gradient of 0-100% EtOAc in cyclohexane to give the title compound as an orange glass (308 mg).
LC-MS (method 2) Rt 3.43min, M/z 526.9,528.9[ M + H]+
Step 2
N- [ 5-bromo-4-methyl-3- (3-trifluoromethyl-phenyl) -pyridin-2-yl]-2- (4-methanesulfonyl-phenyl) -thio Acetamide(intermediate 11)
To a suspension of N- [ 5-bromo-4-methyl-3- (3-trifluoromethyl-phenyl) -pyridin-2-yl ] -2- (4-methanesulfonyl-phenyl) -acetamide (intermediate 10,305mg,0.579mmol) in toluene (15mL) was added lawson's reagent (234mg,0.579mmol) and the reaction mixture was heated at 110 ℃ for 24 h. An additional amount of Lawson's reagent (351mg) was added and heating was continued for 2.5h, then the final addition of Lawson's reagent (234mg) was completed. The reaction mixture was heated for 19h, then cooled, concentrated in vacuo and the resulting residue was purified by flash chromatography, eluting with a gradient of 0-50% ethyl acetate in cyclohexane to give the title compound as an orange glass (191 mg).
LC-MS (method 2) Rt 3.73min, M/z 542.9[ M []+
Step 3
N- [ 5-bromo-4-methyl-3- (3-trifluoromethyl-phenyl) -pyridin-2-yl]-N' -hydroxy-2- (4-methanesulfonyl- Phenyl) -acetamidines(intermediate 12)
To a solution of N- [ 5-bromo-4-methyl-3- (3-trifluoromethyl-phenyl) -pyridin-2-yl ] -2- (4-methanesulfonyl-phenyl) -thioacetamide (intermediate 11,190mg,0.35mmol) in IMS (3mL) was added triethylamine (63 μ L,0.45mmol), followed by hydroxylamine hydrochloride (29mg,0.42 mmol). After stirring at room temperature for 30min, water (10mL) was added and the resulting orange solid was collected by filtration and then dried under vacuum at 50 ℃ to give the title compound (165 mg).
LC-MS (method 1) Rt 3.92min, M/z 541.9[ M []+
Step 4
6-bromo-2- (4-methanesulfonyl-benzyl) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]A triazolo [1 ] group, a triazolo [1 ], 5-a]pyridine compound(intermediate 13)
A suspension of N- [ 5-bromo-4-methyl-3- (3-trifluoromethyl-phenyl) -pyridin-2-yl ] -N' -hydroxy-2- (4-methanesulfonyl-phenyl) -acetamidine (intermediate 12,165mg,0.304mmol) in toluene (6mL) and pyridine (98. mu.L, 1.218mmol) was cooled to 0 deg.C and p-toluenesulfonyl chloride (232mg,1.218mmol) was added. The reaction mixture was stirred at 0 ℃ for 25 minutes, then at room temperature for 6 days. Sodium bicarbonate (saturated solution, 30mL) was added and the mixture was extracted with DCM (2 × 30 mL). The organic phase was concentrated and the resulting residue was purified by flash chromatography, eluting with a gradient of 0-100% EtOAc in cyclohexane to give the title compound (164mg) as a yellow solid.
LC-MS (method 1) Rt 4.03min, M/z 523.9[ M [, M [ ]]+
Step 5
4- {5- [2- (4-methanesulfonyl-benzyl) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2, 4%]A triazolo [1 ] group, a triazolo [1 ], 5-a]pyridin-6-yl]-pyrazol-1-yl } -benzonitrile(example 8)
The title compound (29mg) was prepared from 6-bromo-2- (4-methanesulfonyl-benzyl) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridine (intermediate 13,50mg,0.095mmol) and 4- (5-tributylstannyl-pyrazol-1-yl) -benzonitrile (intermediate 3,100mg,0.218mmol) using a method similar to that used in example 1 (step 4).
LC-MS (method 3) with Rt 5.12min, M/z 613.0[ M + H]+
1H NMR(400MHz,CDCl3)8.53(1H,s),7.92-7.85(3H,m),7.72(1H,d J＝8Hz),7.68-7.58(6H,m),7.53-7.47(3H,m),6.58(1H,d J＝1.9Hz),4.33(2H,s),3.03(3H,s),1.83(3H,s)。
Example 9
4- {5- [ 7-methyl-3-oxo-8- (3-trifluoromethyl-phenyl) -2, 3-dihydro- [1,2,4]Triazolo [4,3-a] Pyridin-6-yl]-pyrazol-1-yl } -benzonitrile
Step 1
5-bromo-2-chloro-4-methyl-3- (3-trifluoromethyl-phenyl) -pyridine(intermediate 14)
To a suspension of copper (II) chloride (421mg,3.92mmol) and tert-butyl nitrite (466 μ L,3.92mmol) in anhydrous MeCN (12mL) at 70 deg.C, a solution of 5-bromo-4-methyl-3- (3-trifluoromethyl-phenyl) -pyridin-2-ylamine (intermediate 1,864mg,2.61mmol) in MeCN (3mL) was added dropwise over 5 minutes the reaction mixture was stirred at 70 deg.C for 3.5h and then poured onto 5N aqueous HCl (20mL), the reaction mixture was extracted with EtOAc (4 × 20mL), and the combined organic extracts were dried (Na2SO4) Filtering and mixing inEvaporated in vacuo. The resulting residue was purified by flash chromatography eluting with a gradient of 0-100% EtOAc in cyclohexane to give the title compound as an orange solid (184 mg).
LC-MS (method 1) Rt 4.40min, M/z 350[ M ]]+
Step 2
6-bromo-7-methyl-8- (3-trifluoromethyl-phenyl) -2H- [1,2,4]Triazolo [4,3-a]Pyridin-3-ones(intermediate 15)
5-bromo-2-chloro-4-methyl-3- (3-trifluoromethyl-phenyl) -pyridine (intermediate 14,176mg,0.503mmol) and hydrazine hydrate (2.5mL,52mmol) in bisA solution in an alkane (5mL) was heated at 90 ℃ for 7 h.an additional amount of hydrazine hydrate (2.5mL) was added and the reaction mixture was heated at 90 ℃ for 18h, then at 100 ℃ for 5 days the reaction mixture was cooled, then poured into water (15mL) and extracted with EtOAc (3 × 15 mL). the combined organic extracts were dried (Na)2SO4) Filtered and evaporated in vacuo to afford a yellow solid. The solid was dissolved in THF (2mL) then N, N' -carbonyldiimidazole (375mg,2.31mmol) was added and the reaction mixture was stirred at room temperature for 22h then concentrated in vacuo. The resulting residue was purified by flash chromatography, eluting with a gradient of 0-100% EtOAc in cyclohexane, to give the title compound as a brown solid (184 mg).
LC-MS (method 2) Rt 3.12min, M/z 371.9[ M []+
Step 3
4- {5- [ 7-methyl-3-oxo-8- (3-trifluoromethyl-phenyl) -2, 3-dihydro- [1,2,4]Triazolo [4,3-a] Pyridin-6-yl]-pyrazol-1-yl } -benzonitrile(example 9)
The title compound (2mg) was prepared using a method analogous to that used in example 1 (step 4) from 6-bromo-7-methyl-8- (3-trifluoromethyl-phenyl) -2H- [1,2,4] triazolo [4,3-a ] pyridin-3-one (intermediate 15,140mg,0.38mmol) and 4- (5-tributylstannyl-pyrazol-1-yl) -benzonitrile (intermediate 3,310mg,0.68 mmol).
LC-MS (method 3) Rt 4.63min, M/z 460.9[ M + H]+
1H NMR(400MHz,DMSO-d6)12.53(1H,br s),7.95(1H,d J＝1.7Hz),7.94-7.92(2H,m),7.92-7.90(1H,m),7.80(1H,d J＝7.9Hz),7.73(1H,d J＝7.9Hz),7.71-7.69(1H,m),7.69-7.65(2H,m),7.61(1H,d J＝7.5Hz),6.76(1H,d J＝1.8Hz),1.55(3H,s)。
Example 10
4- {5- [2- (4-methanesulfonyl-benzyl) -7-methyl-3-oxo-8- (3-trifluoromethyl-phenyl) -2, 3-dihydro- [1,2,4]Triazolo [4,3-a]Pyridin-6-yl]-pyrazol-1-yl } -benzonitrile
Step 1
6-bromo-2- (4-methanesulfonyl-benzyl) -7-methyl-8- (3-trifluoromethyl-phenyl) -2H- [1,2,4]Triazolo compounds [4,3-a]Pyridin-3-ones(intermediate 16)
To 6-bromo-7-methyl-8- (3-trifluoromethyl-phenyl) -2H- [1,2,4]Triazolo [4,3-a]To a solution of pyridin-3-one (intermediate 15,55mg,0.148mmol) in DMF (3mL) was added cesium carbonate (58mg,0.177mmol) followed by 4- (methylsulfonyl) benzyl bromide (40mg,0.163mmol),and the mixture was stirred at room temperature for 20 h.an additional amount of cesium carbonate (25mg) and 4- (methylsulfonyl) benzyl bromide (20mg) was added and stirring was continued for 2 h.water was added and the mixture was extracted with EtOAc (2 × 25 mL.) the combined organic extracts were washed with brine and then dried (Na 8925 mL)2SO4) Filtered and evaporated in vacuo. The resulting residue was purified by flash chromatography, eluting with a gradient of 0-100% EtOAc in cyclohexane, to give the title compound (49mg) as a yellow solid.
LC-MS (method 1) Rt 3.87min, M/z 539.9[ M []+
Step 2
4- {5- [2- (4-methanesulfonyl-benzyl) -7-methyl-3-oxo-8- (3-trifluoromethyl-phenyl) -2, 3-dihydro- [1,2,4]Triazolo [4,3-a]Pyridin-6-yl]-pyrazol-1-yl } -benzonitrile
(example 10)
The title compound (24mg) was prepared by a method analogous to that used in example 1 (step 4) from 6-bromo-2- (4-methanesulfonyl-benzyl) -7-methyl-8- (3-trifluoromethyl-phenyl) -2H- [1,2,4] triazolo [4,3-a ] pyridin-3-one (intermediate 16,45mg,0.083mmol) and 4- (5-tributylstannyl-pyrazol-1-yl) -benzonitrile (intermediate 3,69mg,0.15 mmol).
LC-MS (method 3) Rt 5.01min, M/z 629.0[ M + H]+
1H NMR(400MHz,DMSO-d6)8.06(1H,s),7.95(1H,d J＝1.8Hz),7.94-7.87(4H,m),7.79(1H,d J＝7.9Hz),7.74-7.68(3H,m),7.61(2H,d J＝8.4Hz),7.54(2H,d J＝8.4Hz),6.76(1H,d J＝1.8Hz),5.23(2H,s),3.19(3H,s),1.53(3H,s)。
Example 11
2- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-3-oxo-8- (3-trifluoromethyl-benzene Base) - [1,2,4]Triazolo [4,3-a]Pyridin-2-yl]-N, N-dimethyl-acetamide
To 4- {5- [ 7-methyl-3-oxo-8- (3-trifluoromethyl-phenyl) -2, 3-dihydro- [1,2,4]Triazolo [4,3-a]Pyridin-6-yl]-pyrazol-1-yl } -benzonitrile (example 9,55mg.0.12mmol) in DMF (3mL) was added cesium carbonate (58mg,0.18mmol) followed by 2-chloro-N, N-dimethylacetamide (19 μ L,0.18 mmol). the reaction mixture was stirred at room temperature for 18h, then water was added and the reaction mixture was extracted with EtOAc (2 × 20 mL). the combined organic extracts were dried (Na2SO4) Filtered and evaporated in vacuo. The resulting residue was purified by preparative HPLC eluting with a gradient of 20-70% MeCN in water (+ 0.1% formic acid) to give the title compound (22mg) as a yellow solid.
LC-MS (method 3) Rt 4.69min, M/z 546.0[ M + H]+
1H NMR(400MHz,DMSO-d6)8.03(1H,s),7.98-7.93(3H,m),7.81(1H,d J＝8.0Hz),7.74(1H,d J＝7.8Hz),7.73-7.68(2H,m),7.65-7.59(2H,m),6.77(1H,d J＝1.8Hz),4.84(2H,s),3.00(3H,s),2.81(3H,s),1.56(3H,s)。
Example 12
2- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-3-oxo-8- (3-trifluoromethyl-benzene Base) - [1,2,4]Triazolo [4,3-a]Pyridin-2-yl]-N-methyl-acetamide
The title compound (25mg) was prepared from 4- {5- [ 7-methyl-3-oxo-8- (3-trifluoromethyl-phenyl) -2, 3-dihydro- [1,2,4] triazolo [4,3-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile (example 9,55mg.0.12mmol) and 2-chloro-N-methylacetamide (19 μ L,0.18mmol) using a method analogous to that used in example 11.
LC-MS (method 3) Rt 4.50min, M/z 531.9[ M + H]+
1H NMR(400MHz,DMSO)8.04(1H,s),7.97-7.91(4H,m),7.81(1H,d J＝8.0Hz),7.74(1H,d J＝7.9Hz),7.72-7.68(2H,m),7.66-7.60(2H,m),6.76(1H,d J＝1.8Hz),4.47(2H,s),2.59(3H,d J＝4.5Hz),1.57(3H,s)。
Example 13
4- {5- [2- (3-Methylsulfonyl-propyl) -7-methyl-3-oxo-8- (3-trifluoromethyl-phenyl) -2, 3-dihydro- [1,2,4]Triazolo [4,3-a]Pyridin-6-yl]-pyrazol-1-yl } -benzonitrile
The title compound (27mg) was prepared from 4- {5- [ 7-methyl-3-oxo-8- (3-trifluoromethyl-phenyl) -2, 3-dihydro- [1,2,4] triazolo [4,3-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile (example 9,70mg.0.152mmol) and 1-bromo-3-methanesulfonyl-propane (53mg,0.264mmol) using a method analogous to that employed in example 11.
LC-MS (method 3) Rt 4.71min, M/z 580.9[ M + H]+
1H NMR(400MHz,DMSO-d6)8.01(1H,s),7.96-7.89(3H,m),7.81(1H,d J＝7.8Hz),7.74(1H,d J＝7.8Hz),7.72-7.65(3H,m),7.62(1H,d J＝7.6Hz),6.74(1H,d J＝1.8Hz),3.99(2H,t J＝6.7Hz),3.21-3.14(2H,m),2.94(3H,s),2.13-2.01(2H,m),1.54(3H,s)。
Example 14
N- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2, 4]triazolo [1,5-a]Pyridin-2-yl]-2-dimethylamino-acetamide
Mixing 4- {5- [ 2-amino-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]]Triazolo [1,5-a]Pyridin-6-yl]Pyrazol-1-yl } -benzonitrile (example 1,459mg,1mmol), N-dimethylglycine (206mg,2mmol) and triethylamine (0.278mL,2mmol) were stirred in dry DMF (5mL) and HATU (760mg,2mmol) was added portionwise. The reaction mixture was heated at 70 ℃ for 40min, then an additional amount of HATU (760mg,2mmol) was added and the mixture was heated at 80 ℃ for 1 h. The reaction mixture was cooled and then partitioned between EtOAc and water. The organic layer was washed with water, then brine, then dried (Na)2SO4) Filtered and concentrated in vacuo. The resulting residue was treated with DCM, then the suspension was filtered and the filtrate was purified by flash chromatography, eluting with a gradient of 0-10% MeOH in DCM to give the title compound as a white solid (88 mg).
LC-MS (method 3) Rt 3.62min, M/z 545.1[ M + H]+
1H NMR(400MHz,CDCl3)9.95(1H,s),8.60(1H,s),7.88(1H,d J＝1.8Hz),7.74(1H,d J＝7.8Hz),7.69-7.63(3H,m),7.61(1H,s),7.53(1H,d J＝7.6Hz),7.50-7.45(2H,m),6.59(1H,d J＝1.8Hz),3.16(2H,s),2.35(6H,s),1.85(3H,s)
Example 15
{ [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] Triazolo [1,5-a]Pyridin-2-ylcarbamoyl]-methyl } -trimethyl-ammonium bromide
N- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -2-dimethylamino-acetamide (example 14,10mg,0.018mmol) was stirred in MeCN (0.5mL) and a solution of MeBr (about 30% solution in MeCN, 0.01mL) was added followed after 15min by an additional solution of MeBr (0.05 mL). The reaction mixture was stirred for 18h, then concentrated in vacuo to give the title compound (11mg) as an off-white solid.
LC-MS (method 3) Rt 3.65min, M/z 559.1[ M [, M [ ]]+
1H NMR(400MHz,CDCl3)8.52(1H,s),7.86(1H,d J＝1.8),7.70-7.55(6H,m),7.48(2H,d J＝8.6Hz),6.58(1H,d J＝1.6Hz),5.24(2H,s),3.42(9H,s),1.86(3H,s)
Example 16
N- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2, 4]triazolo [1,5-a]Pyridin-2-yl]-4-dimethylamino-butanamide
The title compound (38mg) was prepared from 4- {5- [ 2-amino-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile (example 1,150mg,0.33mmol) and 4-dimethylamino-butyric acid (107mg,0.64mmol) using a method similar to that employed in example 14.
LC-MS (method 3) Rt 3.65min, M/z 573.1[ M + H]+
1H NMR(400MHz,CDCl3)11.93(1H,br s),8.57(1H,s),7.87(1H,d J＝1.7Hz),7.74(1H,s),7.70(1H,d J＝8.0Hz),7.67-7.62(2H,m),7.60(1H,d J＝8.0Hz),7.51-7.45(3H,m),6.58(1H,d J＝1.7Hz),2.62(2H,s),2.53(2H,t J＝6.5Hz),2.32(6H,s),1.95-1.85(5H,m)。
Example 17
{3- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2, 4]triazolo [1,5-a]Pyridin-2-ylcarbamoyl]-propyl } -trimethyl-ammonium bromide
The title compound (30mg) was prepared from N- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -4-dimethylamino-butyramide (example 16,25mg,0.044mmol) and MeBr (ca. 30% in EtOH,0.15mL) using a method analogous to that employed in example 15.
LC-MS (method 3) Rt 3.67min, M/z 587.1[ M []+
1H NMR(400MHz,CDCl3)9.61(1H,br s),8.52(1H,s),7.87(1H,d J＝1.8Hz),7.71-7.58(5H,m),7.57-7.47(3H,m),6.60(1H,d J＝1.8Hz),3.38-3.78(2H,m),3.34(9H,s),2.79(2H,br s),2.22-2.09(2H,m),1.86(3H,s)。
Example 18
N- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2, 4]triazolo [1,5-a]Pyridin-2-yl]-2- (4-methyl-piperazin-1-yl) -acetamide
Step 1
2-chloro-N- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-acetamide(intermediate 17)
Mixing 4- {5- [ 2-amino-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]]Triazolo [1,5-a]Pyridin-6-yl]-pyrazol-1-yl } -benzonitrile (example 1,400mg,0.87mmol) was stirred in dry THF (5mL) and DIPEA (0.3mL,1.765mmol) was added, followed by dropwise addition of chloroacetyl chloride (104. mu.L, 1.258 mmol). After 45min, an additional amount (69 μ L) of chloroacetyl chloride was added and stirring was continued for 18 h. The reaction mixture was partitioned between EtOAc and water, the organic layer was washed with saturated brine and then dried (Na)2SO4) And concentrated in vacuo. The resulting residue was purified by flash chromatography eluting with 65% EtOAc in cyclohexane to give the title compound (334 mg).
LC-MS (method 1) Rt 3.77min, M/z 536[ M + H]+
Step 2
N- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2, 4]triazolo [1,5-a]Pyridin-2-yl]-2- (4-methyl-piperazin-1-yl) -acetamide(example 18)
Reacting 2-chloro-N- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-acetamide (intermediate 17,150mg,0.28mmol) stirred in anhydrous DMF (3mL) then K was added2CO3(83mg,0.60mmol) and 1-methylpiperazine (56mg,0.56 mmol). Stirring was continued at rt for 2h, then the reaction mixture was partitioned between EtOAc and water. The organic layer was washed with water, then saturated brine, and then dried (Na)2SO4) And concentrated in vacuo. The resulting residue was purified by flash chromatography with 2-5% MeOH in DCMGradient elution followed by 10% (2M NH)3In MeOH) in DCM to give the title compound (128mg) as a white solid.
LC-MS (method 3) Rt 3.60min, M/z 600.1[ M + H-]+
1H NMR(400MHz,CDCl3)9.72(1H,s),8.60(1H,s),7.88(1H,d J＝1.7Hz),7.75(1H,d J＝7.8Hz),7.70-7.61(4H,m),7.54(1H,d J＝7.7Hz),7.50-7.45(2H,m),6.59(1H,dJ＝1.8Hz),3.22(2H,s),2.64(4H,br s),2.49(4H,br s),2.31(3H,s),1.86(3H,s)。
Example 19
4- { [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2, 4]triazolo [1,5-a]Pyridin-2-ylcarbamoyl]-methyl } -1, 1-dimethyl-piperazin-1-ium iodide
The title compound (105mg) was prepared from N- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -2- (4-methyl-piperazin-1-yl) -acetamide (example 18,130mg,0.22mmoL) and MeI (27 μ L,0.880mmoL) using a method analogous to that employed in example 15.
LC-MS (method 3) Rt 3.56min, M/z 614.2[ M [, M [ ]]+
1H NMR(400MHz,CDCl3)10.75(1H,s),9.01(1H,s),8.00(1H,d J＝1.8Hz),7.91-7.86(2H,m),7.83(1H,d J＝7.8Hz),7.77(1H,d J＝7.8Hz),7.75-7.71(1H,m),7.68(1H,dJ＝7.5Hz),7.60-7.56(2H,m),6.82(1H,d J＝1.8Hz),3.46-3.35(6H,m),3.10(6H,s),2.94-2.85(4H,m),1.79(3H,s)。
Example 20
N- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2, 4]triazolo [1,5-a]Pyridin-2-yl]-2-morpholin-4-yl-acetamide
The title compound (50mg) was prepared from 2-chloro-N- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -acetamide (intermediate 17,80mg,0.149mmol) and morpholine (26mg,0.299mmol) using a method analogous to that employed in example 18, step 2.
LC-MS (method 3) Rt 3.73min, M/z 587.1[ M + H]+
1H NMR(400MHz,CDCl3)9.66(1H,s),8.60(1H,s),7.88(1H,d J＝1.9Hz),7.75(1H,d J＝7.9Hz),7.68(1H,d J＝7.7Hz),7.67-7.60(3H,m),7.53(1H,d J＝7.9Hz),7.49-7.44(2H,m),6.60(1H,d J＝1.8Hz),3.75(4H,t J＝4.7Hz),3.22(2H,s),2.61(4H,t J＝4.6Hz),1.86(3H,s)。
Example 21
N- [6- [1- (4-cyano-phenyl) -1H-pyrazol-5-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2, 4]triazolo [1,5-a]Pyridin-2-yl]-2- (1, 1-dioxothiomorpholin-4-yl) -acetamide
The title compound (10mg) was prepared from 2-chloro-N- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -acetamide (intermediate 17,50mg,0.0934mmol) and thiomorpholine 1, 1-dioxide (20mg,0.148mmol) using a method analogous to that employed in example 18, step 2.
LC-MS (method 3) Rt 4.52min, M/z 635.1[ M + H ]]+
1H NMR(400MHz,CDCl3)9.44(1H,s),8.59(1H,s),7.89(1H,d J＝1.8Hz),7.76(1H,d J＝7.9),7.69(1H,d J＝7.9),7.67-7.63(2H,m),7.61(1H,s),7.52(1H,d J＝7.4),7.49-7.44(2H,m),7.60(1H,d J＝1.8Hz),3.42(2H,s),3.22-3.06(8H,m),1.88(3H,s)。
Example 22
N- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2, 4]triazolo [1,5-a]Pyridin-2-yl]-4-methanesulfonyl-benzamide
The title compound (3%) was prepared from 4- {5- [ 2-amino-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile (example 1,100mg,0.218mmol) and 4- (methylsulfonyl) benzoic acid (56.7mg,0.283mmol) using a method analogous to that employed in example 14.
LC-MS (method 3) Rt 4.84min, M/z 642.1[ M + H]+
1H NMR(400MHz,CDCl3)8.95(1H,s),8.64(1H,s),8.12-8.04(4H,m),7.90(1H,s),7.74(1H,d＝8Hz),7.69-7.62(4H,m),7.49(3H,d J＝8.5Hz),6.64(1H,s),3.09(3H,s),1.90(3H,s)。
Example 23
4- {5- [2- (4-methanesulfonyl-benzylamino) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]]Triazole compounds And [1,5-a ]]Pyridin-6-yl]-pyrazol-1-yl } -benzonitrile
6-bromo-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-ylamine (intermediate 2,120mg,0.323mmol) and 4- (methylsulfonyl) benzaldehyde (118mg,0.64mmol) were stirred in anhydrous DCM (3mL), then triethylamine ((0.097mL,0.70mmol) was added to the suspension, titanium (IV) isopropoxide (182mg,0.64mmol) was added, and the mixture was stirred under argon for 65h, the solvent was evaporated in vacuo and IMS (3mL) was added, then sodium borohydride (25mg,0.66mmol) was added, after 3.5h stirring, an additional amount of sodium borohydride (15mg) was added, and after another 1.5h, an additional amount of sodium borohydride (10mg) was added, and the mixture was stirred for another 1h, water and DCM were added, and the mixture was filtered to collect a solid precipitate which was combined with concentrated DCM extract to give 93mg of intermediate [ 6-bromo-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] - (4-methanesulfonyl-benzyl) -amine. The title compound (55mg) was prepared from the thus-obtained crude intermediate (150mg) and 4- (5-tributylstannyl-pyrazol-1-yl) -benzonitrile (intermediate 3,204mg,0.445mmol) using a method similar to that used in example 1 (step 4).
LC-MS (method 3) Rt 5.06min, M/z 628.1[ M + H]+
1H NMR(400MHz,CDCl3)8.31(1H,s),7.90(2H,d J＝8.0Hz),7.85(1H,d J＝1.8Hz),7.71-7.63(3H,m),7.62-7.55(4H,m),7.53-7.45(3H,m),6.55(1H,d J＝1.8Hz),5.09(1H,t J＝6.5Hz),4.67(2H,d J＝6.5Hz),3.04(3H,s),1.77(3H,s)。
Example 24
2- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2, 4]triazolo [1,5-a]Pyridin-2-ylamino]-N, N-dimethyl-acetamide
The title compound (6mg) was prepared from 4- {5- [ 2-amino-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile (example 1,100mg,0.218mmol) and 2-chloro-N, N-dimethylacetamide (40mg,0.332mmol) using a method similar to that used in example 11.
LC-MS (method 3) Rt 4.73min, M/z 545.1[ M + H]+
1H NMR(400MHz,DMSO-d6)8.74(1H,s),7.96(1H,d J＝1.8Hz),7.93-7.88(2H,m),7.79(1H,d J＝7.8Hz),7.76-7.68(2H,m),7.64(1H,d J＝7.6Hz),7.59-7.55(2H,m),6.75(1H,d J＝1.8Hz),6.58(1H,t J＝5.9Hz),4.00(2H,d J＝6.0Hz),2.96(3H,s),2.82(3H,s),1.71(3H,s)。
Example 25
1- { [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2, 4]triazolo [1,5-a]Pyridin-2-ylcarbamoyl]-methyl } -1, 4-dimethyl-piperazin-1-ium chloride
The title compound (38mg) was prepared from 2-chloro-N- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -acetamide (intermediate 17,80mg,0.149mmol) and 1, 4-dimethyl-piperazine (34mg,0.298mmol) using a method analogous to that employed in example 18 (step 2).
LC-MS (method 3) Rt 3.39min, M/z 614.1[ M [, M [ ]]+
1H NMR(400MHz,CDCl3)8.71(1H,s),8.50(1H,s),7.87(1H,d J＝1.8Hz),7.72-7.55(6H,m),7.49-7.43(2H,m),6.60(1H,d J＝1.8Hz),3.65(3H,s),4.03(2H,s),3.43(4H,s),2.88-2.78(2H,m),2.75-2.65(2H,m),2.38(3H,s),1.88(3H,s)。
Example 26
N- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2, 4]triazolo [1,5-a]Pyridin-2-yl]-acetamide
Step 1
N- [ 6-bromo-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]]Triazolo [1,5-a]Pyridin-2-yl]-B Amides of carboxylic acids(intermediate 18)
The title compound (5.65g) was prepared from 6-bromo-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-ylamine (intermediate 2,6.7g,18.06mmol) and acetyl chloride (2.83mL,39.7mmol) using a method analogous to that employed for intermediate 17.
LC-MS (method 2) with Rt 3.32min, M/z 414[ M + H ]]+
Step 2
N- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2, 4]triazolo [1,5-a]Pyridin-2-yl]-acetamide(example 26)
The title compound (26mg) was prepared from N- [ 6-bromo-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -acetamide (intermediate 18,65mg,0.157mmol) and 4- (5-tributylstannyl-pyrazol-1-yl) -benzonitrile (intermediate 3,79mg,0.173mmol) using a method similar to that used in example 1 (step 4).
LC-MS (method 3) Rt 4.57min, M/z 502.0[ M + H ]]+
1H NMR(400MHz,CDCl3)10.88(1H,s),9.01(1H,s),7.99(1H,d J＝1.7Hz),7.91-7.86(2H,m),7.82(1H,d J＝8.2Hz),7.76(1H,d J＝7.7Hz),7.73(1H,s),7.67(1H,d J＝7.7Hz),7.61-7.56(2H,m),6.81(1H,s),2.07(3H,s),1.76(3H,s)。
Example 27
N- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2, 4]triazolo [1,5-a]Pyridin-2-yl]-methanesulfonamide
Mixing 4- {5- [ 2-amino-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]]Triazolo [1,5-a]Pyridin-6-yl]-pyrazol-1-yl } -benzonitrile (example 1,150mg,0.326mmol) was dissolved in pyridine (4mL) and methanesulfonyl chloride (50 μ L,0.652mmol) was added. The reaction mixture was stirred at room temperature for 18h, then at 60 ℃ for 3 h. An additional amount of methanesulfonyl chloride (50 μ L) was added and the mixture was heated at 60 ℃ overnight. The reaction mixture was cooled, then water was added, and the mixture was extracted with EtOAc. The organic extracts were washed with 1M HCl, then water, then saturated brine, and dried (Na)2SO4) Filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography, eluting with a gradient of 0-50% EtOAc in cyclohexane, to give the title compound as a brown solid (85 mg).
LC-MS (method)3) Rt 4.83 min, M/z 537.9[ M + H]+。
1H NMR(400MHz,CDCl3)11.39(1H,s),9.03(1H,s),7.99(1H,d J＝1.8Hz),7.92-7.86(2H,m),7.84-7.79(1H,m),7.75(2H,t J＝7.8Hz),7.70-7.66(1H,m),7.62-7.57(2H,m),6.80(1H,d J＝1.8Hz),3.30(3H,s),1.76(3H,s)。
Example 28
4- {5- [2- (3-dimethylamino-propylamino) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]]III Azolo [1,5-a ]]Pyridin-6-yl]-pyrazol-1-yl } -benzonitrile
Step 1
4- {5- [ 2-chloro-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]]Triazolo [1,5-a]Pyridin-6-yl]- Pyrazol-1-yl } -benzonitriles(intermediate 19)
The title compound (73mg) was prepared from 4- {5- [ 2-amino-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile (example 1,100mg,0.22mmol) using a method similar to that used for intermediate 14.
LC-MS (method 3) Rt 5.46min, M/z 478.9[ M + H]+
1H NMR(400MHz,CDCl3)8.53(1H,s),7.89(1H,d J＝1.7Hz),7.72(1H,app d J＝7.9Hz),7.70-7.62(3H,m),7.58(1H,s),7.55-7.48(3H,m),6.63(1H,d J＝1.7Hz),1.87(3H,s)。
Step 2
4- {5- [2- (3-dimethylamino-propylamino) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]]III Azolo [1,5-a ]]Pyridin-6-yl]-pyrazol-1-yl } -benzonitrile(example 28)
To 4- {5- [ 2-chloro-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]]Triazolo [1,5-a]Pyridin-6-yl]To a solution of-pyrazol-1-yl } -benzonitrile (intermediate 19,68mg,0.14mmol) in NMP (2.5mL) was added N, N-dimethyl-propane-1, 3-diamine (54 μ L,0.43mmol), followed by triethylamine (39 μ L,0.28 mmol). The reaction mixture was heated to 220 ℃ using microwave radiation for 5 h. The cooled reaction mixture was concentrated in vacuo and then loaded onto a SCX-2 column (2g) in MeOH. After washing with DCM/MeOH, the crude product was washed with 2M NH3A solution in MeOH eluted, and after concentration in vacuo, gave a brown oil (53mg) — the oil thus obtained was purified using preparative TLC (20 × 20cm × 1mm), eluting with 20% MeOH in DCM to give the title compound (14mg) as a pale yellow oil which solidified upon standing.
LC-MS (method 3) Rt 3.72min, M/z 545.1[ M + H]+
1H NMR(400MHz,CDCl3)8.32(1H,s),7.85(1H,d J＝1.7Hz),7.71-7.58(5H,m),7.54-7.48(3H,m),6.57(1H,d J＝1.8Hz),5.25(1H br s),3.46(2H,m),2.52(2H,t J＝6.9Hz),2.31(6H,s),1.86(2H,qn J＝6.9Hz),1.77(3H,s)。
Example 29
4- {5- [2- (2-dimethylamino-ethylamino) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]]III Azolo [1,5-a ]]Pyridin-6-yl]-pyrazol-1-yl } -benzonitrile
The title compound (61mg) was prepared from 4- {5- [ 2-chloro-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile (intermediate 19,92mg,0.19mmol) and N, N-dimethyl-ethane-1, 2-diamine (1.5mL) using a method analogous to that used in example 28.
LC-MS (method 3) Rt 3.69min, M/z 531.1[ M + H]+
1H NMR(400MHz,CDCl3)8.32(1H,s),7.85(1H,d J＝1.8Hz),7.70-7.58(5H,m),7.54-7.48(3H,m),6.56(1H,d J＝1.8Hz),5.25(1H app t J＝5.2Hz),3.40(2H,q J＝5.9Hz),2.53(2H,t J＝5.9Hz),2.24(6H,s),1.77(3H,s)。
Example 30
4- {5- [2- (4-dimethylamino-butylamino) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]]III Azolo [1,5-a ]]Pyridin-6-yl]-pyrazol-1-yl } -benzonitrile
The title compound (47mg) was prepared from 4- {5- [ 2-chloro-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile (intermediate 19,93mg,0.19mmol) and N, N-dimethyl-butane-1, 4-diamine (1.0mL) using a method analogous to that used in example 28.
LC-MS (method 3) Rt 3.78min, M/z 559.1[ M + H ]]+
1H NMR(400MHz,CDCl3)8.32(1H,s),7.85(1H,d J＝1.8Hz),7.70-7.58(5H,m),7.54-7.48(3H,m),6.56(1H,app d J＝1.8Hz),4.89(1H,br s),3.37(2H,t J＝6.5Hz),2.32(2H,t J＝7.2Hz),2.23(6H,s),1.76(3H,s),1.67(2H,app qn J＝7.2Hz),1.58(2H,app qn J＝7.5Hz)。
Example 31
4- {5- [ 2-methoxy-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]]Triazolo [1,5-a]Pyridine-6- Base of]-pyrazol-1-yl } -benzonitrile
A cloudy solution of 4- {5- [ 2-chloro-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile (intermediate 19,22mg,0.046mmol) and NaOMe (25% Wt,0.75mL,3.3mmol) in MeOH (0.75mL) was heated at 100 deg.C for 30min using microwave radiation. The cooled reaction mixture was evaporated by preparative TLC (20X 20cm X1 mm) in vacuo eluting with 50% EtOAc in cyclohexane to give the title compound (6mg) as a white solid.
LC-MS (method 3) Rt 5.25min, M/z 474.9[ M + H]+
1H NMR(400MHz,CDCl3)8.40(1H,s),7.88(1H,d J＝1.8Hz),7.72-7.63(3H,m),7.62-7.59(2H,m),7.54-7.48(3H,m),6.80(1H,app d J＝1.8Hz),4.08(3H,s),1.84(3H,s)。
Example 32
{3- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2, 4]triazolo [1,5-a]Pyridin-2-ylamino]-propyl } -trimethyl-benzenesulphonic acid ammonium salt
To 4- {5- [2- (3-dimethylamino-propylamino) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] was added at ambient temperature]Triazolo [1,5-a]Pyridin-6-yl]To a solution of-pyrazol-1-yl } -benzonitrile (example 28,55mg,0.10mmol) in acetone (0.44mL) was added methyl benzenesulfonate (15. mu.L, 0.11 mmol). Will be provided withThe reaction mixture was heated at 55 ℃ for 1.5 h. The cooled reaction mixture was concentrated in vacuo to give a clear colorless oil. The oil thus obtained was triturated in ether and the solid obtained was dissolved in traces of EtOAc and Et was added2O until a white solid is formed. The precipitate was collected by filtration and washed with Et2O washed and dried in vacuo to give the title compound (64mg) as a white solid.
LC-MS (method 3) Rt 3.71min, M/z 559.0[ M [, M [ ]]+
1H NMR(400MHz,CDCl3)8.32(1H,s),7.86-7.83(3H,m),7.68-7.63(3H,m),7.62-7.56(2H,m),7.53-7.47(3H,m),7.29-7.24(3H obs m),6.56(1H,d J＝1.7Hz),5.72(1H,tJ＝6.0Hz),3.62(2H,m),3.42(2H,q J＝6.1Hz),3.20(9H,s),2.12(2H,m),1.75(3H,s)。
Example 33
{3- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2, 4]triazolo [1,5-a]Pyridin-2-ylamino]-ethyl } -trimethyl-benzenesulphonic acid ammonium salt
The title compound (51mg) was prepared from 4- {5- [2- (3-dimethylamino-ethylamino) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile (example 29,50mg,0.094mmol) using a method similar to that used in example 32.
LC-MS (method 3) Rt 3.70min, M/z 545.0[ M [, M [ ]]+
1H NMR(400MHz,CD3OD)8.57(1H,s),7.91(1H,d J＝1.8Hz),7.85-7.66(7H,m),7.62-7.55(3H,m),7.44-7.37(3H,m),6.74(1H,d J＝1.8Hz),3.80(2H,app t J＝6.2Hz),3.58(2H,t J＝6.2Hz),3.18(9H,s),1.83(3H,s)。
Example 34
{4- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2, 4]triazolo [1,5-a]Pyridin-2-ylamino]-butyl } -trimethyl-ammonium formate
To 4- {5- [2- (4-dimethylamino-butylamino) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] was added at ambient temperature]Triazolo [1,5-a]Pyridin-6-yl]To a solution of-pyrazol-1-yl } -benzonitrile (example 30,44mg,0.079mmol) in acetone (0.4mL) was added methyl benzenesulfonate (12 μ L,0.087 mmol). The reaction mixture is stirred under N2The mixture was heated at 55 ℃ for 2.5 h. An additional amount of methyl benzenesulfonate (3.2. mu.L) was added, and the mixture was heated at 55 ℃ for 1 h. After cooling, the volatiles were evaporated in vacuo and the residue was azeotroped with diethyl ether. Subjecting the obtained residue to preparation C18HPLC, eluting with a gradient of 20-70% MeCN in water (+ 0.1% formic acid) gave the title compound (10mg) as a white solid.
LC-MS (method 3) Rt 3.79min, M/z 573.1[ M [, M [ ]]+
1H NMR(400MHz,DMSO-d6)8.70(1H,s),8.46(1H,br s),7.97(1H,d J＝1.8Hz),7.92-7.88(2H,m),7.79(1H,d J＝8.1Hz),7.75-7.67(2H,m),7.64(1H,d J＝7.7Hz),7.59-7.55(2H,m),6.85(1H.t J＝6.0Hz),6.76(1H,d J＝1.8Hz),3.32-3.25(2H,m),3.21(2H,qJ＝6.5Hz),3.02(9H,s),1.80-1.67(5H,m),1.59-1.48(2H,m)。
Example 35
[6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] Triazolo [1,5-a]Pyridine-2-radical]-urethane
A solution of 4- {5- [ 2-amino-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile (example 1,100mg,0.218mmol) and ethyl chloroformate (104. mu.L, 1.089mmol) in pyridine (2.5mL) was heated at 120 ℃ for 20 minutes using microwave radiation. The reaction mixture was azeotroped with toluene in vacuo. The resulting residue was subjected to preparative C18HPLC eluting with a gradient of 40-80% MeCN in water (+ 0.1% formic acid) to give the title compound (24mg) as a white solid.
LC-MS (method 3) Rt 4.99min, M/z 532.0[ M + H]+
1H NMR(400MHz,DMSO-d6)10.52(1H,s),9.00(1H,s),7.98(1H,d J＝1.8Hz),7.91-7.86(2H,m),7.81(1H,d J＝8.0Hz),7.75(1H,t J＝7.8Hz),7.72(1H,s),7.67(1H,dJ＝7.6Hz),7.61-7.56(2H,m),6.81(1H,d J＝1.8Hz),4.10(2H,q J＝7.2Hz),1.74(3H,s),1.20(3H,t J＝6.8Hz)。
Example 36
[6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] Triazolo [1,5-a]Pyridin-2-yl]-carbamic acid 2-methoxyethyl ester
The title compound (15%) was prepared from 4- {5- [ 2-amino-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile (example 1,100mg,0.218mmol) using a method analogous to that used in example 35.
LC-MS (method 3) Rt 4.80min, M/z 562.0[ M + H]+
1H NMR(400MHz,DMSO-d6)10.56(1H,s),8.94(1H,s),7.93(1H,d J＝1.8Hz),7.86-7.81(2H,m),7.76(1H,d J＝7.9Hz),7.70(1H,t J＝7.8Hz),7.63(1H,s),7.62(1H,dJ＝7.7Hz),7.56-7.50(2H,m),6.75(1H,d J＝1.8Hz),4.14(2H,m),3.48(2H,m),3.21(3H,s),1.69(3H,s)。
Example 37
{3- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2, 4]triazolo [1,5-a]Pyridin-2-ylcarbamoyloxy]-propyl } -trimethyl-ammonium formate
Step 1
[6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] Triazolo [1,5-a]Pyridin-2-yl]3-chloro-propyl (carbamic acid) ester(intermediate 20)
3-chloropropyl chloroformate (133. mu.L, 1.089mmol) was added to a mixture of 4- {5- [ 2-amino-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile (example 1,100mg,0.218mmol) and pyridine (107. mu.L, 1.308mmol) in THF (3mL), and the mixture was stirred rapidly at room temperature for 20min and then heated at 60 ℃ for 20min using microwave radiation. The reaction mixture was concentrated in vacuo to give the title compound (125mg of impure product containing chloroformate).
LC-MS (method 2) Rt 3.90 min,m/z＝580[M+H]+
step 2
{3- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2, 4]triazolo [1,5-a]Pyridin-2-ylcarbamoyloxy]-propyl } -trimethyl-ammonium chloride
(example 37)
Reacting [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]A solution of 3-chloro-propyl-carbamate (intermediate 20,125mg,0.218mmol) in MeCN (3.5mL) was treated with a solution of trimethylamine in EtOH (4.2M,1.5mL) and heated at 100 ℃ for 1h using microwave radiation. An additional amount of trimethylamine (1mL) in EtOH was added and heating continued at 100 deg.C for 20 min. The reaction mixture was concentrated in vacuo and then azeotroped with toluene in vacuo. Subjecting the obtained residue to preparation C18HPLC chromatography, eluting with a gradient of 10-70% MeCN in water (+ 0.1% formic acid) gave the title compound (20mg) as a white solid.
LC-MS (method 3) Rt 3.71min, M/z 603.1[ M []+
1H NMR (400MHz, DMSO)10.69(1H, s),8.99(1H, s),8.45(1.4H, s),7.99(1H, d J ═ 1.8Hz),7.91-7.86(2H, m),7.82(1H, d J ═ 7.7Hz),7.78-7.71(2H, m),7.67(1H, d J ═ 7.7Hz),7.61-7.56(2H, m),6.81(1H, d J ═ 1.8Hz),4.14(2H, t d ═ 6.3Hz),3.61-3.30(2H, m (under water peak)), 3.06(9H, s),2.13-2.00(2H, m),1.78(3H, s).
Example 38
(3- {3- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl)]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-ureido } -propyl) -trimethyl-ammonium formate
Step 1
1- (3-chloro-propyl) -3- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl) Phenyl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-urea(intermediate 21)
A solution of 4- {5- [ 2-amino-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile (example 1,100mg,0.218mmol) and 3-chloropropylisocyanate (111. mu.L, 1.089mmol) in THF (2.5mL) was heated at 120 ℃ for 3h using microwave radiation. The reaction mixture was concentrated in vacuo and then subjected to flash chromatography, eluting with a gradient of 25-100% EtOAc in cyclohexane, to give the title compound (125 mg).
LC-MS (method 1) Rt 4.01 min, M/z 579[ M + H ]]+
Step 2
(3- {3- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl)]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-ureido } -propyl) -trimethyl-ammonium formate(example 38)
Reacting 1- (3-chloro-propyl) -3- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]A solution of urea (intermediate 21,125mg,0.216mmol) in MeCN (5mL) was treated with a solution of trimethylamine in EtOH (4.2M,0.5mL,2.16mmol) and heated at 100 ℃ for 20min using microwave radiation. Additional trimethylamine/EtOH solution (0.5mL) was added and heating continued at 120 ℃ for 1 h. The reaction mixture was concentrated in vacuo, then azeotroped with toluene and dried in vacuo. Subjecting the obtained residue to preparation C18HPLC, elution with a gradient of 10-60% MeCN in water (+ 0.1% formic acid)The title compound (24mg) was obtained as a white solid.
LC-MS (method 4) Rt 3.67min, M/z 602.1[ M ]]+
1H NMR(400MHz,DMSO-d6)10.14(1H,s),8.93(1H,s),8.41(1.6H,s),8.04(1H,tJ＝5.5Hz),8.00(1H,d J＝1.8Hz),7.91-7.86(2H,m),7.84(1H,d J＝8.1Hz),7.79-7.74(2H,m),7.70(1H,d J＝7.7Hz),7.61-7.55(2H,m),6.81(1H,d J＝1.8Hz),3.33-3.25(2H,m),3.24-3.16(2H,m),3.03(9H,s),1.91-1.82(2H,m),1.80(3H,s)。
Example 39
N- [6- [2- (4-cyano-phenyl) -2H- [1,2,4]Triazol-3-yl]-7-methyl-8- (3-trifluoromethyl-benzene Base) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-acetamide
Step 1
2-acetylamino-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]Triazolo [1,5-a]6-pyridines Acid amides(intermediate 22)
Using microwave radiation, N- [ 6-bromo-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]]Triazolo [1,5-a]Pyridin-2-yl]-acetamide (intermediate 18,330mg,0.80mmol), hydroxylamine hydrochloride (112mg,1.60mmol), trans-bis (acetoxy) bis [ o- (di-o-tolylphosphino) benzyl]Dipalladium (II) (38mg,0.04mmol), tri-tert-butylphosphonium tetrafluoroborate (22mg,0.08mmol), 1, 8-diazabicyclo [5.4.0]Undec-7-ene (0.12mL,0.80mmol), N-diisopropylethylamine (0.28mL,1.60mmol) and molybdenum hexacarbonyl (106mg,0.40mmol) in bisThe mixture in alkane (2mL) was heated at 150 ℃ for 20 minutes. The reaction mixture was cooled and passed throughAnd (5) filtering. The solvent was concentrated in vacuo and the residue was purified by chromatography, eluting with a gradient of 0-100% cyclohexane in EtOAc, then 10% MeOH in EtOAc, to give the title compound as a beige foam (105 mg).
LC-MS (method 1) Rt 2.63min, M/z 378.1[ M + H]+
Step 2
N- [6- [2- (4-cyano-phenyl) -2H- [1,2,4]Triazol-3-yl]-7-methyl-8- (3-trifluoromethyl-benzene Base) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-acetamide(example 39)
To 2-acetylamino-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2, 4-]Triazolo [1,5-a]To a solution of pyridine-6-carboxylic acid amide (intermediate 22,100mg,0.27mmol) in THF (2mL) was added N, N-dimethylformamide dimethyl acetal (53. mu.L, 0.40mmol) and the reaction mixture was heated using microwave radiation at 100 ℃ for 10 min. The solvent was removed in vacuo to give crude 2-acetylamino-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]Triazolo [1,5-a]Pyridine-6-carboxylic acid 1-dimethylamino- (E) -methyleneamide intermediate to a solution of the material thus obtained in acetic acid (2mL) was added 4-hydrazino-benzonitrile hydrochloride (43mg,0.25 mmol.) the mixture was heated at 90 ℃ for 15 minutes using microwave radiation, the solvent was removed in vacuo and the residue was azeotroped with toluene (2 × 5 mL). the residue obtained was purified by flash chromatography eluting with a gradient of 0-100% cyclohexane in EtOAc and then with a solution of 10% MeOH in EtOAc,followed by preparation of form C18HPLC, eluting with a gradient of 10-90% MeCN in water (+ 0.1% formic acid) gave the title compound (15mg) as a white solid.
LC-MS (method 3) Rt 4.24min, M/z 502.9[ M + H]+
1H NMR(400MHz,DMSO-d6)10.92(1H,bs),9.07(1H,s),8.51(1H,s),7.96(2H,dt),7.81-7.86(2H,m),7.75-7.78(2H,m),7.67(2H,dt),2.06(3H,s),1.97(3H,s)
Example 40
4- {5- [ 2-amino-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]]Triazolo [1,5-a]Pyridine-6- Base of]-pyrazol-1-yl } -3-methanesulfonyl-benzonitrile
Step 1
4-hydrazino-3-methanesulfonyl-benzonitrile(intermediate 23)
A suspension of 4-fluoro-3- (methylsulfonyl) benzonitrile (1.96g,9.83mmol) in IMS (30mL) was treated with hydrazine monohydrate (1.19mL,24.8mmol) and then heated at reflux for 1 h. The reaction mixture was cooled, then filtered, and the solid residue was collected and dried in vacuo to give the title compound (1.64g) as a beige solid.
LC-MS (method 2) with Rt 1.92min, M/z 212[ M + H ]]+
Step 2
N- [ 6-acetyl-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]]Triazolo [1 ],5-a]Pyridine-2- Base of]-acetamide(intermediate 24)
Mixing N- [ 6-bromo-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]]Triazolo [1,5-a]Pyridin-2-yl]Acetamide (intermediate 18,1.07g,2.59mmol), bis (triphenylphosphine) palladium (II) dichloride (91mg,0.13mmol) and tributyl (1-ethoxyvinyl) tin were suspended in anhydrous DMF (8mL) and degassed with argon. The reaction mixture was heated at 120 ℃ for 20min using microwave radiation. 1M HCl (10mL) was added and the reaction mixture was stirred for 1h, then partitioned between EtOAc (100mL) and water (100 mL). The organic layer was washed with saturated brine and then dried (Na)2SO4) And concentrated in vacuo to give a yellow solid. The solid was triturated with EtOAc and the solid was collected by filtration, washed with EtOAc to give the title compound as a beige solid (680 mg).
LC-MS (method 1) Rt 3.16min, M/z 377.2[ M + H]+
Step 3
N- [6- (3-dimethylamino-acryloyl) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2, 4%]Triazolo compounds [1,5-a]Pyridin-2-yl]-acetamide(intermediate 25)
A suspension of N- [ 6-acetyl-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -acetamide (intermediate 24,732mg,1.947mmol) and dimethylformamide dimethyl acetal (4mL) in toluene (10mL) was heated at 100 ℃ for 2 h. The reaction mixture was cooled, then EtOAc (50mL) was added, and the resulting precipitate was collected by filtration to give the title compound (508mg) as a white solid.
LC-MS (method 1) Rt 2.82min, M/z 432[ M + H ]]+
Step 4
4- {5- [ 2-amino-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]]Triazolo [1,5-a]Pyridine-6- Base of]-pyrazol-1-yl } -3-methanesulfonyl-benzonitrile(example 40)
Reacting N- [6- (3-dimethylamino-acryloyl) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]]Triazolo [1,5-a]Pyridin-2-yl]-acetamide (intermediate 25,247mg,0.573mmol) and 4-hydrazino-3-methanesulfonyl-benzonitrile (intermediate 22,181mg,0.86mmol) in a mixture of n-butanol (10mL) and concentrated HCl (0.3mL) was heated at 100 ℃ for 1.5 h. EtOAc was added and the mixture was concentrated in vacuo. Passing the obtained residue through preparation C18Purification by HPLC eluting with a gradient of 40-90% MeCN in water (+ 0.1% formic acid) gave the title compound (10mg) as a yellow solid.
LC-MS (method 3) Rt 4.44min, M/z 538.0[ M + H]+
1H NMR(400MHz,DMSO)8.51(1H,d J＝1.8Hz),8.29(1H,s),8.21(1H,dd J＝8.0,1.8Hz),8.00(1H,d,2.0Hz),7.79(1H,d J＝8.0Hz),7.76-7.70(2H,m),7.68(1H,d J＝7.7Hz),7.56(1H,d J＝8.0Hz),6.84(1H,d J＝1.8Hz),6.10(2H,s),3.64(3H,s),2.07(3H,s)。
EXAMPLE 41
N- [6- [2- (4-cyano-2-fluoro-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-acetamide
The title compound (22mg) was prepared from N- [6- (3-dimethylamino-acryloyl) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -acetamide (intermediate 25,85mg,0.197mmol) and 3-fluoro-4-hydrazino-benzonitrile (45mg,0.298mmol) using methods analogous to those employed in example 40, step 4 and example 26, step 1.
LC-MS (method 3) Rt 4.53min, M/z 519.9[ M + H]+
1H NMR(400MHz,DMSO)10.86(1H,s),8.89(1H,s),8.02-8.00(2H,m),7.88-7.80(3H,m),7.77(1H,d J＝7.8Hz),7.74(1H,s),7.69(1H,dJ＝7.8Hz),6.86(1H,d J＝1.9Hz),2.04(3H,s),1.97(3H,s)。
Example 42
N- [6- [2- (4-cyano-phenyl) -4-methyl-2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-benzene Base) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-acetamide
Step 1
N- [ 7-methyl-6-propionyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]Triazolo [1,5-a]Pyridine-2- Base of]-acetamide(intermediate 26))
Mixing N- [ 6-bromo-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]]Triazolo [1,5-a]Pyridin-2-yl]A mixture of-acetamide (intermediate 18,0.5g,1.21mmol) and ethyl-1-propenyl ether (125mg,1.45mmol), triethylamine (202 μ L,1.45mmol), palladium (II) acetate (3mg,0.012mmol), tri-O-tolylphosphine (15mg,0.048mmol) in DMF (7mL) was degassed and then heated at 130 ℃ for 5 h. An additional amount of palladium (II) acetate (3mg) and ethyl-1-propenyl ether (125mg) were added and heating was continued for 5 days. 1M HCl (5mL) was added and the mixture was dilutedStirring vigorously for 40 min. The mixture was partitioned between EtOAc (100mL) and water (100mL) and the organic layer was washed with saturated brine and then dried (Na)2SO4) And concentrated in vacuo. The resulting residue was purified by chromatography, eluting with a gradient of 0-10% MeOH in DCM, followed by trituration with DCM and ether. The resulting precipitate was collected by filtration and dried to give the title compound (11%) as a white solid
LC-MS (method 1) with Rt 3.37min, M/z 391[ M + H ]]+
Step 2
N- [6- [2- (4-cyano-phenyl) -4-methyl-2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-benzene Base) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-acetamide(example 42)
The title compound was prepared from N- [ 7-methyl-6-propionyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -acetamide (intermediate 26,11mg,0.023mmol) and 4-hydrazino-benzonitrile (7 μ L,0.051mmol) using methods analogous to those employed in example 40, steps 3 and 4. In step 4, the acetyl group was lost and reintroduced by reaction with acetyl chloride using a method analogous to that used for intermediate 18 to give the title compound (3mg) as a beige solid.
LC-MS (method 3) Rt 4.77min, M/z 515.9[ M + H-]+
1H NMR(400MHz,DMSO)10.89(1H,s),9.05(1H,s),7.89-7.83(3H,m),7.81(1H,dJ＝7.7Hz),7.77-7.72(2H,m),7.69(1H,d J＝7.7Hz),7.56-7.51(2H,m),2.07(3H,s),2.03(3H,s),1.69(3H,s)。
Example 43
N- [6- (4' -cyano-biphenyl-2-yl) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]A triazolo [1 ] group, a triazolo [1 ], 5-a]pyridin-2-yl]-acetamide
Step 1
2' - (4,4,5, 5-tetramethyl- [1,3, 2)]Dioxaborolan (dioxaborolan) -2-yl) -biphenyl Radical-4-carbonitrile(intermediate 27)
2' -bromo-biphenyl-4-carbonitrile (prepared according to Tetrahedron 2002,58, 5779-5787) (250mg,0.969mmol), bis (pinacolato diboron) (296mg,1.162mmol) and potassium acetate (332mg,3.391mmol) in bis (p-tert-butyl acetate) were addedThe mixture in alkane (5mL) was degassed under argon and then Pd (dppf) Cl was added2DCM (40mg,0.049mmol) and degassing was repeated. The resulting mixture was heated at 120 ℃ for 1h using microwave radiation. The reaction mixture was concentrated in vacuo and partitioned between water and DCM, and the organic extracts were washed with saturated brine, dried (Na)2SO4) Filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography, eluting with a gradient of 0-50% EtOAc in cyclohexane, to give the title compound (120mg) as a clear oil.
LC-MS (method 1) Rt 4.25min, M/z 306[ M + H [ ]]+
Step 2
N- [6- (4' -cyano-biphenyl-2-yl) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]A triazolo [1 ] group, a triazolo [1 ], 5-a]pyridin-2-yl]-acetamide(example 43)
Reacting 6-bromo-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]]Triazolo [1,5-a]Pyridin-2-ylamine (intermediate 2,121mg,0.328mmol), 2' - (4,4,5, 5-tetramethyl- [1,3, 2)]Dioxaborolan-2-yl) -biphenyl-4-carbonitrile (intermediate 27,120mg,0.393mmol) and 2M Na2CO3(0.5mL) of the mixture in toluene was degassed under argon. Adding Pd (PPh)3)4And degassing was repeated, and then the reaction mixture was heated at 120 ℃ for 30 minutes using microwave radiation. Additional Pd (PPh) was added3)4(10mg) and heating was continued for 30 minutes. The reaction mixture was concentrated in vacuo and partitioned between water and DCM, and the organic extracts were washed with saturated brine, dried (Na)2SO4) Filtered and concentrated in vacuo. After purification by flash chromatography, the intermediate 2' - [ 2-amino-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] is obtained]Triazolo [1,5-a]Pyridin-6-yl]Biphenyl-4-carbonitrile, eluting with a gradient of 0-6% MeOH in DCM, to give a white solid (20 mg). Using a method analogous to that employed in intermediate 18, the title compound was obtained (4 mg).
LC-MS (method 3) Rt 5.22min, M/z 512.9[ M + H]+
1H NMR(400MHz,DMSO-d6)10.74(1H,br.s),8.69(1H,s),7.76-7.64(4H,m),7.61-7.47(6H,m),7.39(2H,m),2.00(3H,s),1.66(3H,s)。
Example 44
N- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethoxy-phenyl) - [1, 2,4]triazolo [1,5-a]Pyridin-2-yl]-acetamide
The title compound was prepared from 5-bromo-3-iodo-4-methyl-pyridin-2-ylamine and 3-trifluoromethoxy-phenyl-boronic acid, followed by intermediate 18, using methods analogous to those employed in example 1, steps 1,2 and 4.
LC-MS (method 3) Rt 4.69min, M/z 517.9[ M + H-]+
1H NMR(400MHz,DMSO)10.89(1H,s),9.01(1H,s),7.98(1H,d J＝1.8Hz),7.91-7.86(2H,m)7.64(1H,t J＝8.0Hz),7.61-7.55(2H,m),7.47-7.39(2H,m),7.35(1H,s),6.81(1H,d J＝1.8Hz),2.07(3H,s),1.74(3H,s)。
Examples 45 and 46
N- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) [1,2,4] Triazolo [1,5-a]Pyridin-2-yl]-3-methanesulfinyl-propionamide(example 45) andn- [6- [2- (4-cyano-benzene) Radical) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]- 3-methanesulfonyl-propionamide(example 46)
Step 1
N- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2, 4]triazolo [1,5-a]Pyridin-2-yl]-3-methylthio (methylsulfanyl) -propionamide(intermediate 28)
The title compound (130mg) was prepared by a method similar to that employed in example 16 from 4- {5- [ 2-amino-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile (example 1,100mg,0.218mmol) and 3-methylsulfanyl-propionic acid (45 μ L,0.436 mmol).
LC-MS (method 2) Rt 3.75min, M/z 562[ M + H ]]+
Step 2
N- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) [1,2,4] Triazolo [1,5-a]Pyridin-2-yl]-3-methanesulfinyl-propionamide(example 45) andn- [6- [2- (4-cyano-benzene) Radical) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]- 3-methanesulfonyl-propionamide(example 46)
To N- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] at 0 DEG C]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]To a stirred solution of-3-methylsulfanyl-propionamide (intermediate 28,127mg,0.113mmol) in DCM (5mL) was added 3-chloroperbenzoic acid (29mg,0.17mmol) and the reaction mixture was stirred for 2 h. An additional amount of 3-chloroperbenzoic acid (30mg) was added and stirring continued at room temperature for 16h, then an additional amount of 3-chloroperbenzoic acid (60mg) was added and stirring continued at room temperature for 22 h. The reaction mixture was partitioned between 1N NaOH (10mL) and DCM and the organic phase was dried (Na)2SO4) Filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography, eluting with a gradient of 0-3% MeOH in DCM, followed by preparative C18HPLC, eluting with a gradient of 40-98% MeCN in water (+ 0.1% formic acid) gave the title compound as a white solid.
Example 45(9 mg); LC-MS (method 3) Rt 4.24min, M/z 578[ M + H ]]+
1H NMR(400MHz,DMSO)11.09(1H,s),9.03(1H,s),8.00(1H,d J＝1.8Hz),7.91-7.86(2H,m),7.82(1H,d J＝8.0Hz),7.78-7.72(2H,m),7.68(1H,d J＝7.6Hz),7.61-7.56(2H,m),6.81(1H,d J＝1.8Hz),3.13-3.01(2H,m),2.92-2.72(2H,m),2.53(3H,s),1.78(3H,s)。
Example 46(12 mg); LC-MS (method 3) Rt 4.50min, M/z 594[ M + H ]]+
1H NMR(400MHz,DMSO)11.13(1H,s),9.03(1H,s),7.99(1H,d J＝1.9Hz),7.91-7.86(2H,m),7.82(1H,d J＝7.8Hz),7.78-7.72(2H,m),7.68(1H,d J＝7.6Hz),7.61-7.56(2H,m),6.81(1H,d J＝1.7Hz),3.40(2H,t J＝7.4Hz),2.99(3H,s),2.86(2H,br s),1.77(3H,s)。
Example 47
4- {5- [2- (3-methanesulfonyl-propylamino) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]]Triazole compounds And [1,5-a ]]Pyridin-6-yl]-pyrazol-1-yl } -benzonitrile
Step 1
6-bromo-2-chloro-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]Triazolo [1,5-a]Pyridine compound(intermediate 29)
The title compound (130mg) was prepared from 6-bromo-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-ylamine (intermediate 2,356mg,0.959mmol) using a method analogous to that employed in intermediate 14.
LC-MS (method 5) Rt 4.20min, M/z 389.9/391.9[ M [ ]]+
Step 2
[ 6-bromo-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]- (3-A) Thio-propyl) -amines(intermediate 30)
To a suspension of 6-bromo-2-chloro-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridine (intermediate 29,125mg,0.32mmol) in IMS (5mL) was added 3-methylthio-propylamine (215 μ L,1.92mmol), and the reaction mixture was heated under microwave radiation at 155 ℃ for 2 h. After this time, more 3-methylthio-propylamine (490 μ L) was added and heating was continued for 3h, then another portion of 3-methylthio-propylamine (490 μ L) was added and heating was continued for 7 h. The resulting residue was loaded onto an SCX-2 column and eluted with MeOH, then further purified by flash chromatography, eluting with a gradient of 0-50% EtOAc in cyclohexane, to give the title compound as colorless glass (57 mg).
LC-MS (method 2) Rt 4.32min, M/z 459/461[ M []+
Step 3
4- {5- [ 7-methyl-2- (3-methylsulfanyl-propylamino) -8- (3-trifluoromethyl-phenyl) - [1,2,4]]Triazolo compounds [1,5-a]Pyridin-6-yl]-pyrazol-1-yl } -benzonitrile(intermediate 31)
The title compound (37mg) was prepared from [ 6-bromo-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] - (3-methylsulfanyl-propyl) -amine (intermediate 30,55mg,0.120mmol) using a method analogous to that employed in example 1, step 4.
LC-MS (method 2) Rt 4.13min, M/z 548[ M + H ]]+
Step 4
4- {5- [2- (3-methanesulfonyl-propylamino) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]]Triazole compounds And [1,5-a ]]Pyridin-6-yl]-pyrazol-1-yl } -benzylNitrile
The title compound (13mg) was prepared from 4- {5- [ 7-methyl-2- (3-methylsulfanyl-propylamino) -8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile intermediate 31,55mg,0.120mmol) using a method similar to that employed in example 46.
LC-MS (method 3) Rt 4.72min, M/z 580[ M + H ]]+
1H NMR(400MHz,DMSO)8.74(1H,s),7.96(1H,d J＝1.7Hz),7.92-7.87(2H,m),7.78(1H,d J＝8.0Hz),7.72(1H,t J＝7.5Hz),7.68(1H,s),7.64(1H,d J＝7.7Hz),7.60-7.55(2H,m),6.89(1H,t J＝6.0Hz),6.76(1H,d J＝1.7Hz),3.33-3.22(2H,m,obs.),3.19-3.08(2H,m),2.94(3H,s),2.00-1.89(2H,m),1.70(3H,s)。
Example 48
4- {5- [2- (2-hydroxy-ethylamino) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]]A triazolo [1 ] group, a triazolo [1 ], 5-a]pyridin-6-yl]-pyrazol-1-yl } -benzonitrile
Mixing 4- {5- [ 2-chloro-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]]Triazolo [1,5-a]Pyridin-6-yl]-pyrazol-1-yl } -benzonitrile intermediate 19,50mg,0.104mmol) was heated in ethanolamine (1.5mL) under microwave irradiation at 150 ℃ for 30 min. The reaction mixture was partitioned between water and DCM and the organic phase was dried (Na)2SO4) Filtered and concentrated in vacuo. The residue obtained is triturated in MeCN and then passed through preparative C18HPLC purification, eluting with a gradient of 20-90% MeCN in water (+ 0.1% formic acid) gave the solid as a white solidThe title compound (8 mg).
LC-MS (method 2) Rt 4.55min, M/z 504[ M + H ]]+
1H NMR(400MHz,DMSO)8.72(1H,s),7.95(1H,d J＝1.7Hz),7.92-7.87(2H,m),7.78(1H,d J＝8.0Hz),7.71(1H t J＝7.4Hz),7.68(1H,s),7.63(1H,d J＝7.6Hz),7.60-7.55(2H,m),6.76(1H,d J＝1.7Hz),6.63(1H,t J＝6.0Hz),4.59(1H,t J＝5.5Hz),3.53-3.46(2H,m),3.27-3.19(2H,m),1.70(3H,s)。
Example 49
4- {5- [2- (2-hydroxy-propylamino) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]]A triazolo [1 ] group, a triazolo [1 ], 5-a]pyridin-6-yl]-pyrazol-1-yl } -benzonitrile
The title compound (16mg) was prepared from 4- {5- [ 2-chloro-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile (intermediate 1960mg,0.105mmol) and 1-amino-propan-2-ol using a method similar to that employed in example 48.
LC-MS (method 2) Rt 4.72min, M/z 518[ M + H ]]+
1H NMR(400MHz,DMSO)8.72(1H,s),7.96(1H,d J＝2.0Hz),7.92-7.87(2H,m),7.78(1H,d J＝7.8Hz),7.72(1H,t J＝7.7Hz),7.78(1H,s),7.63(1H,d J＝7.7Hz),7.60-7.55(2H,m),6.76(1H,d J＝1.8Hz),6.62(1H,d J＝6.1Hz),4.59(1H,d J＝4.7Hz),3.82-3.71(1H,m),3.18-3.00(2H,m),1.70(3H,s),1.05(3H,d J＝6.3Hz)。
Example 50
1- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2, 4]triazolo [1,5-a]Pyridin-2-yl]-3-piperidin-4-yl-urea
Step 1
4- {3- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1, 2,4]triazolo [1,5-a]Pyridin-2-yl]-ureido } -piperidine-1-carboxylic acid tert-butyl ester (intermediate 32)
Mixing 4- {5- [ 2-amino-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]]Triazolo [1,5-a]Pyridin-6-yl]A solution of-pyrazol-1-yl } -benzonitrile (example 1,460mg,1.0mmol), N-BOC piperidine-4-isocyanate (680mg,3mmol) and triethylamine (0.48mL,3.5mmol) in DMF (5mL) was stirred at room temperature for 18 h. The reaction mixture was poured into water and the product was extracted into EtOAc. The organic phase was separated and washed with water, then brine and dried (Na)2SO4) Filtered and concentrated in vacuo. Subjecting the obtained residue to C18HPLC, eluting with a gradient of 30-100% MeCN in water (+ 0.1% formic acid) gave the title compound (190mg) as a yellow solid.
LC-MS (method 3) Rt 5.56min, M/z 686.2[ M + H]+
1H NMR(400MHz,DMSO-d6)10.02(1H,s),8.97(1H,s),8.38(1H,d J＝1.8Hz),7.99(1H,d J＝1.8Hz),7.90-7.84(2H,m),7.80-7.65(4H,m),7.59-7.54(2H,m),6.81(1H,d J＝1.8Hz),3.78-3.69(1H,m),3.44-3.35(2H,m),3.07-2.94(2H,m),1.77(3H,s),1.74-1.65(2H,m),1.37(9H,s),1.17-1.061.07(2H,m)
Step 2
1- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2, 4]triazolo [1,5-a]Pyridin-2-yl]-3-piperidin-4-yl-urea (example 50)
To 4- {3- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]To a solution of tert-butyl-ureido } -piperidine-1-carboxylate (intermediate 32,95mg,0.14mmol) in DCM (2mL) was added TFA (1mL) and the solution was stirred at rt for 1h, then toluene (10mL) was added and the reaction mixture was concentrated in vacuo. The reaction mixture was purified in DCM (15ml) and 2M Na2CO3Partition between aqueous solutions and dry the organic extracts (Na)2SO4) Filtration and concentration in vacuo gave the title compound (61mg) as a white solid.
LC-MS (method 3) Rt 3.50min, M/z 586.2[ M + H]+
1H NMR(400MHz,DMSO-d6)9.92(1H,s),8.96(1H,s),8.21(1H,d J＝6.4Hz),7.99(1H,d J＝1.8Hz),7.90-7.80(3H,m),7.79-7.67(3H,m),7.60-7.54(2H,m),6.81(1H,d J＝1.7Hz),3.64-3.52(1H,m),2.77-2.67(2H,m),2.52-2.43(2H,m),1.76(3H,s),1.74-1.66(2H,m),1.18-1.05(2H,m)。
Example 51
(1-methyl-4-piperidinyl) [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl) Phenyl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-urea
To 1- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]To a solution of (E) -3-piperidin-4-yl-urea (example 50,53mg,0.09mmol) in DCM (2mL) was added 37% aqueous formaldehyde (75. mu.L) and 2 drops of MeOH followed by triacetoxyborohydrogenationSodium (160mg,0.75mmol) and the solution was stirred at room temperature for 18 h. The reaction mixture was purified in DCM (15ml) and 2M Na2CO3Partition between aqueous solutions and dry the organic extracts (Na)2SO4) Filtration and concentration in vacuo gave the title compound (19mg) as a white solid.
LC-MS (method 3) Rt 3.53min, M/z 600.1[ M + H-]+
1H NMR(400MHz,DMSO-d6)9.91(1H,s),8.91(1H,s),8.21(1H,d J＝6.6Hz),7.94(1H,d J＝1.8Hz),7.86-7.77(3H,m),7.75-7.63(3H,m),7.57-7.52(2H,m),6.77(1H,d J＝1.8Hz),3.54-3.40(1H,m),2.27-2.14(2H,m),1.99-1.91(3H,s),1.91(2H,m),1.72(3H,s),1.70-1.62(2H,m),1.16-1.28(2H,m)。
Example 52
1- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2, 4]triazolo [1,5-a]Pyridin-2-yl]-3-ethyl-urea
The title compound (27mg) was prepared from 4- {5- [ 2-amino-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile (example 1,100mg,0.218mmol) and ethyl isocyanate (90 μ L,1.089mmol) using a method analogous to that employed in intermediate 21.
LC-MS (method 3) Rt 5.04 min, M/z 530.9[ M +1 ]]+
1H NMR(400MHz,DMSO-d6)9.88(1H,s),8.90(1H,s),7.94(2H,m),7.83(2H,m),7.80-7.61(4H,m),7.53(2H,m),6.76(1H,d J＝1.8Hz),3.08(2H,m),1.74(3H,s),0.94(3H,t J＝7.1Hz)。
Example 53
4- {5- [2- (3-hydroxy-propylamino) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]]A triazolo [1 ] group, a triazolo [1 ], 5-a]pyridin-6-yl]-pyrazol-1-yl } -benzonitrile
The title compound (13mg) was prepared from 4- {5- [ 2-chloro-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile (intermediate 19,60mg,0.126mmol) using a method similar to that employed in example 48.
LC-MS (method 3) Rt 4.64min, M/z 518.2[ M + H]+
1H NMR(400MHz,DMSO)8.68(1H,s),7.91(1H,d J＝1.8Hz),7.86(2H,m),7.76-7.56(4H,m),7.53(2H,m),6.71(1H,d J＝1.8Hz),6.64(1H,t J＝5.7Hz),4.35(1H,t J＝5.3Hz),3.40(2H,q J＝6.2Hz),3.16(2H,q J＝6.7Hz),1.64(3H,s),1.62(2H,m)。
Example 54
4- {5- [2- (4-hydroxy-butylamino) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]]A triazolo [1 ] group, a triazolo [1 ], 5-a]pyridin-6-yl]-pyrazol-1-yl } -benzonitrile
The title compound (17mg) was prepared from 4- {5- [ 2-chloro-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile (intermediate 19,60mg,0.126mmol) and 4-amino-butan-1-ol (1mL) using a method similar to that employed in example 48.
LC-MS (method 3) Rt 4.72min, M/z 532.1[ M + H-]+
1H NMR(400MHz,DMSO)8.72(1H,s),7.95(1H,d J＝1.8Hz),7.92-7.87(2H,m),7.77(1H,d J＝8.0Hz),7.74-7.66(2H,m),7.63(1H,d J＝7.8Hz),7.60-7.55(2H,m),6.77-6.71(2H,m),4.35(1H,t J＝5.2Hz),3.38(2H,q J＝6.2Hz),3.15(2H,q J＝6.2Hz),1.69(3H,s),1.58-1.49(2H,m),1.48-1.39(2H,m)。
Example 55
N- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2, 4]triazolo [1,5-a]Pyridin-2-yl]-succinamic acid
A mixture of 4- {5- [ 2-amino-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile (example 1,230mg,0.50mmol) and 4-methyl-morpholine (300mg,30.0mmol) in THF (3mL) was treated with dihydro-furan-2, 5-dione (250mg,2.50mmol) and heated under microwave radiation at 120 ℃ for 4h and then 60 ℃ for 4 days. The crude reaction mixture was purified by flash chromatography, eluting with a gradient of 0-10% MeOH in DCM. The product-containing fractions were concentrated in vacuo to give the title compound as a colorless glass which solidified to a white solid (182mg) upon standing.
LC-MS (method 3) Rt 4.44min, M/z 560.1[ M + H]+
1H NMR(400MHz,DMSO)10.94(1H,bs),8.99(1H,s),7.98(1H,d J＝1.9Hz),7.90-7.85(2H,m),7.83-7.65(4H,m),7.61-7.55(2H,m),6.81(1H,d J＝1.9Hz),2.59(1H,bs),2.2-2.44(4H,m),1.76(3H,s)。
Example 56
N- [6- [2- (4-cyano)phenyl-2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2, 4]triazolo [1,5-a]Pyridin-2-yl]-4-methylamino-butyramide
Step 1:
{3- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2, 4]triazolo [1,5-a]Pyridin-2-ylcarbamoyl]-propyl } -methyl-carbamic acid tert-butyl ester(intermediate 33)
A solution of 4- (tert-butoxycarbonyl-methyl-amino) -butyric acid (109mg,0.50mmol) in THF (5mL) was treated with 4-methyl-morpholine (101mg,1.0mmol) followed by isobutyl chloroformate (68mg,0.5mmol) and cooled to-22 deg.C under argon. The reaction mixture was stirred for 20min while warming to-15 ℃. After re-cooling to-24 ℃,4- {5- [ 2-amino-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile (example 1,230mg,0.50mmol) was added and the resulting suspension was slowly warmed to room temperature and stirred for 16 h. The reaction mixture was treated at room temperature with fresh batches of 1- ({ [ (4- { [ (tert-butoxy) carbonyl ] (methyl) amino } butyryl) oxy ] carbonyl } oxy) -2-methylpropane, 4-methyl-morpholine (101mg,1.0mmol) and isobutyl chloroformate (137mg,1.0mmol) prepared from a solution of 4- (tert-butoxycarbonyl-methyl-amino) -butyric acid (218mg,1.0mmol) in THF (5 mL). The reaction mixture was stirred at room temperature for 24h and then heated at 60 ℃ for 7 h. After standing at room temperature for 18h, the volatiles were removed in vacuo and the resulting residue was purified by flash chromatography, eluting with a gradient of 0-100% EtOAc in DCM. The product containing fractions were concentrated in vacuo and the resulting residue (456mg,0.5mmol) in THF (5mL) was treated at room temperature with fresh batches of 1- ({ [ (4- { [ (tert-butoxy) carbonyl ] (methyl) amino } butyryl) oxy ] carbonyl } oxy) -2-methylpropane, 4-methyl-morpholine (760mg,7.55mmol) and isobutyl chloroformate (680mg,5.01mmol) prepared from a solution of 4- (tert-butoxycarbonyl-methyl-amino) -butyric acid (1.09g,5.0mmol) in THF (20 mL). The resulting mixture was heated at 50 ℃ for 65h, then purified by flash chromatography, eluting with a gradient of 0-100% EtOAc in DCM, followed by 10% MeOH in DCM to give the title compound (241 mg).
LC-MS (method 1) Rt 4.06min, M/z 659.3[ M + H-]+
Step 2:
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) [1,2,4] Triazolo [1,5-a]Pyridin-2-yl]-4-methylamino-butyramide(example 56)
The title compound (52mg) was prepared from {3- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-ylcarbamoyl ] -propyl } -methyl-carbamic acid tert-butyl ester (intermediate 33,164mg,0.249mmol) using a method analogous to that employed in example 50, step 2.
LC-MS (method 3) Rt 3.55min, M/z 559.2[ M + H]+
1H NMR(400MHz,DMSO)9.00(1H,s),8.33(1H,s),7.98(1H,d J＝1.9Hz),7.91-7.86(2H,m),7.81(1H,d,J＝7.9Hz),7,78-7.71(2H,m),7.67(1H,d,J＝7.9Hz),7.61-7.55(2H,m),6.81(1H,d J＝1.9Hz),2.69-2.62(2H,m),2.46-2.38(2H,m),2.38(3H,s),1.81-1.71(5H,m)。
Example 57
1- (1-acetyl-piperidin-4-yl) -3- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2, 4[ ]]Triazolo [1,5-a]Pyridin-2-yl]-urea
The title compound (30mg) was prepared from 1- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -3-piperidin-4-yl-urea (example 50,50mg,0.085mmol) and acetyl chloride (80mg,0.102mmol) using a method analogous to that employed for intermediate 17.
LC-MS (method 3) Rt 4.41min, M/z 628.1[ M + H-]+
1H NMR(400MHz,DMSO)10.02(1H,s),8.97(1H,s),8.38(1H,d J＝8.6),7.98(1H,d J＝1.9Hz),7.89-7.85(2H,m),7.80(1H,d J＝7.5Hz),7.77-7.65(3H,m),7.60-7.54(2H,m),6.81(1H,d J＝1.7Hz),3.85-3.75(1H,m),3.63-3.53(1H,m),3.41-3.30(1H,m),3.22-3.13(1H,m),3.08-2.99(1H,m),1.97(3H,s),1.82-1.75(4H,m),1.73-1.65(1H,m),1.28-1.01(2H,m)。
Example 58
1- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2, 4]triazolo [1,5-a]Pyridin-2-yl]-3- (1-methanesulfonyl-piperidin-4-yl) -urea
The title compound (30mg) was prepared from 1- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -3-piperidin-4-yl-urea (example 50,50mg,0.085mmol) and methanesulfonyl chloride (7.9 μ L,0.102mmol) using a method analogous to that employed in example 27.
LC-MS (method 3) Rt 4.75min, M/z 664.0[ M + H [ ]]+
1H NMR(400MHz,DMSO)10.02(1H,s),8.98(1H,s),8.22(1H,d J＝7.4),7.99(1H,d J＝1.9Hz),7.90-7.81(3H,m),7.79-7.67(3H,m),7.60-7.54(2H,m),6.81(1H,d J＝1.7Hz),3.71-3.59(1H,m),3.30-3.20(2H,m),2.94-2.84(2H,m),2.80(3H,s),1.93-1.82(2H,m),1.78(3H,s),1.38-1.20(2H,m)。
Example 59
4- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2, 4]triazolo [1,5-a]Pyridin-2-ylamino]-N-methyl-butanamide
Step 1:
4-bromo-N- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]-butanamide(intermediate 34)
The title compound (362mg) was prepared from 4- {5- [ 2-amino-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile (example 1,400mg,1.0mmol), 4-bromo-butyryl chloride (0.5mL,4.32mmol) and triethylamine (0.84mL,6.02mmol) using a method analogous to that employed for intermediate 17, instead of DIPEA.
LC-MS (method 5) Rt 3.82min, M/z 608.2/610.1[ M + H-]+
Step 2:
4- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2, 4]triazolo [1,5-a]Pyridine-2-alkylamino radical]-N-methyl-butanamide(example 59)
4-bromo-N- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -butyramide (intermediate 34,122mg,0.20mmol) was dissolved in methylamine (33% wt in EtOH, 3mL,24.09mmol) and the resulting mixture was heated at 120 ℃ for 30min under microwave radiation. After cooling, the volatiles were removed in vacuo and the resulting residue was purified by HPLC with a 20min gradient eluting with 40-98% MeCN in water (+ 0.1% formic acid) to give the title compound (67mg) as a white solid.
LC-MS (method 3) Rt 4.53min, M/z 559.1[ M + H]+
1H NMR(400MHz,DMSO)8.73(1H,s),7.9(1H,d J＝1.9Hz),7.92-7.87(2H,m),7.77(1H,d J＝7.7),7.74-7.0(4H,m),7.59-7.55(2H,m),6.78-6.73(2H,m),3.13(2H,q J＝7.2Hz),2.53(3H,d J＝4.5Hz),2.09(2H,t 7.2Hz),1.78-1.67(5H,m)。
Example 60
4- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2, 4]triazolo [1,5-a]Pyridin-2-ylamino]-N- (2-dimethylamino-ethyl) -N-methyl-butyramide formate salt
To 4-bromo-N- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl]-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl]To a solution of butanamide (intermediate 34,105mg,0.173mmol) in IMS (2.0mL) was added N, N' -trimethyl-ethane-1, 2-diamine (1.1mL,18.63mmol) and the reaction mixture was heated under microwave irradiation at 130 ℃ for 3h 15 min. The volatiles were removed in vacuo and an additional amount of N, N, N' -trimethyl-ethane-1, 2-diamine (2.5mL,19.67 mmo) was addedl). The resulting mixture was heated at 150 ℃ for 16h and then allowed to stand at room temperature for 48 h. The volatiles were removed in vacuo and the resulting residue was purified by chromatography on silica gel, eluting with a gradient of 0-80% EtOAc in DCM, followed by 10% MeOH in DCM, followed by 2M NH3The solution in MeOH eluted. The fractions containing the product were combined and concentrated in vacuo. The resulting residue was further purified by HPLC (X-select C18 column), eluting with a gradient of 10-98% MeCN in water (+ 0.1% formic acid) to give the title compound (14mg) as a white solid.
LC-MS (method 3) Rt 3.72min, M/z 630.1[ M + H [ ]]+
1H NMR (400MHz, DMSO)8.72-8.69(1H, m),8.26(0.4H, formate), 7.9(1H, d J ═ 1.8Hz),7.92-7.87(2H, m),7.77(1H, d J ═ 7.9Hz),7.74-7.60(3H, m),7.59-7.55(2H, m),6.79-6.74(2H, m),3.37-3.26(2H, m),3.17(2H, q J ═ 6.3Hz),2.91(1.7H, s, rotamer), 2.78(1.3H, s, rotamer), 2.38-2.25(4H, m),2.12(3.7H, s, rotamer), 2.10(2.3H, s, rotamer), 1.80H-1.5H, m).
Example 61
4- { 3-amino-5- [ 2-amino-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]]Triazolo [1,5-a]Pyridine (II) Pyridin-6-yl]-[1,2,4]Triazol-1-yl } -benzonitrile
Step 1
2-amino-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]Triazolo [1,5-a]Pyridine-6-carboxylic acid methyl ester(intermediate 35)
Reacting 6-bromo-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]]Triazolo [1,5-a]Pyridin-2-ylamine (1.0g,2.695mmol), trans-bis (acetoxy) bis [ o- (di-o-tolylphosphino) benzyl]Dipalladium (II) (253mg,0.27mmol), tri-tert-butylphosphonium tetrafluoroborate (156mg,0.539mmol), 1, 8-diazabicyclo [ 5.4.0%]A mixture of undec-7-ene (0.604mL,4.043mmol) and molybdenum hexacarbonyl (713mg,2.70mmol) in a mixture of MeCN and MeOH (1:1,10mL) was heated under microwave radiation at 150 ℃ for 30 min. The resulting mixture was cooled and passed throughAnd (5) filtering. The solvent was concentrated in vacuo and the residue was purified by chromatography, eluting with 0-80% EtOAc in cyclohexane, to give the title compound (445mg) as an orange solid.
LC-MS (method 2) Rt 3.24min, M/z 351[ M + H ]]+
Step 2
2-amino-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]Triazolo [1,5-a]Pyridine-6-carboxylic acid(intermediate 36)
To a suspension of methyl 2-amino-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridine-6-carboxylate (intermediate 35,1.0g,2.857mmol) in THF (10mL) and water (5mL) was added lithium hydroxide (273mg,11.34mmol) and the reaction mixture was stirred at 45 ℃ for 1.75 h. Cooled and then acidified to pH 1. The resulting precipitate was collected by filtration and washed with water to give the title compound (590mg) as a white solid.
LC-MS (method 1) Rt 2.88min, M/z 337[ M + H ]]+
Step 3
2-amino-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]Triazolo [1,5-a]Pyridine-6-carbonyl imino Methyl-methylthiomethyl-carbamic acid tert-butyl ester(intermediate 37)
2-amino-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] in THF (5mL)]Triazolo [1,5-a]Pyridine-6-carboxylic acid (intermediate 36,246mg,0.732mmol) and N- (tert-butyloxycarbonyl) -S-methylisothiourea (139mg,0.732mmol) were treated with triethylamine (306. mu.L, 2.196mmol) and HATU (384mg,1.098mmol) and the reaction mixture was heated at 80 ℃ for 1.5 h. The reaction mixture was washed with saturated NaHCO3Aqueous (20mL) and DCM (20mL) were treated and the organic phase was separated and concentrated in vacuo. The resulting material was purified by chromatography on silica gel eluting with a gradient of 0-10% MeOH in DCM to give the title compound as a white solid (348 mg).
LC-MS (method 2) Rt 4.32min, M/z 509[ M + H ]]+
Step 4
[5- [ 2-amino-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -1- (4-cyano-phenyl) -1H- [1,2,4] triazol-3-yl ] -carbamic acid tert-butyl ester (intermediate 38)
2-amino-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2, 4%]Triazolo [1,5-a]Pyridine-6-carbonylimino-methylthiomethyl) -carbamic acid tert-butyl ester (intermediate 37,400mg,0.79mmol) and 4-cyanophenylhydrazine hydrochloride (160mg,0.945mmol) were suspended in IMS (25mL) and heated at 80 ℃ for 2 h. The reaction mixture was concentrated in vacuo, and the material was purified by chromatography on silica gel, using 0-5% (2N NH)3In MeOH) gradient wash in DCMTo yield the title compound as an orange solid (478 mg).
LC-MS (method 2) with Rt 3.57min, M/z 576[ M + H]+
Step 5
4- { 3-amino-5- [ 2-amino-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]]Triazolo [1,5-a]Pyridine (II) Pyridin-6-yl]-[1,2,4]Triazol-1-yl } -benzonitrile(example 61)
Trifluoroacetic acid (1mL) was added to [5- [ 2-amino-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4]]Triazolo [1,5-a]Pyridin-6-yl]-1- (4-cyano-phenyl) -1H- [1,2,4]Triazol-3-yl]Tert-butyl carbamate (intermediate 38,325mg,0.565mmol) in DCM (5mL) and the reaction mixture was stirred for 2.5 h. Adding saturated NaHCO3Aqueous (10mL) and the phases were separated, then the organics were concentrated in vacuo. The resulting residue of the resulting material was purified by HPLC (C18 column) eluting with a gradient of 40-80% MeCN in water (+ 0.1% formic acid) to give the title compound (6mg) as a white solid.
LC-MS (method 3) Rt 3.89min, M/z 476[ M + H ]]+
1H NMR(400MHz,DMSO)8.73(1H,s),7.91-7.84(2H,m),7.82-7.67(4H,m),7.52-7.47(2H,m),6.18(2H,s),5.92(2H,s),1.88(3H,s)。
Examples 62 to 971References to H NMR and LCMS and methods for their synthesis are reported below:
biological assay
The compounds of the invention were tested for potency in a Human Neutrophil Elastase (HNE) enzyme activity assay.
HNE enzyme assay
Assays were performed in 96-well plates in a total assay volume of 100. mu.l. The final concentration of elastase (human leukocyte elastase, Sigma E8140) was 0.0036 units/well or 0.00072U/mL. Peptide substrate (MeOSuc-Ala-Ala-Pro-Val-AMC, Calbiochem #324740) was used at a final concentration of 100. mu.M. In assay buffer (0.05M Tris. HCl,0.1M NaCl,0.1M CaCl)20.0005% brij-35, pH 7.5) at a final DMSO concentration of 1%. The enzymatic reaction was initiated by addition of enzyme and incubated for 30 minutes at 25 ℃. After incubation, the reaction was stopped by adding soybean trypsin inhibitor (Sigma T9003) at a final concentration of 50. mu.g/well. Fluorescence was measured using a molecular devices fluorescence plate reader using an excitation wavelength of 380nm and an emission wavelength of 460 nm.
Dose responses to each compound were performed and the effect of the compound in each experiment was expressed as a percentage inhibition of control enzyme fluorescence. Dose response curves were plotted and compound potency (IC) was determined50). Compounds were tested in at least 2 separate experiments.
IC of tested embodiment (representative of the invention)50Shown in the following table:
in the above table, HNE enzyme Inhibition (IC) is indicated as follows50Value):>500nM‘+’；100-500nM‘++’；20-100nM‘+++’；<20nM‘++++’。

Claims (13)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof
Wherein
R1is-CN;
R2is (C)1-C4) A haloalkyl group;
w is (i) a 5-membered heteroaryl ring wherein at least one ring atom is a heteroatom selected from N; or (ii) phenyl;
R3is a group-CH2-R23；
R23Is hydrogen;
R5is hydrogen;
R6is hydrogen;
A1is a group-CR7Or a group-N ═ or;
A2is a radical ═ CR8-or a group ═ N-;
R7is hydrogen;
R8selected from hydrogen, halogen or the group-SO2(C1-C4) An alkyl group;
wherein A is1And A2May not be simultaneously a group-N ═ N;
A3--A4is a moiety selected from: group-CR4-N-group-CR4＝CR9And the group-NR17-CO-；
R9Is hydrogen;
R4is a group selected from: hydrogen, (C)1-C4) Alkyl, -NR10R11、-NHCOR12、-NHCOO-R13、-NHCONR27-R14、(C1-C4) Alkoxy, -NH (CH)2)n-SO2(C1-C4) Alkyl, - (NH)q(CH2)n-(C6H6)-SO2(C1-C4) Alkyl, -NHSO2(C1-C4) Alkyl and- (NH)r(CH2)nCONR15R16；
R17Is a group selected from: hydrogen, (C)1-C4) Alkyl, - (CH)2)n-(C6H6)-SO2(C1-C4) Alkyl, - (CH)2)n-SO2(C1-C4) Alkyl and- (CH)2)nCONR15R16；
n is 0 or an integer in the range of 1-3;
q is 0 or 1;
r is 0 or 1;
R10is hydrogen;
R11is hydrogen, a radical (C)1-C6) Alkyl, radical (C)1-C6) Hydroxyalkyl radical, radical (C)1-C6) Alkylene radical NRaRbOr a group (C)1-C6) Alkylene radical N+RaRbRc；
RaAnd RbIndependently at each occurrence, is hydrogen, (C)1-C4) Alkyl group of (C)1-C4) The alkyl group may optionally be substituted by a group-COOR30Substituted or by radicals (C)5-C7) Heterocycloalkyl, radical (C)5-C7) Heterocycloalkyl or radical (C)1-C6) Alkylene radical NReRfSubstitution; alternatively, RaAnd RbTogether with the nitrogen atom to which they are attached may form a group C optionally substituted by one or more groups1-C6Alkyl substituted (C)5-C7) A heterocycloalkyl ring system, and said (C)5-C7) Heterocycloalkyl optionally containing the group-S (O) -or-S (O)2Or a further heteroatom being oxygen, sulfur or nitrogen, said nitrogen atom being optionally substituted by (C)1-C6) Alkyl substitution;
Ra、Rband RcIf present at the same time, is independently at each occurrence (C)1-C4) Alkyl group of (C)1-C4) The alkyl group may optionally be substituted by a group-COOR30Substitution;
Reand RfIndependently at each occurrence is hydrogen or (C)1-C4) An alkyl group;
R12is selected from (C)1-C6) Alkyl, (C)1-C4) Haloalkyl, (C)5-C7) Heterocycloalkyl, radical- (CH)2)n-S(O)t(C1-C4) Alkyl, radical- (CH)2)n-S(O)t(C1-C4) Alkyl radical NRaRbGroup- (CH)2)n-S(O)t(C1-C4) Alkyl radical N+RaRbRcGroup (C)1-C4) alkylene-NH- (C ═ NH) -NH2Group (C)1-C4) alkylene-CO2H. Group- (C)1-C4) alkylene-CO2NR25R26Group- (C)1-C6) Alkylene radical NRaRbGroup- (C)1-C6) Alkylene radical N+RaRbRcAnd (C)1-C4) Alkyl radical (C)5-C7) Heterocycloalkyl, wherein such groups may be optionally substituted with one or two substituents selected from: (C)1-C4) Alkyl, -SO2(C1-C4) Alkyl or (C)1-C4) An alkylamino group;
t may be 0,1 or 2;
R13is selected from (C)1-C6) Alkyl and- (C)1-C6) Alkylene radical N+RaRbRcWherein such groups may optionally be substituted by one or two (C)1-C4) Alkoxy substitution;
R14is selected from (C)1-C4) Alkyl, (C)5-C7) Heterocycloalkyl group, (C)1-C6) Alkylene radical NRaRb、-(C1-C6) Alkylene radical N+RaRbRcAnd (C)1-C4) Alkyl radical (C)5-C7) Heterocycloalkyl, wherein such a group may be optionally substituted with two substituents selected from: -SO2(C1-C4) Alkyl, amino and (C)1-C4) An alkylcarbonyl group;
R15is hydrogen, a radical (C)1-C6) Alkyl or radical (C)1-C6) Alkylene radical NRaRb；
R16Is hydrogen;
R25is hydrogen or (C)1-C4) An alkyl group;
R26is hydrogen or (C)1-C4) An alkyl group;
R27is hydrogen or (C)1-C4) An alkyl group;
R30is hydrogen or (C)1-C4) An alkyl group;
wherein if one or more radicals- (C)1-C6) Alkylene radical N+RaRbRcWhen present, they form quaternary salts with pharmaceutically acceptable counterions;
and wherein the radical R19、R20、R21、R22、R30、Ra、Rb、Rc、Rd、Re、Rf、RgAnd n, if present in more than one group, may have the same or different meaning at each occurrence.
2. A compound of formula (I) as claimed in claim 1 wherein R is2Is 3-trifluoromethyl.
3. A compound of formula (I) as claimed in any one of claims 1-2 wherein W is a 5 membered heteroaryl ring wherein at least one ring atom is a heteroatom selected from N.
4. A compound of formula (I) as claimed in any one of claims 1-2 wherein a3--A4Is part-CR4＝N-。
5. A compound of formula (I) as claimed in any one of claims 1-2 wherein a1Is a group-CR7＝，R7Is hydrogen, and A2Is a group-CR8Is ═ and R8Is hydrogen or a radical-SO2(C1-C4) An alkyl group.
6. A compound selected from the group consisting of:
4- {5- [ 2-amino-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -2,2, 2-trifluoro-acetamide;
4- {5- [ 7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
4- {5- [2, 7-dimethyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
4- {5- [2, 7-dimethyl-8- (3-trifluoromethyl-phenyl) -imidazo [1,2-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
4- {5- [ 7-methyl-8- (3-trifluoromethyl-phenyl) -imidazo [1,2-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
4- {5- [2- (4-methanesulfonyl-phenylamino) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
4- {5- [2- (4-methanesulfonyl-benzyl) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
4- {5- [ 7-methyl-3-oxo-8- (3-trifluoromethyl-phenyl) -2, 3-dihydro- [1,2,4] triazolo [4,3-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
4- {5- [2- (4-methanesulfonyl-benzyl) -7-methyl-3-oxo-8- (3-trifluoromethyl-phenyl) -2, 3-dihydro- [1,2,4] triazolo [4,3-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
2- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-3-oxo-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [4,3-a ] pyridin-2-yl ] -N, N-dimethyl-acetamide;
2- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-3-oxo-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [4,3-a ] pyridin-2-yl ] -N-methyl-acetamide;
4- {5- [2- (3-methanesulfonyl-propyl) -7-methyl-3-oxo-8- (3-trifluoromethyl-phenyl) -2, 3-dihydro- [1,2,4] triazolo [4,3-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -2-dimethylamino-acetamide;
{ [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-ylcarbamoyl ] -methyl } -trimethyl-ammonium bromide;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -4-dimethylamino-butyramide;
{3- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-ylcarbamoyl ] -propyl } -trimethyl-ammonium bromide;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -2- (4-methyl-piperazin-1-yl) -acetamide;
4- { [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-ylcarbamoyl ] -methyl } -1, 1-dimethyl-piperazin-1-ium iodide;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -2-morpholin-4-yl-acetamide;
4- { [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-ylcarbamoyl ] -methyl } -1, 1-dimethyl-piperazin-1-ium iodide;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -2-morpholin-4-yl-acetamide;
n- [6- [1- (4-cyano-phenyl) -1H-pyrazol-5-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -2- (1, 1-dioxothiomorpholin-4-yl) -acetamide;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -4-methanesulfonyl-benzamide;
4- {5- [2- (4-methanesulfonyl-benzylamino) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
2- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-ylamino ] -N, N-dimethyl-acetamide;
1- { [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-ylcarbamoyl ] -methyl } -1, 4-dimethyl-piperazin-1-ium chloride;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -acetamide;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -methanesulfonamide;
4- {5- [2- (3-dimethylamino-propylamino) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
4- {5- [2- (2-dimethylamino-ethylamino) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
4- {5- [2- (4-dimethylamino-butylamino) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
4- {5- [ 2-methoxy-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
{3- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-ylamino ] -propyl } -trimethyl-benzenesulfonate ammonium;
{3- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-ylamino ] -ethyl } -trimethyl-benzenesulfonate ammonium;
{4- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-ylamino ] -butyl } -trimethyl-ammonium formate;
ethyl [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -carbamate;
2-methoxyethyl [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -carbamate;
{3- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-ylcarbamoyloxy ] -propyl } -trimethyl-ammonium formate;
(3- {3- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -ureido } -propyl) -trimethyl-ammonium formate;
n- [6- [2- (4-cyano-phenyl) -2H- [1,2,4] triazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -acetamide;
4- {5- [ 2-amino-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -3-methanesulfonyl-benzonitrile;
n- [6- [2- (4-cyano-2-fluoro-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -acetamide;
n- [6- [2- (4-cyano-phenyl) -4-methyl-2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -acetamide;
n- [6- (4' -cyano-biphenyl-2-yl) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -acetamide;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethoxy-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -acetamide;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -3-methanesulfinyl-propionamide;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -3-methanesulfonyl-propionamide;
4- {5- [2- (3-methanesulfonyl-propylamino) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
4- {5- [2- (2-hydroxy-ethylamino) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
4- {5- [2- (2-hydroxy-propylamino) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
1- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -3-piperidin-4-yl-urea;
(1-methyl-4-piperidinyl) [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -urea;
1- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -3-ethyl-urea;
4- {5- [2- (3-hydroxy-propylamino) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
4- {5- [2- (4-hydroxy-butylamino) -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] -pyrazol-1-yl } -benzonitrile;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -succinamic acid;
n- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -4-methylamino-butyramide;
1- (1-acetyl-piperidin-4-yl) -3- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -urea;
1- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] -3- (1-methanesulfonyl-piperidin-4-yl) -urea;
4- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-ylamino ] -N-methyl-butyramide;
4- [6- [2- (4-cyano-phenyl) -2H-pyrazol-3-yl ] -7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-ylamino ] -N- (2-dimethylamino-ethyl) -N-methyl-butyramide;
4- { 3-amino-5- [ 2-amino-7-methyl-8- (3-trifluoromethyl-phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] - [1,2,4] triazol-1-yl } -benzonitrile;
and pharmaceutically acceptable salts thereof.
7. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 6 and a pharmaceutically acceptable carrier or excipient.
8. A pharmaceutical composition as claimed in claim 7 which is suitable for oral administration or administration by the pulmonary route.
9. Use of a compound as claimed in any one of claims 1 to 6 in the manufacture of a medicament for the treatment of a disease or condition in which HNE is implicated.
10. The use according to claim 9, wherein the disease or condition is chronic obstructive pulmonary disease, bronchiectasis, chronic bronchitis, pulmonary fibrosis, pneumonia, acute respiratory distress syndrome or cystic fibrosis.
11. The use according to claim 9, wherein the disease or condition is asthma, rhinitis, psoriasis, atopic dermatitis, non-atopic dermatitis, crohn's disease, ulcerative colitis, or irritable bowel disease.
12. The use of claim 9, wherein the disease or disorder is emphysema.
13. The use of claim 9, wherein the disease or condition is smoking-induced emphysema.
HK15107783.9A 2012-07-12 2013-07-10 Inhibition of enzymes HK1207078B (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
EP12176079 2012-07-12
EP12176079.7 2012-07-12
EP13158756.0 2013-03-12
EP13158756 2013-03-12
PCT/EP2013/064603 WO2014009425A1 (en) 2012-07-12 2013-07-10 Inhibition of enzymes

Publications (2)

Publication Number Publication Date
HK1207078A1 HK1207078A1 (en) 2016-01-22
HK1207078B true HK1207078B (en) 2018-02-02

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