WO2013157021A1 - Composés bicycliques, compositions et applications médicinales de ceux-ci - Google Patents

Composés bicycliques, compositions et applications médicinales de ceux-ci Download PDF

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WO2013157021A1
WO2013157021A1 PCT/IN2013/000257 IN2013000257W WO2013157021A1 WO 2013157021 A1 WO2013157021 A1 WO 2013157021A1 IN 2013000257 W IN2013000257 W IN 2013000257W WO 2013157021 A1 WO2013157021 A1 WO 2013157021A1
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phenyl
methyl
pyrrolo
pyrimidin
carboxamide
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PCT/IN2013/000257
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English (en)
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Mahesh THAKKAR
Summon Koul
Debnath Bhuniya
Umesh SINGH
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Advinus Therapeutics Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • 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 disclosure relates to a class of substituted hetero-bicyclic compounds of formula (I), their tautomers, polymorphs, stereoisomers, prodrugs, solvates, hydrates, N-oxides, co-crystals, pharmaceutically acceptable salts and pharmaceutical compositions containing them.
  • the disclosure also relates to the process of preparation of compounds of formula (I).
  • Btk Bruton's tyrosine kinase
  • inflammatory and/or autoimmune disorder cell proliferation, rheumatoid arthritis, psoriasis, psoriatic arthritis, transplant rejection, graft-versus-host disease, multiple sclerosis, inflammatory bowel disease, allergic diseases, asthma, chronic obstructive pulmonary disease (COPD), type 1 diabetes, myasthenia gravis, hematopoetic disfunction, B-cell malignancies, systemic lupus erythematosus, non-Hodgkin's lymphoma, chronic lymphocytic leukemia, Mantle cell lymphoma or other disorders.
  • Btk Bruton's tyrosine kinase
  • Bruton's tyrosine kinase belongs to tyrosine kinases, a subfamily of protein kinases that phosphorylate protein on the phenolic moiety of tyrosine residue. It is a non-receptor cytoplasmic tyrosine kinase and a key regulator for B-cell development, activation, signaling and survival (Schaeffer and Schwartzberg, Curr. Op. Imm. 2000, 282; Niiro and Clark, Nature Rev. Immumol. 2002, 945; Di Paolo and Currie, Nat. Chem. Biol. 2011, 7).
  • Btk is expressed in all hematopoietic cell types, excluding plasma cells, T lymphocytes and natural killer cells. After activation by upstream B-cell antigen receptor or Toll like receptor-4, Btk induces PLC-y2 phosphorylation, which ultimately results in activation of nuclear factor ⁇ (NFKB) and nuclear factor of activated T cell dependent pathways.
  • NFKB nuclear factor ⁇
  • Btk is crucial for number of other hematopoetic cell signaling; such as, Fcy-mediated inflammatory cytokine production (such as TNF-a, IL1 ⁇ and IL6) in monocytes/macrophages, IgE mediated signaling in mast cells, inhibition of Fas/APO-1 apoptotic signaling in B-lineage lymphoid cells etc (Jeffries et al. J. Biol. Chem. 2003, 26258; Horwood et al., J. Experimental Med. 2003, 1603).
  • Fcy-mediated inflammatory cytokine production such as TNF-a, IL1 ⁇ and IL6
  • IgE mediated signaling in mast cells IgE mediated signaling in mast cells
  • Fas/APO-1 apoptotic signaling in B-lineage lymphoid cells etc
  • B-cell depleting protein based therapeutics for example, Rituxan, a CD20 antibody
  • Btk is essential for B-cell activation, this also provides an indirect rational for the role of Btk in autoimmune and/or inflammatory diseases.
  • Btk deficient mice are resistant to develop collagen-induced arthritis (Jansson and Holmdahl Clin. Exp. Immumol. 1993, 459).
  • Btk inhibitors for example, (a) an irreversible Btk inhibitor (Pan et al, Chem. Med. Chem. 2007, 58), and (b) a reversible Btk inhibitor (Di Paolo, Nat. Chem. Biol. 2010, 41). Both the type of inhibitors have demonstrated efficacy in a mouse model of arthritis.
  • PCI-32765 an irreversible Btk inhibitor
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • Btk inhibitors with safer mechanism of action such as reversible mechanism of inhibition.
  • These compounds will have medical application in the disease area of inflammation, autoimmune disorder and cell proliferation, rheumatoid arthritis, psoriasis, psoriatic arthritis, transplant rejection, graft-versus-host disease, multiple sclerosis, inflammatory bowel disease, allergic diseases and asthma, type 1 diabetes, myasthenia gravis, hematopoetic disfunction, B-cell malignancies, systemic lupus erythematosus.
  • the present disclosure provides bicyclic compounds of formula (I), their tautomers, polymorphs, stereoisomers, prodrugs, solvates, hydrates, N-oxides, co-crystals, pharmaceutically acceptable salts, pharmaceutical compositions containing them and methods of treating conditions and diseases that are mediated by Btk activity
  • ring A represents a 5-7 membered ring which is unsaturated or partially unsaturated optionally having upto three heteroatom independently selected from ⁇ ,, ⁇ or S;
  • ring C, ring D and ring E are independently a monocyclic or a bicyclic ring system which is saturated, unsaturated or partially unsaturated and optionally have additional heteroatoms independently selected from O, N or S, said ring system is further optionally substituted with 1 to 4 substituents independently selected from halo, alkyl, alkenyl, alkynyl, nitro, cyano, - (CR a R b ) m OR 8 , -(CR a R b ) m SR 8 , -(CR a R b ) m NR 9 R 10 , oxo, alkylsulfonyl, -(CR a R b ) m COOR 8 , - (CR a R b ) m C(0)NR 9 R 10
  • X represents N or C (R 1 );
  • Y represents -C(O) or -S(0) p -;
  • M is selected from hydrogen, cyano, halogen, haloalkyl, perhaloalkyl, alkyl, alkenyl, alkynyl, cyanoalkyl, acyl, cyanoalkylarbonyl, cyanoalkenylcarbonyl, -(CR R b ) m OR 8 , -SR 8 , - (CR a R b ) m COOR 8 , -(CR a R b ) m NR 9 R 1 °, -(CR a R b ) m C(0)NR 9 R l ° -(CR a R b ) m NR 8 C(0)NR 9 R 10 thiocarbonyl, S(0) 2 NR 9 R 10 , -NR 8 S(0) 2 R 8 , -S(0) p R 8 , - S0 3 H, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloal
  • M is optionally substituted with one or more substituents independently selected from cyano, nitro, keto, oxo, halogen, haloalkyl, perhaloalkyl, hydroxyamino, -(CR a R b ) m OR 8 , - (CR a R b ) m C(0)R 8 , -OC(0)R 8 , -SR 8 , -(CR a R b ) m COOR 8 , -(CR a R ) m NR 9 R 10 , -(CR a R b ) m C(0)N R 9 R 10 -(CR a R b ) m NR 8 C(0)N R 9 R 10 -NR 8 C(0)R 8 , thiocarbonyl, -S(0) 2 N R 9 R 10 , -NR 8 S(0) 2 R 8 , - S(0) p R 8 , -S0 3 H, alkyl, alkenyl, alkynyl
  • alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl, heterocyclyl or heteroaryl are optionally substituted with one or more substituents selected from hydroxy, alkyl, alkoxy, alkoxyalkyl, halogen, haloalkyl, perhaloalkyl, cyano, cyanoalkyl, amino, carboxy, carboxyalkyl, -OC(0)R 8 , -(CR a R b ) m C(0)N R 9 R 10 , -NR 8 C(0)R 8 , -SR 8 , -S(0) p R 8 , - S(0) 2 N R 9 R 10 or -NR 8 S(0) 2 R 8 ;
  • U is a bond or is selected from the group consisting of cycloalkylene, cycloalkenylene, cycloalkylenecarbonyl, cycloalkylenealkoxy, cycloalkyleneamino, arylene, arylenecarbonyl, arylenealkoxycarbonyl, arylenealkoxycarbonylamino, aryleneaminocarbonyl, heterocyclylene, heterocyclylenealkyl, heterocyclylenecarbonyl, heterocyclylenealkylamino, heteroarylene, heteroarylenecarbonyl, heteroarylenealkylamino, (C]. 6 )alkylene, (Ci- )alkenylene or (Ci.
  • alkynylene wherein one or more than one methylene groups of alkylene, alkenylene or alkynylene are optionally replaced by hetero atoms or groups such as -0-, -S(0) p -, -N(R 8 )-, or -C(O);
  • T is selected from hydrogen, cyano, halogen, haloalkyl, perhaloalkyl, alkyl, alkenyl, alkynyl, cyanoalkyl, acyl, cyanoalkylarbonyl, cyanoalkenylcarbonyl, -(CR a R b ) m OR 8 , -SR 8 , (CR a R b ) m COOR 8 , -(CR a R b ) m N R 9 R 10 , -(CR a R b ) m C(0)NR 9 R 10 -(CR a R b ) m NR 8 C(0)NR 9 R 10 thiocarbonyl, S(0) 2 NR 9 R 10 , -NR 8 S(0) 2 R 8 , -S(0) p R 8 , -S0 3 H, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkyloxy,
  • U and T is optionally substituted with one or more substituents independently selected from cyano, nitro, keto, oxo, halogen, haloalkyl, perhaloalkyl, hydroxyamino, -(CR a R b ) m OR 8 , - (CR a R b ) m C(0)R 8 , -OC(0)R 8 , -SR 8 , -(CR a R b ) m COOR 8 , -(CR a R b ) m NR 9 R 10 ,
  • alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl, heterocyclyl or heteroaryl are optionally substituted with one or more substituents selected from hydroxy, alkyl, alkoxy, alkoxyalkyl, halogen, haloalkyl, perhaloalkyl, cyano, cyanoalkyl, amino, carboxy, carboxyalkyl, -OC(0)R 8 , -(CR a R b ) m C(0)N R 9 R 10 , -NR 8 C(0)R 8 , -SR 8 , -S(0) p R 8 , -
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, acyl, acylamino, acyloxy, -(CR a R b ) m C(0)R 8 , -(CR a R b ) m N R 9 R 10 , aminocarbonyl, alkoxycarbonylamino, alkylsulfonylamino, aminocarbonylamino, hydroxyamino, alkoxyamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, haloalkyl, perhaloalkyl, cycloalkyl, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy, -S0 3 H, alkylthio, aminosulfonyl,
  • R 8 is selected from the group consisting of hydrogen, -(CR A R B ) M OR 8 , halogen, haloalkyl, - (CR A R B ) M C(0)R 8 , alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl and heterocyclylalkyl;
  • alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl or heterocyclylalkyl are optionally substituted with one or more substituents selected from hydroxy, alkyl, alkoxy, alkoxyalkyl, halogen, haloalkyl, perhaloalkyl, cyano, cyanoalkyl, amino, carboxy, carboxyalkyl, -OC(0)R 8 , -(CR A R B ) M C(0)N R 9 R 10 , -NR 8 C(0)R 8 -SR 8 , -S(0) P R 8 , -S(0) 2 N R 9 R 10 or -NR 8 S(0) 2 R 8 ;
  • R 9 and R !0 are independently selected from the group consisting of hydrogen, -(CR A R B ) M OR 8 , haloalkyl, -(CR A R B ) M C(0)R 8 , alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl and heterocyclylalkyl, or
  • R 9 and R 10 taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms selected from O, N or S, said ring system is further optionally substituted with 1 to 4 substituents independently selected from halo, alkyl, alkenyl, alkynyl, nitro, cyano, -(CR A R B ) M OR 8 , -SR 8 , -(CR A R B ) M NR 9 R 10 , oxo, alkylsulfonyl, -(CR A R B ) M COOR 8 , -(CR A R B ) M C(0)N R 9 R'°, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;
  • R A and R B are independently selected from the group consisting of hydrogen, -OR 6 , halogen, haloalkyl, perhaloalkyl and alkyl;
  • R A and R B taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms selected from O, N or S;
  • n 0-6;
  • n 0 - 3;
  • p 0, 1 or 2;
  • q 1 or 2.
  • alkyl refers to a monoradical branched or unbranched saturated hydrocarbon chain having 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, preferably 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, more preferably 1 , 2, 3, 4, 5 or 6 carbon atoms.
  • This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, n-decyl, tetradecyl, and the like.
  • alkylene refers to a diradical of a branched or unbranched saturated hydrocarbon chain, having 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 1 1 ,12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, preferably 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, more preferably 1 , 2, 3, 4, 5 or 6 carbon atoms.
  • This term is exemplified by groups such as methylene (-CH 2 -), ethylene (- CH 2 CH 2 -), the propylene isomers (e.g., -CH 2 CH 2 CH 2 - and -CH(CH 3 )CH 2 -) and the like.
  • substituted alkyl or “substituted alkylene” refers to: 1) an alkyl group or alkylene group as defined above, having 1, 2, 3, 4 or 5 substituents, preferably 1 , 2 or 3 substituents, selected from the group consisting of alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, monoalkylamino, dialkylamino, arylamino, heteroarylamino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, keto, thiocarbonyl, carboxy, carboxyalkyl, -SO 3 H, aryl, aryloxy, heteroaryl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro,
  • substituents may optionally be further substituted by 1 , 2, or 3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and -S(0) p R c , where R c is alkyl, aryl, or heteroaryl and p is 0, 1 or 2; or 2) an alkyl group or alkylene group as defined above that is interrupted by 1 , 2, 3, 4, 5, 6, 7, 8, .
  • R d is selected from hydrogen, alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclyl, carbonylalkyl, carboxyester, carboxyamide and sulfonyl. All substituents may be optionally further substituted by alkyl, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, or -S(0) p R c , in. which R c is alkyl, aryl, or heteroaryl and p is 0, 1 , or 2;
  • an alkyl or alkylene as defined above that has 1 , 2, 3, 4 or 5 substituents as defined above, as well as interrupted by 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 atoms as defined above.
  • alkenyl refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, more preferably 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and even more preferably 2, 3, 4, 5 or 6 carbon atoms and having 1 , 2, 3, 4, 5 or 6 double bond (vinyl), preferably 1 double bond.
  • alkenylene refers to a diradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, more preferably 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and even more preferably 2, 3, 4, 5 or 6 carbon atoms and having 1 , 2, 3, 4, 5 or 6 double bond (vinyl), preferably 1 double bond.
  • substituted alkenyl refers to an alkenyl group as defined above having 1 , 2, 3, 4 or 5 substituents, and preferably 1, 2, or 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarboriylamino, azido, cyano, halogen, thiocarbonyl, carboxy, carboxyalkyl, S0 3 H, aryl, aryloxy, heteroaryl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, -S(0) 2 NR a R a , -NR a S(0) 2 R a and -S(0) p R b where each R a is independently selected from the group consisting of alkyl,
  • substituents may optionally be further substituted by 1 , 2, or 3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, and -S(0) p R c , where R c is alkyl, aryl, or heteroaryl and p is 0, 1 or 2.
  • alkynyl refers to a monoradical of an unsaturated hydrocarbon, preferably having from 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, more preferably 2, 3, 4, 5, 6,-7, 8, 9 or 10 carbon atoms and even more preferably 2, 3, 4, 5 or 6 carbon atoms and having 1 , 2, 3, 4, 5 or 6 sites of acetylene (triple bond) unsaturation, preferably 1 triple bond.
  • Preferred alkynyl groups include ethynyl, (-C ⁇ CH), propargyl (or prop-l-yn-3-yl,- CH 2 C ⁇ CH), homopropargyl (or but-l-yn-4-yl, -CH 2 CH 2 C ⁇ CH) and the like.
  • alkynylene refers to a diradical of a branched or an unbranched unsaturated hydrocarbon group preferably having from 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, more preferably 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and even more preferably 2, 3, 4, 5 or 6 carbon atoms and having 1, 2, 3, 4, 5 or 6 sites of acetylene (triple bond) unsaturation, preferably 1 triple bond.
  • substituted alkynyl refers to an alkynyl group as defined above having 1 , 2, 3, 4 or 5 substituents, and preferably 1 , 2, or 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, -SO3H, aryl, aryloxy, heteroaryl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, -S(0) 2 NR a R a , -NR a S(0) 2 R a and -S(0) p R b , where each
  • substituents may optionally be further substituted by 1 , 2, or 3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and-S(0) p R c where R° is alkyl, aryl, or heteroaryl and p is 0, 1 or 2.
  • cycloalkyl refers to unless otherwise mentioned, carbocyclic groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings or spirocyclic rings or bridged rings which may be saturated or partially unsaturated.
  • Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, 1 ,3,3- trimethylbicyclo[2.2.1]hept-2-yl, (2,3,3-trimethylbicyclo[2.2.1]hept-2-yl), or carbocyclic groups to which is fused an aryl group, for example indane, and the like.
  • cycloalkylene refers to a divalent cycloalkyl group as defined above. This term is exemplified by groups such as 1 ,4-cyclohexylene, 1 ,3-cyclohexylene, 1 ,2- cyclohexylene, 1 ,4-cyclohexenyl and the like.
  • substituted cycloalkyl refers to cycloalkyl groups having 1 , 2, 3, 4 or 5 substituents, and preferably 1, 2, or 3 substituents, selected from the group consisting of alkyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, -C(0)R and -S(0) p R b , where R is hydrogen, hydroxyl, alkoxy, alkyl and cyclocalkyl, heterocyclyloxy where R b is alkyl, aryl
  • substituents may optionally be further substituted by 1 , 2, or 3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, and-S(0) p R°, where R c is alkyl, aryl, or heteroaryl and p is 0, 1 or 2.
  • Halo or “Halogen”, alone or in combination with any other term means halogens such as chloro (CI), fluoro.(F), bromo (Br) and iodo (I).
  • Haloalkyl refers to a straight chain or branched chain haloalkyl group with 1 to 6 carbon atoms.
  • the alkyl group may be partly or totally halogenated.
  • Representative examples of haloalkyl groups include but are not limited to fluoromethyl, chloromethyl, bromomethyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, 3-fluoropropyl, 3-chloropropyl, 3-bromopropyl and the like.
  • alkoxy refers to the group R"'-0-, where R'" is optionally substituted alkyl or optionally substituted cycloalkyl, or optionally substituted alkenyl or optionally substituted alkynyl; or optionally substituted cycloalkenyl, where alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl are as defined herein.
  • alkoxy groups include but are not limited to methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n- pentoxy, n-hexoxy, 1 ,2-dimethylbutoxy, trifluoromethoxy, and the like.
  • aminocarbonyl refers to the group -C(0)NR'R ' where each R ' is independently hydrogen, alkyl, aryl, heteroaryl, heterocyclyl or both R' groups are joined to form a heterocyclic group (e. g. morpholino).
  • substituents may optionally be further substituted by 1 -3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, and -S(0) p R°, where R c is alkyl, aryl, or heteroaryl and p is 0, 1 or 2.
  • acylamino refers to the group -NR"C(0)R" where each R" is independently hydrogen, alkyl, aryl, heteroaryl, or heterocyclyl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, and-S(0) p R c , where R° is alkyl, aryl, or heteroaryl and p is 0, 1 or 2.
  • acyloxy refers to the groups -OC(0)-alkyl, -OC(0)-cycloalkyl, -OC(0)-aryl, - OC(0)-heteroaryl, and -OC(0)-heterocyclyl. Unless otherwise constrained by the definition, all substituents may be optionally further substituted by alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, or -S(0) p R c , where R c is alkyl, aryl, or heteroaryl and p is 0, 1 or 2.
  • Alkoxyalkyl refers to alkyl groups as defined above wherein at least one of the hydrogen atoms of the alkyl group is replaced by an alkoxy group as defined above.
  • Representative examples of alkoxyalkyl groups include but are not limited to methoxymethyl, methoxyethyl, ethoxymethyl and the like.
  • Aryloxyalkyl refers to the group -alkyl-O-aryl.
  • Representative examples of aryloxyalkyl include but are not limited to phenoxymethyl, naphthyloxymethyl, phenoxyethyl, naphthyloxyethyl and the like.
  • Di alkylamino refers to an amino group, to which two same or different straight chain or branched chain alkyl groups with 1 to 6 carbon atoms are bound.
  • Representative examples of di alkylamino include but are not limited to dimethylamino, diethylamino, methylethylamino, dipropylamino, dibutylamino and the like.
  • Cycloalkylalkyl refers to an alkyl radical as defined above which is substituted by a cycloalkyl radical as defined above.
  • Representative examples of cycloalkylalkyl include but are not limited to cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 1 - cyclopentylethyl, 1-cyclohexylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, cyclobutylpropyl, cyclopentylpropyl, cyclohexylbutyl and the like.
  • aminoalkyl refers to an amino group that is attached to (C
  • Representative examples of aminoalkyl include but are not limited to aminomethyl, aminoethyl, 1 -aminopropyl, 2-aminopropyl, and the like. The amino moiety of aminoalkyl may be substituted once or twice with alkyl to provide alkylaminoalkyl and dialkylaminoalkyl respectively.
  • alkylaminoalkyl include but are not limited to methylaminomethyl, methylaminoethyl, mefhylaminopropyl, ethylaminoethyl and the like.
  • Representative examples of dialkylaminoalkyl include but are not limited to dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, N-methyl-N-ethylaminoethyl and the like.
  • aryl refers to an aromatic carbocyclic group of 6 to 20 carbon atoms having a single ring (e.g. phenyl) or multiple rings (e.g. biphenyl), or multiple condensed (fused) rings (e.g. naphthyl or anthranyl).
  • Preferred aryls include phenyl, naphthyl and the like.
  • arylene refers to a diradical of an aryl group as defined above. This term is exemplified by groups such as 1 ,4-phenylene, 1 ,3-phenylene, 1 ,2-phenylene, l ,4'-biphenylene, and the like.
  • the aryl or arylene groups may optionally be substituted with 1 , 2, 3 4 or 5 substituents, preferably 1 , 2 or 3 substituents, selected from the group consisting of alkyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, carboxy, carboxyalkyl, - SO3H, aryl, aryloxy, heteroaryl, amino sulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, -S(0) 2 NR a R a , -NR a S(0) 2 R a and -S(0) p R b where each R a is independently selected from the group consisting of hydrogen, alkyl, cyclo
  • substituents may optionally be further substituted by 1 , 2 or 3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, and -S(0) p R c where R c is hydrogen, alkyl, aryl, or heteroaryl and p is 0, 1 or 2.
  • arylalkyl refers to an aryl group covalently linked to an alkylene group, where aryl and alkylene are defined herein.
  • Optionally substituted arylalkyl refers to an optionally substituted aryl group covalently linked to an optionally substituted alkylene group.
  • arylalkyl groups are exemplified by benzyl, phenethyl, naphthylmethyl, and the like.
  • aryloxy refers to the group aryl-O- wherein the aryl group is as defined above, and includes optionally substituted aryl groups as also defined above.
  • arylthio refers to the group -S-aryl, where aryl is as defined herein including optionally substituted aryl groups as also defined above.
  • substituted amino refers to the group -NR R' where each R ' is independently * selected from the group consisting of hydrogen, alkyl, cycloalkyl, carboxyalkyl, alkoxycarbonyl, aryl, heteroaryl and heterocyclyl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1 , 2 or 3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, and -S(0) p R c , where R c is alkyl, aryl, or heteroaryl and p is 0, 1 or 2.
  • carboxyalkyl refers to the groups -alkylene-C(0)OH.
  • alkylcarboxyalkyl refers to the groups -alkylene-C(0)OR d where R d is alkyl, cycloalkyl, where alkyl, cycloalkyl are as defined herein, and may. be optionally further substituted by alkyl, halogen, CF 3 , amino, substituted amino, cyano, or -S(0) p R c , in which R c is alkyl, aryl, or heteroaryl and p is 0, 1 or 2.
  • heteroaryl refers to an aromatic cyclic group having 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, or 15 carbon atoms and 1 , 2, 3 or 4 heteroatoms selected from oxygen, nitrogen and sulphur within at least one ring.
  • Such heteroaryl groups can have a single ring (e.g. pyridyl or furyl) or multiple condensed rings (e.g.
  • heteroaryls include, but are not limited to, [1 ,2,4] oxadiazole, [1 ,3,4] oxadiazole, [1,2,4] thiadiazole, [1 ,3,4] thiadiazole, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine,
  • heteroarylene refers to a diradical of a heteroaryl group as defined above. Unless otherwise constrained the heteroaryl or heterarylene groups can be optionally substituted with 1 , 2, 3, 4 or 5 substituents, preferably 1 , 2 or 3 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, thiocarbonyl, carboxy, carboxyalkyl, -S0 3 H, aryl, aryloxy, heteroaryl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, -S(0) 2 NR a R a , - NR
  • substituents may optionally be further substituted by 1-3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, and-S(0) n R c , where R c is alkyl, aryl, or heteroaryl and n is 0,1 or 2.
  • heteroarylalkyl refers to a heteroaryl group covalently linked to an alkylene group, where heteroaryl and alkylene are defined herein.
  • Optionally substituted heteroarylalkyl refers to an optionally substituted heteroaryl group covalently linked to an optionally substituted alkylene group.
  • Such heteroarylalkyl groups are exemplified by 3-pyridylmethyl, quinolin-8-ylethyl, 4-mefhoxythiazol-2-ylpropyl, and the like.
  • heterocyclyl refers to a saturated or partially unsaturated group having a single ring or multiple condensed rings or spirocyclic rings, or bridged rings unless otherwise mentioned, having from 1 to 40 carbon atoms and from 1 to 10 hetero atoms, preferably 1 , 2, 3 or 4 heteroatoms, selected from nitrogen, sulphur, phosphorus, and/or oxygen within the ring.
  • Heterocyclic groups can have a single ring or multiple condensed rings, and include tetrahydrofuranyl, morpholinyl, piperidinyl, piperazinyl, dihydropyridinyl, tetrahydroquinolinyl and the like.
  • heterocyclic groups can be optionally substituted with 1 , 2, 3, 4 or 5, and preferably 1 , 2 or 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, -C(0)R where R is hydrogen, hydroxyl, alkoxy, alkyl and cyclocalkyl, thiocarbonyl, carboxy, carboxyalkyl, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, b b
  • alkoxyamino, nitro, and -S(0) p R where R is hydrogen, alkyl, aryl, heterocyclyl or heteroaryl and p is 0, 1 or 2.
  • all substituents may optionally be further substituted by 1-3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, and -S(0)R c , where R c is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
  • heterocyclylalkyl refers to a heterocyclyl group covalently linked to an alkylene group, where heterocyclyl and alkylene are defined herein.
  • Optionally substituted heterocyclylalkyl refers to an optionally substituted heterocyclyl group covalently linked to an optionally substituted alkylene group.
  • heteroaryloxy refers to the group heteroaryl-O-.
  • thiol refers to the group -SH.
  • substituted alkylthio refers to the group -S-substituted alkyl.
  • heteroarylthio refers to the group -S-heteroaryl wherein the heteroaryl group is as defined above including optionally substituted heteroaryl groups as also defined above.
  • sulfoxide refers to a group -S(O).
  • Substituted sulfoxide refers to a group -S(0)R, in which R is substituted alkyl, substituted aryl, or substituted heteroaryl, as defined herein.
  • substituted sulfone refers to a group -S(0) 2 R, in which R is alkyl, aryl, or heteroaryl.
  • the compounds of the present disclosure may have the ability to crystallize in more than one form, a characteristic known as polymorphism, and all such polymorphic forms (“polymorphs”) are encompassed within the scope of the disclosure.
  • Polymorphism generally can occur as a response to changes in temperature or pressure or both, and can also result from variations in the crystallization process.
  • Polymorphs can be distinguished by various physical characteristics, and typically the x-ray diffraction patterns, solubility behavior, and melting point of the compound are used to distinguish polymorphs.
  • the compounds described herein may contain one or more chiral centers and/or double bonds and therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), regioisomers, enantiomers or diastereomers. Accordingly, the chemical structures depicted herein encompass all possible enantiomers and stereoisomers of the illustrated or identified compounds including the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) and enantiomeric and stereoisomeric mixtures.
  • stereoisomers such as double-bond isomers (i.e., geometric isomers), regioisomers, enantiomers or diastereomers.
  • Enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to the person skilled in the art.
  • the compounds may also exist in several tautomeric forms including the enol form, the keto form and mixtures thereof. Accordingly, the chemical structures depicted herein encompass all possible tautomeric forms of the illustrated or identified compounds.
  • Compounds may exist in unsolvated forms as well as solvated forms, including hydrated forms and as N-oxides. In general, compounds may be hydrated, solvated or N-oxides. Certain compounds may exist in multiple crystalline or amorphous forms. Also contemplated within the scope of the disclosure are congeners, analogs, hydrolysis products, metabolites and precursor or prodrugs of the compound. In general, unless otherwise indicated, all physical forms are equivalent for the uses contemplated herein and are intended to be within the scope of the present disclosure.
  • Prodrug refers to a derivative of a drug molecule as, for example, esters, carbonates, carbamates, ureas, amides or phosphates that requires a transformation within the body to release the active drug. Prodrugs are frequently, although not necessarily, pharmacologically inactive until converted to the parent drug. Prodrugs may be obtained by bonding a promoiety (defined herein) typically via a functional group, to a drug.
  • Promoiety refers to a group bonded to a drug, typically to a functional group of the drug, via bond(s) that are cleavable under specified conditions of use.
  • the bond(s) between the drug and promoiety may be cleaved by enzymatic or non-enzymatic means. Under the conditions of use, for example following administration to a patient, the bond(s) between the drug and promoiety may be cleaved to release the parent drug.
  • the cleavage of the promoiety may proceed spontaneously, such as via a hydrolysis reaction, or it may be catalyzed or induced by another agent, such as by an enzyme, by light, by acid, or by a change of or exposure to a physical or environmental parameter, such as a change of temperature, pH, etc.
  • the agent may be endogenous to the conditions of use, such as an enzyme present in the systemic circulation to which the prodrug is administered or the acidic conditions of the stomach or the agent may be supplied exogenously.
  • “Pharmaceutically acceptable salt” embraces salts with a pharmaceutically acceptable acid or base.
  • Pharmaceutically acceptable acids include both inorganic acids, for example hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic, hydroiodic and nitric acid and organic acids, for example citric, fumaric, maleic, malic, mandelic, ascorbic, oxalic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p- toluenesulphonic acid.
  • Pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides and organic bases, for example alkyl amines, arylalkyl amines and heterocyclic amines.
  • M- may be an anion of various mineral acids such as, for example, chloride, bromide, iodide, sulphate, nitrate, phosphate, or an anion of an organic acid such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulphonate and p-toluenesulphonate.
  • mineral acids such as, for example, chloride, bromide, iodide, sulphate, nitrate, phosphate
  • organic acid such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulphonate and p-toluenesulphonate.
  • M- is preferably an anion selected from chloride, bromide, iodide, sulphate, nitrate, acetate, maleate, oxalate, succinate or trifluoroacetate. More preferably M- is chloride, bromide, trifluoroacetate or methanesulphonate.
  • Co-crystal refers to a crystalline material comprising two or more compounds at ambient temperature (20 to 25[deg.]C, preferably 20[deg.]C), of which at least two are held together by weak interaction, wherein at least one of the compounds is a co-crystal former.
  • Weak interaction is being defined as an interaction which is neither ionic nor covalent and includes for example: hydrogen bonds, van der Waals forces, and interactions.
  • “Pharmaceutical composition” refers to one or more active ingredients, and one or more inert ingredients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present disclosure encompass any composition comprising a compound of the present disclosure and a pharmaceutically acceptable carrier.
  • Carrier refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered.
  • Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, including but not limited to peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a preferred carrier when the pharmaceutical composition is administered orally.
  • Saline and aqueous dextrose are preferred carriers when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions are preferably employed as liquid carriers for injectable solutions.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • the composition if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations and the like.
  • the composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides.
  • Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences” by E.W. Martin. Such compositions will contain a therapeutically effective amount of the therapeutic, preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient. The formulation should suit the mode of administration.
  • Drug or pharmaceutically active agent includes a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
  • Combined or “in combination” or “combination” should be understood as a functional coadministration, wherein some or all compounds may be administered separately, in different formulations, different modes of administration (for example subcutaneous, intravenous or oral) and different times of administration.
  • the individual compounds of such combinations may be administered either sequentially in separate pharmaceutical compositions as well as simultaneously in combined pharmaceutical compositions.
  • “Therapeutically effective amount” is an amount of a compound of Formula (I) or a combination of two or more such compounds, which inhibits, totally or partially, the progression of the condition or alleviates, at least partially, one or more symptoms of the condition.
  • a therapeutically effective amount can also be an amount which is prophylactically effective. The amount which is therapeutically effective will depend upon the patient's size and gender, the condition to be treated, the severity of the condition and the result sought. For a given patient, a therapeutically effective amount can be determined by methods known to those of skill in the art.
  • the present disclosure provides compounds of formula (I), their tautomers, polymorphs, stereoisomers, prodrugs, solvates, hydrates, N-oxides, co-crystals, pharmaceutically acceptable salts, pharmaceutical compositions containing them and methods of treating conditions and diseases that are mediated by Btk activity
  • 'ring A represents a 5-7 membered ring which is unsaturated or partially unsaturated optionally having upto three heteroatom independently selected from O, N or S; .
  • ring C, ring D and ring E are independently a monocyclic or a bicyclic ring system which is saturated, unsaturated or partially unsaturated and optionally have additional heteroatoms independently selected from O, N or S, said ring system is further optionally substituted with 1 to ' 4 substituents independently selected from halo, alkyl, alkenyl, alkynyl, nitro, cyano, - (C a R b ) m OR 8 , -(CR a R b ) m SR 8 > -(CR a R b ) m NR 9 R 10 , oxo, alkylsulfonyl, -(CR a R b ) m COOR 8 , - (C R a R b ) m C(0)NR 9 R 1 °, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl
  • X represents N or C (R 1 );
  • Y represents -C(O) or -S(0) p -;
  • M is selected from hydrogen, cyano, halogen, haloalkyl, perhaloalkyl, alkyl, alkenyl, alkynyl, cyanoalkyl, acyl, cyanoalkylarbonyl, cyanoalkenylcarbonyl, -(CR a R b )mOR 8 , -SR 8 , - (CR a R b ) m COOR 8 , -(CR a R b ) m NR 9 R 1 °, -(CR a R b ) m C(0)NR 9 R 10 -(CR a R b ) m NR 8 C(0)NR 9 R 10 thiocarbonyl, S(0) 2 NR 9 R 10 , -NR 8 S(0) 2 R 8 , -S(0) p R 8 , - S0 3 H, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkyl
  • M is optionally substituted with one or more substituents independently selected from cyano, nitro, keto, oxo, halogen, haloalkyl, perhaloalkyl, hydroxyamino, -(CR a R b ) m OR 8 , - (CR a R b ) m C(0)R 8 , -OC(0)R 8 , -SR 8 , -(CR a R b ) m COOR 8 , -(CR a R b ) m NR 9 R 10 , -(CR a R b ) m C(0)N R 9 R 10 -(CR a R b ) m NR 8 C(0)N R R 10 -NR 8 C(0)R 8 , thiocarbonyl, -S(0) 2 N R 9 R 10 , -NR 8 S(0) 2 R 8 , - S(0) p R 8 , -S0 3 H, alkyl, alkenyl, alkyny
  • alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl, heterocyclyl or heteroaryl are optionally substituted with one or more substituents selected from hydroxy, alkyl, alkoxy, alkoxyalkyl, halogen, haloalkyl, perhaloalkyl, cyano, cyanoalkyl, amino, carboxy, carboxyalkyl, -OC(0)R 8 , -(CR a R b )mC(0)N R 9 R 10 , -NR 8 C(0)R 8 , -SR 8 , -S(0) p R 8 , - S(0) 2 N R 9 R 10 or -NR 8 S(0) 2 R 8 ;
  • U is a bond or is selected from the group consisting of cycloalkylene, cycloalkenylene, cycloalkylenecarbonyl, cycloalkylenealkoxy, cycloalkyleneamino, arylene, arylenecarbonyl, arylenealkoxycarbonyl, arylenealkoxycarbonylamino, aryleneaminocarbonyl, heterocyclylene, heterocyclylenealkyl, heterocyclylenecarbonyl, heterocyclylenealkylamino, heteroarylene, heteroarylenecarbonyl, heteroarylenealkylamino, (Ci_ 6 )alkylene, (Ci -6 )alkenylene or (Ci_ )alkynylene wherein one or more than one methylene groups of alkylene, alkenylene or alkynylene are optionally replaced by hetero atoms or groups such as -0-, -S(0) p -, -N(R )-, or -C(O
  • T is selected from hydrogen, cyano, halogen, haloalkyl, perhaloalkyl, alkyl, alkenyl, alkynyl, cyanoalkyl, acyl, cyanoalkylarbonyl, cyanoalkenylcarbonyl, -(CR a R b ) m OR 8 , -SR 8 , (CR a R b ) m COOR 8 , -(CR a R b ) m NR 9 R 10 , -(CR a R b ) m C(0)NR 9 R 10 -(CR a R b ) m NR 8 C(0)NR 9 R'° thiocarbonyl, S(0) 2 NR 9 R 10 , -NR 8 S(0) 2 R 8 , -S(0) p R 8 , -S0 3 H, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkyloxy
  • U and T is optionally substituted with one or more substituents independently selected from cyano, nitro, keto, oxo, halogen, haloalkyl, perhaloalkyl, hydroxyamino, -(CR a R b ) m OR 8 , - (CR a R b ) m C(0)R 8 , -OC(0)R 8 , -SR 8 , -(CR a R b ) m COOR 8 , -(CR a R b ) m NR 9 R 10 ,
  • alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl, heterocyclyl or heteroaryl are optionally substituted with one or more substituents selected from hydroxy, alkyl, alkoxy, alkoxyalkyl, halogen, haloalkyl, perhaloalkyl, cyano, cyanoalkyl, amino, carboxy, carboxyalkyl, -OC(0)R 8 , -(CR a R b ) m C(0)N R 9 R 10 , -NR 8 C(0)R 8 , -SR 8 , -S(0) p R 8 , - S(0) 2 N R 9 R 10 or -NR 8 S(0) 2 R 8 ;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, acyl, acylamino; acyloxy, -(CR a R b ) m C(0)R 8 , -(CR a R b ) m N R 9 R 10 , aminocarbonyl, alkoxycarbonylamino, alkylsulfonylamino, aminocarbonylamino, hydroxyamino, alkoxyamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, haloalkyl, perhaloalkyl, cycloalkyl, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy, -SO 3 H, alkylthio, aminosulfonyl, al
  • R 8 is selected from the group consisting of hydrogen, -(CR a R b ) m OR 8 , halogen, haloalkyl, - (CR a R b ) m C(0)R 8 , alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl or heterocyclylalkyl;
  • alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl or heterocyclylalkyl are optionally substituted with one or more substituents selected from hydroxy, alkyl, alkoxy, alkoxyalkyl, halogen, haloalkyl, perhaloalkyl, cyano, cyanoalkyl, amino, carboxy, carboxyalkyl, -OC(0)R 8 , -(CR a R b ) m C(0)N
  • R 9 and R 10 are independently selected from the group consisting of hydrogen, -(CR a R b ) m OR 8 , haloalkyl, -(CR a R b ) m C(0)R 8 , alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl or heterocyclylalkyl, or
  • R 9 and R 10 taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms selected from O, N or S, said ring system is further optionally substituted with 1 to 4 substituents independently selected from halo, alkyl, alkenyl, alkynyl, nitro, cyano, -(CR a R b ) m OR 8 , -SR 8 , -(CR a R b ) m NR 9 R 10 , oxo, alkylsulfonyt, -(CR a R b ) m COOR 8 , -(CR a R b )mC(0)N R 9 R 10 , cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;
  • R a and R b are independently selected from the group consisting of hydrogen, -OR 6 , halogen, haloalkyl, perhaloalkyl or alkyl;
  • n 0-6;
  • n 0 - 3;
  • p 0, 1 or 2;
  • q 1 or 2.
  • the present disclosure relates to compounds of formula (I) or its tautomers, polymorphs, stereoisomers, prodrugs, solvate, co-crystals or a pharmaceutically acceptable salts thereof, wherein,
  • ring A represents a 5 membered ring which is unsaturated or partially unsaturated optionally having upto three heteroatom independently selected from O, N or S;
  • ring C, ring D and ring E are independently a monocyclic or a bicyclic ring system which is saturated, unsaturated or partially unsaturated and optionally have additional heteroatoms independently selected from O, N or S, said ring system is further optionally substituted with 1 to 4 substituents independently selected from halo, alkyl, alkenyl, alkynyl, nitro, cyano, - (CR a R b ) m OR 8 , -(CR a R ) m SR 8 , -(CR a R b ) m NR 9 R 10 , oxo, alkylsulfonyl, -(CR a R b ) m COOR 8 , - (CR a R b ) m C(0)NR 9 R 10 , cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl,
  • X represents N or C (R 1 );
  • Y represents -C(O);
  • M is selected from hydrogen, cyano, halogen, haloalkyl, perhaloalkyi, alkyl, alkenyl, alkynyl, cyanoalkyl, acyl, cyanoalkylarbonyl, cyanoalkenylcarbonyl, -(CR a R b ) m OR 8 , -SR 8 , - (CR'R ⁇ m COOR 8 , -(CR a R b ) m NR 9 R 10 , -(CR a R b ) m C(0)NR 9 R 10 -(CR a R b ) m NR 8 C(0)NR 9 R 10 thiocarbonyl, S(0) 2 NR 9 R 10 , -NR 8 S(0) 2 R 8 , -S(0) p R 8 , - S0 3 H, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkyloxy, cycl
  • M is optionally substituted with one or more substituents independently selected from cyano, nitro, keto, xo, halogen, haloalkyl, perhaloalkyi, hydroxyamino, -(CR a R b ) m OR 8 , - (CR a R b ) m C(0)R 8 , -OC(0)R 8 -SR 8 , -(CR a R b ) m COOR 8 , -(CR a R b ) m NR 9 R 10 , -(CR a R b ) m C(0)N R 9 R 10 -(CR a R b ) m NR 8 C(0)N R 9 R 10 -NR 8 C(0)R 8 > thiocarbonyl, -S(0) 2 N R 9 R 10 , -NR 8 S(0) 2 R 8 , - S(0) p R 8 , -S0 3 H, alkyl, alkenyl, alkynyl,
  • U is a bond or is selected from the group consisting of cycloalkylene, arylene, heterocyclylene, heteroarylene, (Ci ⁇ alkylene, (Ci -6 )alkenylene or (C
  • T is selected from hydrogen, cyano, halogen, haloalkyl, perhaloalkyi, alkyl, alkenyl, cyanoalkyl, acyl, -(CR a R b ) m OR 8 , -SR 8 , -(CR a R b ) m COOR 8 , -(CR a R b ) m N R 9 R 10 , -(CR a R b ) m C(0)NR 9 R 10 - (CR a R b ) m NR 8 C(0)N R 9 R'° thiocarbonyl, S(0) 2 NR 9 R 10 , -NR 8 S(0) 2 R 8 , -S(0) p R 8 , -S0 3 H, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, cycloalkylamino, aryl, arylalkyl, aryloxy, arylamino, hetero
  • U and T is optionally substituted with one or more substituents independently selected from cyano, nitro, keto, oxo, halogen, haloalkyl, perhaloalkyi, hydroxyamino, -(CR a R b ) m OR 8 , - (CR a R b ) m C(0)R 8 , -OC(0)R 8 , -SR 8 , -(CR a R b ) m COOR 8 , -(CR a R b ) m N R 9 R 10 , -(CR a R b ) m C(0)N R 9 R 10 -(CR a R b ) m NR 8 C(0) m R 9 R 10 -NR 8 C(0)R 8 , thiocarbonyl, -S(0) 2 N R 9 R 10 , -NR 8 S(0) 2 R 8 , - S(0) p R , -S0 3 H, alkyl, alkenyl, al
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, acyl, acylamino, acyloxy, -(CR a R b ) m C(0)R 8 , -(CR a R b ) m N R 9 R 10 , aminocarbonyl, alkoxycarbonylamino, alkylsulfonylamino, aminocarbonylamino, hydroxyamino, alkoxyamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, haloalkyl, perhaloalkyl, cycloalkyl, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy, -SO 3 H, alkylfhio, aminosulfonyl
  • R 8 is selected from the group consisting of hydrogen, -(CR a R b ) m OR 8 , halogen, haloalkyl, - (CR a R ) m C(0)R 8 , alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl or heterocyclylalkyl;
  • alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl or heterocyclylalkyl are optionally substituted with one or more substituents selected from hydroxy, alkyl, alkoxy, alkoxyalkyl, halogen, haloalkyl, perhaloalkyl, cyano, cyanoalkyl, amino, carboxy, carboxyalkyl, -OC(0)R , (CR a R b )mC(0)N R 9 R 10 , -NR 8 C(0)R 8 , -SR 8 , -S(0) p R 8 , -S(0) 2 N R 9 R 10 or -NR 8 S(0) 2 R 8 ; R 9 and R 10 are independently selected from the group consisting of hydrogen, -(CR a R b ) m OR 8 , haloalkyl, cycl
  • R 9 and R 10 taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms selected from O, N or. S, said ring system is further optionally substituted with 1 to 4 substituents independently selected from halo, alkyl, alkenyl, alkynyl, nitro, cyano, -(CR a R b ) m OR 8 , -SR 8 , -(CR a R b ) m NR 9 R 1 °, oxo, alkylsulfonyl, -(CR a R b ) m COOR 8 , -(CR a R b ) m C(0)N R 9 R 10 , cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;
  • R a and R b are independently selected from the group consisting of hydrogen, -OR 6 , halogen, haloalkyl, perhaloalkyl or alkyl; R a and R b taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms selected from O, N or S;
  • n 0-3;
  • n 0 - 3;
  • p 0, 1 or 2;
  • q 1 or 2.
  • the present disclosure relates to compounds of formula (I) or its tautomers, polymorphs, stereoisomers, prodrugs, solvate, co-crystals or a pharmaceutically acceptable salts thereof, wherein,
  • ring A represents a 5 membered ring which is unsaturated or partially unsaturated optionally having upto three heteroatom independently selected from O, N or S;
  • ring C, ring D and ring E are independently a monocyclic or a bicyclic ring system which is saturated, unsaturated or partially unsaturated and optionally have additional heteroatoms independently selected from O, N or S;
  • X represents N
  • Y represents -C(O);
  • Li is a bond or is selected from the group consisting of -(CR d R b )- or (Ci -6 )alkylene wherein optionally one or more than one methylene groups are independently replaced by hetero atoms or groups such as -0-, -S(0) p -, -N(R 6 )-, -C(O)-;
  • M is selected from hydrogen, cyano, halogen, haloalkyl, perhaloalkyl, alkyl, cyanoalkyl, acyl, - (CR a R b ) m OR 8 , -SR 8 , -(CR a R b ) m COOR 8 , -(CR a R b ) m NR 9 R 10 , -(CR a R b ) m C(0)NR 9 R 10 thiocarbonyl, S(0) 2 NR 9 R 10 , -NR 8 S(0) 2 R 8 , -S(0) p R 8 , -S0 3 H, cycloalkyl, aryl, heterocyclyl or heteroaryl;
  • M is optionally substituted with one or more substituents independently selected from cyano, nitro, keto, oxo, halogen, haloalkyl, perhaloalkyl, hydroxyamino, -(CR a R b ) m OR 8 , - (CR a R b ) m C(0)R 8 , -OC(0)R 8 , -SR 8 , -(CR a R b ) m COOR 8 , -(CR a R b ) m NR 9 R 10 , -(CR a R b ) m C(0)N
  • U is a bond or is selected from the group consisting of cycloalkylene, arylene, heterocyclylene, heteroarylene or (Ci -6 )alkylene wherein one or more than one methylene groups of alkylene, alkenylene or alkynylene are optionally replaced by hetero atoms or groups such as -0-, -S(0) p -, - N(R 8 )-, or -C(0);
  • T is selected from hydrogen, cyano, halogen, haloalkyl, perhaloalkyl, alkyl, alkenyl, cyanoalkyl, acyl, -(CR a R b ) m OR 8 , -SR 8 , -(CR a R b ) m COOR 8 , -(CR a R b ) m N R 9 R 10 , -(CR a R b ) m C(0)NR 9 R 10 - (CR a R b )
  • U and T is optionally substituted with one or more substituents independently selected from cyano, nitro, keto, oxo, halogen, haloalkyl, perhaloalkyl, hydroxyamino, -(CR a R b ) m OR 8 , - (CR a R b ) m C(0)R 8 , -OC(0)R 8 , -SR 8 , -(CR a R b ) m COOR 8 , -(CR a R b ) nl N R 9 R 10 , -(CR a R b ) m C(0)N R 9 R 10 -(CR a R b ) m NR 8 C(0) m R 9 R 10 -NR 8 C(0)R 8 , thiocarbonyl, -S(0) 2 N R 9 R 10 , -NR 8 S(0) 2 R 8 , - S(0) p R 8 or -S0 3 H;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, acyl, acylamino, acyloxy, -(CR a R b ) m C(0)R 8 , -(CR a R b ) m NR 9 R 10 , aminocarbonyl, alkoxycarbonylamino, alkylsulfonylamino, aminocarbonylamino, hydroxyamino, alkoxyamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, haloalkyl, perhaloalkyl, cycloalkyl, thiocarbonyl, cafboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy, -SO3H, alkylthio, aminosulfonyl
  • R 8 is selected from the group consisting of hydrogen, -(CR a R b ) m OR 8 , halogen, haloalkyl, - (CR a R b ) m C(0)R 8 , alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl or heterocyclylalkyl;
  • R 9 and R 10 are independently selected from the group consisting of hydrogen, -(CR a R b ) m OR 8 , haloalkyl, -(CR a R b ) m C(0)R 8 , alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl or
  • R 9 and R 10 taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms selected from O, N or S;
  • R a and R b are independently selected from the group consisting of hydrogen, -OR 6 , halogen, haloalkyl, perhaloalkyl or alkyl;
  • n 0-3;
  • q 1 or 2.
  • the present disclosure relates to compounds of formula (I) or its tautomers, polymorphs, stereoisomers, prodrugs, solvate, co-crystals or a pharmaceutically acceptable salts thereof, wherein,
  • ring A is selected from pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, triazole, oxadiazole, thiadiazole, dithiazole;
  • ring C, ring D and ring E are independently a monocyclic or a bicyclic ring system which is saturated, unsaturated or partially unsaturated and optionally have additional heteroatoms independently selected from O, N or S;
  • X represents N
  • Y represents -C(O);
  • Li is a bond or (Ci. 6 )alkylene wherein optionally one or more than one methylene groups are independently replaced by hetero atoms or groups such as -0-, -S(0) p -, -N(R 6 )-, -C(O)-;
  • M is selected from hydrogen, cyano, halogen, haloalkyl, perhaloalkyl, alkyl, -(CR a R b ) m OR 8 , - SR 8 , -(CR a R b ) m COOR 8 , -(CR a R b ) m NR 9 R 10 or -(CR a R b ) m C(0)NR 9 R 10 ;
  • U is a bond or (Ci. 6 )alkylene wherein one or more than one methylene groups of alkylene, alkenylene or alkynylene are optionally replaced by hetero atoms or groups such as -0-, -S(0) p -, - N(R 8 )-, or -C(O);
  • T is selected from hydrogen, cyano, halogen, haloalkyl, perhaloalkyl, alkyl, acyl, -(CR a R b ) m OR 8 , - SR 8 , -(CR a R b ) m COOR 8 , -(CR a R b ) m N R 9 R 10 , -(CR a R b ) m C(0)NR 9 R 10 , cycloalkyl, aryl, heterocyclyl or heteroaryl;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are independently selected from hydrogen, alkyl, alkoxy, acyl, acylamino, acyloxy, -(CR a R b ) m C(0)R 8 , -(CR a R b ) m NR 9 R 10 , aminocarbonyl, alkoxycarbonylamino, alkylsulfonylamino, aminocarbonylamino, hydroxyamino, alkoxyamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, haloalkyl, perhaloalkyl, cycloalkyl, carboxy, alkylcarboxy, carboxyalkyl, carboxy alky loxy, alkylcarboxyalkyloxy, -S0 3 H, alkylthio, aminosulfonyl, alkylsulfonyl, or nitro;
  • R 8 is selected from the group consisting of hydrogen, -(CR a R b ) m OR 8 , halogen, haloalkyl, - (CR a R b ) m C(0)R 8 or alkyl;
  • R 9 and R 10 are independently selected from the group consisting of hydrogen, -(CR a R b ) m OR 8 or haloalkyl or
  • R 9 and R 10 taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms selected from O, N or S;
  • R a and R b are independently selected from the group consisting of hydrogen, -OR 6 , halogen, haloalkyl, perhaloalkyl or alkyl;
  • n 0-3;
  • n 0 - 3;
  • p 0, 1 or 2;
  • q 1 or 2.
  • the present disclosure relates to compounds of formula (I) or its tautomers, polymorphs, stereoisomers, prodrugs, solvate, co-crystals or a pharmaceutically acceptable salts thereof, wherein,
  • ring A is selected from pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, triazole, oxadiazole, thiadiazole, dithiazole;
  • ring C, ring D and ring E are independently selected from cyclopropyl, cyclohexyl, phenyl, azetidine, pyrrolidine, piperidine, piperazine, morpholine, octahydro-indole, octahydro-isoindole, dihydro-imidazole, tetrahydro-benzothiophene, tetrahydro-indole, tetrahydro-isoindole, tetrahydro-benzoxazine, tetrahydro-imidazopyridine, aza-spirooctane, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, triazole, oxadiazole, thiadiazole, dithiazole, pyridine, pyrimidine or pyrazine ;
  • X represents N
  • Y represents -C(O);
  • L] is a bond or (Ci -6 )alkylene wherein optionally one or more than one methylene groups are independently replaced by hetero atoms or groups such as -0-, -S(0)p-, -N(R 6 )-, -C(O)-;
  • M is selected from hydrogen, cyano, halogen, haloalkyl, perhaloalkyl, alkyl, -(CR a R b )mOR 8 , -
  • U is a bond or (Ci -6 )alkylene wherein one or more than one methylene groups of alkylene, alkenylene or alkynylene are optionally replaced by hetero atoms or groups such as -0-, -S(0) p -, ⁇ - N(R 8 )-, or -C(0);
  • T is selected from hydrogen, cyano, halogen, haloalkyl, perhaloalkyl, alkyl, acyl, -(CR a R b ) m OR 8 , - SR 8 , -(CR a R b ) m COOR 8 , -(CR a R b ) m N R 9 R 10 , -(CR a R b ) m C(0)NR 9 R 10 or cycloalkyl;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are independently selected from hydrogen, alkyl, alkoxy, acyl, acylamino, acyloxy, -(CR a R b ) m C(0)R 8 , -(CR a R b ) m NR 9 R 10 , aminocarbonyl, alkoxycarbonylamino, alkylsulfonylamino, aminocarbonylamino, hydroxyamino, alkoxyamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, haloalkyl, perhaloalkyl, cycloalkyl, carboxy, alkylcarboxy, carboxyalkyl, carboxy alky loxy, alkylcarboxyalkyloxy, -SO 3 H, alkylthio, aminosulfonyl, alkylsulfonyl, or nitro;
  • R 8 is selected from the group consisting of hydrogen, -(CR R b )mOR 8 , halogen, haloalkyl, - (CR a R b ) m C(0)R 8 or alkyl;
  • R 9 and R 10 are independently selected from the group consisting of hydrogen, -(CR a R b ) m OR 8 or haloalkyl
  • R a and R b are independently selected from the group consisting of hydrogen, -OR 6 , halogen, haloalkyl, perhaloalkyl or alkyl;
  • n 0-3;
  • n 0 - 3;
  • p 0, 1 or 2;
  • q 1 or 2.
  • the present disclosure relates to compounds of formula (I) or its tautomers, polymorphs, stereoisomers, prodrugs, solvate, co-crystals or a pharmaceutically acceptable salts thereof, wherein,
  • ring A is selected from pyrrole, imidazole, pyrazole, oxazole or isoxazole;
  • ring C, ring D and ring E are independently selected from phenyl, azetidine, pyrrolidine, piperidine, piperazine, morpholine, octahydro-indole, octahydro-isoindole, dihydro-imidazole, tetrahydro-benzothiophene, tetrahydro-indole, tetrahydro-isoindole, tetrahydro-benzoxazine, tetrahydro-imidazopyridine, aza-spirooctane, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, triazole, oxadiazole, thiadiazole, dithiazole, pyridine, pyrimidine or pyrazine ; X represents N;
  • Y represents -C(0)
  • L( is a bond or (Ci -6 )alkylene wherein optionally one or more than one methylene groups are independently replaced by hetero atoms or groups such as -0-, -S(0) p -, -N(R 6 )- or -C(O)-;
  • M is selected from hydrogen, cyano, halogen, haloalkyl, perhaloalkyl, alkyl, -(CR a R b )mOR 8 , - SR 8 , -(CR a R b )mCOOR 8 , -(CR a R b )mNR 9 R 10 or -(CR a R b )mC(0)NR 9 R 10 ;
  • U is a bond or (Ci. 6 )alkylene wherein one or more than one methylene groups of alkylene, alkenylene or alkynylene are optionally replaced by hetero atoms or groups such as -0-, -S(0) p -, - N(R 8 )-, or -C(0);
  • T is selected from hydrogen, cyano, halogen, haloalkyl, perhaloalkyl, alkyl, acyl, -(CR a R b ) m OR 8 , - SR 8 , -(CR a R b ) m COOR 8 , -(CR a R b ) m N R 9 R 10 , -(CR a R b ) m C(O)NR 9 R l 0 or cycloalkyl;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are independently selected from hydrogen, alkyl, alkoxy, acyl, acylamino, acyloxy, -(CR a R b ) m C(0)R 8 , -(CR a R b ) m NR 9 R 10 , aminoca ' rbonyl, alkoxycarbonylamino, alkylsulfonylamino, aminocarbonylamino, hydroxyamino, alkoxyamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, haloalkyl, perhaloalkyl, cycloalkyl, carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy, -SO 3 H, alkylthio, aminosulfonyl, alkylsulfonyl, or nitro;
  • R 8 is selected from the group consisting of hydrogen, -(CR a R b ) m OR 8 , halogen, haloalkyl, - (CR a R b ) m C(0)R 8 or alkyl;
  • R 9 and R 10 are independently selected from the group consisting of hydrogen, -(CR a R b ) m OR 8 or haloalkyl
  • R a and R b are independently selected from the group consisting of hydrogen, -OR 6 , halogen, haloalkyl, perhaloalkyl or alkyl;
  • n 0-3;
  • n 0 - 3;
  • p 0, 1 or 2;
  • q 1 or 2.
  • the present disclosure relates to compounds of formula (I) or its tautomers, polymorphs, stereoisomers, prodrugs, solvate, co-crystals or a pharmaceutically acceptable salts thereof, wherein,
  • ring A is pyrrole
  • ring C is selected from azetidine, pyrrolidine, piperidine, piperazine, morpholine, octahydro- indole, octahydro-isoindole, dihydro-imidazole, tetrahydro-benzothiophene, tetrahydro-indole, tetrahydro-isoindole, tetrahydro-benzoxazine, tetrahydro-imidazopyridine, aza-spirooctane, oxazole, isoxazole, thiazole or isothiazole;
  • ring D is selected from phenyl, pyridine, pyrimidine or pyrazine
  • ring E is selected from azetidine, pyrrolidine, piperidine, piperazine, morpholine, octahydro- indole, octahydro-isoindole, dihydro-imidazole, tetrahydro-benzothiophene, tetrahydro-indole, tetrahydro-isoindole, tetrahydro-benzoxazine or tetrahydro-imidazopyridine;
  • X represents N
  • Y represents -C(O);
  • Li is a bond or (C
  • M is selected from hydrogen, cyano, halogen, haloalkyl, perhaloalkyi or alkyl;
  • U is a bond or (Ci -6 )alkylene wherein one or more than one methylene groups of alkylene, alkenylene or alkynylene are optionally replaced by hetero atoms or groups such as -0-, -S(0) p -, - N(R 8 )-, or -C(0);
  • T is selected from hydrogen, cyano, halogen, haloalkyl, perhaloalkyi, alkyl, acyl, -(CR a R b ) m OR 8 , - SR 8 , -(CR a R b ) m COOR 8 , -(CR a R b ) m N R 9 R 10 , -(CR a R b ) m C(0)NR 9 R 10 or cycloalkyl;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are independently selected from hydrogen, alkyl, alkoxy, acyl, acylamino, acyloxy, -(CR a R b ) m C(0)R 8 , -(CR a R b ) m NR 9 R 10 , azido, cyano, halogen, hydroxy, .
  • R 8 is selected from the group consisting of hydrogen, halogen, haloalkyl, -(CR a R b ) m C(0)R 8 or alkyl;
  • R 9 and R 10 are independently selected from the group consisting of hydrogen, -(CR a R b ) m OR 8 or haloalkyl
  • R a and R b are independently selected from the group consisting of hydrogen, -OR 6 , halogen, haloalkyl, perhaloalkyi or alkyl;
  • n 0-3;
  • n 0 - 3;
  • the present invention also relates to the process of preparation of compounds of formula (I), or pharmaceutically acceptable salts thereof.
  • III compounds of formula (III) may be prepared from reaction of compounds of formula (VI) with compounds of formula (VII) using amide coupling reaction conditions as shown in Scheme 3 Scheme 4: Alternate process for preparation of compound of formula (III)
  • compounds of formula (I) may also be prepared from compounds of formulae (XII) using reductive amination reaction conditions as shown in Scheme 5 wherein PG is H or a protecting group selected from Tosyl and LGi is leaving groups selected from halogens, triflate and the like.
  • Intermediates of formula (XII) may be prepared from compounds of formula (XI) with compounds of formula (III) using Suzuki coupling reaction conditions as shown in Scheme5.
  • compounds of formula (I) may also be prepared from compounds of formula (XV) using amide coupling reaction conditions as shown in Scheme 6 wherein PG is H or a protecting group selected from Tosyl and LG
  • Suzuki coupling is the organic reaction of an aryl- or vinyl-boronic acid with an aryl- or vinyl-halide catalyzed by a palladium(O) complex such as tetrakis(triphenylphosphine)palladium [Chemical Reviews 95 (7): 2457-2483].
  • Reductive amination is a form of reaction that involves the conversion of a carbonyl group to an amine via an intermediate imine.
  • the carbonyl group is most commonly a ketone or an aldehyde.
  • the reaction is carried out with reducing agents that are more reactive toward protonated imines than ketones, and that are stable under moderately acidic conditions. These include sodium cyanoborohydride (NaBH 3 CN) and sodium triacetoxyborohydride (NaBH(OCOCH 3 ) 3. [Organic Reactions, 1 , 59, 2002]
  • Amide coupling may be carried out using any suitable amide coupling regents such as oxalyl chloride, thionyl chloride, BOP-C1, DCC, HOBt, HOAt, HATU, EDCI, alkylchloroformate and the like in the presence of organic non-nucleophillic bases such as triethyl amine, di-isopropylethyl amine, pyridine, N-methyl pyrrolidine, N,N- dimethylaminopyridine, DBU, DABCO, other hindered amines and pyridines.
  • suitable amide coupling regents such as oxalyl chloride, thionyl chloride, BOP-C1, DCC, HOBt, HOAt, HATU, EDCI, alkylchloroformate and the like in the presence of organic non-nucleophillic bases such as triethyl amine, di-isopropylethyl amine, pyr
  • the amide coupling reaction may be carried out in the presence of solvents such as dichloromethane, dichloroethane, DMF, dimethylacetamide, THF, acetonitrile or mixture of them may be used at a temperature ranging from -5 to 150 °C.
  • solvents such as dichloromethane, dichloroethane, DMF, dimethylacetamide, THF, acetonitrile or mixture of them may be used at a temperature ranging from -5 to 150 °C.
  • the reaction may be carried out optionally in presence of catalytic amount of DMF.
  • Amide coupling may also be carried out by heating ester and amine either in the absence of solvent or in presence of high boiling solvent like toluene, xylene, DMSO. Amide coupling may be carried out in presence of trialkyl aluminium (Chem. Commun., 2008, 1 100-1 102).
  • any of the compounds of formula (I) may be converted into a pharmaceutically acceptable salt or vice versa or converting one salt form into another pharmaceutically acceptable salt form.
  • the present invention provides co-crystals comprising a compound of formula (I) wherein compounds of formula (I) that contain groups capable of acting as donors and/or acceptors for hydrogen bonds may be capable of forming co-crystals with suitable co-crystal formers.
  • co-crystals may be prepared from compounds of Formula (I) by known co-crystal forming procedures. Such procedures include grinding, heating, co- subliming, co-melting, or contacting in solution compounds of formula I with the co-crystal former under crystallization conditions and isolating co-crystals thereby formed.
  • the present invention provides pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as active ingredient together with a pharmaceutically acceptable carrier, optionally in combination with one or more other pharmaceutical compositions.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or disorder mediated by Btk.
  • compositions can be prepared by mixing one or more compounds described herein, or pharmaceutically acceptable salts or tautomers thereof, with pharmaceutically acceptable carriers or the like, to treat or ameliorate a variety of Btk related conditions.
  • the pharmaceutical compositions of the present disclosure can be manufactured by methods well known in the art such as conventional granulating, mixing, dissolving, encapsulating, lyophilizing, emulsifying or levigating processes, among others.
  • the compositions can be in the form of, for example, granules, powders, tablets, capsule syrup, suppositories, injections, emulsions, elixirs, suspensions or solutions.
  • compositions can be formulated for various, routes of administration, for example, by oral administration, transmucosal administration, rectal administration, topical administration or subcutaneous administration as well as intrathecal, intravenous, intramuscular, intraperitoneal, intranasal, intraocular or intraventricular injection.
  • the compound or compounds of the instant invention can also be administered in a local rather than a systemic fashion, such as injection as a sustained release formulation.
  • pharmaceutically acceptable excipients and carries are generally known to those skilled in the art and are thus included in the instant invention. Such excipients and carriers are described, for example, in "Remington's Pharmaceutical Sciences” Mack Pub. Co., New Jersey (1991 ).
  • the formulations of the invention can be designed for to be short-acting, fast-releasing, long-acting, and sustained-releasing.
  • the pharmaceutical formulations can also be formulated for controlled release or for slow release.
  • compositions of the present disclosure can also comprise, for example, micelles or liposomes, or some other encapsulated form, or can be administered in an extended release form to provide a prolonged storage and/or delivery effect. Therefore, the pharmaceutical formulations can be compressed into pellets or cylinders and implanted intramuscularly or subcutaneously as depot injections or as implants such as stents. Such implants can employ known materials such as silicones and biodegradable polymers.
  • the pharmaceutical compositions may contain, for example, from about 0.1 % by weight, to about 90% or more by weight, of the active material, depending on the method of administration.
  • each unit can contain, for example, from about 0.1 to 500 mg or more of the active ingredient.
  • the dosage as employed for adult human treatment can range, for example, from about 0.1 to 1000 mg per day, depending on the route and frequency of administration. Specific dosages can be adjusted depending on conditions of the BTK related condition, the age, body weight, general health conditions, sex, and diet of the subject, dose intervals, administration routes, excretion rate, and combinations of drugs. Any of the above dosage forms containing effective amounts are well within the bounds of routine experimentation and therefore, well within the scope of the instant invention.
  • the total daily dose can typically range from about 1 mg/kg/day to about 500 mg/kg/day in single or in divided doses.
  • dosages for humans can range from about 5 mg to about 100 mg per day, in a single or multiple doses.
  • a therapeutically effective dose or amount can vary depending upon the route of administration and dosage form.
  • Some compositions of the instant invention is a formulation that exhibits a high therapeutic index.
  • the therapeutic index is the dose ratio between toxic and therapeutic effects which can be expressed as the ratio between LD 50 and ED 50 .
  • the LD 50 is the dose lethal to 50% of the population and the ED50 is the dose therapeutically effective in 50% of the population.
  • the LD50 and ED50 can be determined by standard pharmaceutical procedures in animal cell cultures or experimental models.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition can be formulated for particular routes of administration such as oral administration, parenteral administration, and rectal administration, etc.
  • Compounds of the present invention may be useful in the treatment of an indication selected from: Autoimmune disorders, inflammatory diseases, allergic diseases, airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD), transplant rejection; diseases in which antibody production, antigen presentation, cytokine production or lymphoid organogenesis are abnormal or are undesirable; including rheumatoid arthritis, systemic onset juvenile idiopathic arthritis (SOJIA), gout, pemphigus vulgaris, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Sjogren's syndrome, autoimmune hemolytic anemia, anti-neutrophil cytoplasmic antibodies (ANCA)- associated vasculitides, cryoglobulinemia, thrombotic thrombocytopenic purpura, chronic autoimmune urticaria, allergy (atopic dermatitis, contact dermatitis, allergic rhinitis),
  • the invention provides a method of treating a disease which is treated by the modulation of Btk- comprising administration of a therapeutically acceptable amount of a compound of formula (I) or a salt thereof.
  • the disease is selected from the afore-mentioned list.
  • the compound of the present invention may be administered either simultaneously with, or before or after, one or more other therapeutic agent.
  • the compound of the present invention may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the other agents.
  • compounds of Formula (I) of the invention can be used alone or in combination with one or more additional therapeutic agent selected from the group consisting of a BTK inhibitors such as Ibrutinib, AVL-292, ONO-4059; B-cell depleting protein based therapeutics such as Rituxan, a CD20 antibody; calcineurin inhibitor such as cyclosporin A or FK 506; a mTOR inhibitor such as rapamycin, 40-O-(2-hydroxyethyl)- rapamycin, CCI779, ABT578, AP23573, AP23464, AP23675, AP23841 , TAFA-93, biolimus-7 or biolimus-9; an ascomycin having immunosuppressive properties such as ABT-281 , ASM981 ; corticosteroids such as cortisone, dexamethasone, methylprednisolone, prednisolone, prednisone; cyclophosphamide
  • mono-citrate also called CP-690,550
  • SYK inhibitor such as fostamatinib
  • sphingosine-1 -phosphate receptor modulators such as FTY720 (fingolimod)
  • immunosuppressive monoclonal antibodies such as monoclonal antibodies to leukocyte receptors like MHC, CD2, CD3, CD4, CD7, CD8, CD25, CD28, CD40, CD45, CD52, CD58, CD80, CD86 or their ligands
  • immunomodulatory compounds such as a recombinant binding molecule having at least a portion of the extracellular domain of CTLA4 or a mutant thereof, e.g.
  • CTLA4 an at least extracellular portion of CTLA4 or a mutant thereof joined to a non-CTLA4 protein sequence, e.g. CTLA41g (for ex. designated ATCC 68629) or a mutant thereof, e.g. LEA29Y; adhesion molecule inhibitors, e.g. LFA-1 antagonists, ICAM-1 or -3 antagonists, VCAM-4 antagonists or VLA-4 antagonists; or an anti-infectious agent.
  • Further combination partners to a compound of formula (I) may be selected from a PI3K inhibitor (e.g. pan, or alpha, beta, gamma, delta selectives), TNF inhibitors, ILI beta inhibitors, IL 17 inhibitors, and inhibitors of IL6 or IL receptor.
  • the invention provides methods of treating or preventing a condition associated with BTK in a subject, such as a mammal, i.e., a human or non-human mammal, comprising administering an effective amount of one or more compounds described herein to the subject.
  • Suitable non-human subjects that can be treated include domestic or wild animals, companion animals, such as dogs, cats and the like; livestock, including horses, cows and other ruminants, pigs, poultry, rabbits and the like; primates, for example monkeys, such as macaques including rhesus monkeys and cynomolgus monkeys, marmosets; tamarins and the like, apes, including chimpanzees and orangutans; and rodents, such as rats, mice, gerbils, guinea pigs and the like.
  • the invention provides a product comprising a compound of formula (I) and at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy.
  • the therapy is the treatment of a disease or condition mediated by Btk kinases.
  • Products provided as a combined preparation include a composition comprising the compound of formula (I) and the other therapeutic agent(s) together in the same pharmaceutical composition, or the compound of formula (I) and the other therapeutic agent(s) in separate form, e.g. in the form of a kit.
  • the invention provides a pharmaceutical composition comprising a compound of formula (I) and another therapeutic agent(s).
  • the pharmaceutical composition may comprise a pharmaceutically acceptable excipient, as described above.
  • the invention also provides a compound of formula (I) for use in a method of treating a disease or condition mediated by Btk, wherein the compound of formula (I) is prepared for administration with another therapeutic agent.
  • the invention also provides another therapeutic agent for use in a method of treating a disease or condition mediated by Btk, wherein the other therapeutic agent is prepared for administration with a compound of formula (I).
  • the invention also provides a compound of formula (I) for use in a method of treating a disease or condition mediated by Btk , wherein the compound of formula (I) is administered with another therapeutic agent.
  • the invention also provides another therapeutic agent for use in a method of treating a disease or condition mediated by Btk, wherein the other therapeutic agent is administered with a compound of formula (I).
  • Step-1 Synthesis of ethyl 2-amino-5-(4-methoxycarbonylphenyl)-lH-pyrrole-3-carboxylate (1-1): Na metal (1.96 g, 85.3 mmol) was added portion wise to EtOH (210 mL) and stirred for 30 min to get clear solution. To this was added ethyl 3-amino-3-imino-propanoate hydrochloride (CAS: 57508-48-2, 14.25 g, 85.6 mmol) and stirred at room temperature for additional 30 min. Finally, methyl 4-(2-bromoacetyl) benzoate (1 1 g, 42.8 mmol) was added to the reaction mixture and was stirred for 16-20 h at room temperature.
  • reaction mixture was filtered through celite and the residue was washed with MeOH (50 mL x 2). The combined filtrate was concentrated under reduced pressure and the residue was purified using column chromatography (Si0 2 , 40% EtOAc in hexane) to provide 1-1 (7 g, 56.7% yield).
  • LCMS m/z 289.1 (M + 1) + .
  • Step-2 Synthesis of methyl 4-(4-hydroxy-7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzoate (l-II):
  • Step-3 Synthesis of Methyl 4-(4-chloro-7H-pyrrolo [2, 3-d]pyrimidin-6-yl)benzoate (INT-1- III): l-II (6 g, 22.3 mmol) was suspended in excess of POCl 3 (100 mL) and refluxed for 16- 20 h. After completion of the reaction (as indicated by TLC), POCl 3 was removed under reduced pressure. Saturated NaHC0 3 (100 mL) solution was added to the residue and stirred for 30 min. The solid was filtered and suspended in minimum quantity of MeOH (10 mL). After stirring for 30 min, it was filtered and dried to provide INT-1-III (5.8 g, 90% yield).
  • Step-I ethyl 4-[4-chIoro-l-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin-2- yl]benzoate (I- VI): A solution of K 2 C0 3 (6.7 g, 48.96 mmol) in water (10 mL) was added to a solution of I-V (4 g, 12.24 mmol) and ethyl-4-bromobenzoate (2.0 mL, 12.24 mmol) in 1 ,4- dioxane (40 mL); to which Argon was purged for 30 min.
  • the intermediate I-V was prepared from 4-chloro-lH-pyrrolo[2,3-b]pyridine (CAS No.
  • Step-II To a solution of I-VI (2.0 g, 4.64 mmol) in THF (20 mL) was added NaOH (0.93 g, 23.2 mmol) in water (8 mL) and the reaction mixture was stirred at room temperature for 16 h. It was then acidified using 10% citric acid solution and extraction was carried out using EtOAc (30 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 S0 4 , filtered and concentrated under reduced pressure to provide corresponding acid intermediate (1.3 g, 3.22 mmol), which was dissolved in DMF (15 mL).
  • INT-2-III was synthesized as described in: Ref: WO2009039397A2, WO2006099075A2.
  • Step-1 Synthesis of methyl 4-(2-amino-4-hydroxy-7H-pyrrolo[2,3-d]pyrimidiii-6-yl) benzoate (4-1): A solution of 2,6-diamino-4-hydroxypyrimidine (CAS: 56-06-4, 1 g, 7.93 mmol), NaOAc (0.85 g, 10.32 mmol) in water (180 mL) was stirred at 100 °C for 30 min. Methyl 4-(2-bromoacetyl)benzoate (2.24 g, 8.72 mmol) was suspended in MeOH (25 mL) and was added slowly to the above solution. The reaction mixture was then, stirred at 100 °C for 16-20 h before it was cooled to room temperature.
  • Step-2 Synthesis of methyl 4-[2-(2, 2-dimethylpropanoylamiiio)-4-hydroxy-7H-pyrrolo[2, 3-d] pyrimidin-6-yl] benzoate (4-II): 4-1 (2.0 g, 7.04 mmol) was suspended in trimethylacetic anhydride (5 mL) and refluxed for 3-5 h. After completion of the reaction, the reaction mixture was cooled to room temperature and hexane (10 mL) was added to it.
  • Step-1 Synthesis of 2-amino-6-(4-morphoIinophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ol (5- II): A solution of 5-1 (3.7 g,l 3.03 mmol), 2,6-diamino-4-hydroxypyrimidine (CAS: 56-06-4, 1.5 g, 1 1.88 mmol) in DMF (1 1 mL) was stirred at 60 °C overnight. After completion of the reaction (as indicated by TLC), the reaction mixture was cooled to room temperature and poured over ice- cold water (150 mL). The resulting, solid was filtered, recrystallised using isopropanol (25 mL) and dried under vacuum to afford 5-II (2.3 g crude). LCMS: m/z 312.1 (M+l) + .
  • Step-2 Synthesis of 4-chloro-6-(4-morpholinophenyl)-7H-pyrrolo[2, 3-d] pyrimidin-2- amine (5-HI): 5-II (2.3 g, 7.4 mmol) was suspended in excess of POCl 3 (20 mL) and refluxed for 3-5 h. After completion of the reaction (as indicated by TLC), POCl 3 was removed under reduced pressure and saturated NaHC0 3 solution (100 mL) was added to the residue. Extraction was carried out using EtOAc (150 mL x 2); the combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 S0 4 , filtered and concentrated under reduced pressure.
  • Step 1 - Step 5 3-bromo-2-[[tert-butyl(dimethyl)silyl]oxymethyl] aniline (step-5) was prepared from l-bromo-2-methyl-3-nitro-benzene, following the same sequence of procedures as mentioned in WO2012031004.
  • Step-6 Synthesis of N-[3-bromo-2-[[tert-butyI(dimethyl)siIyl]oxymethyl]phenyl]-6- cyclopropyl-pyridine-3-carboxamide:
  • Step-7 Synthesis of N-[2-[[tert-butyl(dimethyl)siIyI]oxymethyl]-3-(4,4,5,5-tetramethyl- l,3 ? 2-dioxaborolan-2-yl)phenyl]-6-cyclopropyl-pyridine-3-carboxamide:
  • Step-1 Synthesis of methyl 4-[4-[3-[(4-tert-butylbenzoyl)amino]-2-methyl-phenyl]-7H- pyrrolo[2,3-d]pyrimidin-6-yl]benzoate (8-1): INT-l-HI (0.1 g, 0.35 mmol) and ⁇ -2- ⁇
  • Step-2 Synthesis of 4-[4-[3-[(4-tert-butylbenzoyl)amino]-2-methyl-phenyl]-7H-pyrrolo [2, 3-d] pyrimidin-6-yl] benzoic acid (8-II): To a solution of 8-1 (0.08 g, 0.15 mmol) in MeOH (5 mL) was added a solution of NaOH (0.025 g, 0.62mmol) in water (2 mL); and the reaction mixture was refluxed for 3 h. After completion of the reaction (as indicated by TLC), MeOH was removed under reduced pressure and was acidified using 10% acetic acid solution. The resultant solid was filtered, washed with water and dried under vacuum to afford 8-II (0.05 g, crude), which was used further without any purification.
  • LCMS m/z 505.3 (M + 1) + .
  • Step-3 Synthesis of 4-tert-butyl-N-[2-methyl-3-[6-[4-(morpholine-4-carbonyl) phenyl]-7H- pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]benzamide
  • Example Al To a solution of 8-II (0.05 g, 0.1 mmol) and morpholine (0.04 mL, 0.49 mmol) in DMF (3 mL) was added PyBOP (77 mg, 0.14 mmol) and the reaction mixture stirred at room temperature for 16 h. After completion of the reaction (as indicated by TLC), water (10 mL) was added to it and extraction was carried out using EtOAc (25 mL x 2).
  • Step-1 Synthesis of 4-(4-chIor0-7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzoic acid (9-1): To a suspension of INT-l-HI (1.0 g, 3.48 mmol) in a mixture of MeOH (25 mL) and H 2 0 (7 mL) was added NaOH (0.42 g, 10.45 mmol) at room temperature and then stirred at 80 °C for 4 h. After completion of the reaction (as indicated by TLC), the solvent was removed in vacuo and the residue was acidified with saturated solution of citric acid. The resultant solid was filtered, washed with water and dried to afford the title compound 9-1 (1.0 g, quantitative). LCMS: m/z 274.0 (M + l) + .
  • Step-2 Synthesis of [4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl]-(4-methyl piperazin-l-yl)methanone (9- ⁇ ): A mixture of 9-1 (1.0 g, 3.66 mmol) and N-methylpiperazine (2.02 mL, 1.8.30 mmol) in DMF (8 mL) was treated with PyBOP (3.8 g, 7.32 mmol) at room temperature and then stirred for 6 h. After confirming the completion of the reaction by TLC, the mixture was treated with water (20 mL).
  • Pd(PPh 3 ) 4 (0.049 g, 0.042 mmol) was added in to this mixture and then stirred at 100 °C for 18 h. After confirming the completion of the reaction, it was cooled to room temperature and diluted with EtOAc (100 mL). The organic layer was washed successiveively with water (25 mL), brine (20 mL), dried over anhydrous Na 2 S0 4 , filtered and concentrated under reduced pressure.
  • Example-Cl 4-tert-butyl-N-[2-methyI-3-[6-(4-morpholinophenyl)-7H-pyrrolo[2, pyrimidin-4- l] phenyl] benzai ide
  • Step-1 Synthesis of 4-tert-butyl-N-[2-methyl-3-[6-(4-morpholinophenyl)-7H-pyrrolo[2, 3- d]pyrimidin-4-yl]phenyl]benzamide
  • Example-Cl A solution of INT-l-VI (0.1 g, 0.32 mmol), INT- 2- ⁇ (0.15 g, 0.38 mmol) and Na 2 C0 3 (0.082 g, 0.77 mmol) in a mixture of dioxane (10 mL) and water (2 mL) was purged using Ar for 20 min.
  • Step-1 Synthesis of methyl 4-[2-amino-4-[3-[(4-tert-butylbenzoyl)amino]-2-methyl- phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl]benzoate (10-1): 10-1 (0.14 g, 50% yield ) was prepared using INT-5-IV (0.16 g) following the procedure mentioned in step-1 of Example Al .
  • Step-2 Synthesis of 4-[2-amino-4-[3-[(4-tert-butylbenzoyl)amino]-2-methyl-phenyl]-7H- pyrroIo[2,3-d]pyrimidin-6-yl]benzoic acid (10-11): 10-11 (0.10 g, 73% yield) was prepared from 10-1 (0.14 g) following the procedure mentioned in step-2 of Example Al LCMS: m/z 520.4 (M + l) + .
  • Step-3 Synthesis of N-[3-[2-amino-6-[4-(morphoIine-4-carbonyl)phenyl]-7H-pyrrolo [2,3- d]pyrimidin-4-yI]-2-methyl-phenyl]-4-tert-butyl-benzamide( Example Dl ): To a solution of 10-11 (0.10 g, 0.19 mmol) and morpholine (0.05 mL, 0.578 mmol) in DMF (2 mL) was added PyBOP (0.15 g, 0.28 mmol); and the reaction mixture was stirred at room temperature for 16 h.
  • Step-1 Synthesis of N-[3-[2-amino-6-(4-morpholinophenyl)-7H-pyrrolo[2,3-d] pyrimidin-4- yl]-2-methyl-phenyI]-4-tert-butyl-benzamide(Exaniple El): To a suspension of INT-5-III
  • Step-1 4-chIoro-6-(6-morphoiino-3-pyridyI)-7H-pyrrolo [2, 3-d]pyrimidin-2-amine (11-1):
  • Step-2 N-[3-[2-amino-6-(6-morpholino-3-pyridyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2- methyl-phenyl]-4-cyclopropyl-benzamide (Example Fl): A solution of 11-1 (0.09 g, 0.27 mmol), INT-2-IV (0.15 g, 0.32 mmol) and Na 2 C0 3 (0.063 g, 0.59 mmol) in dioxane-water (5 mL + 2.5 mL) was purged using argon for 10 min.
  • Step-1 Synthesis of methyl 4-[4-(2-methyl-3-nitro-phenyI)-7H-pyrrolo[2,3-d]pyrimidin-6- yl]benzoate (12-1): 12-1 (2.5 g crude) was prepared using INT-1-III (2.2 g) and 2-1 (2.4 g) following the procedure described in step-1 of Example-Al .
  • Step-2 Synthesis of 4-[4-(2-methyI-3-nitro-phenyl)-7H-pyrroio [2, 3-d] pyrimidin-6-yl] benzoic acid (12-11): 12-11 (2 g, 83% yield) was obtained from 12-1 (2.5 g crude) following the procedure mentioned in step-2 of Example Al .
  • Step-3 [4-[4-(2-methyl-3-nitro-phenyl)-7H-pyrroIo[2, 3-d]pyrimidin-6-yl]phenyl]- morpholino-methanone (12-111): 12-111 (1.1 g, 46.6% yield) was obtained from 12-11 (2 g, 5.34 mmol) following the procedure described in step-3 of Example-Al .
  • Step-4 Synthesis of [4-[4-(3-amino-2-methyl-phenyl)-7H-pyrrolo[2, 3-d]pyrimidin-6-yl] phenyl]-morpholino-methanone (12-IV): To the solution of , 12-111 ( 1.1 g, 2.48 mmol) in methanol (15 mL) was added 10% Pd/C (0.6 g) and stirred under H 2 atmosphere for a period of 16 h. After completion of reaction, reaction mixture was filtered through celite, washed with 10% MeOH in CH 2 C1 2 (50 mL) and the combined filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (Si0 2 , 2% MeOH in CH 2 C1 2 ) to afford 12-IV (0.70 g, 68.6% yield). LCMS: m/z 414.2 (M + 1) + .
  • Step-5 Synthesis of 5-cyclopropyl-N-[2-methyl-3-[6-[4-(morphoIine-4-carbonyI)phenyl]- 7H-pyrrolo[2, 3-d] pyrimidin-4-yl] phenyl] thiophene-2-carboxamide
  • Example Gl A solution of 5-cyclopropylthiophene-2-carboxylic acid (0.097 g, 0.58 mmol) in SOCl 2 (6 mL) was refluxed for 3 h. After consumption of acid, excess of SOCl 2 was removed under reduced pressure to provide corresponding acid chloride.
  • Step-1 Methyl 4-[4-[3-(isoindoline-2-carbonylamino)-2-methyl-phenyl]-7H-pyrrolo[2,3- d]pyrimidin-6-yI]benzoate (13-1): INT-1-III (0.3 g, 1.07 mmol) and INT- 3-III (0.48 g, 1.29 mmol) were added to a solution of Na 2 C0 3 (0.29 g, 2.77 mmol) in dioxane-water (20 mL + 4 mL) and purged using argon for 15 min.
  • Step-2 4-[4-[3-(isoindoIine-2-carbonylamino)-2-methyl-phenyl]-7H-pyrrolo[2,3-d] pyrimidin-6-yl] benzoic acid (13-11): To a solution of 13-1 (0.35 g, 0.71 mmol) in MeOH (5 mL) was added NaOH (0.14 g, 3.5 mmol) in water (5 mL) and the reaction mixture was re fluxed for 5 h. After completion of the reaction (as indicated by TLC), MeOH was removed under reduced pressure and it was acidified using 10% acetic acid solution. The resultant solid was filtered and dried under vacuum to provide 13-11 (0.29 g, 85% yield), which was used further without any purification. LCMS: m/z 490.2 (M + 1) + .
  • Step-3 N-[2-methyl-3-[6-[4-(morpholine-4-carbonyl)phenyI]-7H-pyrroIo[2,3-d]pyrimidin- 4-yl]phenyl]isoindoline-2-carboxamide (Example HI): To a solution of 13-11 (0.29 g, 0.6 mmol) and morpholine (0.24 mL, 3.01 mmol) in DMF (5 mL) was added PyBOP (0.47 g, 0.904 mmol) and stirred at room temperature for 16 h. After completion of the reaction (as indicated by TLC), water (40 mL) was added to it and extraction was carried out using EtOAc (25 mL x 2).
  • Step-1 N-[2-methyI-3-[6-(4-morpholinophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]phenyl] isoindoline-2-carboxamide
  • Example II To a solution of INT-l-IV (0.1 g, 0.32 mmol) and INT- 3-III (0.144 g, 0.38 mmol) in dioxane (10 mL) was added a solution of Na 2 C0 3 (0.084 g, 0.795 mmol) in water (2 mL); and the reaction mixture was purged using argon for 15 min.
  • Step-1 Methyl 4-[2-amino-4-[3-(isoindoline-2-carbonylamino)-2-methyl-phenyl]-7H- pyrrolo[2,3-d]pyrimidin-6-yI]benzoate (14-1): To a solution of INT-5-IV (0.4 g, 1.32 mmol) and INT- 3-III (0.5 g, 1.32 mmol) in dioxane (10 mL) was added a solution of Na 2 C0 3 (0.28 g, 2.65 mmol) in water (4 mL); and the reaction mixture was purged using Ar for 15 min.
  • Step-2 Methyl 4-[2-amino-4-[3-(isoindoline-2-carbonylamino)-2-methyl-phenylj-7H- pyrrolo[2,3-d]pyrimidin-6-yI]benzoate (14-11): To a solution of 14-1 (0.35 g, 0.67 mmol) in MeOH (5 mL) was added a solution of NaOH (0.197 g, 4.9 mmol) in water (1.5 mL); and the reaction mixture was refluxed for 5 h. After completion of the reaction, MeOH was removed under reduced pressure and was acidified using 10% citric acid solution. The resultant solid was filtered and dried under vacuum to provide 14-II (0.2 g, 58.8% yield). LCMS: m/z 505.3 (M + I ) ' .
  • Step-3 N-[3-[2-amino-6-[4-(morpholine-4-carbonyl)phenyl]-7H-pyrrolo(2,3-d]pyrimidin-4- yl]-2-methyl-phenyljisoindoline-2-carboxamide (Example Jl): To a solution of 14-11 (0.13 g, 0.26 mmol) and morpholine (0.1 1 mL, 1.29 mmol) in DMF (2 mL) was added PyBOP (0.2 g, 0.39 mmol) and the reaction mixture was stirred at room temperature for 16 h.
  • Step-1 N-[3-[2-(2,2-dimethyIpropanoylamino)-6-(6-morpholino-3-pyridyl)-7H-pyrroIo[2,3- d]pyrimidin-4-yl]-2-methyl-phenyl]isoindoline-2-carboxamide
  • INT- 4-IV (0.45 g, 1.08 mmol)
  • INT-3-III (0.49 g, 1.3 mmol
  • Na 2 C0 3 (0.28 g, 2.72 mmol
  • Step-2 N-[3-[2-amino-6-(6-morpholino-3-pyridyl)-7H-pyrrolo[2,3-d]pyriinidin-4-yl]-2- methyl-phenyl]isoindoIine-2-carboxamide
  • Example Kl N-[3-[2-amino-6-(6-morpholino-3-pyridyl)-7H-pyrrolo[2,3-d]pyriinidin-4-yl]-2- methyl-phenyl]isoindoIine-2-carboxamide
  • Example LI (0.016 g, 10% yield) was synthesized using INT-9 0 mmol) and 3-III
  • Step-1 tert-butyl 4-[[4- ⁇ 4-chloro-7-(p-tor : 1007126 Olo[2,3-d]pyrimidin-6- yl]phenyI]methyI]pipera.cine-l-carboxylate (16-1): Argon was purged through a solution of INT-6-VI (1 g, 2.31 mmol), INT-7-V (1 g, 2.54 mmol) and K 2 C0 3 (0.62 g, 4.6 mmol) in 1 ,4 dioxane-water (24 mL + 4.1 mL) for 30 minutes.
  • Step-2 tert-butyl 4-[[4-[4-[3-(isoindoIine-2-carbonylamino)-2-methyl-phenyl]-7-(p- toiylsulfonyI)pyrrolo[2,3-d]py»"iniidin-6-yl]phenyl]methyl]piperazine-l-carboxylate (16-11): 16-11 (0.3 g, 48% yield) was synthesized using 16-1 (0.45 g, 0.77 mmol) and INT-3-III (0.29 g, 0.77 mmol) following the procedure described in step-1 for the synthesis of Example HI .
  • LCMS m/z 798.4 (M + 1) + .
  • Step-3 tert-butyl 4-[[4-[4-[3-(isoindoline-2-carbonylamino)-2-methyl-phenyl]-7H- pyrrolo[2,3-d]pyrimidin-6-yI]phenyl]methyl]piperazine-l-carboxyIate (16-111): To a solution of 16-11 (0.3 g, 0.37 mmol) in THF: MeOH: H 2 0 (3: 1 : 1 , 5 ml) was added LiOH-H 2 0 (0.047 g, 1.12 mmol) and the reaction mixture was stirred at room temperature for 2 h..
  • Step-4 N-[2-methyI-3-[6-[4-(piperazin-l-yImethyl)phenyI]-7H-pyrrolo[2,3-d] pyrimidin-4- yl]phenyl]isoindoline-2-carboxamide (Example Ml): 16-111 (0.1 1 g, 0.17 mmol) was added to 4M HC1 in 1,4 dioxane (3 mL) and the reaction mixture was stirred at room temperature for 1 h. After completion of the reaction, solvent was removed under reduced pressure and saturated NaHC0 3 solution (15 mL) was added to the residue.
  • Step-1 4-[4-chloro-7-(p-tolylsulfonyl)pyrrolo[2,3-d]pyrimidin- ADV- 1007183 I): To a solution of INT-6-VI (0.8 g, 1.84 mmol) and (4-formylphenyl)boronic acid (CAS No.87199- 17-5, 0.29 g, 1.93 mmol) i CH 3 CN (20 mL) was added 1M aqueous Na 2 C0 3 ( 8 mL); and argon was purged through it for 30 min. Finally, PdCl 2 (dppf) (0.18 g, 0.25 mmol) was added to the reaction mixture and it was stirred at 100 °C for 4 h.
  • INT-6-VI 0.8 g, 1.84 mmol
  • (4-formylphenyl)boronic acid CAS No.87199- 17-5, 0.29 g, 1.93 mmol
  • i CH 3 CN 20 mL
  • reaction mixture was diluted with water (50 mL) and extraction was carried out using EtOAc (50 ml x 3). The combined organic layers were washed with water (75 mL), brine (75 mL), dried over anhydrous Na 2 S0 4 , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Si0 2 , 15% EtOAc in hexane) to afford 17-1 (0.26 g, 34% yield). LCMS: m/z 412 .0 (M + 1 ) + .
  • Step-2 N-[3-[6-(4-formylphenyl)-7-(p-tolylsulfonyl)pyrrolo[2,3-d]pyrimidin-4-yl]-2-methyl- phenyl]isoindoline-2-carboxamide (17-11): 17—11 (0.26 g, 59% yield) was prepared from 17-1 (0.29 g, 0.70 mmol) and INT-3-III (0.26 g, 0.70 mmol) following the procedure described in step-1 for preparation of example HI .
  • LCMS m/z 628.3 (M + 1 ) + .
  • Step-3 N-[2-methyl-3-[6-[4-[(4-methylpiperazin-l-yI)methyl]phenyl]-7-(p-toIylsulfonyl) pyrrolo[2,3-d]pyi"imidin-4-yl]phenyl]isoindoline-2-carboxamide (17-111): To a solution of 17-11 (0.26 g, 0.41 mmol), AcOH (catalytic, 1 drop) and activated powdered molecular sieves (0.2 g) in CH 2 C1 2 (5 mL) was added 1 -methylpiperazine (0.06 g, 0.62 mmol); and the reaction mixture was stirred at room temperature for 15 min.
  • Step-4 N-[2-methyl-3-[6-[4-[(4-methyIpiperazin-l-yl)methyl]phenyl]-7H-pyrrolo[2,3-d] pyrimidin-4-yI]phenyl]isoindoline-2-carboxamide
  • Example Nl Example Nl (0.042g, 38% yield) was prepared from 17-111 (0.15 g, 0.21 mmol) as described in step-3; example Ml .
  • LCMS m/z 558.4 (M + 1) + .
  • Step-I N-[2-methyl-3-[6-(4-morpholinosulfonylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl]phenyl]isoindoline-2-carboxamide): O-II (0.26 g, 59 % yield) was prepared from O-I (0.29 g, 0.70 mmol) and INT-3-III (0.26 g, 0.70 mmol) following the procedure described in step-1 for preparation of example HI . LCMS: m/z 595.3 (M + 1) + .
  • hBTK Full length human BTK
  • Genbank#NM_000061.2 was cloned into pFastBac- HTB vector (Invitrogen, cat# 10359-016).
  • hBTK gene was expressed with N'-terminal 6XHis tag in Sf9 cells using Bac-to-Bac (R) Baculovirus expression system (Invitrogen, cat#10359-016) and the recombinant protein was purified by Ni-NTA method.
  • the elution buffer for hBTK consisted of 50 mM Hepes pH 8.0, 300 mM NaCl, 10% glycerol, 1 mM dithiothreitol and 200 mM imidazole.
  • the inhibition assays were performed using the generic tyrosine kinase assay kit from Cis Bio (HTRF ® KinEASE - TKTM # 62TK0PEB).
  • the assay is based on the principle of fluorescence resonance energy transfer (FRET) between the Europium Cryptate labeled anti- phosphotyrosine antibody and streptavidin labeled fluorophore, XL-665.
  • FRET fluorescence resonance energy transfer
  • Tk-Biotin biotinylated peptide substrate gets phosphorylated at an intermediate tyrosine site which is captured by anti-phosphotyrosine antibody which eventually acts as a FRET donor.
  • the streptavidin labeled XL-665 binds strongly to the Tk-Biotin substrate and act as a FRET acceptor.
  • the resultant FRET signal is measured at 665 nm.
  • a ratio of this specific fluorescence (665nm) to the background fluorescence (620nm), conferred by the free antibody, is directly proportional to the kinase activity. Inhibition of the kinase activity by a pharmacological intervention such as a Btk inhibitor of the present disclosure will result into decreased FRET signal.
  • the Btk inhibition assays were performed using 20 ng/ml of rhBtk in a final volume of ⁇ reaction buffer containing 77 ⁇ ATP and 1 ⁇ TK-Biotin Substrate in 50mM HEPES pH 7.0, 5mM MgC12, ImM DTT, 0.01 % Tween 20 and 50nM SEB ® ; with a range of concentrations of the inhibitors.
  • the kinase reaction was carried out at the K M of ATP (77 ⁇ ) as well as that of Tk-Biotin substrate ( ⁇ ⁇ ). After 90 min, the reaction was stopped by addition of SA-XL665 at a concentration of 62.5nM in HTRF ® detection buffer containing EDTA.
  • T antibody-cryptate was added to the reaction and the plate was incubated for additional 60 min.
  • the fluorescence was read using the Flexstation (Molecular Devices) with excitation at 340 nm and emissions at 620nm (for Cryptate) and 665nm (for FRET). A ratio of the 2 emissions was calculated for each well and expressed as follows:
  • % inhibition is calculated based on uninhibited reaction which is considered as 100% activity over no enzyme or substrate controls. Dose response data is then fit using a four parameter logistic equation using Graph-pad Prism 5 software to determine inhibition constant 50 ( IC50).
  • IC 50 of the recombinant human Btk (hBtk) enzyme inhibition is below 10 ⁇ , and more specifically below 1.0 ⁇
  • BTK inhibitors in suppressing B-cell receptor (BCR) mediated activation of B cells
  • BCR B-cell receptor
  • Test compounds were diluted half log starting from 2mM in 100% DMSO (200X). 1X10 5 splenocytes were incubated with luL of diluted test compounds in 200uL culture medium in a U- bottom 96 well plate (Greiner) at 37°C with 5% C0 2 for 30 mins. Control wells received luL of 100% DMSO without any compound. The cells were stimulated with 3ug/mL goat anti-mouse IgM (Sigma, cat#M8644) and incubated for 18-20 hrs.
  • Compounds of present disclosure are considered to be active in the B-cell specific functional assay (inhibition of CD69 expression) if IC 5 o values are less than 10 ⁇ .

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Abstract

La présente invention concerne une classe de composés bicycliques substitués de formule (I), leurs tautomères, polymorphes, stéréoisomères, promédicaments, solvates, hydrates, N-oxydes, co-cristaux, sels pharmaceutiquement acceptables et des compositions pharmaceutiques comprenant ceux-ci. L'invention concerne également le procédé de préparation de composés de formule (I). Ces composés sont utilisés dans le traitement, la prévention, la prophylaxie, la gestion ou le traitement adjoint de toutes les pathologies médicales liées à l'inhibition de la tyrosine kinase de Bruton (Btk), comme par exemple un trouble inflammatoire et/ou auto-immun, une prolifération cellulaire, une polyarthrite rhumatoïde, un psoriasis, un rhumatisme psoriasique, un rejet de greffe, une maladie du greffon contre l'hôte, une sclérose en plaques, une maladie inflammatoire de l'intestin, des maladies allergiques, un asthme, un diabète de type 1, une myasthénie grave, un dysfonctionnement hématopoïétique, des tumeurs malignes des lymphocytes b, un lupus érythémateux disséminé ou d'autres troubles.
PCT/IN2013/000257 2012-04-20 2013-04-18 Composés bicycliques, compositions et applications médicinales de ceux-ci WO2013157021A1 (fr)

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