WO2018002958A1 - Nouveaux composés contenant de l'hydrazide utilisés comme inhibiteurs de btk - Google Patents

Nouveaux composés contenant de l'hydrazide utilisés comme inhibiteurs de btk Download PDF

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WO2018002958A1
WO2018002958A1 PCT/IN2017/050268 IN2017050268W WO2018002958A1 WO 2018002958 A1 WO2018002958 A1 WO 2018002958A1 IN 2017050268 W IN2017050268 W IN 2017050268W WO 2018002958 A1 WO2018002958 A1 WO 2018002958A1
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alkyl
cycloalkyl
compound
ring
hydrogen
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PCT/IN2017/050268
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English (en)
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V.S.N. Murty KADIYALA
Dipali Manubhai DESAI
Virendra Narendra RAUT
Pratit Viram SAVANT
Kiritkumar Parmeshkumar JOSHI
Umesh Vishnu CHAUDHARI
Rajendrasinh Jashvantsinh RATHOD
Tushar Bhupendrabhai BHATT
Trinadha Rao Chitturi
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Sun Pharma Advanced Research Company Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to novel hydrazide containing compounds as Bruton tyrosine kinase (BTK) inhibitors, process of preparation thereof, and to the use of the compounds in the preparation of pharmaceutical compositions for the therapeutic treatment of disorders involving mediation of Bruton tyrosine kinase in humans.
  • BTK Bruton tyrosine kinase
  • BTK BTK signal transduction pathways regulating B-cell proliferation, differentiation and survival has been a ground breaking discovery and has led to developments of drugs for the treatment of B-cell malignancies.
  • Improper /auto activated BTK signaling is considered to be the major cause in several haematological malignancies such as chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL) etc.
  • CLL chronic lymphocytic leukemia
  • MCL mantle cell lymphoma
  • Ibrutinib which is disclosed in US patent number 7514444 is presently marketed for the treatment of mantle cell lymphoma and chronic lymphocytic leukemia under the trade name Imbruvica .
  • the clinical and commercial success of Ibrutinib has led to discovery of newer BTK inhibitors.
  • the present invention pro
  • Rj is selected from a group consisting of C 1 -4 alkyl, C3-14 cycloalkyl, phenyl, Cs_6 heteroaryl containing 1 to 3 heteroatoms selected from oxygen, nitrogen orsulfur, C 4 _6 heterocycloalkyl containing 1 or 2 heteroatoms selected from oxygen, nitrogen, or sulfur; Rj is optionally further substituted with Ci_ 4 alkyl, C 3 _7 cycloalkyl, phenyl, Cs_6 heteroaryl containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulfur, and C 4 _6 heterocycloalkyl containing 1 or 2 heteroatoms selected from oxygen, nitrogen, or sulfur;
  • R2 is either absent or selected from a group consisting of Ci_ 4 alkyl, C 3 _7 cycloalkyl, NH, N(d_ 3 alkyl);
  • R3 and R 4 are each independently selected from hydrogen, C2-6 hydroxyalkyl, C2-6 haloalkyl and Ci-4 alkyl; optionally substituted with C 3 _6 cycloalkyl;
  • R5 is selected form a group consisting of hydrogen, Ci_6 alkyl, C 3 _6 cycloalkyl, C2-5 alkenyl, C2-5 alkynyl, C(0)d_6 alkyl, C(0)C 3 - 6 cycloalkenyl, C(S)d_ 6 alkyl, C(S)C 3 - 6 cycloalkyl, S0 2 d-6 alkyl, -CHO, C(S)C 3 - 6 cycloalkenyl and CN; or R5 is a moiety selected from the groups provided in Figure- 1
  • R 6 is selected from a group consisting hydrogen, d-6 alkyl, d-6 haloalkyl, d-6 cycloalkyl, CN, S0 2 d- 6 alkyl, S0 2 C 3 - 6 cycloalkyl, C(0)OH, C(0)0 d-6 alkyl and C(0)NR ! o ii wherein Rjo and Rn are independently selected from d-6 alkyl or Rjo and Rn together with the nitrogen atom to which they are attached form a 4 to 7 membered heterocyclic ring;
  • R 7 , Rg, R9 are independently selected from a group consisting of hydrogen, d-6 alkyl, halogen, d-6 cycloalkyl, d-6 haloalkyl, d-6 halocycloalkyl, d-6 hydroxyalkyl, d-6 hydroxycycloalkyl, d-6 alkyl-0-C 3 - 6 cycloalkyl, CN, C(0)NR 12 Ri 3 , (CH 2 ) n C(0)NR 12 Ri3, d-6 cyanoalkyl, C(0)OH, C(0)Od_ 6 alkyl, (CH 2 ) n C(0)OH, (CH 2 ) n C(0)0 d-e alkyl, (CH 2 ) n NR 12 Rj 3 , C 4 _7 heterocycloalkyl containing 1 or 2 heteroatoms wherein the heteroatom is selected from oxygen, sulfur or N(Ri 4 ); wherein n is an integer selected from 0 to 4; or Rg and R taken
  • Ri 2 and R13 are independently selected from hydrogen, d-6 alkyl or Ri 2 and R13 together with the nitrogen atom to which they are attached forms a 4 to 7 membered heterocyclic ring;
  • R14 is selected from hydrogen, d_6 alkyl, d-6 cycloalkyl, d_6 haloalkyl, d_6 hydroxyalkyl, d_6 alkyl-0-d_6 alkyl, d_6 aminoalkyl and d-6 cycloalkyl-0-Ci_6 alkyl; wherein the alkyl and the cycloalkyl groups are optionally substituted with 5 or 6 membered heterocycle containing 1 or 2 heteroatoms selected from oxygen, sulfur and nitrogen;
  • X, Y and Z at each occurrence are independently selected from CH or N;
  • Hal is a halogen
  • EWG is selected from a group consisting of C(0)OR 15 , C(0)N(R 15 ) 2 , CN, N0 2 , S0 3 H, S0 2 N(R 15 ) 2 and SO2R 1 5 wherein R 15 is selected from hydrogen, Q_3 alkyl and C 4 _6 cycloalkyl;
  • R2 and R 3 along with the carbon atom and the nitrogen atom to which they are attached, respectively, together form a 4 to 7 membered cyclic ring;
  • Rj and R 3 along with R2, carbon of C T and nitrogen atom to which R 3 is attached form a 5 to 7 membered cyclic ring;
  • R 4 and R2 together with the intermediate groups form a 5 to 7 membered cyclic ring
  • Q is selected from CH or nitrogen
  • Rj6 and R 17 together form a phenyl ring optionally substituted with halogen, -0-Ci_3 alkyl, - COOH, -COOd_ 3 alkyl, -C 1-3 alkyl, -OH;
  • Ri6 and Rn together form a 5 or 6 membered heterocyclic ring containing 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur;
  • V is selected from R 18 , halogen, -C 1 -4 haloalkyl, -C2-4 alkenyl, -C2-4 alkynyl, -SRis, -ORis, - SOR 18 , -SO2R 18 , -N(R 18 ) 2 , -NHCHO, -NHCOCH 3 , -C 4 - 6 heterocycloalkyl, -C 4 - 6 cycloalkenyl, -CO-R18, -CN and -CHO wherein Ris is selected from hydrogen, -C 1 -4 alkyl and -C3-6 cycloalkyl;
  • Rjg is one or more groups selected from hydrogen, halogen, hydroxyl, -N(Ci_6 alkyl) 2 , -NH(d-6 alkyl), -d-6 haloalkyl, -C 2 - 6 alkenyl, -C 2 - 6 alkynyl, -Od-6 alkyl, -O ⁇ , alkenyl, -OC3-6 alkynyl,-SCi- 6 alkyl, -CN, -C(0)Ci-4 alkyl, -C(0)C 3 - 6 cycloalkyl, -C(0)OH, - C(0)NH 2 , -C(0)N(d_ 6 alkyl) 2 , -C(0)NH(d_ 6 alkyl), -NHC(0)d_ 4 alkyl, -N(Ci_4 alkyl)C(0)Ci alkyl and when R1 is -OC3-6 alkenyl or -OC3-6 alkynyl the double and triple
  • Yj, Y2, Y3 and Y are independently and appropriately selected from CH, NR 2 o, O, or S; wherein, R2 0 is either absent or selected from hydrogen, -C 1 -3 alkyl and -C 4 -6 cycloalkyl; r is an integer selected from 1 to 3;
  • Group D is optionally substituted with one or more groups selected from a group consisting of halogen, hydroxyl, d-6 alkyl, -N(d-6 alkyl) 2 , -NH(d-6 alkyl), -d-6 haloalkyl, -C 2- 6 alkenyl, -C2-6 alkynyl, -OCi_6 alkyl, -OC3-6 cycloalkyl, -OC3-6 alkenyl, -OC3-6 alkynyl,-SCi_6 alkyl, -CN, -C(0)d_ 4 alkyl, -C(0)C 3-6 cycloalkyl, -C(0)OH, -C(0)NH 2 , -C(0)N(d_ 6 alkyl) 2 , -C(0)NH(d_ 6 alkyl), -NHC(0)Cj alkyl and -N(d_ 4 alkyl)C(O) d_ 4 alkyl; or B, W and D taken together forms
  • the compounds of the present invention were found to be potent and selective BTK inhibitors and can be useful in treatment of the diseases mediated by BTK receptors.
  • Salts include those formed with either organic and inorganic acids or bases.
  • Pharmaceutically acceptable acid addition salts include those formed from hydrochloric, hydrobromic, sulfuric, citric, tartaric, phosphoric, acetic, trifluoroacetic, triphenylacetic, phenylacetic, succinic, oxalic, fumaric, maleic, glutamic, aspartic, oxaloacetic, methanesulphonic, ethanesulphonic, p-toluenesulphonic, benzenesulphonic, naphthalenesulphonic or naphthalenedisulphonic, salicylic, glutaric, gluconic, mandelic, cinnamic, ascorbic, oleic, naphthoic, hydroxynaphthoic (for example 1- or 3-hydroxy-2- naphthoic), benzoic, 4-methoxybenzoic, 2- or 4-hydroxybenzoic, 4-chlorobenz
  • Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium and salts with organic bases such as dicyclohexylamine and N-methyl-D-glucamine.
  • alkyl refers to a saturated hydrocarbon chain radical that includes solely carbon and hydrogen atoms in the backbone, either linear or branched and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, w-propyl, 1-methylethyl (isopropyl), «-butyl, «-pentyl, and 1,1-dimethylethyl (i-butyl).
  • the alkyl chain may have 1 to 13 carbon atoms unless specified otherwise.
  • alkyl groups described or claimed herein may be unsubstituted or substituted with groups selected from halogen, -Od_ 6 alkyl, -OC 3 - 6 cycloalkyl, CN, -COOH, -COO-d_ 3 alkyl, -CON(-d_ 3 alkyl), - N0 2 , -S0 2 d_ 3 alkyl, -S0 2 N-d_ 3 alkyl, -CO-d_ 3 alkyl.
  • d-4 refers that there are 1 to 4 carbon atoms in the chain.
  • C 1 -4 alkyl refers to an alkyl chain having 1 to 4 carbon atoms.
  • cycloalkyl denotes a non-aromatic mono, multicyclic, bridged multicyclic or spiromulticyclic ring system.
  • the cycloalkyl ring may consist of 3 to about 13 carbon atoms, unless specified otherwise.
  • Monocyclic rings include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • Examples of simple multicyclic cycloalkyl groups include perhydronapththyl, perhydroindenyl etc; bridged multicyclic groups include adamantyl and norbornyl etc, and spiromulticyclic groups for e.g., spiro(4,4)non-2-yl.
  • all cycloalkyl groups described or claimed herein may be unsubstituted or substituted with groups selected from halogen, -Od-6 alkyl, -OC3-6 cycloalkyl, CN, -COOH, -COO-d_ 3 alkyl, -CON(-d_ 3 alkyl), -N0 2 , -S0 2 d_ 3 alkyl, -S0 2 N- Ci-3 alkyl, -CO-Ci -3 alkyl.
  • heterocycloalkyl refers to a cycloalkyl ring containing one or more heteroatoms. Unless specifically specified, the heteroatom is selected from nitrogen, oxygen and sulfur.
  • C4-6 heterocycloalkyl refers to a cyclic ring containing 4 to 6 atoms.
  • aryl as used herein, include aromatic ring containing 5 to 10 carbon atoms, unless specified otherwise.
  • the non-limiting examples of aryl group are phenyl and naphthyl.
  • heteroaryl as used herein, include an aryl group containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur.
  • heteroaryl group examples include oxazolyl, isoxazolyl, imidazolyl, furyl, pyrrolyl, triazolyl, triazinyl, tetrazoyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzopyranyl, quinolinyl, isoquinolinyl, quinazolinyl
  • heterocyclic refers to substituted or unsubstituted non- aromatic 3 to 15 membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from nitrogen, oxygen and sulfur.
  • the heterocyclic ring radical may be a mono-, bi- or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states.
  • the nitrogen atom may be optionally quarternized; also, unless otherwise constrained by the definition the heterocyclic ring may optionally contain one or more olefinic bond(s).
  • heterocyclic ring radicals include, but are not limited to azepinyl, azetidinyl, benzodioxolyl, benzodioxanyl, chromanyl, dioxolanyl, dioxaphospholanyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, oxadiazolyl, 2-oxopiperazinyl, 2- oxopiperidinyl, 2-oxopyrrolidinyl, 2- oxoazepinyl, octahydroindolyl, octahydroisoindolyl, perhydroazepinyl, piperazinyl, 4- piperidonyl, pyrrolidinyl, piperidinyl, phenothiazinyl, phenoxazinyl, quinuclidinyl, tetrahydrois
  • heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
  • all heterocyclic groups described or claimed herein may be unsubstituted or substituted with groups selected from halogen, -OCi-6 alkyl, -OC3-6 cycloalkyl, CN, -COOH, -COO-C1-3 alkyl, -CON(-d_ 3 alkyl), -N0 2 , -S0 2 C!_ 3 alkyl, -SOaN-Q.s alkyl, -CO-d_ 3 alkyl.
  • alkenyl refers to a hydrocarbon chain containing at least one carbon-carbon double bond, and may have (E) or (Z) configuration.
  • An alkenyl group may contain 2 to 8 carbon atoms unless specified otherwise.
  • Non-limiting examples of alkenyl groups include 2- propenyl (allyl), 2-methyl-2-propenyl, and (Z)-2-butenyl.
  • alkenyl groups described or claimed herein may be straight chain or branched, unsubstituted or substituted with groups selected from halogen, -OCi_6 alkyl, -OC 3 _6 cycloalkyl, CN, -COOH, -COO-d_ 3 alkyl, -CON(-d_ 3 alkyl), -N0 2 , -S0 2 d_ 3 alkyl, -S0 2 N- Ci-3 alkyl, -CO-C1-3 alkyl.
  • alkynyl refers to a hydrocarbon chain having at least one carbon-carbon triple bond.
  • alkynyl group may contain 2 to 8 carbon atoms unless specified otherwise.
  • Non- limiting examples of alkynyl groups include 2-propynyl and 3-butynyl. Unless set forth or recited to the contrary all alkynyl groups described or claimed herein may form part of a straight or branched, substituted or unsubstituted chains.
  • the alkynyl group may be unsubstituted or substituted with the groups selected from halogen, -OCi_6 alkyl, -OC 3 _6 cycloalkyl, CN, -COOH, -COO-d_ 3 alkyl, -CON(-d_ 3 alkyl), -N0 2 , -S0 2 d_ 3 alkyl, -S0 2 N- Ci-3 alkyl, -CO-d_ 3 alkyl.
  • halo as used herein includes chloro, fluoro, bromo and iodo.
  • haloalkyl refers to halo substituted alkyl chain.
  • cycloalkenyl refers to a non-aromatic monocyclic or bicyclic, 3 to 14 membered cycloalkyl ring system, which is unsaturated.
  • Representative examples of cycloalkenyl include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl and cyclohexenyl.
  • carboxyxlic refers to a saturated or unsaturated ring containing 3 to 13 carbon atoms, unless specified otherwise.
  • carboxyxlic ring are cycloalkyl and cycloalkenyl rings as defined earlier in the specification.
  • the present invention provides a compound of Formula I
  • Rj is selected from a group consisting of C 1 -4 alkyl, C 3 _i 4 cycloalkyl, phenyl, Cs_6 heteroaryl containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulfur, C 4 _6 heterocycloalkyl containing 1 or 2 heteroatoms selected from oxygen, nitrogen, or sulfur; Ri is optionally further substituted with Ci_ 4 alkyl, C 3 _7 cycloalkyl, phenyl, Cs_6 heteroaryl containing 1 to 3 heteroatoms selected from oxygen, nitrogen orsulfur, and C 4 _6 heterocycloalkyl containing 1 or 2 heteroatoms selected from oxygen, nitrogen, or sulfur.
  • Rj is selected from a group consisting of Ci_ 4 alkyl and C3_i 4 cycloalkyl.
  • Ri is a cycloalkyl or heterocycloalkyl forming moieties as represented
  • Rj is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In a preferred embodiment, Rj is cyclobutyl.
  • R2 in the compound of Formula I is either absent or selected from a group consisting of C 1 -4 alkyl, C3_7 cycloalkyl, NH, N(Ci_3 alkyl). In another embodiment, R2 is absent.
  • R 3 and R4 are independently selected from hydrogen, C2-6 hydroxyalkyl, C2-6 haloalkyl and Ci-4 alkyl optionally substituted with C3-6 cycloalkyl.
  • R 3 and R 4 are independently selected from hydrogen and Ci_ 4 alkyl.
  • R 3 and R ⁇ are independently selected from hydrogen and methyl.
  • R5 is selected form a group consisting of hydrogen, Ci-6 alkyl, C3-6 cycloalkyl, C2-5 alkenyl, C2-5 alkynyl, C(0)d_ 6 alkyl, C(0)C 3 - 6 cycloalkenyl, C(S)d_ 6 alkyl, C(S)C 3 - 6 cycloalkyl, SO2Q-6 alkyl, -CHO, C(S)C 3 _ 6 cycloalkenyl and CN.
  • R 5 is selected from a group consisting hydrogen, Ci-6 alkyl, C3-6 cycloalkyl, C(0)Ci-6 alkyl, C(0)C 3 -6 cycloalkenyl, C(S)d_ 6 alkyl, C(S)C 3 - 6 cycloalkyl, S0 2 d_6 alkyl, -CHO and CN.
  • R5 is selected from a group consisting of hydrogen, Ci_6 alkyl, C(0)C3_6 cycloalkenyl, C(S)C ! _ 6 alkyl, C(S)C 3 _ 6 cycloalkyl, S0 2 C ! _ 6 alkyl, -CHO and CN.
  • R6 is selected from a group consisting hydrogen, Ci_6 alkyl, Ci_6 haloalkyl, C 3 _6 cycloalkyl, CN, S0 2 d_ 6 alkyl, S0 2 C 3 - 6 cycloalkyl, C(0)OH, C(0)0 d_ 6 alkyl and C(0)NRioRii wherein Rio and Rn are independently selected from Ci-6 alkyl or Rio and Rn together with the nitrogen atom to which they are attached form a 4 to 7 membered heterocyclic ring.
  • R7, Rg, R9 are independently selected from a group consisting of hydrogen, Ci_6 alkyl, halogen, C 3 _6 cycloalkyl, Ci_6 haloalkyl, C 3 _6 halocycloalkyl, Ci_6 hydroxyalkyl, C 3 _6 hydroxycycloalkyl, Ci-e alkyl-0-C 3 - 6 cycloalkyl, CN, C(0)NRi 2 Ri 3 , (CH 2 ) n C(0)NRi 2 Ri 3 , Ci-e cyanoalkyl, C(0)OH, C(0)OCi_ 6 alkyl, (CH 2 ) n C(0)OH, (CH 2 ) n C(0)0 Ci_ 6 alkyl, (CH 2 ) n NRi 2 Ri 3 , C 4 _7 heterocycloalkyl containing 1 or 2 heteroatoms wherein the heteroatom is selected from oxygen, sulfur or N(Ri 4 ); wherein n is an integer selected from 0 to
  • Rg and R taken together forms a bond or a 3 to 6 membered carbocyclic ring.
  • R J2 and R 13 are independently selected from hydrogen, Ci_6 alkyl or R 12 and R 13 together with the nitrogen atom to which they are attached forms a 4 to 7 membered heterocyclic ring.
  • R 14 is selected from hydrogen, Ci_6 alkyl, C 3 _6 cycloalkyl, Ci_6 haloalkyl, Ci_6 hydroxyalkyl, Ci_6 alkyl-0-Ci_6 alkyl, Ci_6 aminoalkyl and C 3 _6 cycloalkyl-0-Ci_6 alkyl; wherein the alkyl and the cycloalkyl groups are optionally substituted with 5 or 6 membered heterocycle containing 1 or 2 heteroatoms selected from oxygen, sulfur and nitrogen.
  • X, Y and Z at each occurrence are independently selected from CH or N. Hal is a halogen.
  • EWG is selected from a group consisting of C(0)OR 15 , C(0)N(R 15 ) 2 , CN, N0 2 , S0 3 H, S02N(Rj5)2 and SO2R 1 5 wherein RJS is selected from hydrogen, Ci_3 alkyl and C 4 _6 cycloalkyl.
  • R5 is selected form a group consisting of hydrogen, Ci-6 alkyl, C3-6 cycloalkyl, C(0)d_ 6 alkyl, C(0)C 3 - 6 cycloalkenyl, C(S)d_ 6 alkyl, C(S)C 3 - 6 cycloalkyl, S02Ci_6 alkyl, -CHO and CN.
  • R5 is a moiety selected from the
  • R6 is selected from a group consisting of hydrogen, Ci_6 alkyl, Ci_6 haloalkyl, C3_6 cycloalkyl, CN and R 7 , Rg, R9, are independently selected from a group consisting of hydrogen, Ci_6 alkyl, halogen, Ci_6 haloalkyl, Ci_6 hydroxyalkyl, CN, Ci_6 cyanoalkyl. lowing groups
  • R6 is selected from a group consisting hydrogen, Ci_6 alkyl, Ci_6 haloalkyl, CN and R7, Rg, R9, are independently selected from a group consisting of hydrogen, Ci_6 alkyl, halogen, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl. Rs and R9 taken together forms a bond or a 4 to 6 membered carbocyclic ring.
  • R5 is a moiety selected from the following groups
  • I3 ⁇ 4 is selected from a group consisting hydrogen, and CN;
  • R 7 , Rg, R9, are independently selected from a group consisting of hydrogen, Ci-6 alkyl and halogen. Alternatively, Rg and R taken together form a bond.
  • Rg and R taken together forms a bond to form an alkynyl group.
  • Rg and R9 taken together forms a 3 to 6 membered carbocyclic ring i.e. a cycloalkenyl ring.
  • the examples of 5 or 6 membered heterocycloalkyl ring include piperidine, pyrazole, pyrrolidine, morpholine, piperazine etc.
  • R2 and R 3 along with the carbon atom and the nitrogen atom to which they are attached, respectively, form a 4 to 7 membered cyclic ring thus forming a re
  • R2 and R 3 together forms a 5 to 6 membered ring.
  • Rj and R3 together form a five membered
  • R 4 and R2 together with the intermediate groups form a 5 to 7 ound represented by the following structure
  • R 2 and R4 together form a five or six membered ring.
  • Rin A is a heterocycle selected from moieties provided in Figure-2
  • Q is selected from CH or nitrogen.
  • Rj6 and R 17 together form a phenyl ring optionally substituted with halogen, -0-Ci_3 alkyl, - COOH, -COOd_ 3 alkyl, -C 1-3 alkyl, -OH;
  • Rj6 and R 17 together form a 5 or 6 membered heterocyclic ring containing 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur;
  • V is selected from R 18 , halogen, -Ci_ 4 haloalkyl, -C2 alkenyl, -C2-4 alkynyl, -SRis, -ORis, - SOR 18 , -SO2R 1 8, -N(R 18 ) 2 , -NHCHO, -NHCOCH3, -C 4 - 6 heterocycloalkyl, -C 4 - 6 cycloalkenyl, -CO-R18, -CN and -CHO wherein Rjg at each occurrence is independently selected from hydrogen, -Ci_ 4 alkyl and -Cj,.(, cycloalkyl;
  • V is selected from R 18 , -C 1 -4 haloalkyl and halogen, wherein Rjg is selected from hydrogen, -C 1 -4 alkyl and -C3-6 cycloalkyl in another embodiment V is selected from Ris and halogen wherein R 18 is selected from hydrogen, -d-4 alkyl and - -6 cycloalkyl In preferred embodiment ring A is selected from
  • Q is nitrogen and V is selected from hydrogen and halogen.
  • R 19 is one or more groups selected from hydrogen, halogen, hydroxyl, -N(Ci_6 alkyl) 2 , -NH(d-6 alkyl), -d-6 haloalkyl, -C 2 - 6 alkenyl, -C 2 - 6 alkynyl, -Od-6 alkyl, -O ⁇ , alkenyl, -OC 3 - 6 alkynyl,-Sd-6 alkyl, -CN, -C(0)C 1 alkyl, -C(0)C 3 - 6 cycloalkyl, -C(0)OH, - C(0)NH 2 , -C(0)N(d- 6 alkyl) 2 , -C(0)NH(d- 6 alkyl), -NHC(0)d- 4 alkyl, -N(Ci-4 alkyl)C(0)Ci alkyl.
  • R 19 is -OC 3 _ 6 alkenyl or -OC _ 6 alkynyl,
  • Yi, Y 2 , Y 3 and Y 4 are independently selected from CH, NR 2 o, O, or S; wherein, R 2 o is either absent or selected from hydrogen, -d- 3 alkyl and -C4-6 cycloalkyl;
  • r is an integer selected from 1 to 3.
  • ' ⁇ ' represents the position of attachment to ring A and '[' represents the position of attachment to W.
  • R 9 is one or more groups selected from hydrogen, halogen, hydroxyl, -Ci_6 haloalkyl, -OCi_6 alkyl, -SCi_6 alkyl, -CN, -C(0)d_4 alkyl, -C(0)C 3 - 6 cycloalkyl and -C(0)OH.
  • R 19 is selected from hydrogen, halogen, and -OCi_6 alkyl.
  • ring B is phenyl or pyridyl and is optionally substituted with halogen, -OCi_6 alkyl, hydroxyl, -Ci_6 haloalkyl and -Ci_6 alkyl group, preferably with halogen.
  • Yj and Y2 are independently selected from CH, nitrogen and oxygen.
  • Yj and Y2 are nitrogen.
  • W is selected from a group consisting of -0-, -S-, -NH- , -N(d_ 3 alkyl)-, -NCO(d_ 3 alkyl)-, -C(0)NH-, -OCH 2 - and -N(CH 2 CN)-.
  • W is selected from a group consisting of -0-, -S-, -NH-, -N(d-3 alkyl)-, -N(d-3 alkyl)C(O)-, -C(0)NH-, -OCH 2 - and -N(CH 2 CN)-.
  • D in compound of Formula I is a ring containing 5 to 13 membered aryl, fused aryl, heteroaryl, fused heteroaryl, saturated or unsaturated monocyclic, bicyclic or tricyclic carbocyclic ring containing 0-3 heteroatoms selected from nitrogen, oxygen and sulfur.
  • ring D is a 5 to 6 membered aryl or heteroaryl containing 1 to 2 heteroatom selected from nitrogen, oxygen and sulfur. More preferably, D is a ring selected from phenyl and pyridyl.
  • D is selected from a group consisting of - -Ci_6 alkyl, -Cj,-e cycloalkyl, -Cj,.(, cycloalkenyl, -C 1 -4 alkyl-0-Ci_4 alkyl, -C3_6 cycloalkyl-0-C2 alkyl, -C 1 -4 alkyl-0-C3_6 cycloalkyl, -C 1 -4 haloalkyl-0-Ci_4 alkyl, -C 1 -4 haloalkyl-S-Ci_4 alkyl and -C 1 -4 alkyl-S-Ci-4 alkyl.
  • D is selected from the group consisting -Ci_6 alkyl, -C3-6 cycloalkyl, -C1-4 alkyl-0-C2-4 alkyl, -C3-6 cyclolkyl-O-Ci-4 alkyl and -C1-4 alkyl-S-Ci-4 alkyl.
  • D is selected from a group consisting -Ci_6 alkyl, -C3_6 cycloalkyl, -Cj,.(, cycloalkenyl and -C 1 -4 alkyl-0-C2 ⁇ alkyl.
  • Group D can be unsubstituted or substituted with one or more groups, represented as R in the figure provided above, selected from halogen, hydroxyl, Ci_6 alkyl, -N(Ci_6 alkyl)2, -NH(Ci_6 alkyl), -Ci_6 haloalkyl, -C 2- 6 alkenyl, -C2-6 alkynyl, -OCi_6 alkyl, -OC3-6 cycloalkyl, -OC3-6 alkenyl, -OC 3 - 6 alkynyl,-SCi-6 alkyl, -CN, -C(0)C 1 alkyl, -C(0)C 3 - 6 cycloalkyl, -C(0)OH, - C(0)NH 2 , -C(0)N(d_ 6 alkyl) 2 , -C(0)NH(d_ 6 alkyl), -NHC(0)d_ 4 alkyl and -N(Ci_4 alkyl)C(
  • group D is substituted with one or more groups selected from halogen, hydroxyl, Ci_6 alkyl, -Ci_6 haloalkyl, -OCi_6 alkyl, -S-Ci_6 alkyl, -CN, - CO-C1 alkyl, -CO— C 3 _6 cycloalkyl and-COOH.
  • D is substituted with one or more groups selected from Ci_6 alkyl, Ci_6 haloalkyl, -0-Ci_6 alkyl and halogen.
  • D is substituted with one or more halogen.
  • group B, W and D taken together forms a 13 or 14 membered tricyclic fused heteroaryl ring which is unsubstituted or substituted with one or more groups selected from halogen, hydroxyl, Ci_6 alkyl, -N(Ci_6 alkyl)2, -NH(Ci_6 alkyl), -Ci_6 haloalkyl, - C2-6 alkenyl, -C 2-6 alkynyl, -OCi_6 alkyl, -OC 3 _6 cycloalkyl.
  • the examples of the 13 or 14 membered tricyclic fused heteroaryl ring can be dibenzo[Z?,(i]furan and 9H-carbazole, dibenzo[3 ⁇ 4,(i]thiophene.
  • T in the compound of Formula I is selected from oxygen or sulfur.
  • T is oxygen.
  • the compounds of the present invention can be used as selective agents as inhibitors of BTK either alone or in combination with other related kinases inhibitors, or any other appropriate drugs.
  • the compound of present invention finds use in treating cancer, particularly in haematological malignancies such as chronic lymphocytic leukaemia (CLL), mantle cell lymphoma (MCL), follicular lymphoma (FL) or even disorder such as diffused large B-cell lymphoma (DLBCL) etc., in which the activated B-cell need to be controlled or the proliferation needs to be down regulated.
  • CLL chronic lymphocytic leukaemia
  • MCL mantle cell lymphoma
  • FL follicular lymphoma
  • DLBCL diffused large B-cell lymphoma
  • Compounds of Formula I can be prepared by any suitable processes, for example, as provided
  • compound 1 is treated with a compound 2 to obtain compound 3.
  • Compound 3 can be condensed with an appropriately substituted hydrazine compound 4 to obtain compound 5.
  • the compound 5 can then be treated with a compound 6 to obtain compound of Formula I.
  • Representative compounds of Formula I are presented in Table 1.
  • STEP 3 This step was performed in analogous manner as described for synthesis of compound (X) (Example 3, step 2) starting from compound (XV) to get title compound (XVI).
  • step 1 This step was performed in analogous manner as described for synthesis of compound (XI) (example 4, step 1), starting from compound (VI) and compound (XVI) to get compound (XVII).
  • STEP 2 This step was performed in analogous manner as described for synthesis of compound (XII) (example 4, step 2), from compound (XVII) and hydrazine hydrate to get title compound (XVIII).
  • STEP 2 This step was performed in analogous manner as described for synthesis of compound (XII) (example 4, step 2), from compound (XXIII) and hydrazine hydrate to get title compound (XXIV).
  • Example 11 Preparation of 3-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-(i]pyrimidin-l- yl]cyclobutanecarboxylic acid(Compound (XXV)).
  • STEP 2 This step was performed in analogous manner as described in example 1 (step 1), from compound (XXX) and teri-butyl-ethylbromoacetate (XXXI) to afford compound (XXXII).
  • STEP 3 To a stirred solution of compound (XXXII, 55 g) in 1,4-dioxane (400 mL) was charged 25% aqueous ammonia (250 mL) . The reaction mass was autoclaved at 85+ 5°C for 16 hrs. The reaction mass was concentrated under reduced pressure and residue was filtered from water (100 mL). The wet cake was washed with water (40 mL) and suck dried in air.
  • Example 17 Preparation of N-[2-[4-amino-5-(4-phenoxyphenyl)pyrrolo[2,3-(f]pyrimidin-7- yl] acetyl] but-2-ynehydrazide (1.16). This compound was prepared in analogous manner as described for I.l (example 1, step 3), from compound (XXXVII) and acrylic acid to get title compound (1.16).
  • STEP 2 This step was performed in analogous manner as described for compound (XXXVII), from compound (XXXVIII) to get compound (XXXIX).
  • Example 21 Preparation of N-[2-[4-amino-2-chloro-5-(4-phenoxyphenyl)pyrrolo[2,3- (f]pyrimidin-7-yl]acetyl]prop-2-enehydrazide (1.24) This compound was synthesized in analogous manner as described in example- 14, from compound (XXXIX) and acryloyl chloride to get title compound 1.24.
  • STEP 1 This step was performed in analogous manner as described for synthesis of compound (IX), from cyclohexyl amine (XXXX) and 4-bromobenzoic acid (VII) to get compound (XXXXI).
  • STEP 2 This step was performed in analogous manner as described for synthesis of compound (X) from compound (XXXXI) to get compound (XXXXII).
  • STEP 3 This step was performed in analogous manner as described for synthesis of compound (XI), from compound (VI) and compound (XXXXII) to get compound (XXXXIII).
  • Example 23 Preparation of 4-[4-amino-l-[2-(2-but-2-ynoylhydrazino)-2-oxo-ethyl] pyrazolo[3,4-(i]pyrimidin-3-yl]-N-cyclohexyl-benzamide. (1.31)
  • STEP 2 This step was performed in analogous manner as described for synthesis of compound (X) (example 3, step 2), from compound (XXXXVII) to get compound (XXXXVIII).
  • Example 25 Preparation of 4-[4-amino-l-(2-hydrazino-2-oxo-ethyl)pyrazolo[3,4- d] pyrimidin-3 -yl] -N- [3 -(trifluoromethyl)phenyl] benzenesulf onamide (Compound (L)) .
  • STEP 1 This step was performed in analogous manner as described for synthesis of compound (XI) (example 4, step 1), from compound (VI) and compound (XXXXVIII), to get compound (XXXXIX).
  • STEP 2 This step was performed in analogous manner as described for synthesis compound (XII) (example 4, step 2), from compound (XXXXIX) and hydrazine hydrate get title compound (L).
  • Example 26 Preparation of 4-[4-amino-l-[2-oxo-2-(2-prope-2-enoxylhydrazino)ethyl]pyra zolo[3 ,4-(f ]pyrimidin-3-yl] -N- [3-(trifluoromethyl)phenyl] benzenesulfonamide(1.34).
  • Example 27 Preparation of eth l 2-(6-amino-2-chloro-purin-9-yl)acetate compound (LII).
  • STEP 1 This step was performed in analogous manner as described for synthesis of compound (XI), from compound (LII) and (4-phenoxyphenyl)boronic acid to get compound (LIII).
  • STEP-2 This step was performed in analogous manner as described for synthesis of compound (XII), from compound (LIII) and hydrazine hydrate to get title compound (LIV).
  • Example 29 Preparation of N'-[2-[6-amino-2-(4-phenoxyphenyl)purin-9-yl]acetyl]but-2- ynehydrazide (1.35)
  • Example 32 Preparation of N'-[2-[6-amino-2-[4-(2-methoxyethoxy)anilino]purin-9- yl] acetyl] but-2-ynehydrazide (1.37) This compound was prepared in analogous manner as described in example 18, from compound (LVII) and 2-butynoic acid to get title compound (1.37).
  • STEP-4 This step was performed in analogous manner as described for synthesis of compound (XI), from compound (LIX) and compound (LX) to give compound (LXI).
  • STEP-5 This step was performed in analogous manner as described for synthesis of compound (XII) from compound (LXI) and hydrazine hydrate to give title compound (LXII).
  • Example 34 Preparation of 3-[4-amino-3-(4-benzylxoyphenyl)pyrazolo[3,4-(i]pyrimidine-l- yl]-N'-but-2-ynoyl-cyclobutanecarbohydrazide (1.41).
  • Example 35 Preparation of 3-[6-amino-8-oxo-7-(4-phenoxyphenyl)purin-9-yl] cyclobutane carbohydrazide (Com ound (LXXI)).
  • STEP 2 This step was performed in analogous manner as described in US2013/0217880, from compound (LXVI) to get compound (LXVII).
  • STEP 3 This step was performed in analogous manner as described in US2013/0217880, from compound (LXVII) to get compound (LXVIII).
  • STEP 4 This step was performed in analogous manner as described in US2013/0217880, from compound (LXVIII) to get compound (LXIX).
  • STEP 5 This step was performed in analogous manner as described in US2013/0217880, From compound (LXIX) to get compound (LXX).
  • STEP 6 This step was performed in analogous manner as described for synthesis of compound (XII), from compound (LXX) and hydrazine hydrate to get title compound.
  • Example 36 Preparation of 3-[6-amino-8-oxo-7-(4-phenoxyphenyl)purin-9-yl]-N-but- 2ynoylcyclobutanecarbohydrazide (1.56).
  • STEP 1 This step was performed in analogous manner as described in example 18, from compound (XXV) and teri-butyl-2-methylcarbazate to get compound (LXXII).
  • STEP 2 To a stirred solution of compound (LXXII, 1 g) in 1,4-dioxane (5 mL) was added 4M HCI in 1,4-dioxane (5 mL) and stirred overnight at 50°C. Reaction mixture was concentrated under reduced pressure and triturated with diethyl ether to get title compound (LXXIII).
  • Example 38 Preparation of 3-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-(i]pyrimidin-l-yl]- N'-methyl-N'-prop-2-enoylcyclobutanecarbohydrazide (1.62).
  • STEP 1 This step was performed in analogous manner as described for synthesis of example 18, from compound (XXV) and teri-butyl N-(methylamino)carbamate to get compound (LXXIV).
  • STEP 2 This step was performed in analogous manner as described for synthesis of compound (LXXIII), from compound (LXXIV) to get title compound (LXXV).
  • Example 40 Preparation of 3-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-(i]pyrimidin-l-yl]- N'-but-2-ynoyl-N'-methyl-cyclobutanecarbohydrazide (1.63).
  • STEP 1 This step was performed in analogous manner as described for synthesis of compound (II), from compound (I) and ethyl 2-bromo-2-methylpropanoate to get compound (LXXVI).
  • STEP 2 This step was performed in analogous manner as described for synthesis of compound (III), from compound (LXXVI) and hydrazine hydrate to get title compound (LXXVII).
  • Example 42 Preparation of 2-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-(i]pyrimidin-l-yl]- 2-methyl-N-prop-2-enoyl-propanehydrazide (1.73).
  • Example 44 Preparation of 3-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-(i]pyrimidin-l-yl]- N'-(cyclopropanecarbonyl)cyclobutanecarbohydrazide (1.78).
  • STEP 1 This step was performed in analogous manner as described for synthesis of compound (XI), from compound (LX) and compound (LXVIII) (prepared as described in US2014/011819) to get compound (LXXIX).
  • STEP 2 This step was performed in analogous manner as described for synthesis of compound (XII), from compound (LXXIX) and hydrazine hydrate to get title compound (LXXX).
  • Example 46 Preparation of 3-[4-amino-3-(3-fluoro-4-isopropoxy-phenyl)pyrazolo[3,4- (f]pyrimidin-l-yl]-N'-but-2-ynoyl-cyclobutanecarbohydrazide (1.80).
  • Example 48 Preparation of 3-[4-amino-3-(6-ethoxy-2-naphthyl)pyrazolo[3,4-(i]pyrimidin-l- yl]cyclobutanecarbohydrazide (Compound (LXXXIII)).
  • step 1 This step was performed in analogous manner as described for synthesis of compound (XI) (example 4, step 1), from compound (LX) and compound (LXXXI) (prepared as described by Yan Shen, Medicinal Chemistry,2014,vol-10,no-5,pg 533-539) to get compound (LXXXII).
  • STEP 2 This step was performed in analogous manner as described for synthesis of compound (XII) (example 4, step 2), from compound (LXXXII) and hydrazine hydrate to get title compound (LXXXIII).
  • Example 49 Preparation of 3-[4-amino-3-(6-ethoxy-2-naphthyl)pyrazolo[3,4-(i]pyrimidin-l- yl] -N-but-2-ynoyl-cyclobutanecarbohydrazide (1.92).
  • Example 50 Preparation of 2-[(£T)-2-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phen l] vinyl] pyridine (Compound (LXXX VII)).
  • STEP 3 This step was performed in analogous manner as described for synthesis of compound (X) (Example 3, step 2), from compound (LXXXVI) to get title compound (LXXXVII)
  • Example 51 Preparation of l-(3-methylcyclobutyl)-3-[4-[(£T)-2-(2- pyrid l)vinyl]phenyl]pyrazolo[3,4-(f]pyrimidin-4-amine (Compound (LXXXIX)).
  • STEP 1 This step was performed in analogous manner as described for synthesis of compound (XI) (example 4, step 1), from compound (LX) and compound (LXXXVII) to get compound (LXXXVIII).
  • STEP 2 This step was performed in analogous manner as described for synthesis of compound (XII) (example 4, step 2), from compound (LXXXVIII) and hydrazine hydrate to get title compound (LXXXIX).
  • STEP 1 This step was performed according to process described in US2014/0155385 (intermediate- 1) to get compound (XCI).
  • STEP 2 This step was performed in analogous manner as described in US2014/0155385 (intermediate- 1) from compound (XCI) and mono-ethyl malonate to get compound (XCII).
  • STEP 3 This step was performed in analogous manner as described in US2014/0155385 (intermediate- 1) to get compound (XCIII).
  • STEP 4 This step was performed in analogous manner as described in US2014/0155385 (intermediate- 1) to get compound (XCIV).
  • STEP 5 This step was performed in analogous manner as described in WO2016109223 to get compound (XCV).
  • STEP 7 This step was performed analogous to synthesis of compound (XI) (example 4, step 1), from compound (XCVI) and (4-phenoxyphenyl)boronic acid to get compound (XCVII).
  • STEP 8 This step was performed analogous to synthesis of compound (XII) (example 4, step 2), from compound (XCVII) and hydrazine hydrate to get compound (XCVIII).
  • Example 54 Preparation of N'-[2-[8-amino-l-(4-phenoxyphenyl)imidazo[l,5-a]pyrazin-3- yl] acetyl] but-2-ynehydrazide. (1.106).
  • Table 2 provides the characterization data (proton NMR) of compound of Formula I.
  • BT (h) was incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 250 ⁇ KVEKIGEGTYGVVYK (Cdc2 peptide), 10 mM MgAcetate and [ ⁇ -33 ⁇ - ⁇ ] (specific activity approx. 500 cpm/pmol, concentration as required).
  • the reaction was initiated by the addition of the MgATP mix. After incubation for 40 minutes at room temperature, the reaction was stopped by the addition of 3% phosphoric acid solution. 10 ⁇ - of the reaction was then spotted onto a P30 filtermat and washed three times for 5 minutes with 75 mM phosphoric acid and once with methanol prior to drying and scintillation counting.
  • ITK (h) is incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 0.33 mg/mL myelin basic protein, 10 mM MgAcetate and [ ⁇ -33 ⁇ - ⁇ ] (specific activity approx. 500 cpm/pmol, concentration as required). The reaction is initiated by the addition of the MgATP mix. After incubation for 40 minutes at room temperature, the reaction is stopped by the addition of 3 % phosphoric acid solution. 10 iL of the reaction is then spotted onto a P30 filtermat and washed three times for 5 minutes in 75 mM phosphoric acid and once in methanol prior to drying and scintillation counting. The percentage inhibition for representative compounds of Formula I are provided below in table 3
  • A > 60 %
  • B 30-60 %
  • C ⁇ 30 % Inhibition at respective concentration.
  • test compounds The inhibitory activity of test compounds was evaluated in an enzyme assay employing the ADP-GloTM Platform. Briefly lOng of hBTK is pre-incubated with vehicle/test compound (varying concentrations) for 15 minutes in the reaction buffer (40mM Tris buffer pH 7.5 containing 20mM MgC12.6H20, 2mM MnC12, 0.05mM DTT and 0.1% BSA). The enzymatic reaction is initiated by addition of 0 ⁇ g of substrate Poly (Glu4, Tyrl) with 15 ⁇ ultrapure ATP. After incubation of 30 minutes, ADP-GloTM Reagent is added and incubated for 40 minutes at room temperature to terminate the kinase reaction and deplete the remaining ATP.
  • reaction buffer 40mM Tris buffer pH 7.5 containing 20mM MgC12.6H20, 2mM MnC12, 0.05mM DTT and 0.1% BSA.
  • the enzymatic reaction is initiated by addition of 0 ⁇ g of substrate Poly (Glu4,
  • Kinase detection reagent is added to and the reaction is further continued for 30 minutes at room temperature.
  • the kinase detection reagent converts the ADP to ATP and the ATP generated is measured in luminescence mode in a micro plate reader.
  • the luminescence in the control is compared to that of the test compound treated sample to determine the inhibitory activity of the compound.
  • test compounds The inhibitory activity of test compounds was evaluated in an enzyme assay employing the ADP-GloTM Platform. Briefly 5ng of hBTK (C481S) is pre-incubated with vehicle/test compound (varying concentrations) for 15 minutes in the reaction buffer ( 40mM Tris buffer pH 7.5 containing 20mM MgC12.6H20, 2mM MnC12, 0.05mM DTT and 0.1% BSA). The enzymatic reaction is initiated by addition of 0 ⁇ g of substrate Poly (Glu4, Tyrl) with 15 ⁇ ultrapure ATP. After incubation of 30 minutes, ADP-GloTM Reagent is added and incubated for 40 minutes at room temperature to terminate the kinase reaction and deplete the remaining ATP.
  • reaction buffer 40mM Tris buffer pH 7.5 containing 20mM MgC12.6H20, 2mM MnC12, 0.05mM DTT and 0.1% BSA.
  • the enzymatic reaction is initiated by addition of 0 ⁇ g of substrate
  • Kinase detection reagent is added to and the reaction is further continued for 30 minutes at room temperature.
  • the kinase detection reagent converts the ADP to ATP and the ATP generated is measured in luminescence mode in a micro plate reader.
  • the luminescence in the control is compared to that of the test compound treated sample to determine the inhibitory activity of the compound.
  • test compounds were evaluated in an enzyme assay employing the ADP-GloTM Platform. Briefly 6ng of hITK is pre-incubated with vehicle/test compound (varying concentrations) for 15 minutes in the reaction buffer (40mM Tris buffer pH 7.5 containing 20 mM MgCl 2 .6H 2 0, 2mM MnCl 2 , 0.05 mM DTT and 0.1 % BSA). The enzymatic reaction is initiated by addition of 0.5 ⁇ g of substrate Poly (Glu4, Tyrl) with 10 ⁇ ultrapure ATP. After incubation of 30 minutes, ADP-GloTM Reagent is added and incubated for 40 minutes at room temperature to terminate the kinase reaction and deplete the remaining ATP.
  • reaction buffer 40mM Tris buffer pH 7.5 containing 20 mM MgCl 2 .6H 2 0, 2mM MnCl 2 , 0.05 mM DTT and 0.1 % BSA.
  • the enzymatic reaction is initiated by addition
  • Kinase detection reagent is added to and the reaction is further continued for 30 minutes at room temperature.
  • the kinase detection reagent converts the ADP to ATP and the ATP generated is measured in luminescence mode in a micro plate reader.
  • the luminescence in the control is compared to that of the test compound treated sample to determine the inhibitory activity of the compound.
  • Percentage inhibition for the compound of Formula I when tested in enzyme assays on ADP- GloTM Platform for BTK wild type, BTK (C481S) mutant and ITK are provided in table 4.
  • Table 4 Graded percentage inhibition BTK(h), BTK (C48 IS) mutant and ITK tested in enzyme assay by ADP-GloTM Platform

Abstract

La présente invention concerne de nouveaux composés contenant de l'hydrazide utilisés comme inhibiteurs de la tyrosine kinase de Bruton, leur procédé de préparation, et l'utilisation desdits composés dans la préparation de compositions pharmaceutiques pour le traitement thérapeutique de troubles impliquant une médiation de la tyrosine kinase de Bruton chez l'homme.
PCT/IN2017/050268 2016-06-30 2017-06-30 Nouveaux composés contenant de l'hydrazide utilisés comme inhibiteurs de btk WO2018002958A1 (fr)

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WO2020188015A1 (fr) 2019-03-21 2020-09-24 Onxeo Molécule dbait associée à un inhibiteur de kinase pour le traitement du cancer
WO2021011428A1 (fr) * 2019-07-12 2021-01-21 Gb005, Inc. Inhibiteurs de kinase hétérocycliques
WO2021038540A1 (fr) 2019-08-31 2021-03-04 Sun Pharma Advanced Research Company Limited Acides cycloalkylidènecarboxyliques et dérivés en tant qu'inhibiteurs de la btk
WO2021089791A1 (fr) 2019-11-08 2021-05-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes pour le traitement de cancers qui ont acquis une résistance aux inhibiteurs de kinase
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof
WO2021148581A1 (fr) 2020-01-22 2021-07-29 Onxeo Nouvelle molécule dbait et son utilisation
WO2022140246A1 (fr) 2020-12-21 2022-06-30 Hangzhou Jijing Pharmaceutical Technology Limited Procédés et composés destinés à l'autophagie ciblée

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US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof
WO2020188015A1 (fr) 2019-03-21 2020-09-24 Onxeo Molécule dbait associée à un inhibiteur de kinase pour le traitement du cancer
WO2021011428A1 (fr) * 2019-07-12 2021-01-21 Gb005, Inc. Inhibiteurs de kinase hétérocycliques
WO2021038540A1 (fr) 2019-08-31 2021-03-04 Sun Pharma Advanced Research Company Limited Acides cycloalkylidènecarboxyliques et dérivés en tant qu'inhibiteurs de la btk
CN111018865A (zh) * 2019-10-17 2020-04-17 山东大学 1-取代苄基吡唑并嘧啶衍生物及其制备方法与应用
CN111018865B (zh) * 2019-10-17 2021-01-15 山东大学 1-取代苄基吡唑并嘧啶衍生物及其制备方法与应用
WO2021089791A1 (fr) 2019-11-08 2021-05-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes pour le traitement de cancers qui ont acquis une résistance aux inhibiteurs de kinase
WO2021148581A1 (fr) 2020-01-22 2021-07-29 Onxeo Nouvelle molécule dbait et son utilisation
WO2022140246A1 (fr) 2020-12-21 2022-06-30 Hangzhou Jijing Pharmaceutical Technology Limited Procédés et composés destinés à l'autophagie ciblée

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