WO2017134685A2 - Nouveaux composés hydrazino utilisés comme inhibiteurs de btk - Google Patents

Nouveaux composés hydrazino utilisés comme inhibiteurs de btk Download PDF

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WO2017134685A2
WO2017134685A2 PCT/IN2017/050048 IN2017050048W WO2017134685A2 WO 2017134685 A2 WO2017134685 A2 WO 2017134685A2 IN 2017050048 W IN2017050048 W IN 2017050048W WO 2017134685 A2 WO2017134685 A2 WO 2017134685A2
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alkyl
nitrogen
ring
group
hydrogen
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WO2017134685A3 (fr
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V.S.N. Murty KADIYALA
Virendra Narendra RAUT
Pratit SAVANT
Chetana Kaushal SHETH
Umesh Vishnu CHAUDHARI
Rajendrasinh Jashvantsinh RATHOD
Tushar Bhupendrabhai BHATT
Trinadha Rao Chitturi
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Sun Pharma Advanced Research Co Ltd
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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

Definitions

  • the present invention relates to novel hydrazino 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 provides a compound of Formula I and pharmaceutically acceptable salts thereof
  • Rj is selected from a group consisting of hydrogen, -C 1 -4 alkyl, -C3 alkenyl, -C3 alkynyl, -C 1 -4 haloalkyl, -C2-4 haloalkenyl, -C3 haloalkylalkynyl, -C 1 -4 cyanoalkyl, -C2-4 cyanoalkenyl, -C2 cyanoalkynyl, -C2-5 O-alkyl, -C2-5 O-haloalkyl, -Cj,.(, cycloalkyl, -C 4 _6 heterocycloalkyl containing 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur and when the heteroatom is nitrogen it is optionally further substituted with -C 1 -4 alkyl or -CO-Q_ 4 alkyl group; and when Rj is alkenyl or alkynyl, the double and triple bond, respectively, is not on
  • R2 is selected from hydrogen, -Ci_ 4 alkyl, -C3 alkenyl, -C3_ 4 alkynyl, -C 1 -4 haloalkyl, -C2 haloalkenyl, -C3_ 4 haloalkylalkynyl, -C 1 -4 cyanoalkyl, -C2-4 cyanoalkenyl, -C2 cyanoalkynyl, - C2-5 O-alkyl, -C 2 - 5 O-haloalkyl, -C 3 - 6 cycloalkyl, -CN, -C(0)R 5 , -C(S)R 5 , -S0 2 R 5 , -SOR5, - CONHSO2R5, -CSNHSO2R5, -CONHCOR5, -CSNHCOR5, -CON(d_ 4 alkyl)COR 5 , , - C(S)N(Ci-4 al
  • Rs and R are independently selected from hydrogen, Ci-6 alkyl, C2-6 alkenyl, C3-7 cycloalkyl or Rg and R together forms 4 to 10 membered mono or bicyclic carbocyclic ring optionally substituted with one or more Ci_3 alkyl group or a 5 to 6 membered heterocyclic ring containing 1 to 2 heteroatoms selected from oxygen, nitrogen, or sulfur and when the heteroatom is nitrogen it is optionally further substituted with -C 1 -4 alkyl or -CO-C 1 -4 alkyl group;
  • EWG is an electron withdrawing group selected from -COOR 1 0, -CON(Rio) 2 , -CN, -NO2, - SO3H, -S0 2 N(Rio) 2 , -SO2R 1 0 wherein Rjo is selected from hydrogen, -Ci_3 alkyl and -C 4 _6 cycloalkyl;
  • T is a heteroatom selected from oxygen, nitrogen, or sulfur and when the heteroatom is nitrogen it is optionally further substituted with -Ci_ 4 alkyl or -CO-Ci_ 4 alkyl group; p is an integer selected from 1 and 2;
  • EWG2 is an electron withdrawing group selected from -COOR 1 5, -CON(Rj5)2, -CN, -NO2, - SO 3 H, -S02N(Rj5)2, -SO2R 1 5 wherein RJS at each occurrence is independently selected from hydrogen, -Ci_3 alkyl and -C 4 _6 cycloalkyl; q is an integer selected from 1 and 2;
  • R3 and R 4 are independently selected from hydrogen, halogen, Ci_6 alkyl and C3-6 cycloalkyl; ring P is 4 to 13 membered saturated or unsaturated monocyclic, bicyclic or tricyclic ring optionally containing one additional heteroatom selected from oxygen, nitrogen and sulfur; ring A is a heterocycle selected from moieties provided in Figure 3
  • Q is selected from CH or nitrogen
  • Rj6 and R 17 together forms a phenyl ring optionally substituted with halogen, -0-Ci_3 alkyl, - COOH, -COOd_ 3 alkyl, -C 1-3 alkyl, -OH; or Rj6 and R 17 together forms a 5 to 6 membered heterocyclic ring containing 1 to 2 heteroatoms selected from oxygen, nitrogen and sulfur; V independently selected from R 18 , halogen, -C 1 -4 haloalkyl, -C2-4 alkenyl, -C2 alkynyl, - SR18, -OR18, -SORig, -SO2R18, -N(R 18 ) 2 , -NHCHO, -NHCOCH3, -C 4 - 6 hetrocycloalkyl, -C 4 _ 6 cycloalkenyl, -CO-Ris, -CN and -CHO wherein Ris at each occurrence is independently selected from hydrogen,
  • R 19 is selected from hydrogen, halogen, hydroxyl, -N(Ci_6 alkyl)2, -NH(Ci_6 alkyl), - Cj_6 haloalkyl, -C 2- 6 alkenyl, -C 2-6 alkynyl, -Od-6 alkyl, -O d-6 alkenyl, -O d-6 alkynyl,-S- Ci-6 alkyl, -CN, -CO-C1-4 alkyl, -CO— C3-6 cycloalkyl, -COOH, -CONH 2 , -CON(d-6 alkyl) 2 , - CONH(d_6 alkyl), -NHC(O) -d-4 alkyl, -N(C 1 alkyl)C(O) d-4 alkyl and when R 19 is -OC 3 - 6 alkenyl or -O d-6 alkynyl the double and triple bond, respectively,
  • Yi, Y 2 , Y3 and Y 4 are independently and appropriately selected from CH, NR2 0 , O, or S; wherein, R20 is selected from hydrogen, -C 1 -3 alkyl and -d-6 cycloalkyl;
  • r is an integer selected from 1 to 3;
  • D 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; optionally substituted with d_3 alkyl; or D is selected from -d-6 alkyl, -C3-6 cycloalkyl, -C1-4 alkyl-O-d ⁇ alkyl, -C3-6 cyclolkyl-O- d- 4 alkyl, -C1-4 alkyl-0-C3_6 cycloalkyl, -d_ 4 haloalkyl-O-d ⁇ alkyl, -C1-4 haloalkyl-S-d-4 alkyl and -C 1 -4 alkyl-S-C2- 4 alkyl; with the proviso that when:
  • ring B and D are phenyl
  • Z is selected from -0-, -S-, -NH-, -N(d_4 alkyl)- or -C(O)-;
  • Ring A is selected from
  • R 2 is not selected from -C(0)R 5 , -C(S)R 5 , -S0 2 R 5 , -SOR 5 wherein R 5 is R y ;
  • 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, oxalacetic, 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-ch
  • 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.
  • the numerical in phrases like "C1-4 alkyl" refers that there are 1 to 4 carbon atoms in the alky chain.
  • 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- d_ 3 alkyl, -CO-d_ 3 alkyl.
  • alkynyl refers to a hydrocarbon chain having at least one carbon-carbon triple bond.
  • An 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, -Od_6 alkyl, -Od_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 haloalkeny and haloalkyny refers to halo substituted alkyl, alkenyl and alkynyl chain, respectively.
  • cycloalkyl denotes a non-aromatic mono-, or multicyclic ring system of 3 to about 13 carbon atoms.
  • Monocyclic rings include, but are not limited to cylcopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • Examples of simple multicyclic cycloalkyl groups include perhydronapththyl, perhydroindenyl etc; bridged multicyclic groups include adamantyl and norbornyl etc, and spriromulticyclic groups for e.g., spiro(4,4)non-2-yl.
  • heterocycloalkyl refers to a cycloalkyl ring containing a heteroatom. Unless specifically specified, the heteroatom is selected from N, O and S.
  • cycloalkenyl refers to a monocyclic or bicyclic, 3 to 14 membered ring system, which is unsaturated.
  • Representative examples of cycloalkenyl include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl and cyclohexenyl.
  • alkenylaryl and “alkynylaryl” refers to alkeny and alkynyl group, respectively, are further substituted with an aryl group.
  • alkenylheteroaryl and “alkynylheteroaryl” refers to akenyl chain is substituted with a heteroaryl group.
  • aryl as used herein, include aromatic mono or bi-cyclic compound having 5-10 atoms which may be optionally fused with a cycloalkyl ring.
  • aryl group are phenyl and naphthyl.
  • heteroaryl refers to an aryl group containing 1-4 heteroatoms. Unless specifically specified, the heteroatom is selected from N, O and S.
  • the non-limiting examples of heteroaryl group are oxazolyl, isoxazolyl, imidazolyl, furyl, pyrrolyl, triazolyl, triazinyl, tetrazoyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzopyranyl, quinolinyl, isoquinolinyl, quinazolinyl, pyrazolo[3,4-(f]pyrimidin and pyrrolo [2 , 3 -d] pyrimidin .
  • heterocyclic or “heterocyclyl” unless otherwise specified 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, phosphorus, 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 or heterocyclyl may optionally contain one or more olefinic bond(s) thus forming heterocycloalkenyl group.
  • 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, tetrahydroisquino
  • 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. Unless set forth or recited to the contrary, all heterocyclyl groups described or claimed herein may be substituted or unsubstituted.
  • heterocycloalkenylalkyl refers to alky chain substituted with a heterocycloalkenyl ring.
  • the present invention provides a compound of Formula I and pharmaceutically acceptable salts thereof
  • Ri is selected from a group consisting of hydrogen, -C 1 -4 alkyl, -C 3 alkenyl, -C 3 alkynyl, -Q_ 4 haloalkyl, -C2-4 haloalkenyl, -C 3 haloalkylalkynyl, -C 1 -4 cyanoalkyl, -C2-4 cyanoalkenyl, -C2 cyanoalkynyl, -C2-5 O-alkyl, -C2-5 O-haloalkyl, -Cj,.(, cycloalkyl, -C 4 _6 heterocycloalkyl containing 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur and when the heteroatom is nitrogen it is optionally further substituted with -C 1 -4 alkyl or -CO-Ci_ 4 alkyl group; and when Rj is alkenyl or alkynyl, the double and triple bond, respectively, is not on the
  • R2 is selected from hydrogen, -Ci_ 4 alkyl, -C 3 alkenyl, -C 3 _ 4 alkynyl, -C 1 -4 haloalkyl, -C2-A haloalkenyl, -C 3 _ 4 haloalkylalkynyl, -C 1 -4 cyanoalkyl, -C2-4 cyanoalkenyl, -C2 cyanoalkynyl, - C2-5 O-alkyl, -C 2 - 5 O-haloalkyl, -C 3 - 6 cycloalkyl, -CN, -C(0)R 5 , -C(S)R 5 , -S0 2 R 5 , -SOR5, - CONHSO2R5, -CSNHSO2R5, -CONHCOR5, -CSNHCOR5, -CON(d_ 4 alkyl)COR 5 , - C(S)N(Ci-4
  • Rs and R are independently selected from hydrogen, d-6 alkyl, -6 alkenyl, C 3 - 7 cycloalkyl or Rg and R together forms 4 to 10 membered mono or bicyclic carbocyclic ring optionally substituted with one or more d_ 3 alkyl group or a 5 to 6 membered heterocyclic ring containing 1 to 2 heteroatoms selected from oxygen, nitrogen, or sulfur and when the heteroatom is nitrogen it is optionally further substituted with -C 1 -4 alkyl or -CO-d_4 alkyl group;
  • EWG is an electron withdrawing group selected from -COOR 10 , -CON(R J O) 2 , -CN, -N0 2 , S0 3 H, -S0 2 N(R J O) 2 , -S0 2 Rio wherein Rjo is selected from hydrogen, -d_ 3 alkyl and -C 4 cycloalkyl;
  • T is a heteroatom selected from oxygen, nitrogen, or sulfur and when the heteroatom nitrogen it is optionally further substituted with -d-4 alkyl or -CO-d_ 4 alkyl group; p is an integer selected from 1 and 2;
  • Rj3 and R 14 are independently selected from hydrogen, Ci_6 alkyl, C 2 _6 alkenyl, C3_7 cycloalkyl or Ri 3 and Ri 4 together forms 4 to 10 membered mono or bicyclic carbocyclic ring or a 5 to 6 membered heterocyclic ring containing 1 to 2 heteroatoms selected from oxygen, nitrogen, or sulfur and when the heteroatom is nitrogen it is optionally further substituted with -Ci_ 4 alkyl or -CO-C1 alkyl group;
  • EWG 2 is an electron withdrawing group selected from -COOR 1 5, -CON(R 15 ) 2 , -CN, -N0 2 , - SO 3 H, -S0 2 N(Ri5) 2 , -S0 2 Ri5 wherein R15 at each occurrence is independently selected from hydrogen, -Ci_3 alkyl and -C 4 _6 cycloalkyl; q is an integer selected from 1 and 2;
  • R3 and R 4 are independently selected from hydrogen, halogen, Ci_6 alkyl and C3_6 cycloalkyl;
  • ring P is 4 to 13 membered saturated or unsaturated monocyclic, bicyclic or tricyclic ring optionally containing one additional heteroatom selected from oxygen, nitrogen and sulfur;
  • ring A is a heterocycle selected from moieties provided in Figure 3
  • Q is selected from CH or nitrogen
  • Rj6 and R 17 together forms a phenyl ring optionally substituted with halogen, -0-Ci_3 alkyl, - COOH, -COOd_ 3 alkyl, -C 1-3 alkyl, -OH; or Rj6 and R 17 together forms a 5 to 6 membered heterocyclic ring containing 1 to 2 heteroatoms selected from oxygen, nitrogen and sulfur; V independently selected from R 18 , halogen, -C 1 -4 haloalkyl, -C2-4 alkenyl, -C2 alkynyl, - SR18, -OR18, -SORig, -SO2R18, -N(R 18 ) 2 , -NHCHO, -NHCOCH3, -C 4 - 6 hetrocycloalkyl, -C 4 _ 6 cycloalkenyl, -CO-Ris, -CN and -CHO wherein Rjg at each occurrence is independently selected from hydrogen,
  • R 19 is selected from hydrogen, halogen, hydroxyl, -N(Ci_6 alkyl)2, -NH(Ci_6 alkyl), - Cj_6 haloalkyl, -C 2- 6 alkenyl, -C 2-6 alkynyl, -Od-6 alkyl, -O d-6 alkenyl, -O d-6 alkynyl,-S- Ci-6 alkyl, -CN, -CO-C1-4 alkyl, -CO— C3-6 cycloalkyl, -COOH, -CONH 2 , -CON(d-6 alkyl) 2 , - CONH(d_6 alkyl), -NHC(O) -d-4 alkyl, -N(C 1 alkyl)C(O) d-4 alkyl and when R 19 is -OC 3 - 6 alkenyl or -O d-6 alkynyl the double and triple bond, respectively, is not
  • Yi, Y 2 , Y3 and Y 4 are independently and appropriately selected from CH, NR2 0 , O, or S; wherein, R20 is selected from hydrogen, -C 1 -3 alkyl and -d-6 cycloalkyl;
  • r is an integer selected from 1 to 3;
  • D 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; optionally substituted with d_3 alkyl; or D is selected from -d-6 alkyl, -C3-6 cycloalkyl, -C1-4 alkyl-O-d ⁇ alkyl, -C3-6 cyclolkyl-O- d- 4 alkyl, -C1-4 alkyl-0-C3_6 cycloalkyl, -d_ 4 haloalkyl-O-d ⁇ alkyl, -C1-4 haloalkyl-S-d-4 alkyl and -C 1 -4 alkyl-S-C2- 4 alkyl; with the proviso that when:
  • ring B and D are phenyl
  • Z is selected from -0-, -S-, -NH-, -N(d_4 alkyl)- or -C(O)-;
  • Ring A is selected from
  • R 2 is not selected from -C(0)R 5 , -C(S)R 5 , -S0 2 R 5 , -SOR 5 wherein R 5 is R y ;
  • the present invention provides a compound of Formula I; wherein
  • Rj is hydrogen
  • R 2 is selected from -CN, -C(0)R 5 , -C(S)R 5 , -S0 2 R 5 wherein,
  • R5 is selected from a group comprising Ry, -Ci_6 alkyl, -C3-6 cycloalkyl, -Ci_3 heterocycloalkenylalkyl, NH C6-10 aryl, Cs_io heteroaryl containing 1-3 heteroatoms selected from oxygen, nitrogen or sulfur, wherein
  • alkyl and cycloalkyl are optionally further substituted with CN group; and aryl, heteroaryl and heterocycloalkenylalkyl are optionally substituted with one or more halogen;
  • n is an integer and at each occurrence is selected from 0 to 3;
  • R 6 is selected from hydrogen, -Ci_3 alkyl; or R 2 is a 6 membered heteroaryl ring substituted with at least one group selected from halogen, C3-6 alkenyl, C3-6 alkynyl and -SH group; and optionally further substituted with one or more groups selected from S-C 2 ⁇ alkenyl, -COOH, -OCi_ 6 alkyl, -CON(-Ci_ 3 alkyl), -N0 2 and -CONH 2 ; or R 2 is a group selected from following moieties
  • Rs and R9 are independently selected from hydrogen and Ci-6 alkyl, or Rs and R9 together forms 4 to 10 membered mono-cyclic ring optionally substituted with one or more d_3 alkyl group;
  • EWG is-C(0)Od_ 3 alkyl
  • Rn and Rj2 are independently selected from hydrogen, Ci_6 alkyl, C2-6 alkenyl, - COOR and -C 4 _6 heteroaryl containing 1-3 heteroatoms selected from oxygen, nitrogen or sulfur; wherein R is hydrogen or Ci_6 alkyl and the heteroaryl is optionally substituted with one or more halogen atoms; or Rn and Rj2 together forms substituted or unsubstituted 5 to 6 membered saturated or unsaturated mono carbocyclic ring or a 5 to 6 membered heterocyclic ring containing 1 to 2 heteroatoms selected from oxygen and nitrogen; and the carbocyclic and the heterocyclic rings are optionally further substituted with one or more halogen atoms;
  • ring P is 4 to 6 membered saturated monocyclic, ring containing one additional heteroatom selected from nitrogen;
  • ring A is a heterocycle selected from followin moieties
  • Q is selected from CH or nitrogen
  • ring B is phenyl
  • Z is selected from -0-, -C(0)NH- and -NHC(O)-;
  • D is phenyl or pyridine ring unsubstituted or substituted with Ci_3 alkyl.
  • the present invention provides a compound of Formula I, wherein Rj is hydrogen; R2 is -C(0)Rs or a 6 membered heteroaryl ring substituted with one or more halogen radical;
  • R2 is a group selected from following moieties wherein, Rg and R are independently selected from hydrogen and Ci_6 alkyl, or Rg and R together forms 4 to 10 membered mono-cyclic ring optionally substituted with one or more Ci-3 alkyl group;
  • EWG is-C(0)Od_ 3 alkyl
  • ring A is a heterocycle selected from following moieties.
  • 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
  • the compounds of present invention can be prepared by any of the following me
  • PG represents an amino protecting group such as a Boc, Fmoc or CBZ which can be cleaved easily under acidic, basic or neutral conditions to the substituted hydrazines of interest.
  • L is leaving group such as halogen or a alkyl-sulfonate.
  • cyclic amines represented by (i) are treated with alkali nitrites under acidic condition or by the use of an alkyl nitrite, to obtain the nitroso derivatives such as (ii), which on further reduction results in some of the hydrazines of interest as in (iii).
  • Hydrazines (iii) can also be prepared by direct displacement of a leaving group (LG) on nitrogen such as mesylate, tosylate, brosylate, triflates or nonaflates to give protected hydrazino derivatives such as (iv) which on deprotection render compounds represented by (iii) as depicted in Method B
  • hydrazines are prepared by treatment of acyclic compounds such as (v) with mono-N-protected hydrazides to obtained directly the cyclic product represented by (iv) which on de -protection under suitable conditions result in required hydrazines (iii).
  • the hydrazines of Formula iii can be converted into compound of Formula I by reacting them
  • LG-R and/or LG-R groups wherein LG is a leaving group are optionally substituted with LG-R and/or LG-R groups wherein LG is a leaving group.
  • 'A' ring as a pyrazinopyrimidine can be prepared by a sequence starting with condensation of melanonitrile with properly substituted acid chlorides and the condensation product on treatment with hydrazines can give the cyclized amino-pyrazoles as shown.
  • pyrazolo compound on treatment with formaldehyde and ammonia results in the central A ring of requirement.
  • 'A' ring as a starting material can be elaborated to the required hydrazines by functional transformations as outlined in Scheme-3.
  • 'L' can be a hydroxyl group which participate in Mitsunobu reaction to form C-N bond.
  • the halogenated derivative can further be elaborated by treating with a boronate under Suzuki coupling condition to obtain the skeletons of the requirement which can be transformed to the hydrazines of choice.
  • 'A' ring is an imidazole -pyrazine envisioned can be synthesized as er the brief Scheme-4 outlined hereunder.
  • a commercially available 2-chloro-3-cyanopyrazole can be reduced either by known hydrogenation method or by involving reducing agents such as lithium aluminium hydride to convert into an amine which can be treated with an acid chloride or appropriately activated acid to form an amide bond as shown in Scheme-4.
  • the amide intermediate can be ring closed to obtain the 'A' ring as an imidazole-pyrazine scaffold of choice.
  • 'A' ring can be modified as pyrazolo- pyrimidine or pyrazolo-pyridine scaffolds which are differently disposed from the earlier described embodiments.
  • chlorofluropyrimidine or chlorofluropyridine can be acylated with suitable acid chloride moiety and then treated with hydrazine to form the scaffold of interest. Further elaboration can result in some of the hydrazines of current interest.
  • the 'A' ring scaffold can be modified to a 2-imidazalone fused
  • Bz in Scheme-6 is a benzyl group which may be substituted of unsubstituted.
  • the A-ring can be synthesized by successive substitutions with different amines of choice followed by the reduction of the nitro group to obtain a 1,2- diamino function which can be ring closed to form the urea linkage by either CDI or 4- nitrophenyl chloroformate.
  • These intermediates can be further elaborated by a Suzuki or by Buchwald coupling methods to obtain the needed disposition of groups and the hydrazines of choice.
  • the linkage of the groups is not confined to one of the fused heterocyclic rings such as pyrazole or imidazole but can be viewed as a substituents attached in both the rings as given in some of the scaffolds of Figure-3.
  • Scheme-7 given below outlines the synthesis of such hyrdrazines.
  • substituted dichloropurine can be functionalized to obtain the required hydrazine in few steps.
  • Hydrazines prepared as per the above methods described in Scheme- 1 to Scheme-7 can be treated with suitable electrophilic compounds to afford the compounds of Formula I.
  • Some of the representative electrophilic compounds are provided in Figure-5.
  • the electrophilic compound may require some functional modifications depending upon the type .
  • Ar in Figure-5 is an aryl group and Het.Ar is a heteroaryl group.
  • R a and R are independently H, alkyl Ci_6, cycloalkyl Cj,.(,-
  • the hydrazines prepared as per the process provided in Scheme- 1 to Scheme-7 were treated with aromatic electrophiles.
  • Some of the representative aromatic electrophilic compounds are provided in Figure-6.
  • the aromatic electrophilic compound may also require some functional modifications depending upon the type of the substitution on them and such modifications are under the purview of a person skilled in the art.
  • the hydrazines prepared according to the methods described above can be treated with substrates containing aldehydes and ketones containing either saturated or unsaturated functionalities as condensing agents to obtain the compound of Formula I.
  • substrates containing aldehydes and ketones containing either saturated or unsaturated functionalities as condensing agents to obtain the compound of Formula I.
  • Representative aldehydes and ketones are provided in Figure-7.
  • hydrazines prepared according to the methods described above can be treated with 1,3 diketones, 1,3 ketoesters or 1,2 ketoesters to afford compound of Formula I having ene- amide, ene-ester etc. linked substitution.
  • the representative 1,3 diketones, 1,3 ketoesters or 1,2 ketoesters are provided in Figure-8
  • Example 1 fert-Butyl N-(4-hvdroxy-l-piperidyl)carbamate
  • THF 100 mL
  • RB bottom
  • triethylamine 16.4 mL
  • Boc 21.4 mL
  • the content of the flask was concentrate under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was subjected to column chromatography to afford the title compound as an off-white solid.
  • Example 5 l-Nitrosopiperidin-4-ol To a cold (0-10 °C) and stirred solution of 4-hydroxypiperidine (50 g, 0.49 mole) in a mixture of 300 ml water and acetic acid (45 g, 0.741 mole), sodium nitrite (68.2 g, 0.99 mole) was added and the mixture was stirred for 1-2 h at ambient temperature. The reaction mixture was quenched with sodium carbonate extracted with ethyl acetate and the organic layer was concentrated to obtain title compound as off white solid.
  • 4-hydroxypiperidine 50 g, 0.49 mole
  • acetic acid 45 g, 0.741 mole
  • sodium nitrite 68.2 g, 0.99 mole
  • Example 8 jV-(4-Methyl-pyridin-2-yl)-4-(4,4,5,5-tetramethviri,3,21dioxaborolan-2-yl)- benzamide (8-6)
  • Example 15 l-Cyano-cyclopropanecarboxylic acid ⁇ 4-r4-amino-3-(4-phenoxy-phenyl)- Pyrazolor3,4- ⁇ flpyrimidin-l-vnpiperidine-l-yl)-amide 1.11:
  • Example 18 4-ri-(l-Acryloylamino-piperidine-4-yl)-4-amino-iH-pyrazolo-r3,4- ⁇ flpyrimidine-3-vn-jV-(5-methyl-pyridin-2-yl)-benzamide 1.33
  • N,N-Dibenzyl-6-chloro-5-nitro-pyrimidin-4-amine (18g) and teri-butyl 4-aminopiperidine-l- carboxylate (15.15 g) were dissolved in dioxane (90.0 mL). Triethylamine (10.5 mL) was added and the mixture was stirred for 16 hours at 60 °C. The reaction mixture was cooled to room temperature and the solvent was distilled off. Residue was extracted with ethyl acetate and the organic layer was washed with water, saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate.
  • Example 21 fert-Butyl 4-rr5-amino-6-(dibenzylamino)pyrimidin-4-vnamino1piperidine- 1-carboxylate (9.4)
  • Example 26 6-Amino-9-(l-nitroso-4-piperidyl)-7-(4-phenoxyphenyl)purin-8-one (9.9)
  • a solution of sodium nitrite (0.42 g) in water (10 mL) was added drop-wise into a solution of compound 9.8 (1.0 g) in acetic acid (15.0 mL) at low temperature (-5 to 0 C) and stirred at room temperature for 6 hours.
  • the solvent was distilled off from the reaction mixture, water was added, and the extraction with ethyl acetate was performed.
  • the organic layer was washed with saturated aqueous sodium chloride solution then dried over anhydrous sodium sulfate, and the solvent was distilled off.
  • the residue was purified by silica gel column chromatography to obtain the title compound (0.8 g) as an off-white solid.
  • Example 28 N- ⁇ 4- ⁇ 6- Amino-8-oxo-7-(4-phenoxyphenyl)purin-9- yll - 1 -piperidyll -3- (2,5- dioxopyrrol-l-yl)propanamide (1.39)
  • Example 35 7-(l-amino-4-piperidyl)-2-chloro-5-(4-phenoxyphenyl)pyrrolor2,3- ⁇ flpyrimidin-4-amine (10.8)
  • Example 36 ⁇ V-[4-f4-amino-2-chloro-5-(4-phenoxyphenyl)pyrrolo[2,3- ⁇ /
  • BTK (h) was incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA. 250 ⁇ VEKJGEGTYG V V YK (Cdc2 peptide), 10 mM MgAcetate and [ ⁇ -33 ⁇ - ⁇ ] (specific activity approx. 500 cprn/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. 1 0 ⁇ . 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.
  • the compounds of present invention showed more than 50 % inhibition of BTK at 100 nM.
  • Table 2 provides percentage inhibition at 10 nM and 100 nM for few representative compounds in radioligand binding assay.

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Abstract

La présente invention concerne de nouveaux composés hydrazino de Formule (I) utilisés comme inhibiteurs de tyrosine kinase de Bruton, leur procédé de préparation, et l'utilisation des 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/IN2017/050048 2016-02-02 2017-02-02 Nouveaux composés hydrazino utilisés comme inhibiteurs de btk Ceased WO2017134685A2 (fr)

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WO2020028258A1 (fr) 2018-07-31 2020-02-06 Loxo Oncology, Inc. Dispersions et formulations séchées par pulvérisation de (s)-5-amino-3-(4-((5-fluoro-2-méthoxybenzamido) méthyle)phényle)-1-(1,1,1-trifluoropropane-2-yl)-1 h-pyrazole-4-carboxamide
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
WO2020239103A1 (fr) * 2019-05-31 2020-12-03 四川海思科制药有限公司 Dérivé de cycle inhibiteur de btk, son procédé de préparation et son application pharmaceutique
EP3643716A4 (fr) * 2017-06-22 2021-03-31 Shanghai Dude Medical Technology Co., Ltd Composé hétéroaryle ayant une activité pharmaceutique
WO2022111448A1 (fr) * 2020-11-25 2022-06-02 四川海思科制药有限公司 Procédé de préparation d'un agent de dégradation de btk
WO2022111447A1 (fr) * 2020-11-25 2022-06-02 四川海思科制药有限公司 Procédé de préparation d'un agent de dégradation de btk
WO2023023537A1 (fr) * 2021-08-17 2023-02-23 Endotarget Inc. Composés et méthodes pour la dégradation ciblée de la tyrosine kinase de bruton

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DK2526933T3 (en) * 2006-09-22 2015-05-18 Pharmacyclics Inc Inhibitors of Bruton's tyrosine kinase
WO2013177668A1 (fr) * 2012-05-31 2013-12-05 Pharmascience, Inc. Inhibiteurs de protéine kinases
CA2782774A1 (fr) * 2012-07-06 2014-01-06 Pharmascience Inc. Inhibiteurs de proteine kinase

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EP3643716A4 (fr) * 2017-06-22 2021-03-31 Shanghai Dude Medical Technology Co., Ltd Composé hétéroaryle ayant une activité pharmaceutique
WO2020028258A1 (fr) 2018-07-31 2020-02-06 Loxo Oncology, Inc. Dispersions et formulations séchées par pulvérisation de (s)-5-amino-3-(4-((5-fluoro-2-méthoxybenzamido) méthyle)phényle)-1-(1,1,1-trifluoropropane-2-yl)-1 h-pyrazole-4-carboxamide
WO2020239103A1 (fr) * 2019-05-31 2020-12-03 四川海思科制药有限公司 Dérivé de cycle inhibiteur de btk, son procédé de préparation et son application pharmaceutique
US11542266B1 (en) 2019-05-31 2023-01-03 Haisco Pharmaceuticals Pte. Ltd. Substituted piperidines as BTK inhibitors
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
WO2022111448A1 (fr) * 2020-11-25 2022-06-02 四川海思科制药有限公司 Procédé de préparation d'un agent de dégradation de btk
WO2022111447A1 (fr) * 2020-11-25 2022-06-02 四川海思科制药有限公司 Procédé de préparation d'un agent de dégradation de btk
CN116568679A (zh) * 2020-11-25 2023-08-08 四川海思科制药有限公司 一种btk降解剂的制备方法
WO2023023537A1 (fr) * 2021-08-17 2023-02-23 Endotarget Inc. Composés et méthodes pour la dégradation ciblée de la tyrosine kinase de bruton
US12139492B2 (en) 2021-08-17 2024-11-12 Endotarget Inc. Substituted pyrimidines for the targeted degradation of Bruton's tyrosine kinase

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