Bruton's tyrosine kinase inhibitors

Abstract

Bruton's tyrosine kinase (Btk) inhibitors have the following Formula (I): ##STR00001##

Claims

1. A compound of Formula (I) having the following structure: ##STR00292## wherein: A is CR.sup.1; B is N; C and D are CR.sup.1; R.sup.1 is hydrogen, OH, CN, NHOH or CONH.sub.2; R.sup.2 is ##STR00293## X-E is one of the followings: (1) X is O, OCR.sup.aR.sup.b, S(O), S(O).sub.2, CR.sup.aR.sup.b, NR.sup.c(CO), CONR.sup.c or a bond; and E is a hydrogen, an aryl or a heteroaryl substituted with one to three R.sup.5 substituents; or a 3-7 membered saturated or partially unsaturated carbocyclic ring, an 8-10 membered bicyclic saturated, partially unsaturated or aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or (2) X-E is hydrogen, halogen, OR.sup.a, O(CH.sub.2).sub.1-4R.sup.a, CN, or NO.sub.2; R.sup.4 and R.sup.5 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, OCF.sub.3, OCF.sub.2H, C.sub.1-6 alkyl, optionally substituted with one to five fluorines, C.sub.3-6 cycloalkyl, optionally substituted with one to five fluorines, C.sub.1-4 alkoxy, optionally substituted with one to five fluorines, C.sub.1-4 alkylthio, optionally substituted with one to five fluorines, C.sub.1-4 alkylsulfonyl, optionally substituted with one to five fluorines, carboxy, C.sub.1-4 alkyloxycarbonyl, and C.sub.1-4 alkylcarbonyl; R.sup.a and R.sup.b are each independently hydrogen, fluorine, or C.sub.1-3 alkyl, optionally substituted with one to five fluorines; R.sup.c is hydrogen or C.sub.1-3 alkyl, optionally substituted with one to five fluorines; R.sup.3 is a group having a double bond, a tautomer thereof, or a pharmaceutical acceptable solvate thereof.

2. The compound of claim 1, wherein R.sup.3 is selected from the group consisting of: ##STR00294## Y is C(O); OC(O), NHC(O), SO, S(O).sub.2, or NHS(O).sub.2; R.sup.6, R.sup.7, and R.sup.8 are each independently selected from the group consisting of hydrogen, halogen, CN, C.sub.1-4 alkyl, C.sub.1-6 alkoxyalkyl, C.sub.1-8 alkylaminoalkyl, and C.sub.1-4 alkylphenyl; or R.sup.7 and R.sup.8 taken together form a bond.

3. The compound of claim 1, wherein R.sup.3 is selected from the group consisting of: ##STR00295## Y is C(O); OC(O), NHC(O), SO, S(O).sub.2, or NHS(O).sub.2; R.sup.6, R.sup.7, and R.sup.8 are each independently selected from the group consisting of hydrogen, halogen, CN, C.sub.1-4 alkyl, C.sub.1-6 alkoxyalkyl, C.sub.1-8 alkylaminoalkyl, and C.sub.1-4 alkylphenyl.

4. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1, and a pharmaceutically acceptable excipient.

5. A compound selected from the group consisting of ##STR00296## ##STR00297## ##STR00298## ##STR00299## ##STR00300## ##STR00301## ##STR00302## ##STR00303## ##STR00304## ##STR00305## ##STR00306## ##STR00307## ##STR00308## ##STR00309## ##STR00310## ##STR00311## ##STR00312## ##STR00313## ##STR00314## ##STR00315## ##STR00316## ##STR00317## ##STR00318## ##STR00319## ##STR00320## ##STR00321## ##STR00322## ##STR00323## ##STR00324## ##STR00325## ##STR00326## ##STR00327## ##STR00328## ##STR00329## ##STR00330## ##STR00331## ##STR00332## ##STR00333## ##STR00334## ##STR00335## ##STR00336## ##STR00337## ##STR00338## ##STR00339## ##STR00340## ##STR00341## ##STR00342## ##STR00343## ##STR00344## ##STR00345## ##STR00346## ##STR00347## ##STR00348## ##STR00349## ##STR00350## ##STR00351## ##STR00352## ##STR00353## ##STR00354## ##STR00355## ##STR00356## ##STR00357## ##STR00358## ##STR00359## ##STR00360## ##STR00361## ##STR00362## ##STR00363## ##STR00364## ##STR00365## ##STR00366## ##STR00367## ##STR00368## ##STR00369## ##STR00370## ##STR00371## ##STR00372## ##STR00373## ##STR00374## ##STR00375## ##STR00376## ##STR00377##

6. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 5, and a pharmaceutically acceptable excipient.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) The methods described herein include administering to a subject in need a composition containing a therapeutically effective amount of one or more Btk inhibitor compounds described herein.

(2) Prodrugs means any compound which releases an active parent drug according to Formula I in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of Formula I are prepared by modifying functional groups present in the compound of Formula I in such a way that the modifications may be cleaved in vivo to release the parent compound. Prodrugs may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds.

(3) Tautomers mean compounds produced by the phenomenon wherein a proton of one atom of a molecule shifts to another atom. Tautomers also refer to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. One of ordinary skill in the art would recognize that other tautomeric ring atom arrangements are possible. All such isomeric forms of these compounds are expressly included in the present disclosure.

(4) Isomers mean compounds having identical molecular formulae but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed stereoisomers. Stereoisomers that are not mirror images of one another are termed diastereomers, and those that are non-superimposable mirror images of each other are termed enantiomers. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. A chiral compound can exist as either individual enantiomer or as a mixture thereof. Unless otherwise indicated, the description is intended to include individual stereoisomers as well as mixtures.

(5) Certain compounds of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. Solvates refer to a complex formed by combination of solvent molecules with the compound of Formula I. The solvent can be an organic compound, an inorganic compound, or a mixture thereof.

(6) Pharmaceutically acceptable salts represent those salts which are, within the scope of medical judgement, suitable for use in contact for the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. They may be obtained during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable mineral acid such as hydrochloric acid, phosphoric acid, or sulfuric acid, or with an organic acid such as for example ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid, methanesulfonic acid, and the like. The acid function can be reacted with an organic or a mineral base, like sodium hydroxide, potassium hydroxide or lithium hydroxide.

(7) Therapeutically effective amount means an amount of compound or a composition of the present invention effective in inhibiting Bruton's tyrosine kinase and thus producing the desired therapeutic effect.

(8) As used herein, the term alkyl refers to a monovalent straight or branched chain, saturated aliphatic hydrocarbon radical having a number of carbon atoms in the specified range. For example, C.sub.1-6 alkyl refers to any of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and t-butyl, n- and iso-propyl, ethyl and methyl. Alkyl also includes saturated aliphatic hydrocarbon radicals wherein one or more hydrogens are replaced with deuterium, for example, CD.sub.3.

(9) The term branched alkyl refers to an alkyl group as defined above except that straight chain alkyl groups in the specified range are excluded. As defined herein, branched alkyl includes alkyl groups in which the alkyl is attached to the rest of the compound via a secondary or tertiary carbon. For example, isopropyl is a branched alkyl group.

(10) The term cycloalkyl refers to any monocyclic ring of an alkane having a number of carbon atoms in the specified range. For example, C.sub.3-6cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

(11) The term halogen refers to fluorine, chlorine, bromine and iodine (alternatively referred to as fluoro, chloro, bromo, and iodo).

(12) The term haloalkyl refers to an alkyl group as defined above in which one or more of the hydrogen atoms have been replaced with a halogen (i.e., F, Cl, Br and/or I). For example, C.sub.1-6 haloalkyl refers to a C.sub.1 to C.sub.6 linear or branched alkyl group as defined above with one or more halogen substituents. The term fluoroalkyl has an analogous meaning except that the halogen substituents are restricted to fluoro. Suitable fluoroalkyls include the series (CH.sub.2).sub.0-4CF.sub.3.

(13) The term C(O) or CO refers to carbonyl. The terms S(O).sub.2 or SO.sub.2 refers to sulfonyl. The term S(O) or SO refers to sulfinyl.

(14) The term aryl refers to phenyl, naphthyl, tetrahydronaphthyl, idenyl, dihydroindenyl and the like. An aryl of particular interest is phenyl.

(15) The term heteroaryl refers to (i) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, or (ii) is a heterobicyclic ring selected from quinolinyl, isoquinolinyl, and quinoxalinyl. Suitable 5- and 6-membered heteroaromatic rings include, for example, pyridyl (also referred to as pyridinyl), pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thienyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl, oxatriazolyl, thiazolyl, isothiazolyl, and thiadiazolyl. A class of heteroaryls of interest consists of (i) 5- and 6-membered heteroaromatic rings containing from 1 to 3 heteroatoms independently selected from N, O and S, and (ii) heterobicyclic rings selected from quinolinyl, isoquinolinyl, and quinoxalinyl. Heteroaryls of particular interest are pyrrolyl, imidazolyl, pyridyl, pyrazinyl, quinolinyl (or quinolyl), isoquinolinyl (or isoquinolyl), and quinoxalinyl.

(16) Examples of 4- to 7-membered, saturated heterocyclic rings within the scope of this invention include, for example, azetidinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, pyrrolidinyl, imidazolidinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, hexahydropyrimidinyl, thiazinanyl, thiazepanyl, azepanyl, diazepanyl, tetrahydropyranyl, tetrahydrothiopyranyl, and dioxanyl. Examples of 4- to 7-membered, unsaturated heterocyclic rings within the scope of this invention include mono-unsaturated heterocyclic rings corresponding to the saturated heterocyclic rings listed in the preceding sentence in which a single bond is replaced with a double bond (e.g., a carbon-carbon single bond is replaced with a carbon-carbon double bond).

(17) It is understood that the specific rings listed above are not a limitation on the rings which can be used in the present invention. These rings are merely representative.

(18) Synthetic methods for preparing the compounds of the present invention are illustrated in the following Schemes, Methods, and Examples. Starting materials are commercially available or may be prepared according to procedures known in the art or as described herein. The compounds of the invention are illustrated by means of the specific examples shown below. However, these specific examples are not to be construed as forming the only genus that is considered as the invention. These examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily appreciate that known variations in the conditions and processes can be used to prepare such compounds.

(19) ##STR00006##

(20) The Btk inhibitor compounds of Formula I can be prepared by methods well known in the art of organic chemistry. The starting material used for the synthesis of these compounds can be either synthesized or obtained from commercial sources, such as, but not limited to, China chemical companies or Sigma-Aldrich Chemical Co. (St. Louis, Mo.) at China. The compounds described herein, and other related compounds having different substituents are optionally synthesized using techniques and materials, such as described, for example, in March, ADVANCED ORGANIC CHEMISTRY 4th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4th Ed., Vols. A and B (Plenum 2000, 2001); Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). Other methods for the synthesis of compounds described herein may be found in United States Patent Application Publication No. US 2011/0130429 A1, Burgey et al. Bioorganic & Medicinal Chemistry Letters 10 (2006) 5052-5056. The definitions of chemistry terms used in this application may be found in these reference (if not otherwise defined herein). As a guide the following synthetic methods may be utilized.

(21) During the synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This is achieved by means of conventional protecting groups, such as those described in T. W Greene and P. G. M. Wutts Protective groups in Organic Synthesis 3rd Edition, John Wiley and Sons, 1999. The protective groups are optionally removed at a convenient subsequent stage using methods well known in the art. The products of the reactions are optionally isolated and purified. If desired, using conventional techniques, but not limited to, filtration, distillation crystallization, chromatography and the like. Such materials are optionally characterized using conventional means, including physical constant and spectra data.

(22) Compounds described herein may possess one or more stereocenters and each center may exist in the R or S configuration. The compounds presented herein include all diasteromeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof.

(23) The Btk inhibitor compounds of Formula I can be, for example, 1H-imidazo[4,5-c]pyridin-2(3H)-one derivatives. Specifically, the Btk inhibitor compounds of Formula I can be, for example, compounds F, wherein R.sub.1-R.sub.2 have the previously defined meanings. A non-limiting example of a synthetic approach towards the preparation of compounds F can be prepared by the general synthetic route shown in Scheme I.

(24) ##STR00007##

(25) Referring to Scheme I, amine (B) could be added to a range of substituted o-halonitroaromatics A, followed by nitro group reduction of the product C with Fe metal in NH.sub.4Cl in acidic methanol to deliver the o-amino anilines D. Ring closure with carbonyldiimidazole to obtain the key intermediates E, which then are derivatized by copper catalyst coupling reaction using appropriately substituted phenylboronic acid (corresponding boronic esters may also be used) directly affords the desired compounds F. In a typical procedure, a mixture of intermediates E, a copper catalyst (e.g. Cu(OAc).sub.2), base (e.g. TEA, DIPEA or the like) and an aryl boronic acid or aryl boronic ester in a suitable solvent such as DCM, or toluene to form compounds F.

(26) Alternatively, compounds F or I may be obtained from compounds G or H, in which FG is a functional group (e.g. ester, protected anilines, protected phenols, bromide) that can be easily converted to groups defined for XAr. Non-limiting examples of suitable functional groups in compounds G are a benzyl ether, dibenzyl anime, or methyl ester, which can be treated with base or Pd/C/H.sub.2 to form the key intermediates G-1a, G-2a, G-3a, then form corresponding compounds F-1, F-2, F-3, F-4 at Scheme II.

(27) ##STR00008## ##STR00009## ##STR00010## ##STR00011##

(28) The deprotection reactions for the protective groups of compound F in Scheme III are known and can be run by the methods described below. Examples here are (a) deprotection reaction under acidic conditions for Boc protecting group and (b) deprotection reactions based on hydrogenolysis for benzyl protecting group. After deprotection with these conditions, coupling with, but not limited to, an acid chloride, such as, but not limited to, aryloyl chloride, completes the synthesis to provide compound F-b.

(29) ##STR00012##

(30) General experimental conditions: Preparative thin layer chromatography (PTLC) was performed on 2020 cm plates (500 micron thick silica gel). Silica gel chromatography was performed on a Biotage Horizon flash chromatography system. 1H NMR spectra were recorded on a Bruker Ascend TM 400 spectrometer at 400 MHz at 298 K, and the chemical shifts are given in parts per million (ppm) referenced to the residual proton signal of the deuterated solvents: CHCl.sub.3 at =7.26 ppm and CH.sub.3OH or CH.sub.3OD at =3.30 ppm. LCMS spectra were taken on an Agilent Technologies 1260 Infinity or 6120 Quadrupole spectrometer. The mobile phase for the LC was acetonitrile (A) and water (B) with 0.01% formic acid, and the eluent gradient was from 5-95% A in 6.0 min, 60-95% A in 5.0 min, 80-100% A in 5.0 min and 85-100% A in 10 min using a SBC18 50 mm4.6 mm2.7 m capillary column. Mass spectra (MS) were measured by electrospray ion-mass spectroscopy (ESI). All temperatures are in degrees Celsius unless otherwise noted.

(31) Analytical HPLC mass spectrometry conditions:

(32) LC1: Column: SB-C18 50 mm4.6 mm2.7 m

(33) Temperature: 50 C.

(34) Eluent: 5:95 v/v acetonitrile/water+0.01% formic acid in 6 min.

(35) Flow Rate: 1.5 mL/min, Injection 5 L

(36) Detection: PDA, 200-600 nm

(37) MS: mass range 150-750 amu; positive ion electrospray ionization

(38) LC2: Column: SB-C18 50 mm4.6 mm2.7 m

(39) Temperature: 50 C.

(40) Eluent: 5:95 to 95:5 v/v acetonitrile/water+0.05% TFA over 3.00 min.

(41) Flow Rate: 1.5 mL/min, Injection 5 L

(42) Detection: PDA, 200-600 nm

(43) MS: mass range 150-750 amu; positive ion electrospray ionization

(44) LC3: Column: SB-C18 50 mm4.6 mm2.7 m

(45) Temperature: 50 C.

(46) Eluent: 10:90 to 98:2 v/v acetonitrile/water+0.05% TFA over 3.75 min.

(47) Flow Rate: 1.0 mL/min, Injection 10 L

(48) Detection: PDA, 200-600 nm

(49) MS: mass range 150-750 amu; positive ion electrospray ionization

List of Abbreviations

(50) AcOH=acetic acid

(51) Alk=alkyl

(52) Ar=aryl

(53) Boc=tert-butyloxycarbonyl

(54) bs=broad singlet

(55) CH.sub.2Cl.sub.2=dichloromethane

(56) d=doublet

(57) dd=doublet of doublets

(58) DBU=1,8-diazabicyclo[5.4.0]undec-7-ene

(59) DCM=dichloromethane

(60) DEAD=diethyl azodicarboxylate

(61) DMF=N,N-dimethylformamide

(62) DMSO=dimethyl sulfoxide

(63) EA=ethyl acetate

(64) ESI=electrospray ionization

(65) Et=ethyl

(66) EtOAc=ethyl acetate

(67) EtOH=ethyl alcohol

(68) h=hours

(69) HOAc=acetic acid

(70) LiOH=lithium hydroxide

(71) m=multiplet

(72) Me=methyl

(73) MeCN=acetonitrile

(74) MeOH=methyl alcohol

(75) MgSO.sub.4=magnesium sulfate

(76) min=minutes

(77) MS=mass spectroscopy

(78) NaCl=sodium chloride

(79) NaOH=sodium hydroxide

(80) Na.sub.2SO.sub.4=sodium sulfate

(81) NMR=nuclear magnetic resonance spectroscopy

(82) PE=petroleum ether

(83) PG=protecting group

(84) Ph=phenyl

(85) rt=room temperature

(86) s=singlet

(87) t=triplet

(88) TFA=trifluoroacetic acid

(89) THF=tetrahydrofuran

(90) Ts=p-toluenesulfonyl (tosyl)

(91) The compounds of the present invention can be prepared following general methods detailed below. In certain embodiments, provided herein are methods of making the tyrosine kinase inhibitor compounds described herein. In certain embodiments, compounds described herein are synthesized using the following synthetic schemes. In other embodiments, compounds are synthesized using methodologies analogous to those described below by the use of appropriate alternative starting materials. All key intermediates were prepared according to the following methods.

Example 1

(R)-1-(1-acryloylpyrrolidin-3-yl)-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one

(92) ##STR00013## ##STR00014##

Step 1: (R)N-(1-benzylpyrrolidin-3-yl)-3-nitropyridin-4-amine (3)

(93) A mixture of 4-chloro-3-nitropyridine (12.2 g, 77.4 mmol), (R)-1-benzylpyrrolidin-3-amine (15 g, 85.2 mmol), and N,N-diisopropylethylamine (47 mL, 271.1 mmol) in 2-propanol (309 mL) was heated at reflux for 4 h. Volatile components were removed under vacuum and the residue was purified by column chromatography on silica gel (gradient: PE/EA=10/1) to provide the title product 22.1 g, yield 96%.

(94) .sup.1H NMR (400 MHz, DMSO-d.sub.6): 9.03 (s, 1H), 8.27 (d, J=6 Hz, 1H), 8.22 (d, J=7.2 Hz, 1H), 7.34-7.26 (m, 4H), 7.25 (d, J=4 Hz, 1H), 7.02 (d, J=6.4 Hz, 1H), 4.31-4.29 (m, 1H), 3.65 (s, 2H), 2.80-2.73 (m, 2H), 2.65-2.61 (m, 1H), 2.41-2.33 (m, 2H), 1.74-1.73 (m, 1H).

Step 2: (R)N4-(1-benzylpyrrolidin-3-yl)pyridine-3,4-diamine (4)

(95) To a solution of (3) 22.1 g (74.1 mmol) in EtOH (504 mL) was added. Fe (22.55 g, 400 mmol), NH.sub.4Cl (127 mL), THF (257 mL), and H.sub.2O (127 mL). Then the reaction mixture was stirred at 85 degree for 2 h. The precipitate was filtered off. Solvent was removed. The reaction mixture was extracted with EA. Organic phase was purified by column chromatography on silica gel gradient: (DCM/MeOH=100/1-50/1) to give the title product 17 g, yield 85.5%.

(96) .sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.62 (s, 1H), 7.55 (d, J=5.2 Hz, 1H), 7.34-7.31 (m, 5H), 7.25-7.23 (m, 1H), 6.28 (d, J=5.2 Hz, 1H), 5.30 (d, J=6.4 Hz, 1H), 4.64 (s, 2H), 3.95-3.94 (m, 1H), 3.59 (d, J=4.4 Hz, 2H), 2.83-2.80 (m, 1H), 2.79-2.62 (m, 1H), 2.46-2.41 (m, 2H), 2.27-2.22 (m, 1H), 1.69-1.65 (m, 1H). LC-MS: m/z=268 [M+H].sup.+.

Step 3: (R)-1-(1-benzylpyrrolidin-3-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (5)

(97) A mixture of (4) (9.5 g, 35.4 mmol) and carbonyldiimodazole (11.48 g, 70.8 mmol) in toluene (200 mL) was reflux for 3 h. Volatile components were removed under vacuum, before being poured into H.sub.2O, The reaction mixture was extracted with EA, Organic phase was purified by column chromatography on silica gel (gradient: DCM/MeOH=100/1-50/1) to give the title product (7 g, yield 67.3%).

(98) .sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.62 (s, 1H), 7.55 (d, J=5.2 Hz, 1H), 7.34-7.31 (m, 5H), 7.25-7.23 (m, 1H), 6.28 (d, J=5.2 Hz, 1H), 5.30 (d, J=6.4 Hz, 1H), 4.64 (s, 2H), 3.95-3.94 (m, 1H), 3.59 (d, J=4.4 Hz, 2H), 2.83-2.80 (m, 1H), 2.79-2.62 (m, 1H), 2.46-2.41 (m, 2H), 2.27-2.22 (m, 1H), 1.69-1.65 (m, 1H). LC-MS: m/z=295 [M+H].sup.+.

Step 4: (R)-1-(1-benzylpyrrolidin-3-yl)-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (6)

(99) Intermediate 5 (0.1 g, 0.34 mmol), (4-phenoxyphenyl)boronic acid (0.145 g, 0.68 mmol), TEA (68 mg, 0.68 mmol) and 4 A molecular sieves (130 mg) were added to DCM (3 mL) in a vial Copper (II) acetate (67 mg, 0.34 mmol) was added in one portion. The mixture was stirred for about 22 h at rt. Volatile components were removed under vacuum, before being poured into H.sub.2O, The reaction mixture was extracted with EA, Organic phase was purified by column chromatography on silica gel (gradient: DCM/MeOH=100/1-50/1) to give the title product (63 mg, yield 40.1%).

(100) .sup.1H NMR (400 MHz, CDCl.sub.3): 8.29 (s, 1H), 8.23 (s, 1H), 7.80 (s, 1H), 7.39-7.37 (m, 2H), 7.36-7.31 (m, 5H), 7.27 (s, 2H), 7.07-7.01 (m, 5H), 5.19 (s, 1H), 3.72 (d, J=12.8 Hz, 1H), 3.57 (d, J=12.8 Hz, 1H), 3.15 (s, 1H), 3.30-2.98 (m, 1H), 2.64-2.59 (m, 1H), 2.35-2.29 (m, 2H), 2.118 (s, 1H). LC-MS: m/z=462 [M+H].sup.+.

Step 5: (R)-3-(4-phenoxyphenyl)-1-(pyrrolidin-3-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (7)

(101) A suspension of 6 (50 mg, 0.1 mmol) and 10% Pd(OH).sub.2/C (20 mg) in MeOH (10 mL) was hydrogenated at 50 psi H.sub.2 for 8 h. The suspension was filtered through Celite and concentrated. The residue was dried in vacuo to provide the title product (35 mg). LC-MS: m/z=373 [M+H].sup.+.

Step 6: (R)-1-(1-acryloylpyrrolidin-3-yl)-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (8)

(102) Intermediates 7 (35 mg, 0.094 mmol), HATU (39.3 mg, 0.10 mmol), TEA (19 mg, 0.18 mmol) and acrylic acid (7.4 mg, 0.10 mmol) were added to DCM (3 mL) was added in one portion. The mixture was stirred for about 2 h at rt. Volatile components were removed under vacuum, before being poured into H.sub.2O, The reaction mixture was extracted with EA, Organic phase was purified by P-TLC to give the title product (10 mg).

(103) .sup.1H NMR (400 MHz, CDCl.sub.3): 8.35 (s, 2H), 7.47-7.45 (m, 2H), 7.41-7.37 (m, 2H), 7.17 (d, J=8.4 Hz, 3H), 7.10 (d, J=7.6 Hz, 2H), 7.03 (d, J=8.4 Hz, 1H), 6.51-6.41 (m, 2H), 5.78-5.73 (m, 1H), 5.22-5.13 (m, 1H), 4.11-3.99 (m, 3H), 3.76-3.64 (m, 1H), 2.73-2.65 (m, 1H), 2.47-2.39 (m, 1H). LC-MS-8: m/z=427 [M+H].sup.+.

Example 2

(R)-1-(1-acryloylpyrrolidin-3-yl)-3-(4-(3-methoxyphenoxy)phenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one

(104) ##STR00015## ##STR00016##

Step 1: (R)-3-(4-(benzyloxy)phenyl)-1-(1-benzylpyrrolidin-3-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (9)

(105) To a solution of intermediate 5 (2 g, 6.8 mmol), (4-(benzyloxy)phenyl)boronic acid (3.1 g, 13.6 mmol), TEA (1.57 g, 13.6 mmol) and 4 A molecular sieves (3 g) were added to DCM (50 mL) in a vial Copper (II) acetate (1.23 g, 6.8 mmol) was added in one portion. The mixture was stirred for about 15 h at rt. Volatile components were removed under vacuum, before being poured into H.sub.2O. The reaction mixture was extracted with EA, Organic phase was purified by column chromatography on silica gel (gradient: DCM/MeOH=100/1-50/1), give the title product (0.8 mg, yield 25%).

(106) .sup.1H NMR (400 MHz, CDCl.sub.3): 8.36-8.28 (m, 2H), 7.87 (s, 1H), 7.46-7.31 (m, 12H), 7.11 (d, J=4.4 Hz, 2H), 5.26-5.23 (m, 1H), 5.09 (s, 2H), 3.78 (d, J=6.4 Hz, 1H), 3.63 (d, J=6.4 Hz, 1H), 3.23-3.19 (m, 1H), 3.06-3.03 (m, 1H), 2.69-2.64 (m, 1H), 2.44-2.36 (m, 2H), 2.17-2.14 (m, 1H). LCMS: m/z=477 [M+H].sup.+.

Step 2: (R)-3-(4-hydroxyphenyl)-1-(pyrrolidin-3-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (10)

(107) A suspension of 9 (0.8 g, 1.68 mmol) and 10% Pd/C (0.1 g) in MeOH (15 mL) was hydrogenated at 50 psi H.sub.2 for 20 h. The suspension was filtered through Celite and concentrated. The residue was dried in vacuo to provide the title crude product 0.49 g. LCMS: m/z=297 [M+H].sup.+.

Step 3: (R)-tert-butyl 3-(3-(4-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)pyrrolidine-1-carboxylate (11)

(108) To a suspension of 10 (0.49 g; 1.68 mmol) and TEA (0.17 g, 1.68 mmol) in CH.sub.2Cl.sub.2 (15 mL) at 0 C. was added di-tert-butylcarbonate (0.31 g, 1.68 mmol) The solution was then stirred to room temperature for 1 h. before being poured into H.sub.2O, The reaction mixture was extracted with DCM, Organic phase was purified by column chromatography on silica gel (gradient: DCM/MeOH=100/1-50/1) to give the title product (0.58 g, yield 87.8%).

(109) .sup.1H NMR (400 MHz, CDCl.sub.3) 9.29 (br, 1H), 8.35 (d, J=2.8 Hz 1H), 8.23 (s, 1H), 7.27 (d, J=4 Hz, 2H), 7.11 (d, J=2.8 Hz 1H), 6.96 (d, J=5.2 Hz 2H), 5.19-5.13 (m, 1H), 3.85 (br, 3H), 3.54-3.48 (m, 1H), 2.60-2.54 (m, 1H), 2.38-2.30 (m, 1H), 1.50 (s, 9H). LCMS: m/z=397 [M+H].sup.+.

Step 4: (R)-tert-butyl 3-(3-(4-(3-methoxyphenoxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)pyrrolidine-1-carboxylate (12)

(110) To a solution of 11 (30 mg, 0.075 mmol), (3-methoxyphenyl)boronic acid (23 mg, 0.15 mmol), TEA (15.3 mg, 0.15 mmol) and 4 A molecular sieves (0.1 g) were added to DCM (5 mL) in a vial Copper (II) acetate (13.7 mg, 0.075 mmol) was added in one portion. The mixture was stirred for about 20 h at rt. Volatile components were removed under vacuum, before being poured into H.sub.2O, The reaction mixture was extracted with EA, Organic phase was purified by column chromatography on silica gel (gradient: DCM/MeOH=100/1-50/1), give the title product (32 mg, yield 86.4%).

(111) .sup.1H NMR (400 MHz, CDCl.sub.3): 8.36 (br, 2H), 7.46 (d, J=4.4 Hz 2H), 7.30-7.26 (m, 1H), 7.16 (d, J=4.4 Hz, 2H), 7.08 (br, 1H), 6.73-6.65 (m, 3H), 5.19-5.15 (m, 1H), 3.81 (s, 3H), 3.75-3.76 (m, 3H), 3.51-3.4 (m, 1H), 2.59-2.54 (m, 1H), 2.37-2.30 (m, 1H), 1.49 (s, 9H). LCMS: m/z=503 [M+H].sup.+.

Step 5: (R)-1-(1-acryloylpyrrolidin-3-yl)-3-(4-(3-methoxyphenoxy)phenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (13)

(112) Intermediate 12 (32 mg, 0.063 mmol) were added to CF.sub.3COOH/DCM=4/1 (5 mL) in one portion. The mixture was stirred for about 1 h at rt. Volatile components were removed under vacuum to give a crude title product, and directly used in next step without further purification. LCMS: m/z=403 [M+H].sup.+.

(113) To a solution of Acryloyl chloride (5.7 mg, 0.068 mmol) in DCM (I mL) was added to a stirred solution of a crude product (25.3 mg, 0.063 mmol) and TEA (12.7 mg, 0.126 mmol) in DCM (5 mL) at 0 C. The reaction mixture was stirred for 1 h, poured onto brine and extracted with DCM. The organic layer was dried, concentrated and recrystallized from DCM/MeOH=100/1 to give the title product (5 mg, yield 17.4%).

(114) .sup.1H NMR (400 MHz, CDCl.sub.3): 8.38-8.34 (m, 2H), 7.46 (d, J=3.6 Hz, 2H), 7.30-7.26 (m, 1H), 7.17 (d, J=4.2 Hz, 2H), 7.05-7.01 (m, 1H), 6.73-6.65 (m, 3H), 6.51-6.41 (m, 2H), 5.79-5.72 (m, 1H), 5.22-5.15 (m, 1H), 4.11-3.98 (m, 3H), 3.81 (s, 3H), 3.78-3.71 (m, 1H), 2.79-2.60-2.39 (m, 1H), 2.50-2.37 (m, 1H). LCMS: m/z=457 [M+H].sup.+.

Example 3

N-(3-(2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl) (19)

(115) ##STR00017##

Step 1: tert-butyl (3-((3-nitropyridin-4-yl)amino)phenyl)carbamate (15)

(116) 4-chloro-3-nitropyridine (1.614 g, 10.18 mmol, 1.0 eq) was dissolved in isopropanol (30 mL), added tert-butyl (3-aminophenyl)carbamate (2.12 g, 10.18 mmol, 1.0 eq) and DIPEA (2.63 g, 20.36 mmol, 2.0 eq), the mixture solution was stirred reflux for 5 h. Then stopped and removed the solution under reduce pressure, the residue was added EA and saturated NaHCO.sub.3, extracted with EA and dried with Na.sub.2SO.sub.4, filtered and concentrated, purified with silica column (PE:EA=5:12:1) to obtain the title product (2.9 g), yellow solid, Yield: 2.9 g, 86.3%. .sup.1H NMR (400 MHz, CDCl.sub.3): =9.62 (s, 1H), 9.28 (s, 1H), 8.26 (d, J=6.0 Hz, 1H), 7.57 (s, 1H), 7.38-7.34 (m, 1H), 7.15 (d, J=8.0 Hz, 1H), 7.01-6.95 (m, 2H), 6.61 (s, 1H), 1.52 (s, 9H).

Step 2: tert-butyl (3-((2-aminophenyl)amino)phenyl)carbamate (16)

(117) Intermediate 15 (2.9 g) was dissolved in Mathanol (50.0 mL), added Pd/C (200 mg), under H.sub.2 atmosphere the mixture was stirred for 3 h at RT, stopped the reaction, filtered and concentrated under reduce pressure to obtain the title product used next step without purification, tan solid, Yield: 2.6 g, 98.9%. .sup.1H NMR (400 MHz, CDCl.sub.3): =8.05 (s, 1H), 7.97 (d, J=5.6 Hz, 1H), 7.29 (s, 1H), 7.24-7.20 (m, 1H), 7.04 (d, J=5.2 Hz, 1H), 6.89 (d, J=8.0 Hz, 1H), 6.78-6.76 (m, 1H), 6.55 (s, 1H), 5.83 (s, 1H), 3.34 (s, 2H), 1.51 (s, 9H). LCMS (ESI) m/z=301[M+H].sup.+.

Step 3: tert-butyl (3-(2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)phenyl)carbamate (17)

(118) Intermediate 16 (740 mg, 1.0 eq) was dissolved in toluene (30 mL), added CDI (800 mg, 2.0 eq), the mixture solution were stirred under reflux for 4 h. Then allowed the reaction was cooled to room temperature, added water and extracted with EA, dried with Na.sub.2SO.sub.4, filtered and concentrated, purified with silica column (DCM:MeOH=50:120:1) to obtain the title product, yellow solid, Yield: 700 mg, 86.8%. .sup.1H NMR (400 MHz, DMSO-d.sub.6): =11.41 (s, 1H), 9.58 (s, 1H), 8.30 (s, 1H), 8.20 (d, J=5.2 Hz, 1H), 7.68 (s, 1H), 7.50-7.42 (m, 2H), 7.14 (d, J=7.6 Hz, 1H), 7.04-7.01 (m, 2H), 1.48 (s, 9H). LCMS (ESI) m/z=327 [M+H].sup.+.

Step 4: tert-butyl (3-(2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo [4,5-c]pyridin-1-yl)phenyl)carbamate (18)

(119) Intermediate 17 (101 mg, 0.308 mmol, 1.0 eq) was dissolved in DCM (3.0 mL), added Cupric acetate (56 mg, 0.308 mmol, 1.0 eq), (4-phenoxyphenyl)boronic acid (132 mg, 0.617 mmol, 2.0 eq), 4 A molecular sieve (131 mg) and TEA (62 mg, 0.617 mmol, 2.0 eq), the mixture solution were stirred under for 30 h at RT. Then filtered the solution and removed the solution under reduce pressure, added water and extracted with EA, dried with Na.sub.2SO.sub.4, filtered and concentrated, purified with silica column (PE:EA=4:11:1) to obtain the title product, brown solid, Yield: 50 mg, 32.7%. .sup.1H NMR (400 MHz, CDCl.sub.3): =8.40 (s, 1H), 8.37 (d, J=5.6 Hz, 1H), 7.78 (s, 1H), 7.55 (d, J=8.8 Hz, 2H), 7.48-7.44 (m, 1H), 7.42-7.38 (m, 2H), 7.32 (d, J=8.8 Hz, 1H), 7.24 (d, J=7.6 Hz, 1H), 7.19-7.10 (m, 6H), 6.69 (s, 1H), 1.52 (s, 9H). LCMS (ESI) m/z=495 [M+H].sup.+.

Step 5: N-(3-(2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl) (19)

(120) Intermediate 18 (50 mg) was dissolved in DCM (5.0 mL), added TFA (2.0 mL), the mixture was stirred for 1 h at RT, stopped and removed the solution under reduce pressure, the residue was added saturated NaHCO.sub.3, extracted with EA and dried with Na.sub.2SO.sub.4, filtered and concentrated, obtained crude product (tan solid, 45 mg) used next step without purification. .sup.1H NMR (400 MHz, CDCl.sub.3): =8.39 (s, 1H), 8.35 (d, J=5.2 Hz, 1H), 7.55 (d, J=8.8 Hz, 2H), 7.42-7.38 (m, 2H), 7.34-7.30 (m, 1H), 7.19-7.16 (m, 3H), 7.12-7.10 (m, 3H), 6.91-6.87 (m, 2H), 6.77-6.74 (m, 1H), 3.87 (s, 2H). LCMS (ESI) m/z=395 [M+H].sup.+.

(121) Crude intermediate (23 mg, 0.058 mmol, 1.0 eq) and DIEA (9 mg, 0.070 mmol, 1.2 eq) were dissolved in THF (2.0 mL), added acryloyl chloride (5.6 mg, 0.061 mmol, 1.05 eq) slowed at 0 C., the mixture solution was stirred for 0.5 h at RT, followed the reaction with LCMS, stopped the reaction added water and extracted with EA, dried with Na.sub.2SO.sub.4, filtered and concentrated, the residue was purification with silica gel plate (PE:EA=20:80) obtain the title product (8 mg) colorless oil, Yield: 8 mg, 30.6%. .sup.1H NMR (400 MHz, CDCl.sub.3): =8.40 (s, 1H), 8.38 (d, J=5.2 Hz, 1H), 8.01 (s, 1H), 7.76 (s, 1H), 7.55 (d, J=8.8 Hz, 2H), 7.49 (d, J=5.6 Hz, 2H), 7.42-7.38 (m, 2H), 7.34-7.32 (m, 1H), 7.20-7.17 (m, 4H), 7.12 (d, J=7.6 Hz, 2H), 6.44 (d, J=16.8 Hz, 1H), 6.27-6.20 (m, 1H), 5.78 (d, J=10.4 Hz, 1H). LCMS (ESI) m/z=449 [M+H].sup.+.

Example 4

(R)-1-(1-acryloylpyrrolidin-3-yl)-3-(4-(m-tolyloxy)phenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one

(122) ##STR00018##

Step 1: (R)-tert-butyl 3-(2-oxo-3-(4-(m-tolyloxy)phenyl)-2,3-dihydro-1H-imidazo[4,5-c] pyridin-1-yl)pyrrolidine-1-carboxylate (20)

(123) To a solution of intermediate 11 (100 mg, 0.25 mmol), m-tolylboronic acid (68 mg, 0.5 mmol), TEA (45 mg, 0.5 mmol) and 4 A molecular sieves (0.1 g) were added to DCM (5 mL) in a vial Copper (II) acetate (45 mg, 0.25 mmol) was added in one portion. The mixture was stirred for about 20 h at rt. Volatile components were removed under vacuum, before being poured into H.sub.2O, The reaction mixture was extracted with EA, organic phase was purified by column chromatography on silica gel (gradient: DCM/MeOH=100/1-50/1) to give the title product (68 mg, yield 56.2%). LCMS: m/z=487 [M+H].sup.+.

Step 2: (R)-1-(1-acryloylpyrrolidin-3-yl)-3-(4-(m-tolyloxy)phenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (21)

(124) Intermediate 20 (68 mg, 0.13 mmol) were added to CF.sub.3COOH/DCM=4/1 (10 mL) in one portion. The mixture was stirred for about 1 h at rt. Volatile components were removed under vacuum to give a crude title product and directly used in next step without further purification. LCMS: m/z=387 [M+H].sup.+.

(125) A solution of Acryloyl chloride (11.8 mg, 0.13 mmol) in DCM (5 mL) was added to a stirred solution of crude intermediate (54 mg, 0.13 mmol) and TEA (131 mg, 1.3 mmol) in DCM (5 mL) at 0 C. The reaction mixture was stirred for 1 h, poured onto brine and extracted with DCM. The organic layer was dried, concentrated and recrystallized from DCM/MeOH=100/1 to give the title product (29 mg, yield 53.7%).

(126) .sup.1H NMR (400 MHz, CDCl.sub.3): 8.36 (br, 2H), 7.47-7.44 (m, 2H), 7.29-7.25 (m, 1H), 7.14 (d, J=8 Hz, 2H), 7.06-6.98 (m, 2H), 6.90 (d, J=8 Hz, 2H), 6.52-6.41 (m, 2H), 5.79-5.72 (m, 1H), 5.22-5.16 (m, 1H), 4.12-4.00 (m, 3H), 3.76-3.74 (m, 1H), 2.74-2.61 (m, 1H), 2.47-2.39 (m, 1H), 2.36 (s, 3H).

(127) LCMS: m/z=441 [M+H].sup.+.

Example 5

(R)-1-(1-acryloylpyrrolidin-3-yl)-3-(3-chloro-4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one

(128) ##STR00019##

Step 1: 4-bromo-2-chloro-1-phenoxybenzene (22)

(129) 4-bromo-2-chlorophenol (10 g, 48.2 mmol, 1.0 eq) was dissolved in DCM (120.0 mL), added Cupric acetate (4.38 g, 24.1 mmol, 0.5 eq), phenylboronic acid (8.82 g, 72.3 mmol, 1.5 eq), 4 A molecular sieve (15 g) and added TEA (13.4 m, 96.4 mmol, 2.0 eq), the mixture solution was stirred for overnight at RT under Oxygen atmosphere. Then filtered the solution and removed the solution under reduce pressure, added water and extracted with EA dried with Na.sub.2SO.sub.4, filtered and concentrated, purified with silica column (PE:EA=100:110:1) to provide title product as colorless oil, Yield: 5.5 g, 40.2%. .sup.1H NMR (400 MHz, CDCl.sub.3): =7.61 (d, J=1.6 Hz, 1H), 7.32-7.37 (m, 3H), 7.12-7.15 (m, 1H), 6.95-7.02 (m, 2H), 6.84 (d, J=8.4 Hz, 1H).

Step 2: (3-chloro-4-phenoxyphenyl)boronic acid (23)

(130) n-BuLi (2.45 M in hexane, 5.4 mL, 13.3 mmol) at 78 C. under nitrogen was added to a solution of 22 (2.9 g, 10.23 mmol) in THF (15 mL). After stirring for 15 min at 78 C., triisopropy borate (2.5 g, 13.3 mmol) was added in one portion. The mixture was warmed to 25 C., stirred for 30 min, and quenched with dilute HCl solution. The mixture was extracted with EtOAc (150 mL), washed with water, dried (Na.sub.2SO.sub.4) and evaporated to obtain a crude title product used directly for the step 6 without further purification.

Step 3: (R)-tert-butyl 3-((3-nitropyridin-4-yl)amino)pyrrolidine-1-carboxylate (24)

(131) 4-chloro-3-nitropyridine (10.145 g, 63.99 mmol, 1.0 eq) was dissolved in isopropanol (1200 mL), added (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (11.92 g, 63.99 mmol, 1.0 eq) and DIPEA (16.5 g, 127.98 mmol, 2.0 eq), the mixture solution was stirred reflux for 3.5 h. Then stopped and removed the solution under reduce pressure, added water, extracted with EA and dried with Na.sub.2SO.sub.4, filtered and concentrated to obtain a crude title product as yellow oil: 20 g. .sup.1H NMR (400 MHz, CDCl.sub.3): =9.24 (s, 1H), 8.35 (d, J=4.8 Hz, 1H), 8.23 (d, J=4.8 Hz, 1H), 6.73 (d, J=6.4 Hz, 1H), 4.23 (s, 1H), 3.78-3.83 (m, 1H), 3.56 (s, 2H), 3.35-3.44 (m, 1H), 2.32-2.36 (m, 1H), 2.05 (s, 1H), 1.48 (s, 9H). LCMS (ESI) m/z=309 [M+H].sup.+.

Step 4: (R)-tert-butyl 3-((3-aminopyridin-4-yl)amino)pyrrolidine-1-carboxylate (25)

(132) Intermediate 25 (20 g, 64.94 mmol, 1.0 eq) was dissolved in MeOH (150.0 mL), added Pd/C (4.0 g), the mixture solution was stirred for 6 h at room temperature under Hydrogen atmosphere. Then filtered the solution and removed the solution under reduce pressure to obtain a crude title product as yellow solid, Yield: 17 g, 94.2%. .sup.1H NMR (400 MHz, CDCl.sub.3): =8.00 (s, 1H), 7.94 (s, 1H), 6.48 (d, J=5.2 Hz, 1H), 4.19 (s, 1H), 4.07 (s, 1H), 3.74 (s, 1H), 3.49 (s, 3H), 3.25-3.36 (m, 1H), 3.09 (s, 2H), 2.21-2.26 (m, 1H), 1.95 (s, 1H), 1.72 (s, 1H), 1.47 (s, 9H). LCMS (ESI) m/z=279 [M+H].sup.+.

Step 5: (R)-tert-butyl 3-(2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)pyrrolidine-1-carboxylate (26)

(133) Intermediate 25 (17 g, 61.15 mmol, 1.0 eq) was dissolved in toluene (200 mL), added CDI (19.8 g, 122.3 mmol, 2.0 eq), the mixture solution were stirred under reflux for 4 h. Then allowed the reaction was cooled to room temperature, added water and extracted with EA, dried with Na.sub.2SO.sub.4, filtered and concentrated, purified with silica column (DCM:MeOH=200:150:1) to obtain the title product as canary yellow solid, Yield: 13 g, 59.4%. .sup.1H NMR (400 MHz, CDCl.sub.3): =10.35 (s, 1H), 8.43 (s, 1H), 8.33 (s, 1H), 7.03 (d, J=3.6 Hz, 1H), 5.12 (s, 1H), 3.71-3.80 (m, 3H), 3.50 (s, 1H), 2.50-2.56 (m, 1H), 2.30-2.32 (m, 1H), 1.50 (s, 9H). LCMS (ESI) m/z=305 [M+H].sup.+.

Step 6: (R)-tert-butyl 3-(3-(3-chloro-4-phenoxyphenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c] pyridin-1-yl)pyrrolidine-1-carboxylate (27)

(134) Intermediate 26 (2.17 g, 7.1 mmol, 1.0 eq) was dissolved in DCM (100.0 mL), added Cupric acetate (646 mg, 3.55 mmol, 0.5 eq), Boronic acid 23 (3.53 g, 14.2 mmol, 2.0 eq), 4 A molecular sieve (3.0 g) and TEA (2.0 mL, 14.2 mmol, 2.0 eq), the mixture solution was stirred for overnight at RT under Oxygen atmosphere. Then filtered the solution and removed the solution under reduce pressure, added water and extracted with EA, dried with Na.sub.2SO.sub.4, filtered and concentrated, purified with silica column (DCM:MeOH=200:150:1) to obtain the title product 27 as gray solid, Yield: 1.7 g, 47.0%. .sup.1H NMR (400 MHz, CDCl.sub.3): =8.40 (s, 2H), 7.68 (s, 1H), 7.36-7.42 (m, 3H), 7.17-7.21 (m, 1H), 7.07-7.10 (m, 4H), 5.14-5.18 (m, 1H), 3.83 (s, 3H), 3.51 (d, J=8.4 Hz, 1H), 2.54-2.59 (m, 1H), 2.33-2.36 (m, 1H), 1.50 (s, 9H). LCMS (ESI) m/z=507 [M+H].sup.+.

Step 7: (R)-3-(3-chloro-4-phenoxyphenyl)-1-(pyrrolidin-3-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (28)

(135) Intermediate 27 (920 mg) was dissolved in DCM (20.0 mL), added TFA (4.0 mL), the mixture was stirred for 2.5 h at RT, and the solvent was removed under reduce pressure, the residue was added saturated NaHCO.sub.3, extracted with EA and dried with Na.sub.2SO.sub.4, filtered and concentrated to provide a crude product 28 used next step without further purification. LCMS (ESI) m/z=407 [M+H].sup.+.

Step 8: (R)-1-(1-acryloylpyrrolidin-3-yl)-3-(3-chloro-4-phenoxyphenyl)-1H-imidazo[4,5-c] pyridin-2(3H)-one (29)

(136) Intermediate 28 (738 mg, 1.82 mmol, 1.0 eq) was dissolved in THF (10.0 mL), added TEA (368 mg, 3.64 mmol, 2.0 eq), acryloyl chloride (197 mg, 2.18 mmol, 1.2 eq) slowly at 0 C., the mixture solution was stirred for 0.5 h at RT, followed the reaction with LCMS, water was added to the reaction mixture and extracted with EA, dried with Na.sub.2SO.sub.4, filtered and concentrated, the residue was purification with silica column (DCM:MeOH=200:130:1) to obtain the title product as canary yellow solid, Yield: 489 mg, 58.3%. .sup.1H NMR (400 MHz, CDCl.sub.3): =8.40 (s, 1H), 7.68 (s, 1H), 7.36-7.42 (m, 3H), 7.17-7.21 (m, 1H), 7.04-7.10 (m, 4H), 6.41-6.52 (m, 2H), 5.74-5.80 (m, 1H), 5.13-5.24 (m, 1H), 3.97-4.14 (m, 3H), 3.65-3.77 (m, 1H), 2.62-2.77 (m, 1H), 2.38-2.49 (m, 1H). LCMS (ESI) m/z=461 [M+H].sup.+.

Example 6

1-(1-acryloylpyrrolidin-3-yl)-3-(3-chloro-4-(3-(trifluoromethyl)phenoxy)phenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one

(137) ##STR00020##

Step 1: tert-butyl 3-(3-(4-(benzyloxy)-3-chlorophenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)pyrrolidine-1-carboxylate (30)

(138) To a solution of 26 (1 g, 3.28 mmol), (4-(benzyloxy)-3-chlorophenyl)boronic acid (1.72 g, 3.57 mmol), TEA (0.66 g, 6.57 mmol) and 4 A molecular sieves (1 g) were added to DCM (30 mL) in a vial Copper (II) acetate (0.59 g, 6.57 mmol) was added in one portion. The mixture was stirred for about 21 h at rt. Volatile components were removed under vacuum, before being poured into H.sub.2O, The reaction mixture was extracted with EA, Organic phase was purified by column chromatography on silica gel (gradient: DCM/MeOH=100/1-50/1) to give the title product (0.83 g, yield 48.8%).

(139) .sup.1H NMR (400 MHz, CDCl.sub.3): 8.7 (br, 2H), 7.58 (d, J=4.0 Hz, 1H), 7.49 (d, J=4.0 Hz, 2H), 7.45-7.28 (m, 5H), 7.12-7.08 (m, 2H), 5.23 (s, 2H), 5.18-5.12 (m, 1H), 3.82-3.76 (m, 3H), 3.53-3.48 (m, 1H), 2.57-2.52 (m, 1H), 2.36-2.30 (m, 1H), 1.49 (s, 9H). LCMS: m/z 521, 523 [M+H].sup.+.

Step 2: tert-butyl 3-(3-(3-chloro-4-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c] pyridin-1-yl)pyrrolidine-1-carboxylate (31)

(140) To a solution of 30 (0.83 g, 1.59 mmol), HCOONH.sub.4 (1 g, 15.9 mmol) and 10% Pd/C (0.35 g) in MeOH (30 mL) was added in one portion. The mixture was stirred for about 10 min at 70 deg. The suspension was filtered through Celite and concentrated. before being poured into H.sub.2O, The reaction mixture was extracted with EA, Organic phase was purified by column chromatography on silica gel (gradient: DCM/MeOH=100/1-50/1) to give the title product (0.4 g, yield 58.8%).

(141) .sup.1H NMR (400 MHz, CDCl.sub.3): 8.39 (br, 1H), 8.31 (br, 1H), 7.51 (s, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.15 (d, J=8.0 Hz, 1H), 7.09 (br, 1H), 5.17-5.13 (m, 1H), 3.83 (br, 3H), 3.53-3.47 (m, 1H), 2.60-2.50 (m, 1H), 2.35-2.32 (m, 1H), 1.50 (s, 9H). LCMS: m/z=431, 433 [M+H].sup.+.

Step 3: tert-butyl 3-(3-(3-chloro-4-(3-(trifluoromethyl)phenoxy) phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)pyrrolidine-1-carboxylate (32)

(142) To a solution of 31 (30 mg, 0.069 mmol), (3-(trifluoromethyl)phenyl)boronic acid (26.5 mg, 0.139 mmol), TEA (14 mg, 0.139 mmol) and 4 A molecular sieves (0.2 g) were added to DCM (4 mL) in a vial Copper (II) acetate (12.6 mg, 0.069 mmol) was added in one portion. The mixture was stirred for about 14 h at rt. Volatile components were removed under vacuum, before being poured into H.sub.2O. The reaction mixture was extracted with EA, Organic phase was purified by column chromatography on silica gel (gradient: DCM/MeOH=(100/1-50/1) to give the title product (20 mg, yield 50.5%).

(143) .sup.1H NMR (400 MHz, CDCl.sub.3): 8.14 (s, 1H), 7.71 (d, J=2.0 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.53-7.47 (m, 2H), 7.45-7.40 (m, 2H), 7.34 (s, 1H), 7.21-7.09 (m, 2H), 5.18-5.14 (m, 1H), 3.84-3.69 (m, 3H), 3.55-3.48 (m, 1H), 2.59-2.50 (m, 1H), 2.39-2.31 (m, 1H), 1.49 (s, 9H). LCMS: m/z=575, 576 [M+H].sup.+.

Step 4:3-(3-chloro-4-(3-(trifluoromethyl)phenoxy)phenyl)-1-(pyrrolidin-3-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (33)

(144) 22 (20 mg, 0.034 mmol) were added to CF.sub.3COOH/DCM=4/1 (5 mL) in one portion. The mixture was stirred for about 1 h at rt. Volatile components were removed under vacuum to give a crude title product, and directly used in next step without further purification. LCMS: m/z=475, 476 [M+H].sup.+.

Step 5:1-(1-acryloylpyrrolidin-3-yl)-3-(3-chloro-4-(3-(trifluoromethyl)phenoxy)-phenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (34)

(145) A solution of Acryloyl chloride (3.0 mg, 0.034 mmol) in DCM (1 mL) was added to a stirred solution of 33 (16 mg, 0.034 mmol) and TEA (13.7 mg, 0.136 mmol) in DCM (3 mL) at 0 C. The reaction mixture was stirred for 1 h, poured onto brine and extracted with DCM. The organic layer was dried, concentrated and recrystallized from DCM/MeOH=100/1 to give the title product (8 mg, yield 44.69%).

(146) .sup.1H NMR (400 MHz, CDCl.sub.3): 8.42 (br, 2H), 7.72 (s, 1H), 7.52-7.41 (m, 3H), 7.32 (s, 1H), 7.20-7.16 (m, 2H), 7.08-7.03 (m, 1H), 6.52-6.41 (m, 2H), 5.80-5.73 (m, 1H), 5.21-5.12 (m, 1H), 4.12-3.97 (m, 3H), 3.77-3.68 (m, 1H), 2.77-2.64 (m, 1H), 2.49-2.40 (m, 1H). LCMS: m/z=529, 531 [M+H].sup.+.

Example 7

N-(3-(2-oxo-3-(3-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)phenyl)acrylamide

(147) ##STR00021##

Step 1: tert-butyl (3-(2-oxo-3-(3-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridine-1-yl)phenyl)carbamate (35)

(148) Intermediate 17 (1.25 g, 3.83 mmol, 1.0 eq) was dissolved in MeOH (20.0 mL), added Cupric acetate (70 mg, 0.38 mmol, 0.1 eq), (3-phenoxyphenyl)boronic acid (0.9 g, 4.21 mmol, 1.1 eq), the mixture solution was stirred for 5 h under reflux. Then filtered the solution and removed the solution under reduce pressure, added water and extracted with EA, dried with Na.sub.2SO.sub.4, filtered and concentrated, purified with silica column (DCM:MeOH=100:1-50:1) to obtain the title product as gray solid, Yield: 430 mg, 22.7%. .sup.1H NMR (400 MHz, CDCl.sub.3, 298 K): =8.38-8.40 (m, 2H), 7.75 (s, 1H), 7.44-7.52 (m, 2H), 7.33-7.40 (m, 4H), 7.20-7.25 (m, 2H), 7.08-7.17 (m, 5H), 6.67 (s, 1H), 1.51 (s, 9H). LCMS (ESI) m/z=495 [M+H].sup.+.

Step 2: 1-(3-aminophenyl)-3-(3-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (36)

(149) Intermediate 35 (420 mg) was dissolved in DCM (8.0 mL), added TFA (2.0 mL), the mixture was stirred for 1 h at RT. The solvent was removed under reduce pressure, the residue was added saturated NaHCO.sub.3, extracted with EA and dried with Na.sub.2SO.sub.4, filtered and concentrated, obtained crude product 13 used next step without purification, colorless oil, Yield: 28 mg, 72.7%. .sup.1H NMR (400 MHz, CDCl.sub.3): =8.44 (s, 1H), 8.35 (s, 1H), 7.49-7.54 (m, 1H), 7.29-7.40 (m, 4H), 7.25 (s, 1H), 7.08-7.17 (m, 5H), 6.85-6.88 (m, 2H), 6.74-6.76 (m, 1H), 3.86 (s, 2H). LCMS (ESI) m/z=395 [M+H].sup.+.

Step 3: N-(3-(2-oxo-3-(3-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)phenyl)acrylamide (37)

(150) Intermediate 36 (35 mg, 0.089 mmol, 1.0 eq) was dissolved in THF (4.0 mL), added acryloyl chloride (9 mg, 0.098 mmol, 1.1 eq) slowly at 0 C., the mixture solution was stirred for 0.5 h at RT, the reaction was added water and extracted with EA, dried with Na.sub.2SO.sub.4, filtered and concentrated, the residue was purification with silica gel plate (DCM:MeOH=40:1) to obtain product 14, colorless oil, Yield: 21 mg, 52.7%. .sup.1H NMR (400 MHz, CDCl.sub.3): =8.45 (s, 1H), =8.37 (d, J=5.2 Hz, 1H), 7.98 (s, 1H), 7.75 (s, 1H), 7.47-7.55 (m, 3H), 7.34-7.40 (m, 3H), 7.28-7.30 (m, 1H), 7.09-7.17 (m, 5H), 6.43 (d, J=16.8 Hz, 1H), 6.19-6.25 (m, 1H), 5.77 (d, J=10.4 Hz, 1H). LCMS (ESI) m/z=449 [M+H].sup.+.

Example 8

(S)-1-(1-acryloylpiperidin-3-yl)-3-(4-(2-chloro-3-methoxyphenoxy)phenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one

(151) ##STR00022##

Step 1: 1-(4-bromophenoxy)-2-chloro-3-methoxybenzene (38)

(152) To a solution of 1-bromo-4-iodobenzene (2 g, 7.04 mmol) in dioxane (30 ml), was added 2-chloro-3-methoxyphenol (1 g, 7.04 mmol), CuI (0.134 g, 0.704 mmol), Cs.sub.2CO.sub.3 (4.59 g, 14.08 mmol), 3-(dimethylamino)propanoic acid hydrochloride (0.294 g, 0.212 mmol). The mixture was stirred at 105 C. for 18 h, the mixture was filtered, before being poured into H.sub.2O, The reaction mixture was extracted with DCM, Organic phase was purified by column chromatography on silica gel (PE) to give title product (1.2 g, yield 49.5%).

(153) .sup.1H-NMR (400 MHz, CDCl.sub.3): 7.59 (d, J=8.0 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.20-7.16 (m, 1H), 6.83 (d, J=8.0 Hz, 1H), 6.77 (d, J=8.0 Hz, 1H), 6.71 (d, J=8.0 Hz, 1H), 6.62 (d, J=8.0 Hz, 1H), 3.93 (s, 3H).

Step 2: (4-(2-chloro-3-methoxyphenoxy)phenyl)boronic acid (39)

(154) To a solution of 1-(4-bromophenoxy)-2-chloro-3-methoxybenzene (38) (1.2 g, 3.08 mmol) in THF was cooled to 78 deg under N.sub.2, n-BuLi (1.82 mL, 4.61 mmol) was added dropwise under same condition. The mixture was stirred for 30 min at 78 deg. triisopropyl borate (0.868 g, 4.61 mmol) was added dropwise at 68 deg. After 15 min, the mixture warm to 8 deg and stirred for 2 h, then 2N HCl was added to adjust to pH=3 and stirred for 30 min, was added H.sub.2O (15 mL), the mixture was extracted three times with EA and dried Na.sub.2SO.sub.4, to give title product for crude (0.4 g).

Step 3: (S)-tert-butyl 3-(3-(4-(2-chloro-3-methoxyphenoxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate (41)

(155) (R)-tert-butyl 3-(2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate (40, prepared as described in Example 1, Step 1, 2 and 3), 0.1 g, 0.314 mmol), (4-(2-chloro-3-methoxyphenoxy) phenyl) boronic acid (39) (0.174 g, 0.628 mmol), TEA (63 mg, 0.628 mmol) and 4 A molecular sieves (0.1 g) were added to DCM (10 mL) in a vial Copper (II) acetate (57 mg, 0.314 mmol) was added in one portion. The mixture was stirred for about 22 h at 25 deg. Volatile components were removed under vacuum, before being poured into H.sub.2O, The reaction mixture was extracted with EA, Organic phase was purified by column chromatography on silica gel (gradient: DCM/MeOH=100/1-50/1) to give the title product (25 mg, yield 14.4%). LCMS: m/z=552 [M+H].sup.+.

Step 4: (S)-3-(4-(2-chloro-3-methoxyphenoxy)phenyl)-1-(piperidin-3-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (42)

(156) To a solution of (R)-tert-butyl-3-(3-(4-(2-chloro-3-methoxyphenoxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate (5) (25 mg, 0.045 mmol) were added to CF.sub.3COOH/DCM=4/1 (5 mL) in one portion. The mixture was stirred for about 1 h at it. Volatile components were removed under vacuum to give the title product of crude product (20 mg), and directly used in next step without further purification. LCMS: m/z=451 [M+H].sup.+.

Step 5: (S)-1-(1-acryloylpiperidin-3-yl)-3-(4-(2-chloro-3-methoxyphenoxy)-phenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (43)

(157) To a solution of Acryloyl chloride (4 mg, 0.044 mmol) in DCM (1 mL) was added to a stirred solution of (R)-3-(4-(2-chloro-3-methoxyphenoxy)phenyl)-1-(piperidin-3-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (6)(20 mg, 0.044 mmol) and TEA (9 mg, 0.88 mmol) in DCM (5 mL) at 0 C. The reaction mixture was stirred for 1 h, poured onto brine and extracted with DCM. The organic layer was dried, concentrated and recrystallized from DCM/MeOH=10)/I to give the title product (3.5 mg, yield 15.7%).

(158) .sup.1H-NMR (400 MHz, CDCl.sub.3): 8.41 (br, 1H), 8.34 (br, 1H), 7.44 (d, J=8.0 Hz, 2H), 7.30-7.23 (m, 2H), 7.11 (d, J=8.0 Hz, 2H), 6.82 (d, J=8.0 Hz, 1H), 6.74 (d, J=8.0 Hz, 1H), 6.61-6.58 (m, 1H), 6.43-6.14 (m, 1H), 5.74 (br, 1H), 4.84 (br, 1H), 4.22-4.09 (m, 2H), 3.96 (s, 3H), 3.48 (br, 0.6H), 3.18 (br, 0.6H), 2.64-2.54 (m, 1H), 2.16-2.13 (m, 1H), 2.02-2.00 (m, 1H), 1.68 (br, 1H). LCMS: m/z=506 [M+H].sup.+.

(159) The following additional Examples 9-165 shown in the Table below were prepared following the procedures outlined in the general methods above and detailed in Examples 1-8.

(160) TABLE-US-00001 MS (cald) [M + H].sup.+/MS Entry Structure (found) Name 9 491.14/491.1, 492.1 (R)-1-(1-acryloylpyrrolidin-3-yl)-3- (4-(3-chloro-5- methoxyphenoxy)phenyl)-1H- imidazo[4,5-c]pyridin-2(3H)-one 10 467.20/467.2 (R)-1-(1-acryloylpyrrolidin-3-yl)- 3-(4-(3-cyclopropylphenoxy)phenyl)- 1H-imidazo[4,5-c]pyridin-2(3H)-one 11 457.16/457.1 (R)-1-(3-(2-thioxo-3-(4-(m- tolyloxy)phenyl)-2,3-dihydro-1H- imidazo[4,5-c]pyridin-1-yl) pyrrolidin-1-yl)prop-2-en-1-one 12 459.18/459.2 (R)-1-(1-acryloylpiperidin-3-yl)-3- (3-fluoro-4-phenoxyphenyl)-1H- imidazo[4,5-c]pyridin-2(3H)-one 13 455.20/455.2 (R)-1-(1-acryloylpiperidin-3-yl)-3- (4-(m-tolyloxy)phenyl)-1H- imidazo[4,5-c]pyridin-2(3H)-one 14 499.23/499.2 (R)-1-(1-acryloylpiperidin-3-yl)-3- (4-(3-isopropoxyphenoxy)phenyl)- 1H-imidazo[4,5-c]pyridin-2(3H)-one 15 456.20/456.2 1-((1-acryloylpiperidin-4-yl)methyl)- 3-(4-phenoxyphenyl)-1H- imidazo[4,5-c]pyridin-2(3H)-one 16 0 441.18/441.2 (R)-1-(1-acryloylpyrrolidin-3-yl)-3- (3-(p-tolyloxy)phenyl)-1H- imidazo[4,5-c]pyridin-2(3H)-one 17 457.18/457.2 (R)-1-(1-acryloylpyrrolidin-3-yl)-3- (3-(4-methoxyphenoxy)phenyl)-1H- imidazo[4,5-c]pyridin-2(3H)-one 18 546.18/560.1, 561.1, 280.7, 281.4 (R,E)-3-(3-chloro-4-phenoxyphenyl)- 1-(1-(3-morpholinoacryloyl) pyrolidin-3-yl)-1H-imidazo[4,5-c]- pyridin-2(3H)-one 19 475.15/475.2, 477.2 (R)-1-(1-acryloylpyrrolidin-3-yl)-3- (3-chloro-4-(m-tolyloxy)phenyl)- 1H-imidazo[4,5-c]pyridin-2(3H)-one 20 441.18/441.2 (R)-1-(1-acryloylpiperidin-3-yl)-3- (4-phenoxyphenyl)-1H- imidazo[4,5-c]pyridin-2(3H)-one 21 441.18/441.2 1-((1-acryloylpyrrolidin-2-yl) methyl)-3-(4-phenoxyphenyl)-1H- imidazo[4,5-c]pyridin-2(3H)-one 22 537.16/537.1, 538.1 (R,E)-3-(3-chloro-4-phenoxyphenyl)- 1-(1-cinnamoylpyrrolidin-3-yl)-1H- imidazo[4,5-c]pyridin-2(3H)-one 23 497.10/497.1, 498.1 (R)-3-(3-chloro-4-phenoxyphenyl)- 1-(1-(vinylsulfonyl)pyrrolidin-3-yl)- 1H-imidazo[4,5-c]pyridin-2(3H)-one 24 471.20/471.2 (R)-1-(1-acryloylpyrrolidin-3-yl)-3- (4-(3-ethoxyphenoxy)phenyl)- 1H-imidazo[4,5-c]pyridin-2(3H)-one 25 485.21/485.2 (R)-1-(1-acryloylpyrrolidin-3-yl)-3- (4-(3-isopropoxyphenoxy)phenyl)- 1H-imidazo[4,5-c]pyridin-2(3H)-one 26 0 495.09/495.0, 497.1 (R)-1-(1-acryloylpyrrolidin-3-yl)-3- (3-chloro-4-(3-chlorophenoxy)phenyl)- 1H-imidazo[4,5-c]pyridin-2(3H)-one 27 463.17/463.2 N-(3-(3-(3-methyl-4-phenoxyphenyl)- 2-oxo-2,3-dihydro-1H-imidazo [4,5-c]pyridin-1-yl)phenyl)acrylamide 28 441.18/441.1 (R)-1-(1-methacryloylpyrrolidin-3-yl)- 3-(4-phenoxyphenyl)-1H- imidazo[4,5-c]pyridin-2(3H)-one 29 503.20/503.2 (R,E)-1-(1-cinnamoylpyrrolidin-3- yl)-3-(4-phenoxyphenyl)-1H- imidazo[4,5-c]pyridin-2(3H)-one 30 441.08/441.0 1-(1-acryloylpiperidin-4-yl)-3- (4-phenoxyphenyl)-1H- imidazo[4,5-c]pyridin-2(3H)-one 31 442.14/442.1 (R)-1-(1-acryloylpyrrolidin-3-yl)-3-(4- (phenylthio)phenyl)-1H-imidazo[4,5- c]pyridin-2(3H)-one 32 415.17/415.1 (R)-1-(1-acetylpyrrolidin-3-yl)-3- (4-phenoxyphenyl)-1H- imidazo[4,5-c]pyridin-2(3H)-one 33 427.17/427.2 (R)-1-(1-acryloylpyrrolidin-3-yl)-3- (4-phenoxyphenyl)-1H- imidazo[4,5-c]pyridin-2(3H)-one 34 439.17/439.2 (R)-1-(1-(but-2-ynoyl)pyrrolidin-3-yl)- 3-(4-phenoxyphenyl)-1H-imidazo [4,5-c]pyridin-2(3H)-one 35 457.18/457.2 (R)-1-(1-acryloylpyrrolidin-3-yl)-3- (4-(4-methoxyphenoxy)phenyl)-1H- imidazo[4,5-c]pyridin-2(3H)-one 36 0 495.16/495.2 (R)-1-(1-acryloylpyrrolidin-3-yl)-3-(4- (4-(trifluoromethyl)phenoxy)phenyl)- 1H-imidazo[4,5-c]pyridin-2(3H)-one 37 495.09/495.1, 496.1, 497.1, 498.1 (R)-1-(1-acryloylpyrrolidin-3-yl)-3- (4-(3,4-dichlorophenoxy)phenyl)-1H- imidazo[4,5-c]pyridin-2(3H)-one 38 456.16 (R)-1-(1-acryloylpiperidin-3-yl)-3-(4- (phenylthio)phenyl)-1H-imidazo[4,5- c]pyridin-2(3H)-one 39 497.11/497.1, 498.1 (R)-1-(1-acryloylpyrrolidin-3-yl)-3- (3-chloro-4- (3,5-difluorophenoxy)phenyl)-1H- imidazo[4,5-c]pyridin-2(3H)-one 40 487.19/487.1 (R)-1-(1-acryloylpyrrolidin-3-yl)-3- (4-(3,4-dimethoxyphenoxy)phenyl)- 1H-imidazo[4,5-c]pyridin-2(3H)-one 41 479.12/479.1, 481.1 (R)-1-(1-acryloylpyrrolidin-3-yl)-3- (3-chloro-4-(3-fluorophenoxy)phenyl)- 1H-imidazo[4,5-c]pyridin-2(3H)-one 42 491.14/491.1, 492.1 (R)-1-(1-acryloylpyrrolidin-3-yl)-3- (3-chloro-4-(4-methoxyphenoxy) phenyl)-1H-imidazo[4,5-c]pyridine- 2(3H)-one 43 529.12/529.1, 530.1 (R)-1-(1-acryloylpyrrolidin-3-yl)- 3-(3-chloro-4-(4- (trifluoromethyl)phenoxy)phenyl)- 1H-imidazo[4,5-c]pyridin-2(3H)-one 44 529.05/529.0, 530.1, 531.0, 532.0 (R)-1-(1-acryloylpyrrolidin-3-yl)- 3-(3-chloro-4- (3,4-dichlorophenoxy)phenyl)-1H- imidazo[4,5-c]pyridin-2(3H)-one 45 491.14/491.1, 493.1 (R)-1-(1-acryloylpyrrolidin-3-yl)- 3-(3-chloro-4-(3- methoxyphenoxy)phenyl)-1H- imidazo[4,5-c]pyridin-2(3H)-one 46 0 521.21/521.2 N-(3-(3-(4-(3-isopropoxyphenoxy)- 3-methylphenyl)-2-oxo- 2,3-dihydro-1H-imidazo[4,5-c] pyridin-1-yl)phenyl)acrylamide 47 477.18/477.2 N-(3-(3-(3-methyl-4-(m-tolyloxy) phenyl)-2-oxo-2,3-dihydro-1H- imidazo[4,5-c]pyridin-1-yl)phenyl) acrylamide 48 525.19/525.2 N-(3-(3-(3-fluoro-4-(3-isopropoxy phenoxy)phenyl)-2-oxo-2,3-dihydro- 1H-imidazo[4,5-c]pyridin-1-yl) phenyl)acrylamide 49 481.16/481.2 N-(3-(3-(3-fluoro-4-(m-tolyloxy) phenyl)-2-oxo-2,3-dihydro-1H- imidazo[4,5-c]pyridin-1-yl) phenyl)acrylamide 50 501.11/501.1 (N-(3-(3-(4-(3-chlorophenoxy)-3- fluorophenyl)-2-oxo-2,3-dihydro-1H- imidazo[4,5-c]pyridin-1-yl)phenyl) acrylamide 51 455.20/455.2 (R)-1-(1-acryloylpyrrolidin-3-yl)- 3-(4-(2,3-dimethylphenoxy) phenyl)-1H-imidazo[4,5-c] pyridin-2(3H)-one 52 503.20/503.2 (R)-1-(1-acryloylpyrrolidin-3-yl)-3- (3-fluoro-4-(3- isopropoxyphenoxy)phenyl)-1H- imidazo[4,5-c]pyridin-2(3H)-one 53 475.17/475.2 (R)-1-(1-acryloylpyrrolidin-3-yl)-3- (3-fluoro-4-(3- methoxyphenoxy)phenyl)-1H- imidazo[4,5-c]pyridin-2(3H)-one 54 501.11/501.1 N-(3-(3-(4-(3-chloro-2-fluoro phenoxy)phenyl)-2-oxo-2,3-dihydro- 1H-imidazo[4,5-c]pyridin-1-yl) phenyl)acrylamide 55 459.18/459.2 (R)-1-(1-acryloylpyrrolidin-3-yl)-3- (3-(3-fluoro-2-methylphenoxy) phenyl)-1H-imidazo[4,5-c]pyridin- 2(3H)-one 56 0 483.20/483.2 (R)-1-(1-acryloylpyrrolidin-3-yl)-3- (3-(3-cyclopropoxyphenoxy)phenyl)- 1H-imidazo[4,5-c]pyridin-2(3H)-one 57 473.19/473.2 (R)-1-(1-acryloylpiperidin-3-yl)-3- (4-(3-fluoro-2- methylphenoxy)phenyl)-1H- imidazo[4,5-c]pyridin-2(3H)-one 58 469.22/469.2 (R)-1-(1-acryloylpiperidin-3-yl)-3- (4-(2,3-dimethylphenoxy)phenyl)- 1H-imidazo[4,5-c]pyridin-2(3H)-one 59 493.14/493.2 (R)-1-(1-acryloylpiperidin-3-yl)-3- (4-(3-chloro-2-fluorophenoxy)phenyl)- 1H-imidazo[4,5-c]pyridin-2(3H)-one 60 463.15/463.2 (R)-1-(1-acryloylpyrrolidin-3-yl)-3- (4-(2,3-difluorophenoxy)phenyl)- 1H-imidazo[4,5-c]pyridin-2(3H)-one 61 477.17/477.2 (R)-1-(1-acryloylpiperidin-3-yl)-3- (4-(2,3-difluorophenoxy)phenyl)- 1H-imidazo[4,5-c]pyridin-2(3H)-one 62 493.18/493.2 N-(3-(3-(4-(3-methoxyphenoxy)- 3-methylphenyl)-2-oxo-2,3-dihydro- 1H-imidazo[4,5-c]pyridin-1-yl) phenyl)acrylamide 63 491.14/491.2 (R)-1-(1-acryloylpyrrolidin-3-yl)-3- (4-(3-chloro-2-methoxyphenoxy) phenyl)-1H-imidazo[4,5-c]pyridine- 2(3H)-one 64 505.16/505.2 (R)-1-(1-acryloylpiperidin-3-yl)-3-(4- (3-chloro-2-methoxyphenoxy)phenyl)- 1H-imidazo[4,5-c]pyridin-2(3H)-one 65 452.16/452.2 ((R)-1-(1-acryloylpyrrolidin-3-yl)-2- oxo-3-(4-phenoxyphenyl)-2,3- dihydro-1H-imidazo[4,5-c]pyridine- 4-carbonitrile 66 0 485.21/485.2 (R)-1-(1-acryloylpiperidin-3-yl)-3- (4-(2-methoxy-3-methylphenoxy) phenyl)-1H-imidazo[4,5-c] pyridin-2(3H)-one 67 471.20/471.2 (R)-1-(1-acryloylpyrrolidin-3-yl)-3- (4-(2-methoxy-3- methylphenoxy)phenyl)-1H- imidazo[4,5-c]pyridin-2(3H)-one 68 428.16/428.2 (R)-1-(1-acryloylpyrrolidin-3-yl)-3- (4-(pyridin-3-yloxy)phenyl)-1H- imidazo[4,5-c]pyridin-2(3H)-one 69 484.11/484.1 N-(3-(3-(4-(3-chlorophenoxy)phenyl)- 2-oxo-2,3-dihydro-1H-imidazo[4,5- c]pyridin-1-yl)phenyl)acrylamide 70 533.14/533.1 N-(3-(2-oxo-3-(4-(3- (trifluoromethoxy)phenoxy)phenyl)- 2,3-dihydro-1H-imidazo[4,5- c]pyridin-1-yl)phenyl)acrylamide 71 514.12/514.1 N-(3-(3-(4-(3-chloro-5- methoxyphenoxy)phenyl)-2-oxo-2,3- dihydro-1H-imidazo[4,5-c]pyridin- 1-yl)phenyl)acrylamide 72 462.13/462.1 (R)-1-(1-acryloylpyrrolidin-3-yl)-3- (4-(3-chlorophenoxy)phenyl)-1H- imidazo[4,5-c]pyridin-2(3H)-one 73 484.11/484.1 N-(3-(3-(3-chloro-4-phenoxyphenyl)- 2-oxo-2,3-dihydro-1H-imidazo[4,5- c]pyridin-1-yl)phenyl)acrylamide 74 484.11/484.1 N-(3-(3-(3-(3-chlorophenoxy)phenyl)- 2-oxo-2,3-dihydro-1H-imidazo[4,5- c]pyridin-1-yl)phenyl)acrylamide 75 467.15/467.2 N-(3-(3-(3-(3-fluorophenoxy)phenyl)- 2-oxo-2,3-dihydro-1H-imidazo[4,5- c]pyridin-1-yl)phenyl)acrylamide 76 0 463.17/463.2 N-(3-(2-oxo-3-(3-(p-tolyloxy)phenyl)- 2,3-dihydro-1H-imidazo[4,5- c]pyridin-1-yl)phenyl)acrylamide 77 463.15/463.2 (R)-1-(1-acryloylpyrrolidin-3-yl)-3- (3-fluoro-4-(3-fluorophenoxy)phenyl)- 1H-imidazo[4,5-c]pyridin-2(3H)-one 78 459.18/459.2 (R)-1-(1-acryloylpyrrolidin-3-yl)-3- (3-fluoro-4-(m-tolyloxy)phenyl)-1H- imidazo[4,5-c]pyridin-2(3H)-one 79 481.16/481.2 N-(3-(3-(4-(3-fluoro-2- methylphenoxy)phenyl)-2-oxo-2,3- dihydro-1H-imidazo[4,5-c]pyridin-1- yl)phenyl)acrylamide 80 479.17/479.2 N-(3-(3-(4-(4- methoxyphenoxy)phenyl)-2-oxo-2,3- dihydro-1H-imidazo[4,5-c]pyridin-1- yl)phenyl)acrylamide 81 445.16/445.1 (R)-1-(1-acryloylpyrrolidin-3-yl)-3- (4-(4-fluorophenoxy)phenyl)-1H- imidazo[4,5-c]pyridin-2(3H)-one 82 461.13/461.1 (R)-1-(1-acryloylpyrrolidin-3-yl)-3- (4-(4-chlorophenoxy)phenyl)-1H- imidazo[4,5-c]pyridin-2(3H)-one 83 441.18/441.2 (R)-1-(1-acryloylpyrrolidin-3-yl)- 3-(4-(o-tolyloxy)phenyl)-1H- imidazo[4,5-c]pyridin-2(3H)-one 84 445.16/445.1 (R)-1-(1-acryloylpyrrolidin-3-yl)-3- (4-(3-fluorophenoxy)phenyl)-1H- imidazo[4,5-c]pyridin-2(3H)-one 85 506.20/507.2 N-(3-(3-(4-(3- isopropoxyphenoxy)phenyl)-2-oxo-2,3- dihydro-1H-imidazo[4,5-c]pyridin-1- yl)phenyl)acrylamide 86 00 512.13/513.1 N-(3-(3-(3-chloro-4-(3- methoxyphenoxy)phenyl)-2-oxo-2,3- dihydro-1H-imidazo[4,5-c]pyridin-1- yl)phenyl)acrylamide 87 01 478.16/479.2 N-(3-(3-(3-(3-methoxyphenoxy)phenyl)- 2-oxo-2,3-dihydro-1H-imidazo[4,5- c]pyridin-1-yl)phenyl)acrylamide 88 02 462.17/463.2 N-(3-(2-oxo-3-(3-(o-tolyloxy)phenyl)- 2,3-dihydro-1H-imidazo[4,5-c]pyridin- 1-yl)phenyl)acrylamide 89 03 478.16/479.2 N-(3-(3-(3-(2-methoxyphenoxy)phenyl)- 2-oxo-2,3-dihydro-1H-imidazo[4,5- c]pyridin-1-yl)phenyl)acrylamide 90 04 484.13/485.0 N-(3-(3-(3-fluoro-4-(3- fluorophenoxy)phenyl)-2-oxo-2,3- dihydro-1H-imidazo[4,5-c]pyridin-1- yl)phenyl)acrylamide 91 05 440.18/441.2 1-(1-acryloylpyrrolidin-3-yl)-3-(3- methy1-4-phenoxyphenyl)-1,3-dihydro- 2H-imidazo[4,5-c]pyridin-2-one 92 06 470.20/471.2 1-(1-acryloylpyrrolidin-3-yl)-3-(4-(3- methoxyphenoxy)-3-methylphenyl)- 1,3-dihydro-2H-imidazo[4,5-c]pyridin- 2-one 93 07 466.14/467.1 N-(3-(3-(3-fluoro-4-phenoxyphenyl)-2- oxo-2,3-dihydro-1H-imidazo[4,5- c]pyridin-1-yl)phenyl)acrylamide 94 08 496.15/497.2 N-(3-(3-(3-fluoro-4-(3- methoxyphenoxy)phenyl)-2-oxo-2,3- dihydro-1H-imidazo[4,5-c]pyridin-1- yl)phenyl)acrylamide 95 09 444.16/445.2 (R)-1-(1-acryloylpyrrolidin-3-yl)-3-(3- fluoro-4-phenoxyphenyl)-1,3-dihydro- 2H-imidazo[4,5-c]pyridin-2-one 96 0 500.11/501.1 N-(3-(3-(3-(3-chloro-2- fluorophenoxy)phenyl)-2-oxo-2,3- dihydro-1H-imidazo[4,5-c]pyridin-1- yl)phenyl)acrylamide 97 478.12/479.1 (R)-1-(1-acryloylpyrrolidin-3-yl)-3-(3- (3-chloro-2-fluorophenoxy)phenyl)-1,3- dihydro-2H-imidazo[4,5-c]pyridin-2-one 98 516.08/517.1 N-(3-(3-(4-(2,3- dichlorophenoxy)phenyl)-2-oxo-2,3- dihydro-1H-imidazo[4,5-c]pyridin-1- yl)phenyl)acrylamide 99 494.09/495.1 (R)-1-(1-acryloylpyrrolidin-3-yl)-3-(4- (2,3-dichlorophenoxy)phenyl)-1,3- dihydro-2H-imidazo[4,5-c]pyridin-2- one 100 508.11/509.1 (R)-1-(1-acryloylpiperidin-3-yl)-3-(4- (2,3-dichlorophenoxy)phenyl)-1,3- dihydro-2H-imidazo[4,5-c]pyridin-2- one 101 496.11/497.1 (R)-1-(1-acryloylpyrrolidin-3-yl)-3- (4-(3-chloro-2-fluorophenoxy)-3- fluorophenyl)-1,3-dihydro-2H- imidazo[4,5-c]pyridin-2-one 102 478.12/479.1 (R)-1-(1-acryloylpyrrolidin-3-yl)-3-(4- (2-chloro-3-fluorophenoxy)phenyl)-1,3- dihydro-2H-imidazo[4,5-c]pyridin-2- one 103 492.14/493.2 (R)-1-(1-acryloylpiperidin-3-yl)-3-(4- (2-chloro-3-fluorophenoxy)phenyl)- 1,3-dihydro-2H-imidazo[4,5-c] pyridin-2-one 104 427.16/428.2 (R)-1-(1-acryloylpyrrolidin-3-yl)-3-(4- (pyridin-2-yloxy)phenyl)-1,3-dihydro- 2H-imidazo[4,5-c]pyridin-2-one 105 473.19/473.2 (R)-1-(1-acryloylpiperidin-3-yl)-3- (3-fluoro-4-(m-tolyloxy)phenyl)-1H- imidazo[4,5-c]pyridin-2(3H)-one 106 0 475.15/475.2 (R)-1-(1-acryloylpiperidin-3-yl)-3- (4-(3-chlorophenoxy)phenyl)-1H- imidazo[4,5-c]pyridin-2(3H)-one 107 475.15/475.2 (R)-1-(1-acryloylpiperidin-3-yl)-3- (3-chloro-4-phenoxyphenyl)-1H- imidazo[4,5-c]pyridin-2(3H)-one 108 488.16/488.1 (R)-1-(1-acryloylpiperidin-3-yl)-3- (3-chloro-4-(m-tolyloxy)phenyl)-1H- imidazo[4,5-c]pyridin-2(3H)-one 109 525.18/525.2 N-(3-(2-oxo-3-(4-phenoxyphenyl)-2,3- dihydro-1H-imidazo[4,5-c]pyridin-1- yl)phenyl)cinnamamide 110 463.17/463.2 N-(3-(2-oxo-3-(4-phenoxyphenyl)-2,3- dihydro-1H-imidazo[4,5-c]pyridin-1- yl)phenyl)methacrylamide 111 551.10/551.1 N-(3-(3-(3-chloro-4-(4- (trifluoromethyl)phenoxy)phenyl)-2- oxo-2,3-dihydro-1H-imidazo[4,5-c] pyridin-1-yl)phenyl)acrylamide 112 511.15/511.2 1-(1-acryloylpyrrolidin-3-yl)-3-(4-(3- (trifluoromethoxy)phenoxy)phenyl)- 1H-imidazo[4,5-c]pyridin-2(3H)-one 113 493.18/493.2 N-(3-(3-(4-(3-ethoxyphenoxy)phenyl)- 2-oxo-2,3-dihydro-1H-imidazo[4,5- c]pyridin-1-yl)phenyl)acrylamide 114 491.20/491.2 N-(3-(3-(4-(3- isopropylphenoxy)phenyl)-2-oxo-2,3- dihydro-1H-imidazo[4,5-c]pyridin-1- yl)phenyl)acrylamide 115 507.17/507.2 4-(4-(1-(3-acrylamidophenyl)-2-oxo- 1H-imidazo[4,5-c]pyridin-3(2H)- yl)phenoxy)-N-methylpicolinamide 116 0 449.15/449.2 N-(3-(2-oxo-1-(4-phenoxyphenyl)-1H- imidazo[4,5-b]pyridin-3(2H)- yl)phenyl)acrylamide 117 459.18/459.2 (R)-1-(1-acryloylpiperidin-3-yl)-3-(4- (3-fluorophenoxy)phenyl)-1H-imidazo [4,5-c]pyridin-2(3H)-one 118 471.20/471.2 (R)-1-(1-acryloylpiperidin-3-yl)-3-(4- (3-methoxyphenoxy)phenyl)-1H- imidazo[4,5-c]pyridin-2(3H)-one 119 449.15/449.2 N-(3-(2-oxo-3-(4-phenoxyphenyl)-2,3- dihydro-1H-imidazo[4,5-b]pyridin-1- yl)phenyl)acrylamide 120 427.17/427.2 (R)-3-(1-acryloylpyrrolidin-3-yl)-1-(4- phenoxyphenyl)-1H-imidazo[4,5- b]pyridin-2(3H)-one 121 449.15/449.2 N-(3-(2-oxo-1-(4-phenoxyphenyl)- 1H-imidazo[4,5-c]pyridin-3(2H)- yl)phenyl)acrylamide 122 441.18/441.2 (R)-3-(1-acryloylpiperidin-3-yl)-1-(4- phenoxyphenyl)-1H-imidazo[4,5- c]pyridin-2(3H)-one 123 517.14/517.1 N-(3-(2-oxo-3-(4-(4- (trifluoromethyl)phenoxy)phenyl)-2,3- dihydro-1H-imidazo[4,5-c]pyridin-1- yl)phenyl)acrylamide 124 479.16/479.2 N-(3-(3-(4-(4-methoxyphenoxy)phenyl)- 2-oxo-2,3-dihydro-1H-imidazo[4,5- c]pyridin-1-yl)phenyl)acrylamide 125 485.13/485.1 N-(3-(3-(4-(2,3- difluorophenoxy)phenyl)-2-oxo-2,3- dihydro-1H-imidazo[4,5-c]pyridin-1- yl)phenyl)acrylamide 126 0 485.13/485.1 N-(3-(3-(4-(3,4- difluorophenoxy)phenyl)-2-oxo-2,3- dihydro-1H-imidazo[4,5-c]pyridin-1- yl)phenyl)acrylamide 127 485.13/485.1 N-(3-(3-(4-(3,5- difluorophenoxy)phenyl)-2-oxo-2,3- dihydro-1H-imidazo[4,5-c]pyridin-1- yl)phenyl)acrylamide 128 501.11/501.1 503.1 N-(3-(3-(4-(3-chloro-2- fluorophenoxy)phenyl)-2-oxo-2,3- dihydro-1H-imidazo[4,5-c]pyridin-1- yl)phenyl)acrylamide 129 501.11/501.1 503.1 N-(3-(3-(4-(3-chloro-5- fluorophenoxy)phenyl)-2-oxo-2,3- dihydro-1H-imidazo[4,5-c]pyridin- 1-yl)phenyl)acrylamide 130 517.08/517.1 519.1 N-(3-(3-(4-(3,5- dichlorophenoxy)phenyl)-2-oxo-2,3- dihydro-1H-imidazo[4,5-c]pyridin-1- yl)phenyl)acrylamide 131 509.17/509.2 N-(3-(3-(4-(3,4- dimethoxyphenoxy)phenyl)-2-oxo-2,3- dihydro-1H-imidazo[4,5-c]pyridin-1- yl)phenyl)acrylamide 132 467.14/467.1 N-(3-(3-(3-fluoro-4-phenoxyphenyl)- 2-oxo-2,3-dihydro-1H-imidazo[4,5- c]pyridin-1-yl)phenyl)acrylamide 133 479.12/479.1 (R)-1-(1-acryloylpyrrolidin-3-yl)-3-(4- (3-chloro-2-fluorophenoxy)phenyl)- 1H-imidazo[4,5-c]pyridin-2(3H)-one 134 489.16/489.1, 490.1 (R)-1-(1-acryloylpiperidin-3-yl)-3-(4-(3- chloro-2-methylphenoxy)phenyl)-1H- imidazo[4,5-c]pyridin-2(3H)-one 135 491.14/491.1 492.1 (R)-1-(1-acryloylpyrrolidin-3-yl)-3-(4- (2-chloro-3-methoxyphenoxy)phenyl)- 1H-imidazo[4,5-c]pyridin-2(3H)-one 136 0 497.15/497.2 N-(3-(3-(4-(3-fluoro-2- methoxyphenoxy)phenyl)-2-oxo-2,3- dihydro-1H-imidazo[4,5-c]pyridin-1- yl)phenyl)acrylamide 137 475.17/475.2 (R)-1-(1-acryloylpyrrolidin-3-yl)-3-(4- (3-fluoro-2-methoxyphenoxy)phenyl)- 1H-imidazo[4,5-c]pyridin-2(3H)-one 138 459.18/459.2 (R)-1-(1-acryloylpyrrolidin-3-yl)-3-(4- (2-fluoro-3-methylphenoxy)phenyl)-1H- imidazo[4,5-c]pyridin-2(3H)-one 139 475.15/475.2 476.2 (R)-1-(1-acryloylpyrrolidin-3-yl)-3-(4- (3-chloro-2-methylphenoxy)phenyl)- 1H-imidazo[4,5-c]pyridin-2(3H)-one 140 489.19/489.2 (R)-1-(1-acryloylpiperidin-3-yl)-3-(4-(3- fluoro-2-methoxyphenoxy)phenyl)- 1H-imidazo[4,5-c]pyridin-2(3H)-one 141 473.19/473.2 (R)-1-(1-acryloylpiperidin-3-yl)-3-(4- (2-fluoro-3-methylphenoxy)phenyl)- 1H-imidazo[4,5-c]pyridin-2(3H)-one 142 485.21/485.2 (R)-1-(1-acryloylpiperidin-3-yl)-3- (4-(3-methoxy-2-methylphenoxy) phenyl)-1H-imidazo[4,5-c]pyridin- 2(3H)-one 143 471.2/471.2 (R)-1-(1-acryloylpyrrolidin-3-yl)-3-(4- (3-methoxy-2-methylphenoxy)phenyl)- 1H-imidazo[4,5-c]pyridin-2(3H)-one 144 497.13/497.1 498.1 N-(3-(3-(3-chloro-4-(m- tolyloxy)phenyl)-2-oxo-2,3-dihydro- 1H-imidazo[4,5-c]pyridin-1- yl)phenyl)acrylamide 145 541.16/541.2 542.2 N-(3-(3-(3-chloro-4-(3- isopropoxyphenoxy)phenyl)-2-oxo- 2,3-dihydro-1H-imidazo[4,5-c] pyridin-1-yl)phenyl)acrylamide 146 0 481.16/481.1 N-(3-(3-(4-(3-fluorophenoxy)-3- methylphenyl)-2-oxo-2,3-dihydro- 1H-imidazo[4,5-c]pyridin-1- yl)phenyl)acrylamide 147 477.18/477.2 N-(3-(3-(4-(2,3- dimethylphenoxy)phenyl)-2-oxo-2,3- dihydro-1H-imidazo[4,5-c]pyridin-1- yl)phenyl)acrylamide 148 511.15/511.2 N-(3-(3-(3-chloro-4-(2,3- dimethylphenoxy)phenyl)-2-oxo-2,3- dihydro-1H-imidazo[4,5-c]pyridin-1- yl)phenyl)acrylamide 149 479.12/479.1 480.1 (R)-1-(1-acryloylpyrrolidin-3-yl)-3-(4- (3-chlorophenoxy)-3-fluorophenyl)- 1H-imidazo[4,5-c]pyridin-2(3H)-one 150 497.13/497.1 480.1 N-(3-(3-(4-(3-chloro-2- methylphenoxy)phenyl)-2-oxo-2,3- dihydro-1H-imidazo[4,5-c]pyridin-1- yl)phenyl)acrylamide 151 461.13/461.2 (R)-1-(1-acryloylpyrrolidin-3-yl)-7- chloro-3-(4-phenoxyphenyl)-1H- imidazo[4,5-c]pyridin-2(3H)-one 152 463.17/463.2 N-(3-(2-oxo-3-(3-(m-tolyloxy)phenyl)- 2,3-dihydro-1H-imidazo[4,5-c]pyridin- 1-yl)phenyl)acrylamide 153 469.22/469.2 (R)-1-(1-acryloylpyrrolidin-3-yl)-3-(4- (3-isopropylphenoxy)phenyl)-1H- imidazo[4,5-c]pyridin-2(3H)-one 154 497.13/497.1 498.1 N-(3-(3-(4-(3-chlorophenoxy)-3- methylphenyl)-2-oxo-2,3-dihydro- 1H-imidazo[4,5-c]pyridin-1- yl)phenyl)acrylamide 155 427.17/427.2 (R)-1-(1-acryloylpyrrolidin-3-yl)-3-(3- phenoxyphenyl)-1H-imidazo[4,5- c]pyridin-2(3H)-one 156 0 441.18/441.2 (R)-1-(1-methacryloylpyrrolidin-3-yl)- 3-(3-phenoxyphenyl)-1H-imidazo[4,5- c]pyridin-2(3H)-one 157 464.13 N-(3-(2-oxo-3-(4-(phenylthio)phenyl)- 2,3-dihydro-1H-imidazo[4,5-c]pyridin- 1-yl)phenyl)acrylamide 158 479.16/479.2 N-(3-(3-(4-(3-methoxyphenoxy) phenyl)-2-oxo-2,3-dihydro-1H- imidazo[4,5-c]pyridin-1-yl)phenyl) acrylamide 159 517.08/517.1 N-(3-(3-(4-(3,4- dichlorophenoxy)phenyl)-2-oxo-2,3- dihydro-1H-imidazo[4,5-c]pyridin-1- yl)phenyl)acrylamide 160 501.11/501.1 N-(3-(3-(4-(4-chloro-3- fluorophenoxy)phenyl)-2-oxo-2,3- dihydro-1H-imidazo[4,5-c]pyridin-1- yl)phenyl)acrylamide 161 497.15/497.2 N-(3-(3-(4-(3-fluoro-4- methoxyphenoxy)phenyl)-2-oxo-2,3- dihydro-1H-imidazo[4,5-c]pyridin-1- yl)phenyl)acrylamide 162 474.15/474.2 N-(3-(3-(4-(4-cyanophenoxy)phenyl)- 2-oxo-2,3-dihydro-1H-imidazo[4,5- c]pyridin-1-yl)phenyl)acrylamide 163 493.18/493.2 N-(3-(3-(4-(4-methoxy-3- methylphenoxy)phenyl)-2-oxo-2,3- dihydro-1H-imidazo[4,5-c]pyridin-1- yl)phenyl)acrylamide 164 427.16/428.2 1-(1-acryloylpyrrolidin-3-yl)-3-(4- (pyridin-4-yloxy)phenyl)-1H- imidazo[4,5-c]pyridin-2(3H)-one 165 428.16/429.1 1-(1-acryloylpyrrolidin-3-yl)-3-(4- (pyridazin-3-yloxy)phenyl)-1H- imidazo[4,5-c]pyridin-2(3H)-one 166 0 519.20/519.2 (R)-1-(1-acryloylpiperidin-3-yl)-3-(4-(2- fluoro-3-methoxyphenoxy)phenyl)-7- methoxy-1H-imidazo[4,5-c]pyridin- 2(3H)-one 167 533.21/533.2 (R)-1-(1-acryloylpiperidin-3-yl)-7- ethoxy-3-(4-(2-fluoro-3- methoxyphenoxy)phenyl)-1H-imidazo [4,5-c]pyridin-2(3H)-one 168 503.20/503.2 (R)-1-(1-acryloylpiperidin-3-yl)-3-(4- (2-fluoro-3-methoxyphenoxy)phenyl)- 7-methyl-1H-imidazo[4,5-c]pyridin- 2(3H)-one 169 515.20/515.2 (R)-1-((1-(but-2-ynoyl)pyrrolidin-2- yl)methyl)-3-(4-(2-fluoro-3- methoxyphenoxy)phenyl)-7-methyl- 1H-imidazo[4,5-c]pyridin-2(3H)-one 170 503.20/503.2 (R)-1-((1-acryloylpyrrolidin-2-yl) methyl)-3-(4-(2-fluoro-3- methoxyphenoxy)phenyl)-7-methyl- 1H-imidazo[4,5-c]pyridin-2(3H)-one 171 515.20/515.2 (R)-1-(1-(but-2-ynoyl)piperidin-3-yl)-3- (4-(2-fluoro-3-methoxyphenoxy)phenyl)- 7-methyl-1H-imidazo[4,5-c]pyridin- 2(3H)-one 172 489.19/489.2 (R)-1-(1-acryloylpyrrolidin-3-yl)-3-(4- (2-fluoro-3-methoxyphenoxy)phenyl)- 7-methyl-1H-imidazo[4,5-c]pyridin- 2(3H)-one 173 501.19/501.2 (R)-1-(1-(but-2-ynoyl)pyrrolidin-3-yl)- 3-(4-(2-fluoro-3-methoxyphenoxy) phenyl)-7-methyl-1H-imidazo[4,5-c] pyridin-2(3H)-one 174 562.25/562.2 (E)-N-(3-(6-amino-8-oxo-7-(4- phenoxyphenyl)-7H-purin-9(8H)- yl)phenyl)-4-(cyclopropyl(methyl) amino)-N-methylbut-2-enamide 175 501.19/501.2 (R)-1-(1-(but-2-ynoyl)piperidin-3-yl)- 3-(4-(2-fluoro-3-methoxyphenoxy) phenyl)-1H-imidazo[4,5-c]pyridin- 2(3H)-one 176 0 441.18/441.2 (R)-1-(1-acryloylpyrrolidin-3-yl)-7- methyl-3-(4-phenoxyphenyl)-1H- imidazo[4,5-c]pyridin-2(3H)-one 177 459.17/459.2 (S,Z)-9-(1-acryloylpyrrolidin-3-yl)-6- (hydroxyimino)-7-(4-phenoxyphenyl)- 7,9-dihydro-1H-purin-8(6H)-one 178 440.52 440.5 1-(1-Acryloyl-pyrrolidin-2-ylmethyl)-3- (4-phenoxy-phenyl)-1,3-dihydro-imidazo [4,5-c]pyridin-2-one 179 485.19/485.2 (S,Z)-1-(1-acryloylpyrrolidin-3-yl)-N- hydroxy-2-oxo-3-(4-phenoxyphenyl)- 2,3-dihydro-1H-imidazo[4,5-c] pyridine-4-carboximidamide 180 521.62 521.6 4,4-Dimethyl-2-{2-[2-oxo-3-(4- phenoxy-phenyl)-2,3-dihydro- imidazo[4,5-c]pyridin-1-ylmethyl]- pyrrolidine-1-carbonyl}-pent-2- enenitrile 181 452.16/452.2 (R)-1-(1-acryloylpyrrolidin-3-yl)- oxo-3-(4-phenoxyphenyl)-2,3- dihydro-1H-imidazo[4,5-c] pyridine-7-carbonitrile 182 457.18/457.2 (R)-1-(1-acryloylpyrrolidin-3-yl)-4- methoxy-3-(4-phenoxyphenyl)-1H- imidazo[4,5-c]pyridin-2(3H)-one 183 443.16/443.2 (R)-1-(1-acryloylpyrrolidin-3-yl)-4- hydroxy-3-(4-phenoxyphenyl)-1H- imidazo[4,5-c]pyridin-2(3H)-one 184 461.13/461.1 (R)-1-(1-acryloylpyrrolidin-3-yl)-7- chloro-3-(4-phenoxyphenyl)-1H- imidazo[4,5-c]pyridin-2(3H)-one 185 505.16/505.2 (R)-1-(1-acryloylpiperidin-3-yl)-3-(4- (2-chloro-3-methoxyphenoxy)phenyl)- 1H-imidazo[4,5-c]pyridin-2(3H)-one 186 00 489.19/489.2 (R)-1-(1-acryloylpiperidin-3-yl)-3-(4- (2-fluoro-3-methoxyphenoxy)phenyl)- 1H-imidazo[4,5-c]pyridin-2(3H)-one 187 01 510.24/501.2 (R,E)-1-(1-(4- (cyclopropyl(methyl)amino)but-2- enoyl)pyrrolidin-3-yl)-3-(4- phenoxyphenyl)-1H-imidazo[4,5- c]pyridin-2(3H)-one 188 02 524.26/524.3 (R,E)-1-(1-(4- (cyclopropyl(methyl)amino)but-2- enoyl)piperidin-3-yl)-3-(4- phenoxyphenyl)-1H-imidazo[4,5- c]pyridin-2(3H)-one 189 03 471.16/471.2 (R)-1-(1-acryloylpyrrolidin-3-yl)-4- nitro-3-(4-phenoxyphenyl)-1H- benzo[d]imidazol-2(3H)-one 190 04 441.18/441.2 (R)-1-(1-acryloylpyrrolidin-3-yl)-4- amino-3-(4-phenoxyphenyl)-1H- benzo[d]imidazol-2(3H)-one 191 05 475.17/475.2 (R)-1-(1-acryloylpyrrolidin-3-yl)-3-(4- (2-fluoro-3-methoxyphenoxy)phenyl)- 1H-imidazo[4,5-c]pyridin-2(3H)-one 192 06 459.16/459.1 2-oxo-2-(3-(2-oxo-3-(4-phenoxyphenyl)- 2,3-dihydro-1H-imidazo[4,5-c] pyridin-1-yl)piperidin-1-yl)acetic acid 193 07 430.17/430.1 3-(2-oxo-3-(4-phenoxyphenyl)-2,3- dihydro-1H-imidazo[4,5-c]pyridin- 1-yl)cyclohexanecarboxylic acid 194 08 458.18/458.2 2-oxo-2-(3-(2-oxo-3-(4- phenoxyphenyl)-2,3-dihydro- 1H-imidazo[4,5-c]pyridin-1-yl) piperidin-1-yl)acetamide

Example 195

N-(3-(2-oxo-3-(4-((2,4,5-trifluorobenzyl)oxy) phenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)phenyl)acrylamide

(161) ##STR00209##

Step 1: tert-butyl (3-(3-(4-(benzyloxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)phenyl)carbamate (44)

(162) Intermediate 17 (0.914 g, 2.80 mmol, 1.0 eq) was dissolved in MeOH (20.0 mL), added Cupric acetate (59 mg, 0.28 mmol, 0.1 eq), (4-(benzyloxy)phenyl)boronic acid (0.83 g, 3.64 mmol, 1.3 eq), the mixture solution was stirred for 5 h under reflux. Then filtered the solution and removed the solution under reduce pressure, added water and extracted with EA, dried with Na.sub.2SO.sub.4, filtered and concentrated, purified with silica column (DCM:MeOH=100:11-50:1) to obtain the title product as gray solid, Yield: 160 mg, 11.2%. .sup.1H NMR (400 MHz, CDCl.sub.3): =8.37-8.43 (m, 1H), 7.77 (s, 1H), 7.31-7.51 (m, 10H), 7.24 (d, J=8.0 Hz, 1H), 7.15 (d, J=8.8 Hz, 2H), 6.66 (s, 1H), 5.14 (s, 2H), 1.52 (s, 9H). LCMS (ESI) m/z=509 [M+H].sup.+.

Step 2: tert-butyl (3-(3-(4-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)phenyl)carbamate (45)

(163) Intermediate 44 (120 mg, 0.24 mmol, 1.0 eq) was dissolved in MeOH (10.0 mL), added Pd/C (40 mg), the mixture solution was stirred for 3 h under H.sub.2 atmosphere. Then filtered the solution and the solvent was removed under reduce pressure to obtain the title product as gray solid, Yield: 83 mg, 84.1%. .sup.1H NMR (400 MHz, CDCl.sub.3): =8.36 (d, J=4.4 Hz, 1H), 8.30 (s, 1H), 7.79 (s, 1H), 7.45-7.49 (m, 1H), 7.37 (d, J=8.4 Hz, 2H), 7.32 (d, J=8.8 Hz, 1H), 7.23 (s, 1H), 7.16 (d, J=5.6 Hz, 1H), 6.97 (d, J=8.4 Hz, 2H), 6.71 (s, 1H), 1.52 (s, 9H). LCMS (ESI) m/z=419 [M+H].sup.+.

Step 3: tert-butyl (3-(3-(4-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)phenyl)carbamate (46)

(164) To a solution of intermediate 45 (0.05 g, 0.12 mmol) in DMF (5 mL) was added 2,4,5-trifluorobenzyl bromide (0.027 g, 0.12 mmol) and Cs.sub.2CO.sub.3 (0.078 g, 0.24 mmol). The mixture was stirred at 25 C., after 2 hrs, the reaction mixture was partitioned between H.sub.2O and DCM, the organic layer was washed by brine, dried over Na.sub.2SO.sub.4, filtered, concentrated to give the title product as a crude product (0.04 g). LCMS (ESI) m/z=563 [M+H].sup.+.

Step 4: N-(3-(2-oxo-3-(4-((2,4,5-trifluorobenzyl)oxy)phenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)phenyl)acrylamide (47)

(165) To a solution of intermediate 46 (0.04 g, crude) in DCM (4 mL) was added TFA (1.5 mL) at 0 C., the mixture was allowed to warm to 25 C., after 1 h, the mixture was adjusted to pH=7 with NaHCO.sub.3 solution, the residue was partitioned between H.sub.2O and DCM, the organic layer was washed by brine, dried over Na.sub.2SO.sub.4, filtered, concentrated to give a crude title product (0.02 g). LCMS (ESI) m/z=463 [M+H].sup.+.

(166) To a stirred solution of crude product (0.02 g, 0.043 mmol) in DCM (10 mL) was added acryloyl chloride (0.004 g, 0.043 mmol) and TEA (0.009 g, 0.086 mmol). The mixture was stirred at 15 C., after 0.5 h, the mixture was partitioned between H.sub.2O and DCM, the organic layer was washed by brine, dried over Na.sub.2SO.sub.4, filtered, concentrated and purified by Pre-TLC to give the title product (5 mg, 22.4%).

(167) .sup.1H NMR (400 MHz, CDCl.sub.3): 5.06 (s, 1H), 5.67-5.70 (d, 1H), 6.13-6.16 (d, 1H), 6.29-6.33 (d, 1H), 6.91-6.93 (m, 1H), 7.04-7.09 (m, 3H), 7.16-7.19 (m, 1H), 7.31-7.34 (m, 3H), 7.45-7.47 (m, 2H), 7.94 (s, 1H), 8.28-8.34 (m, 3H). LCMS (ESI) m/z=517 [M+H].

Example 196

N-(3-(2-oxo-3-(4-(pyridin-2-ylmethoxy)phenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)phenyl)acrylamide

(168) ##STR00210##

Step 1: tert-butyl (3-(2-oxo-3-(4-(pyridin-2-ylmethoxy)phenyl)-2,3-dihydro-1H-imidazo [4,5-c]pyridin-1-yl)phenyl)carbamate (48)

(169) Intermediate 39 (76 mg, 0.183 mmol, 1.0 eq) was dissolved in DMF (2.0 mL), added Cesium carbonate (178 mg, 0.548 mmol, 3.0 eq), 2-(bromomethyl)pyridine hydrobromide salt (51 mg, 0.201 mmol, 1.1 eq), the mixture solution was stirred for 2 h at room temperature. Then added water and extracted with EA, washed with brine, dried with Na.sub.2SO.sub.4, filtered and concentrated, purified with silica column (DCM:MeOH=100:150:1) to obtain the title product, Yield: 48 mg, 51.9%. .sup.1H NMR (400 MHz, CDCl.sub.3): =8.63 (d, J=4.4 Hz, 1H), 8.36 (s, 1H), 8.35 (s, 1H), 7.75-7.77 (m, 2H), 7.55 (d, J=7.6 Hz, 1H), 7.50 (d, J=8.8 Hz, 2H), 7.44-7.48 (m, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.23 (d, J=7.2 Hz, 1H), 7.17 (d, J=9.2 Hz, 2H), 7.13 (d, J=5.6 Hz, 1H), 6.67 (s, 1H), 5.29 (s, 2H), 1.52 (s, 9H). LCMS (ESI) m/z=510 [M+H].sup.+.

Step 2: 1-(3-aminophenyl)-3-(4-(pyridin-2-ylmethoxy)phenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (49)

(170) Intermediate 48 (48 mg) was dissolved in DCM (5.0 mL), added TFA (2.0 mL), the mixture was stirred for 1.5 h at RT, stopped and removed the solution under reduce pressure, the residue was added saturated NaHCO.sub.3, extracted with EA and dried with Na.sub.2SO.sub.4, filtered and concentrated to obtain crude title product used next step without purification, yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3): =8.63 (d, J=4.4 Hz, 1H), 8.35 (s, 2H), 7.73-7.77 (m, 1H), 7.55 (d, J=7.6 Hz, 1H), 7.50 (d, J=9.2 Hz, 2H), 7.30-7.34 (m, 1H), 7.24 (s, 1H), 7.16 (d, J=9.2 Hz, 2H), 7.11 (d, J=4.8 Hz, 1H), 6.90 (d, J=8.0 Hz, 1H), 6.87 (s, 1H), 6.74-6.76 (m, 1H), 5.29 (s, 2H), 3.87 (s, 2H). LCMS (ESI) m/z=410 [M+H].sup.+.

Step 3: N-(3-(2-oxo-3-(4-(pyridin-2-ylmethoxy)phenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)phenyl)acrylamide (50)

(171) Crude intermediate 49 (42 mg, 0.103 mmol, 1.0 eq) was dissolved in THF (4.0 mL), added DIEA (20 mg, 0.154 mmol, 1.5 eq), acryloyl chloride (10.2 mg, 0.113 mmol, 1.1 eq) slowly at 0 C., the mixture solution was stirred for 0.5 h at RT, followed the reaction with LCMS, stopped the reaction added water and extracted with EA, dried with Na.sub.2SO.sub.4, filtered and concentrated, the residue was purification with silica gel plate (DCM:MeOH=30:1) to obtain the title product, colorless oil, Yield: 8.0 mg, 16.8%. .sup.1H NMR (400 MHz, CDCl.sub.3): =8.63 (d, J=4.4 Hz, 1H), 8.36 (s, 1H), 8.35 (s, 1H), 8.32 (s, 1H), 7.99 (s, 1H), 7.73-7.77 (m, 1H), 7.56 (d, J=7.6 Hz, 1H), 7.51 (d, J=8.8 Hz, 2H), 7.41 (d, J=7.2 Hz, 2H), 7.24-7.28 (m, 1H), 7.48 (d, J=8.8 Hz, 2H), 7.11 (d, J=5.2 Hz, 1H), 6.39 (d, J=16.4 Hz, 1H), 6.16-6.23 (m, 1H), 5.71 (d, J=10.4 Hz, 1H), 5.29 (s, 2H). LCMS (ESI) m/z=464 [M+H].sup.+.

(172) The following additional Examples 197-248 shown in the Table below were prepared following the procedures outlined in the general methods above and detailed in Examples 195-196.

(173) TABLE-US-00002 MS(cald) [M + H].sup.+/ Entry Structure MS (found) Name 197 475.15/ 475.1, 477.1 (R)-1-(1-acryloylpyrrolidin-3-yl)- 3-(4-(benzyloxy)-3-chlorophenyl)- 1H-imidazo[4,5-c]pyridin-2(3H)- one 198 509.11/ 509.1, 511.1, 510.1, 513.1 (R)-1-(1-acryloylpyrrolidin-3-yl)- 3-(4-((3,4- dichlorobenzyl)oxy)phenyl)- 1H-imidazo[4,5-c]pyridin-2(3H)- one 199 477.17/ 477.1 (R)-1-(1-acryloylpyrrolidin-3-yl)- 3-(4-((2,4- difluorobenzyl)oxy)phenyl)- 1H-imidazo[4,5-c]pyridin- 2(3H)-one 200 543.13/ 543.1, 545.1, 544.1, 546.1 (R)-1-(1-acryloylpyrrolidin-3-yl)- 3-(3-chloro-4-((3- (trifluoromethyl)benzyl) oxy)phenyl)-1H-imidazo[4,5- c]pyridine-2(3H)-one 201 511.13/ 511.1, 512.1 (R)-1-(1-acryloylpyrrolidin-3-yl)- 3-(3-chloro-4-((3,4- difluorobenzyl) oxy)phenyl)-1H-imidazo[4,5- c]pyridine-2(3H)-one 202 511.13/ 511.1, 512.2 (R)-1-(1-acryloylpyrrolidin-3-yl)- 3-(3-chloro-4-((2,4- difluorobenzyl)oxy)phenyl)- 1H-imidazo[4,5-c]pyridin-2(3H)- one 203 543.13/ 543.1, 544.1 (R)-1-(1-acryloylpyrrolidin-3-yl)- 3-(3-chloro-4-((2- (trifluoromethyl)benzyl)oxy) phenyl)-1H-imidazo[4,5-c]pyridin- 2(3H)-one 204 476.14/ 476.1, 477.1, 238.6, 239.3 (R)-1-(1-acryloylpyrrolidin-3-yl)- 3-(3-chloro- 4-(pyridin-2-ylmethoxy)phenyl)- 1H-imidazo[4,5-c]pyridin- 2(3H)-one 205 543.13/ 543.2, 544.1 (R)-1-(1-acryloylpyrrolidin-3-yl)- 3-(3-chloro-4-((4- (trifluoromethyl)benzyl)oxy) phenyl)-1H-imidazo[4,5-c]pyridin- 2(3H)-one 206 0 511.13/ 511.1, 512.2 (R)-1-(1-acryloylpyrrolidin-3-yl)- 3-(3-chloro-4-((2,5- difluorobenzyl)oxy)phenyl)- 1H-imidazo[4,5-c]pyridin- 2(3H)-one 207 511.13/ 511.1, 513.1 (R)-1-(1-acryloylpyrrolidin-3-yl)- 3-(3-chloro-4-((3,5- difluorobenzyl)oxy)phenyl)- 1H-imidazo[4,5-c]pyridin-2(3H)- one 208 543.07/ 543.1, 544.1 (R)-1-(1-acryloylpyrrolidin-3-yl)- 3-(3-chloro-4-((2,4- dichlorobenzyl)oxy)phenyl)-1H- imidazo[4,5-c]pyridin-2(3H)-one 209 477.17/ 477.1 (R)-1-(1-acryloylpyrrolidin-3-yl)-3-(4- ((2,5-difluorobenzyl)oxy)phenyl)-1H- imidazo[4,5-c]pyridin-2(3H)-one 210 509.17/ 509.1 (R)-1-(1-acryloylpyrrolidin-3-yl)- 3-(4-((2- (trifluoromethyl)benzyl)oxy) phenyl)-1H-imidazo[4,5- c]pyridine-2(3H)-one 211 509.17/ 509.2 (R)-1-(1-acryloylpyrrolidin-3-yl)-3- (4-((3-(trifluoromethyl)benzyl)oxy) phenyl)-1H-imidazo[4,5- c]pyridin-2(3H)-one 212 509.17/ 509.2 (R)-1-(1-acryloylpyrrolidin-3-yl)- 3-(4-((4- (trifluoromethyl)benzyl)oxy) phenyl)-1H-imidazo[4,5-c]pyridin- 2(3H)-one 213 442.18/ 442.2 (R)-1-(1-acryloylpyrrolidin-3-yl)- 3-(4-(pyridin-2-ylmethoxy)phenyl)- 1H-imidazo[4,5-c]pyridin-2(3H)- one 214 477.17/ 477.2 (R)-1-(1-acryloylpyrrolidin-3-yl)-3-(4- ((3,4-difluorobenzyl)oxy)phenyl)- 1H-imidazo[4,5-c]pyridin-2(3H)-one 215 543.07/ 543.1, 544.1, 545.0, 546.1 (R)-1-(1-acryloylpyrrolidin-3-yl)- 3-(3-chloro-4-((3,4- dichlorobenzyl)oxy) phenyl)-1H-imidazo[4,5- c]pyridin-2(3H)-one 216 0 459.18/ 459.2 (R)-1-(1-acryloylpyrrolidin-3-yl)-3- (4-((2-fluorobenzyl)oxy)phenyl)- 1H-imidazo[4,5-c]pyridin-2(3H)-one 217 499.15/ 499.2 N-(3-(3-(3-fluoro-4-((2- fluorobenzyl)oxy)phenyl)- 2-oxo-2,3-dihydro-1H- imidazo[4,5-c] pyridin-1-yl)phenyl)acrylamide 218 532.09/ 532.1 N-(3-(3-(4-((3,4- dichlorobenzyl)oxy)phenyl)-2- oxo-2,3-dihydro-1H-imidazo[4,5- c]pyridin-1-yl)phenyl)acrylamide 219 499.15/ 499.2 N-(3-(3-(4-((3,5- difluorobenzyl)oxy)phenyl)-2- oxo-2,3-dihydro-1H-imidazo[4,5- c]pyridin-1-yl)phenyl)acrylamide 220 499.15/ 499.2 N-(3-(3-(4-((2,5- difluorobenzyl)oxy)phenyl)-2- oxo-2,3-dihydro-1H-imidazo[4,5- c]pyridin-1-yl)phenyl)acrylamide 221 498.13/ 498.1 N-(3-(3-(4-((4- chlorobenzyl)oxy)phenyl)-2-oxo- 2,3-dihydro-1H-imidazo[4,5- c]pyridin-1-yl)phenyl)acrylamide 222 481.16/ 481.2 N-(3-(3-(4-((3- fluorobenzyl)oxy)phenyl)-2-oxo- 2,3-dihydro-1H-imidazo[4,5- c]pyridin-1-yl)phenyl)acrylamide 223 566.11/ 566.1 N-(3-(3-(3-chloro-4-((4- (trifluoromethyl)benzyl)oxy)phenyl)- 2-oxo-2,3-dihydro-1H- imidazo[4,5-c]pyridin-1- yl)phenyl)acrylamide 224 498.13/ 498.1 N-(3-(3-(4-(benzyloxy)-3- chlorophenyl)-2-oxo-2,3-dihydro- 1H-imidazo[4,5-c]pyridin-1- yl)phenyl)acrylamide 225 477.19/ 477.2 N-(3-(3-(4-((2- methylbenzyl)oxy)phenyl)-2-oxo- 2,3-dihydro-1H-imidazo[4,5- c]pyridin-1-yl)phenyl)acrylamide 226 0 499.15/ 499.2 N-(3-(3-(4-((2,6- difluorobenzyl)oxy)phenyl)-2-oxo- 2,3-dihydro-1H-imidazo[4,5-c]pyridin- 1-yl)phenyl)acrylamide 227 517.14/ 517.1 N-(3-(3-(4-((2,6-difluorobenzyl)oxy)- 3-fluorophenyl)-2-oxo-2,3-dihydro- 1H-imidazo[4,5-c]pyridin-1- yl)phenyl)acrylamide 228 481.16/ 481.2 N-(3-(3-(4-((2- fluorobenzyl)oxy)phenyl)-2-oxo-2,3- dihydro-1H-imidazo[4,5-c]pyridin-1- yl)phenyl)acrylamide 229 531.09/ 531.1 N-(3-(3-(4-((2,4- dichlorobenzyl)oxy)phenyl)-2-oxo- 2,3-dihydro-1H-imidazo[4,5- c]pyridin-1-yl)phenyl)acrylamide 230 497.13/ 497.1 N-(3-(3-(4-((3- chlorobenzyl)oxy)phenyl)-2-oxo-2,3- dihydro-1H-imidazo[4,5-c]pyridin-1- yl)phenyl)acrylamide 231 497.13/ 497.1 N-(3-(3-(4-((2- chlorobenzyl)oxy)phenyl)-2-oxo-2,3- dihydro-1H-imidazo[4,5-c]pyridin-1- yl)phenyl)acrylamide 232 531.16/ 531.2 N-(3-(2-oxo-3-(4-((2- (trifluoromethyl)benzyl)oxy)phenyl)-2,3- dihydro-1H-imidazo[4,5-c]pyridin-1- yl)phenyl)acrylamide 233 463.17/ 463.2 N-(3-(3-(3-(benzyloxy)phenyl)-2-oxo- 2,3-dihydro-1H-imidazo[4,5-c]pyridin- 1-yl)phenyl)acrylamide 234 481.16/ 481.2 N-(3-(3-(4-(benzyloxy)-3-fluorophenyl)- 2-oxo-2,3-dihydro-1H-imidazo[4,5- c]pyridin-1-yl)phenyl)acrylamide 235 515.12/ 515.1 N-(3-(3-(3-chloro-4-((2- fluorobenzyl)oxy)phenyl)-2-oxo-2,3- dihydro-1H-imidazo[4,5-c]pyridin-1- yl)phenyl)acrylamide 236 0 493.14/ 493.1 (R)-1-(1-acryloylpyrrolidin-3-yl)-3-(3- chloro-4-((2-fluorobenzyl)oxy)phenyl)- 1,3-dihydro-2H-imidazo[4,5-c]pyridin-2- one 237 459.18/ 459.2 (R)-1-(1-acryloylpyrrolidin-3-yl)-3-(4- (benzyloxy)-3-fluorophenyl)-1,3-dihydro- 2H-imidazo[4,5-c]pyridin-2-one 238 533.11/ 533.1 N-(3-(3-(4-((3-chloro-2- fluorobenzyl)oxy)-3-fluorophenyl)-2- oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin- 1-yl)phenyl)acrylamide 239 463.17/ 463.2 (N-(3-(3-(4-(benzyloxy)phenyl)-2-oxo- 2,3-dihydro-1H-imidazo[4,5-c]pyridin-1- yl)phenyl)acrylamide 240 531.16/ 531.2 N-(3-(2-oxo-3-(4-((3- (trifluoromethyl)benzyl)oxy)phenyl)-2,3- dihydro-1H-imidazo[4,5-c]pyridin-1- yl)phenyl)acrylamide 241 499.15/ 499.1 N-(3-(3-(4-((3,4- difluorobenzyl)oxy)phenyl)-2-oxo-2,3- dihydro-1H-imidazo[4,5-c]pyridin-1- yl)phenyl)acrylamide 242 531.16/ 531.2 N-(3-(2-oxo-3-(4-((4- (trifluoromethyl)benzyl)oxy)phenyl)-2,3- dihydro-1H-imidazo[4,5-c]pyridin-1- yl)phenyl)acrylamide 243 565.12/ 565.1 N-(3-(3-(3-chloro-4-((3- (trifluoromethyl)benzyl)oxy)phenyl)-2- oxo-2,3-dihydro-1H-imidazo[4,5- c]pyridin-1-yl)phenyl)acrylamide 244 493.12/ 493.1 (R)-1-(1-acryloylpyrrolidin-3-yl)-3-(4-((4- chloro-2-fluorobenzyl)oxy)phenyl)-1H- imidazo[4,5-c]pyridin-2(3H)-one 245 515.14/ 515.1 N-(3-(3-(4-((4-chloro-2- fluorobenzyl)oxy)phenyl)-2-oxo-2,3- dihydro-1H-imidazo[4,5-c]pyridin-1- yl)phenyl)acrylamide 246 0 441.18/ 441.2 ((R)-1-(1-acryloylpyrrolidin-3-yl)-3-(4- (benzyloxy)phenyl)-1H-imidazo[4,5- c]pyridin-2(3H)-one 247 481.16/ 481.2 N-(3-(3-(4-((4-fluorobenzyl)oxy)phenyl)- 2-oxo-2,3-dihydro-1H-imidazo[4,5- c]pyridin-1-yl)phenyl)acrylamide 248 499.15/ 499.2 N-(3-(3-(4-((2,4- difluorobenzyl)oxy)phenyl)-2-oxo-2,3- dihydro-1H-imidazo[4,5-c]pyridin-1- yl)phenyl)acrylamide

Example 249

4-(1-(3-acrylamidophenyl)-2-oxo-1H-imidazo[4,5-c]pyridin-3(2H)-yl)-N-(4-fluorobenzyl)benzamide

(174) ##STR00263##

Step 1: methyl 4-(1-(3-((tert-butoxycarbonyl)amino)phenyl)-2-oxo-1H-imidazo[4,5-c]pyridin-3(2H)-yl)benzoate (51)

(175) Intermediate 17 (0.96 g, 2.94 mmol, 1.0 eq) was dissolved in DCM (30.0 mL), added Cupric acetate (530 mg, 2.94 mmol, 1.0 eq), (4-(methoxycarbonyl)phenyl)boronic acid (1.06 g, 5.88 mmol, 2.0 eq), 4 A molecular sieve (1.3 g) and TEA (1.23 mL, 0.617 mmol, 2.0 eq), the mixture solution was stirred for 20 h at RT. Then filtered the solution and removed the solution under reduce pressure, added water and extracted with EA, dried with Na.sub.2SO.sub.4, filtered and concentrated, purified with silica column (PE:EA=4:11:1) to obtain the title product, brown solid, Yield: 420 mg, 33.2%. .sup.1H NMR (400 MHz, CDCl.sub.3): =8.25 (d, J=8.0 Hz, 2H), 7.80 (s, 1H), 7.85 (d, J=7.6 Hz, 2H), 7.45-7.49 (m, 1H), 7.31 (d, J=7.6 Hz, 1H), 7.22 (d, J=7.2 Hz, 2H), 6.74 (s, 1H), 3.97 (s, 3H), 1.52 (s, 9H). LCMS (ESI) m/z=461[M+H].sup.+.

Step 2: 4-(1-(3-((tert-butoxycarbonyl)amino)phenyl)-2-oxo-1H-imidazo[4,5-c]pyridine-3(2H)-yl)benzoic acid (52)

(176) Intermediate 51 (420 mg, 1.0 eq) was dissolved in EtOH (10 mL), added lithium hydroxide (192 mg, 5.0 eq), the mixture solution were stirred for 2 h at 50 C. Then added 1 M HCl to PH=6-5, extracted with EA, dried with Na.sub.2SO.sub.4, filtered and concentrated to obtain product used next step without in purification, gray solid, Yield: 338 mg, 83.0%. .sup.1H NMR (400 MHz, DMSO-d.sub.6): =12.60 (s, 1H), 9.67 (s, 1H), 8.17 (d, J=8.4 Hz, 2H), 7.82-7.86 (m, 3H), 7.50 (d, J=6.0 Hz, 2H), 7.22-7.23 (m, 1H), 1.49 (s, 9H). LCMS (ESI) m/z=447 [M+H].sup.+.

Step 3: tert-butyl (3-(3-(4-((4-fluorobenzyl)carbamoyl)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)phenyl)carbamate (53)

(177) Intermediate 52 (66 mg, 0.148 mmol, 1.0 eq) was dissolved in DCM (30 mL), added (4-fluorophenyl)methanamine (22.2 mg, 0.178 mmol, 1.2 eq), TEA (45 mg, 0.444 mmol, 3.0 eq), HATU (67.5 mg, 0.178 mmol, 1.2 eq), the mixture solution were stirred for 2 h at room temperature. Then stopped and removed the solution under reduce pressure, the residue was added saturated NaHCO.sub.3, extracted with EA washed with brine, dried with Na.sub.2SO.sub.4, filtered and concentrated, purified with silica column (DCM:MeOH=100:150:1) to obtain the title product as colorless oil, Yield: 47 mg, 57.4%. LCMS (ESI) m/z=554 [M+H].sup.+.

Step 4: 4-(1-(3-acrylamidophenyl)-2-oxo-1H-imidazo[4,5-c]pyridin-3(2H)-yl)-N-(4-fluorobenzyl)benzamide (54)

(178) Intermediate 53 (47 mg) was dissolved in DCM (5.0 mL), added TFA (2.0 mL), the mixture was stirred for 1 h at RT, stopped and removed the solution under reduce pressure, the residue was added saturated NaHCO.sub.3, extracted with EA and dried with Na.sub.2SO.sub.4, then filtered and concentrated to provide a crude product used next step without purification, colorless oil, Yield: 28 mg, 72.7%. LCMS (ESI) m/z=454 [M+H].sup.+.

(179) Crude product (28 mg, 0.062 mmol, 1.0 eq) and DIEA (9 mg, 0.070 mmol, 1.1 eq) were dissolved in THF (2.0 mL), added acryloyl chloride (6 mg, 0.065 mmol, 1.05 eq) slowly at 0 C., the mixture solution was stirred for 0.5 h at RT, followed the reaction with LCMS, stopped the reaction added water and extracted with EA, dried with Na.sub.2SO.sub.4, filtered and concentrated, the residue was purification with silica gel plate (DCM:MeOH=20:1) to obtain the title product, colorless oil, Yield: 2 mg, 6.4%. .sup.1H NMR (400 MHz, CD.sub.3OD): =8.60 (s, 1H), =8.23 (s, 1H), 8.13 (d, J=8.0 Hz, 2H), 7.83 (d, J=8.4 Hz, 2H), 7.63-7.66 (m, 3H), 7.39-7.44 (m, 3H), 7.05-7.10 (m, 2H), 6.41-6.50 (m, 2H), 5.81-5.84 (m, 1H), 4.61 (d, J=4.4 Hz, 2H). LCMS (ESI) m/z=507 [M+H].sup.+.

(180) The following additional Examples 250-256 shown in the Table below were prepared following the procedures outlined in the general methods above and detailed in Example 249.

(181) TABLE-US-00003 MS(cald) [M + H].sup.+/ Entry Structure MS (found) Name 250 448.19/ 448.2 (R)-1-(1-acryloylpyrrolidin-3-yl)-3- (4-(morpholine-4-carbonyl)phenyl)- 1H-imidazo[4,5-c]pyridin-2(3H)-one 251 544.16/ 544.2 4-(1-(3-acrylamidophenyl)-2-oxo-1H- imidazo[4,5-c]pyridin-3(2H)-yl)-N-(3- (trifluoromethyl)phenyl)benzamide 252 520.19/ 520.2 4-(1-(3-acrylamidophenyl)-2-oxo-1H- imidazo[4,5-c]pyridin-3(2H)-yl)-N- (3-methoxybenzyl)benzamide 253 470.18/ 470.2 N-(3-(3-(4-(morpholine-4- carbonyl)phenyl)-2-oxo-2,3-dihydro- 1H-imidazo[4,5-c]pyridin-1- yl)phenyl)acrylamide 254 476.16/ 476.2 4-(1-(3-acrylamidophenyl)-2-oxo- 1H-imidazo[4,5-c]pyridin-3(2H)-yl)- N-phenylbenzamide 255 490.18/ 490.2 4-(1-(3-acrylamidophenyl)-2-oxo-1H- imidazo[4,5-c]pyridin-3(2H)-yl)-N- (m-tolyl)benzamide 256 0 498.21/ 498.2 (R)-4-(1-(1-acryloylpyrrolidin-3-yl)-2- oxo-1H-imidazo[4,5-c]pyridin-3(2H)- yl)-N-(3-methoxybenzyl)benzamide

Example 257

N-(4-(1-(3-acrylamidophenyl)-2-oxo-1H-imidazo[4,5-c]pyridin-3(2H)-yl)phenyl)benzamide

(182) ##STR00271##

Step 1: tert-butyl (3-(3-(4-(dibenzylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)phenyl)carbamate (55)

(183) The mixture of intermediate 17 (2 g, 6.1 mmol), (4-(dibenzylamino)phenyl)-boronic acid (3.8 g, 12.2 mmol), TEA (1.23 g, 12.2 mmol) and 4 A molecular sieves (1 g) were added to DCM (40 mL) in a vial Copper(II) acetate (1.1 g, 6.1 mmol) was added in one portion. The mixture was stirred for about 22 h at it. Volatile components were removed under vacuum, before being poured into H.sub.2O. The reaction mixture was extracted with EA, Organic phase was purified by column chromatography on silica gel (gradient: DCM/MeOH=100/1-50/1), give the title product (1.2 g, yield 33.3%).

(184) .sup.1HNMR (400 MHz, CD.sub.3OD): 8.33 (br, 2H), 7.73 (s, 1H), 7.46-7.11 (m, 16H), 6.85 (d, J=8.0 Hz, 2H), 6.67 (s, 1H), 4.72 (s, 4H), 1.50 (s, 9H). LCMS: m/z=598 [M+H].sup.+.

Step 2: tert-butyl (3-(3-(4-aminophenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)phenyl)carbamate (56)

(185) A suspension of 55 (1.2 g, 1.68 mmol) and 10% Pd/C (0.3 g) in MeOH (20 mL) was hydrogenated at 50 psi H.sub.2 for 20 h. The suspension was filtered through Celite and concentrated. The residue was dried in vacuo to provide the title product (0.2 g crude).

(186) LCMS: m/z=372 [M+H].sup.+.

Step 3: tert-butyl (3-(2-oxo-3-(4-(3-(trifluoromethyl)benzamido)phenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)phenyl)carbamate (57)

(187) To a stirred solution of 56 (60 mg, 0.14 mmol) in DCM (6 mL) was added SM2 (33 mg, 0.16 mmol) and TEA (17.4 mg, 0.17 mmol). The mixture was stirred at 15 C., after 1.0 h, the mixture was washed with H.sub.2O, extracted with DCM, dried over Na.sub.2SO.sub.4, filtered, concentrated to give a crude title product which was used for the next step without further purification. LCMS (ESI) m/z=590 [M+H].sup.+.

Step 4: N-(4-(1-(3-acrylamidophenyl)-2-oxo-1H-imidazo[4,5-c]pyridin-3(2H)-yl)phenyl)benzamide (58)

(188) To a stirred solution of 57 in DCM (4 mL) was added CF.sub.3COOH (1 mL), The mixture was stirred at 15 C., after 1.0 h, the mixture was added NaHCO.sub.3 to adjust the Ph=8, extracted with DCM, dried over Na.sub.2SO.sub.4, filtered, concentrated and purified by Pre-TLC to give the product (42 mg). LCMS (ESI) m/z=490 [M+H].sup.+.

(189) To a stirred solution of de-Boc intermediate (42 mg, 0.086 mmol) in DCM (6 mL) was added acryloyl chloride (8.5 mg, 0.09 mmol) and TEA (17.3 mg, 0.17 mmol). The mixture was stirred at 15 C., after 1.0 h, the mixture was washed with H.sub.2O, extracted with DCM, dried over Na.sub.2SO.sub.4, filtered, concentrated and purified by Pre-TLC to give the title product (21 mg, 51.4%).

(190) .sup.1HNMR (CD.sub.3OD, 400 MHz) 5.79-5.82 (d, 1H), 6.41-6.45 (m, 2H), 7.39-7.41 (d, 1H), 7.56-7.58 (q, 1H), 7.70-7.73 (m, 2H), 7.74-7.76 (m, 2H), 7.77-7.79 (m, 2H), 7.90-7.92 (d, 1H), 7.92-8.01 (m, 3H), 8.03 (s, 1H), 8.08-8.11 (d, 1H), 8.24 (s, 1H). LCMS (ESI) m/z=544 [M+H].sup.+.

(191) The following additional Examples 258-269 shown in the Table below were prepared following the procedures outlined in the general methods above and detailed in Example 257.

(192) TABLE-US-00004 MS(cald) [M + H].sup.+/ Entry Structure MS (found) Name 258 506.18/ 506.2 N-(4-(1-(3-acrylamidophenyl)-2-oxo- 1H-imidazo[4,5-c]pyridin-3(2H)- yl)phenyl)-2-methoxybenzamide 259 510.13/ 510.1 N-(4-(1-(3-acrylamidophenyl)- 2-oxo-1H-imidazo[4,5-c]pyridin- 3(2H)-yl)phenyl)-3-chlorobenzamide 260 532.23/ 532.2 N-(3-(1-(3-acrylamidophenyl)-2-oxo- 1H-imidazo[4,5-c]pyridin-3(2H)- yl)phenyl)-4-(tert-butyl)benzamide 261 576.17/ 576.2 N-(4-(1-(3-acrylamidophenyl)-2-oxo- 1H-imidazo[4,5-c]pyridin-3(2H)- yl)phenyl)benzamide 262 544.15/ 544.2 N-(4-(1-(3-acrylamidophenyl)-2-oxo- 1,2-dihydro-3H-imidazo[4,5-c]pyridin- 3-yl)phenyl)-2- (trifluoromethyl)benzamide 263 544.15/ 544.2 N-(4-(1-(3-acrylamidophenyl)-2-oxo- 1,2-dihydro-3H-imidazo[4,5-c]pyridin- 3-yl)phenyl)-4- (trifluoromethyl)benzamide 264 506.18/ 506.2 N-(4-(1-(3-acrylamidophenyl)-2-oxo- 1H-imidazo[4,5-c]pyridin-3(2H)- yl)phenyl)-4-methoxybenzamidee 265 494.16/ 494.2 N-(4-(1-(3-acrylamidophenyl)-2-oxo- 1H-imidazo[4,5-c]pyridin-3(2H)- yl)phenyl)-3-fluorobenzamide 266 0 506.18/ 506.2 N-(4-(1-(3-acrylamidophenyl)-2-oxo- 1H-imidazo[4,5-c]pyridin-3(2H)- yl)phenyl)-3-methoxybenzamide 267 490.18/ 490.2 N-(4-(1-(3-acrylamidophenyl)-2-oxo- 1H-imidazo[4,5-c]pyridin-3(2H)- yl)phenyl)-3-methylbenzamide 268 552.18/ 552.2 (R)-N-(4-(1-(1-acryloylpyrrolidin-3-yl)- 2-oxo-1H-imidazo[4,5-c]pyridin-3(2H)- yl)phenyl)-4-methoxy-3- (trifluoromethyl)benzamide 269 536.18/ 536.2 (S)-N-(4-(1-(1-acryloylpyrrolidin-3-yl)- 2-oxo-1H-imidazo[4,5-c]pyridin-3(2H)- yl)phenyl)-4-methyl-3- (trifluoromethyl)benzamide

Example 270

Step 1: tert-butyl (3-(3-(4-bromophenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)phenyl)carbamate (59)

(193) Intermediate 17 (0.5 g, 1.53 mmol), (4-bromophenyl)boronic acid (0.61 g, 3.0 mmol), TEA (0.3 g, 3.0 mmol) and 4 A molecular sieves (0.1 g) were added to DCM (15 mL) in a vial Copper (II) acetate (0.27 g, 1.53 mmol) was added in one portion. The mixture was stirred for about 22 h at rt. Volatile components were removed under vacuum, before being poured into H.sub.2O. The reaction mixture was extracted with EA, Organic phase was purified by column chromatography on silica gel (gradient: DCM/MeOH=100/1-50/1) to give the title product (0.26 g, yield=33.3%).

(194) .sup.1H NMR (400 MHz, CDCl.sub.3): =7.83-7.80 (m, 2H), 7.71 (d, J=8.0 Hz, 2H), 7.51-7.44 (m, 3H), 7.30-7.26 (m, 1H), 7.21 (d, J=8.0 Hz, 1H), 6.68 (s, 1H), 1.51 (s, 9H). LCMS: m/z=481.1, 483.1 [M+H].sup.+.

Step 2: tert-butyl (3-(3-(3-methyl-[1,1-biphenyl]-4-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)phenyl)carbamate (60)

(195) To a solution of 59 (50 mg, 0.1 mmol) and m-tolylboronic acid (28 mg, 0.2 mmol) in dioxane (5 mL) and water 1 mL) was added K.sub.2CO.sub.3 (28 mg, 0.2 mmol) followed by (Ph.sub.3P).sub.4Pd (10 mg, 0.05 mmol) under N.sub.2 with stirring. The mixture was refluxed for 8 h until the material was disappeared. The reaction mixture was cooled to room temperature. The dioxane was removed by rotary evaporation. The residue was poured into water and extracted with EA. The organic layer was dried over Na.sub.2SO.sub.4, filtered and the solvent was removed by rotary evaporation. The product was isolated by flash chromatography on silica gel using 100:1-50:1 DCM:MeOH to give the title product (20 mg, yield 39.1%). LCMS: m/z=493[M+H].sup.+.

Step 3: 1-(3-aminophenyl)-3-(3-methyl-[1,1-biphenyl]-4-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (61)

(196) Intermediate 60 (20 mg, 0.040 mmol) were added to CF.sub.3COOH/DCM=4/1 (5 mL) in one portion. The mixture was stirred for about 1 h at rt. Volatile components were removed under vacuum, give a crude title product, and directly used in next step without further purification. LCMS: m/z=393[M+H].sup.+.

Step 4: N-(3-(3-(3-methyl-[1,1-biphenyl]-4-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)phenyl)acrylamide (62)

(197) To a solution of Acryloyl chloride (3.6 mg, 0.04 mmol) in DCM (1 mL) was added to a stirred solution of 61 (16 mg, 0.04 mmol) and TEA (41 mg, 0.4 mmol) in DCM (5 mL) at 0 C. The reaction mixture was stirred for 1 h, poured onto brine and extracted with DCM. The organic layer was dried, concentrated and recrystallized from DCM/MeOH=100/1 to give the title product (3 mg, yield 6.5%).

(198) .sup.1H NMR (400 MHz, CDCl.sub.3): =8.45 (br, 1H), 8.37 (br, 1H), 7.98 (br, 1H), 7.81 (br, 1H), 7.54-7.45 (m, 3H), 7.34-7.23 (m, 3H), 7.13 (d, J=4.0 Hz, 1H), 7.10 (d, J=4.0 Hz, 1H), 6.97-6.90 (m, 3H), 6.45-6.40 (m, 1H), 6.24-6.18 (m, 1H), 5.77-5.75 (m, 1H), 2.35 (s, 3H). LCMS: m/z=447 [M+H].sup.+.

(199) The following additional Examples 271-278 shown in the Table below were prepared following the procedures in Examples 270.

(200) TABLE-US-00005 MS(cald) [M + H].sup.+/ Entry Structure MS (found) Name 271 433.16/ 433.1 N-(3-(3-([1,1-biphenyl]-4-yl)- 2-oxo-2,3- dihydro-1H-imidazo[4,5-c] pyridin-1-yl)phenyl)acrylamide 272 447.17/ 447.2 N-(3-(3-(4-methyl-[1,1- biphenyl]-3-yl)-2- oxo-2,3-dihydro-1H-imidazo [4,5-c]pyridin-1- yl)phenyl)acrylamide 273 425.19/ 425.2 (R)-1-(1-acryloylpyrrolidin-3- yl)-3-(2-methyl-[1,1-biphenyl]- 3-yl)-1H- imidazo[4,5-c]pyridin-2(3H)- one 274 459.18/ 459.2 (R)-1-(1-acryloylpiperidin-4- yl)-3-(2-fluoro-4-methoxy- [1,1-biphenyl]-4-yl)-1H- imidazo[4,5-c]pyridin-2(3H)- one 275 479.10/ 479.1, 480.2, 481.1, 483.1 (R)-1-(1-acryloylpiperidin-4- yl)-3-(2,4-dichloro-[1,1- biphenyl]-4-yl)-1H- imidazo[4,5-c]pyridin-2(3H)- one 276 447.17/ 447.2 N-(3-(3-(4-methyl-[1,1- biphenyl]-4-yl)-2-oxo-2,3- dihydro-1H-imidazo[4,5- c]pyridin-1- yl)phenyl)acrylamide 277 0 411.17/ 411.2 (R)-3-([1,1-biphenyl]-3-yl)-1- (1-acryloylpyrrolidin-3-yl)-1H- imidazo[4,5-c]pyridin-2(3H)- one 278 397/397 N-(3-(3-(4-cyclopropylphenyl)- 2-oxo-2,3-dihydro-1H- imidazo[4,5-c]pyridin-1- yl)phenyl)acrylamide
Btk Kinase Assay and Other Kinases Assay

(201) Btk kinase activity was determined using a homogenous time resolved fluorescence (HTRF) methodology. Measurements were performed in a reaction volume of 15 L using 384-well assay plates. Kinase enzyme, inhibitor, ATP and 1 M peptide substrate were incubated in a reaction buffer compose of Hepes 50 mM (pH7.0), NaN.sub.3 0.02%, BSA 0.01%, Orthocanadate 0.1 mM. After one hour, the kinase reaction was quenched by the addition of E-labeled antibody and XL-665 in 1 Detection buffer containing 60 mM EDTA (Cisbio), and the mixture was allowed to incubate for one hour. The HTRF signal was measured on a multimode plate reader (EnVision Multilabel Reader, Perkin Elmer) with an excitation wavelength (.sub.Ex) of 330 nm and detection wavelengths (.sub.Em) of 615 and 665 nrm. Activity was determined by the ratio of the fluorescence at 665 nm to that at 615 nm. For each compound, enzyme activity as measured at various concentrations of compound, Negative control reactions were performed in the absence of inhibitor in two replicates and eight no enzyme controls were used to determine baseline fluorescence levels. IC.sub.50s were obtained according to the equation:
Y=100/(1+10{circumflex over ()}((Log IC50X)*HillSlope)).
For BTK assay, [ATP]=80 M, BTK=3.4 nM.

(202) For LYN assay, [ATP]=20 M, LYN=0.12 n M. For LCK assay, [ATP]=20 M, LCK=0.2 nM. For BLK assay, [ATP]=20 M, BLK=0.6 n M.

Example 279

(203) The following Table shows the activity of selected compounds of this invention in the BTK inhibition assay. The compound numbers correspond to the compound numbers in previous Tables. Compounds having an activity designated as A provided an IC.sub.5010 nM; Compounds having an activity designated as B provided an IC.sub.50 10-100 nM; Compounds having an activity designated as C provided an IC.sub.50 100-1000 nM; Compounds having an activity designated as D provided an IC.sub.50 1000-10000 nM; Compounds having an activity designated as E provided an IC.sub.5010000 nM.

(204) TABLE-US-00006 BTK Inhibition Data Compound BTK Compound BTK Compound BTK Compound BTK # Inhibition # Inhibition # Inhibition # Inhibition 1 B 2 A 3 B 4 A 5 A 6 B 7 B 8 A 9 B 10 C 11 C 12 B 13 B 14 B 15 C 16 B 17 C 18 C 19 B 20 B 21 B 22 E 23 B 24 B 25 A 26 A 27 D 28 D 29 E 30 E 31 A 32 E 33 B 34 E 35 B 36 C 37 C 38 A 39 B 40 B 41 A 42 B 43 C 44 B 45 B 46 D 47 D 48 B 49 B 50 C 51 A 52 C 53 B 54 B 55 B 56 B 57 B 58 B 59 B 60 A 61 B 62 B 63 B 64 C 65 D 66 B 67 B 68 C 69 B 70 D 71 C 72 B 73 B 74 B 75 B 76 B 77 B 78 B 79 B 80 C 81 C 82 C 83 B 84 B 85 B 86 C 87 B 88 B 89 B 90 B 91 B 92 B 93 A 94 B 95 B 96 B 97 B 98 B 99 B 100 B 101 B 102 B 103 B 104 C 105 B 106 B 107 B 108 B 109 E 110 C 111 D 112 B 113 B 114 B 115 C 116 C 117 B 118 B 119 D 120 D 121 C 122 D 123 E 124 C 125 B 126 C 127 C 128 A 129 C 130 C 131 B 132 A 133 A 134 B 135 B 136 B 137 C 138 B 139 B 140 C 141 B 142 B 143 B 144 B 145 C 146 B 147 B 148 B 149 B 150 B 151 A 152 B 153 B 154 D 155 B 156 D 157 A 158 B 159 B 160 C 161 C 162 C 163 C 164 D 165 C 166 A 167 A 168 A 169 C 170 C 171 C 172 A 173 B 174 B 175 C 176 A 177 C 178 B 179 E 180 C 181 B 182 E 183 E 184 A 185 A 186 A 187 C 188 C 189 E 190 C 191 A 192 D 193 D 194 E 195 B 196 C 197 C 198 C 199 C 200 C 201 B 202 C 203 C 204 C 205 C 206 C 207 C 208 C 209 C 210 B 211 C 212 C 213 D 214 D 215 D 216 C 217 C 218 C 219 C 220 C 221 B 222 B 223 C 224 C 225 C 226 C 227 C 228 C 229 B 230 B 231 B 232 B 233 B 234 C 235 B 236 C 237 B 238 C 239 C 240 B 241 C 242 C 243 C 244 C 245 C 246 C 247 B 248 C 249 B 250 D 251 D 252 C 253 D 254 D 255 D 256 D 257 D 258 B 259 C 260 B 261 C 262 C 263 C 264 C 265 C 266 C 267 E 268 C 269 C 270 E 271 B 272 C 273 C 274 C 275 E 276 D 277 C 278 B

Example 280

(205) The following Table shows the activity of selected compounds of this invention in the BTK, BLK, LYN, LCK inhibition assay. The compound numbers correspond to the compound numbers in previous Tables. Compounds having an activity designated as A provided an IC.sub.5010 nM; Compounds having an activity designated as B provided an IC so 10-100 nM; Compounds having an activity designated as C provided an IC.sub.50 100-1000 nM; Compounds having an activity designated as D provided an IC.sub.50 1000-10000 nM; Compounds having an activity designated as E provided an IC.sub.5010000 nM; N/A is not available.

(206) TABLE-US-00007 TABLE 2 BTK BLK LYN LCK Compound IC.sub.50 IC.sub.50 IC.sub.50 IC.sub.50 1 B B E E 2 A B E E 3 B C E N/A 4 A B D D 5 A B E E 8 A C D E 20 B B E D 26 A C D E 31 A C D E 38 A B E E 51 A B E E 60 A B E E 103 B C D E 128 B C E E 132 A C E E 133 A B E E 138 B C E E
Calcium FluxAssay

(207) Calcium flux fluorescence-based assays were performed in aFDSS7000EX (Hamamatsu Photonics) fluorometric imaging plate reader according to manufacturer instructions. Compounds to be assayed were dissolved in DMSO, diluted to appropriate concentrations in Ca.sup.2+ buffer ranging from 0 to 10 M (at a dilution factor of 0.1), added 5 l (6) to each well (the final DMSO concentration was 0.1% in each well). Then 12.5 L 2 dye loading solution (Fluo-4 NW Calcium Assay Kits, Invitrogen) was added per well of a 384-well plate. Afterwards, actively growing Ramos cells (ATCC) in RPM1640 medium supplemented with 10% FBS (Invitrogen) were washed and re-plated in assay buffer (from Fluo-4 NW Calcium Assay Kits, Invitrogen) to approximately 6.410.sup.6/ml (80000 cells/12.5 L in 384-well plates). The plates were incubated at 37 C. for 30 minutes, then at room temperature for an additional 30 minutes. The plates were now ready to be used in an experiment Immediately after the transfer and a 10-s recording of baseline fluorescence, the compound treated cells were stimulated with a goat anti-human IgM antibody (10 g/ml; Jackson Immuno Research) and read in a FDSS for 240 seconds. Difference between the signal and that at baseline, designated adjusted relative fluorescence unit, was calculated by using a custom Excel (Microsoft, Redmond, Wash.) template to determine IgM-induced calcium influx and its inhibition by compounds. The table belows show the result. Compounds having an activity designated as A provided an IC.sub.5010 nM; Compounds having an activity designated as B provided an IC.sub.50 10-100 nM; Compounds having an activity designated as C provided an IC.sub.50 100-1000 nM.

(208) TABLE-US-00008 TABLE 3 Cmpd. Ramos Ca Flux (nM) Example 4 B Example 5 B
Btk Occupancy in Cellular Assays

(209) For PCI-33380 labeling of human B cells, 10.sup.6 Jeko-1 cells were pre-incubated with compound for 1.5 h before labeling. Then cells were treated with PCI-33380 at 5 M for 1 h. Washed, lysed in Ripa buffer containing sample reducing agent, and analyzed by SDS/PAGE and fluorescent gel scanning using a Typhoon scanner 9500 (GE Healthcare) (Ex, 532 nm; Em, 555 nm). The gel was then blotted and total Btk levels detected by standard Western blot with Btk antibody (CST).

(210) By using the fluorescently tagged derivative PCI-33380, we found that 100 nM of Compound 4 and 5 were sufficient to fully occupy the active site of Btk in human mantle cell lymphoma cell lines Jeko-1 cells in culture.

(211) Btk Occupancy In Vivo

(212) For analysis of Btk occupancy in Babc/L mice following oral dosing of compounds after 4 hours. Isolating peripheral blood mononuclear cells (PBMCs) with mouse peripheral blood separation kit (Hao Yang Biological Manufacture CO., LTD, Tianjin) were collected from Babc/L mice (1 ml blood from two mice). Spleens were processed to splenocytes followed by 5 min incubation in red blood cell lysing buffer (from mouse peripheral blood separation kit). PBMCs or splenocytes were then PCI-33380-labeled and lysates analyzed by fluorescent gel scanning as described in cellular assays. Compound 5 was achieved full occupancy at 25 mg/kg single oral dose in all Babc/L mice.