WO2015170266A1 - Composés pyrimidine substitués en tant qu'inhibiteurs de la tyrosine kinase de bruton (btk) - Google Patents

Composés pyrimidine substitués en tant qu'inhibiteurs de la tyrosine kinase de bruton (btk) Download PDF

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WO2015170266A1
WO2015170266A1 PCT/IB2015/053306 IB2015053306W WO2015170266A1 WO 2015170266 A1 WO2015170266 A1 WO 2015170266A1 IB 2015053306 W IB2015053306 W IB 2015053306W WO 2015170266 A1 WO2015170266 A1 WO 2015170266A1
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amino
spiro
indolin
fluoro
pyrimidin
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PCT/IB2015/053306
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Bhavesh Dave
Milind Dattatraya Sindkhedkar
Abhijit Datta Khoje
Jitendra Sambhaji Jadhav
Venkata P. Palle
Rajender Kumar Kamboj
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Lupin Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present invention relates to substituted pyrimidine compounds of Formula (I) pharmaceutically acceptable salts thereof and pharmaceutical compositions for the treatment, management, and/or lessening the severity of diseases, disorders, syndromes or conditions associated with the inhibition of Bruton's tyrosine kinase (BTK).
  • BTK Bruton's tyrosine kinase
  • the invention also relates to method of treating, managing and/or lessening the severity of the diseases disorders, syndromes or conditions associated with the inhibition of Bruton's tyrosine kinase (BTK).
  • Protein kinases the largest family of human enzymes, consisting of more than 500 proteins are responsible for the control of a variety of signal transduction processes within the cell.
  • Protein kinases exert their physiological functions by catalysing the phosphorylation of protein(s) and thereby modulating the cellular activities. Because protein kinases have profound effect on cells, their activities are highly regulated. Kinases are turned on or off by phosphorylation (sometimes by auto-phosphorylation), by binding of activator proteins or inhibitor proteins. Dysfunctions in the activities of these kinases, arising from genetic abnormalities or environmental factors are known to be associated with many diseases. Several pathological states, including cancer and chronic inflammation are associated with stimulation of intra-cellular signalling and since kinases are crucial in relaying signalling events, their inhibition/modulation offers a powerful way to control signal transduction cascades [Mohamed AJ et al, Immunol Rev . (2009), 228, 58-73].
  • BTK Bruton's Tyrosine Kinase
  • Tec family of non-receptor tyrosine kinases is a key signalling enzyme expressed in all hematopoietic cell types except T lympocytes and natural killer cells.
  • BTK plays an essential role in B-cell signalling pathway thus controlling of B-cell survival in certain B-cell cancers (Kurosaki, Curr Op Imm, 2000, 276-281; Schaeffer and Schwartzberg, Curr Op Imm. 2000, 282-288).
  • the magnitude and duration of BCR signals must be precisely regulated.
  • BTK has been found to be an important enzyme for the survival of BCR-Abl-positive B-cell acute lymphoblastic and leukemia cells.
  • the inhibition of BTK enzyme activity can treat B-cell lymphoma and Leukemia [Quek et al. Current Biology (1998), 8, 1137-1140].
  • BTK is also expressed in osteoclasts, mast cells and monocytes and plays an important role in the function of these cells. Mutation of BTK in humans results in X-linked agammaglobulinaemia (XLA). Aberrant BCR-mediated signalling can cause dysregulated B-cell activation and/or the formation of pathogenic auto-antibodies leading to multiple autoimmune and/or inflammatory diseases. This disease is associated with the impaired maturation of B-cells, diminished immunoglobulin production, compromised T- cell-independent immune response and marked attenuation of the sustained calcium signalling upon BCR stimulation. Thus, the inhibition of BTK activity can be useful for the treatment of allergies and/or autoimmune diseases and/or inflammatory diseases.
  • XLA X-linked agammaglobulinaemia
  • BTK inhibitors Several compounds have been reported in the art as BTK inhibitors.
  • BTK is among a group of 11 kinases out of more than 500 kinases found in human. These 11 kinases are BLK, JAK3, MAP2K7, Tec family which includes Bmx, BTK, ITK, RLK, Tec and EGFR family which includes EGFR, HER2, HER4 kinases. There have been several approaches to develop different BTK inhibitors, however there is a need for selective BTK inhibitors.
  • the invention provides compounds having the structure of Formula (I),
  • Li is bond or -NR 3a -;
  • Ri which may be same or different at each occurrence, is independently selected fromhalogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, -C(0)R 6 , -C(0)NR a R b , - S0 2 NR a R b , -S0 2 R 6 , -NR a R b , -NR a C(0)R 6 , -NR a S(0) 2 R 6 and -OR 6 ;
  • R 2 is selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl and -C(0)NR a Rt,;
  • R a and R are independently hydrogen or substituted or unsubstituted alkyl
  • R3 and R 3a are each independently selected fromhydrogen or substituted or unsubstituted alkyl
  • R5 is selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted cycloalkyl and -OR 6 ; at each occurrence, R 6 is substituted or unsubstituted alkyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocyclyl;
  • 'n' is an integer ranging from 0 to 3, both inclusive; and the substituents on alkyl, alkenyl, alkynyl, alkoxyalkyl,cycloalkyl, aryl, heteroaryl, heterocyclyl, may be one or more, same or different and are independently selected from hydroxy, halogen, cyano, alkyl, alkenyl, haloalkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heterocyclic ring, -C(0)OR x , -C(0)R x , -CH 2 -OR x , -C(0)NR x R y , -NR x C(0)NR y R z , - N(R x )S(0) 2 R y , -NR x R y , -CH 2 NR x R y , -NR x C(0)R y , -S(0) 2 NR x R y
  • the invention provides compounds having the structure of Formula (la),
  • Li is bond or -NR 3 ;
  • Ri which may be same or different at each occurrence, is independently selected fromhalogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl and -OR 6 ;
  • R 2 is selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl and -C(0)NR a Rt,;
  • R a and R are each independently hydrogen or substituted or unsubstituted alkyl; at each occurrence, R 3 is hydrogen or substituted or unsubstituted alkyl; R 4 , which may be same or different at each occurrence, is independently selected from substituted or unsubstituted -C(0)-alkyl, substituted or unsubstituted -S(0)2-alkyl, substituted or unsubstituted -S(0)2-alkenyl, substituted or unsubstituted -C(0)-alkenyl, substituted or unsubstituted -C(0)-alkynyl, substituted or unsubstituted -C(0)-cycloalkyl and substituted or unsubstituted -S(0)2-cycloalkyl;
  • R5 is selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted cycloalkyl and OR 6 ; at each occurrence, R 6 is substituted or unsubstituted alkyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl; and
  • 'n' is an integer ranging from 0 to 3, both inclusive; or pharmaceutically acceptable salt thereof.
  • Li when ring system A is attached to the rest of the molecule via a carbon atom in the tricyclic ring system, Li is -NR 3a -. It may be that when ring system A is attached to the rest of the molecule via the nitrogen atom in the ring system, Li is a bond. It may be that, when ring system A is attached to the rest of the molecule via a carbon atom in the tricyclic ring system, Li is -NR 3 - and when ring system A is attached to the rest of the molecule via the nitrogen atom in the ring system, Li is a bond.
  • Li is -NR 3a - wherein R 3a is H.
  • Li is a bond
  • embodiment Li is a bond
  • R 2 is F.
  • R 3 is H.
  • R5 is H.
  • R 4 is substituted or unsubstituted -C(0)-alkenyl, substituted or unsubstituted -C(0)-alkynyl, substituted or unsubstituted -S(0) 2 -alkenyl or substituted or unsubstituted -S(0) 2 -alkynyl
  • the carbon-carbon double or triple bond of the alkene or alkyne group will typically attached with the -C(O)- or -S(0) 2 - moiety;
  • R 4 may be selected from:
  • L 2 and L 3 are each independently selected from -C(O)- and -S(0) 2 -; wherein R is selected from hydrogen, cyano, halo and substituted and unsubstituted Ci-C 4 -alkyl; R 8 and R 9 are each independently selected from hydrogen, -CH 2 - N(CH 3 ) 2 , substituted and unsubstituted Ci-C 4 -alkyl, C 3 -C 6 cycloalkyl and ⁇ ⁇ — f and Rio is hydrogen or substituted and unsubstituted Ci-C 4 -alkyl.
  • R 4 is hydrogen
  • R 4 is substituted -C(0)-alkyl or substituted- S(0) 2 -alkyl, where the alkyl is preferably substituted with a halogen (e.g. chloro) or -
  • R 4 may be: W , wherein L 4 is-C(O)- or -S(0) 2 -; Rn is H orsubstituted and unsubstituted Ci-C4-alkyl; and W is halogen (e.g. chloro) or - NHC(0)alkenyl.
  • R 4 is selected from (i) to (xxiii):
  • n 1 ; in this embodiment Ri is situated para to the -NR 3 - group.
  • Ri is selected fromhalogen (e.g. CI or F.,) cyano, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, -C(0)NR a R b , -S0 2 R 6 , -NR a R b , -NR a C(0)R 6 , - and -OR 6 ; wherein each of R 6 isindependently selectedfrom substituted or unsubstituted alkyl (e.g. methyl), substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl (e.g.
  • halogen e.g. CI or F.
  • Ri is heterocyclyl, e.g. an N-heterocyclyl group attached to the rest of the molecule via a nitrogen atom.
  • Ri may be morpholine or piperazine (e.g. N- methyl piperazine) attached to the rest of the molecule via a nitrogen atom.
  • Ri is -S0 2 R 6 where R 6 is alkyl or cycloalkyl.
  • ring system A and substituent R 4 together form a structure selected from (a), (c), (f) and (h):
  • Ri a is selected fromhalogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, - C(0)R 6 , -C(0)NR a R b , -S0 2 NR a R b , -S0 2 R 6 , -NR a R b , -NR a C(0)R 6 , -NR a S(0) 2 R 6 and -OR 6 ;
  • Ri b is selected from hydrogen, halogen and substituted or unsubstituted alkyl
  • R a and R b are independently hydrogen or substituted or unsubstituted alkyl
  • R 4 is selected from:
  • L 2 , L3 and L 4 are each independently selected from -C(O)- and -S(0) 2 -; wherein R is selected from hydrogen, cyano, halo and substituted and unsubstituted Ci-C 4 -alkyl; Rg and Rgare each independently selected from hydrogen, -
  • R 6 is substituted or unsubstituted alkyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocyclyl; or pharmaceutically acceptable salt thereof.
  • embodiment of the invention provides compounds having the structure of Formula (II),whereinRi a is selected fromhalogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, -C(0)NR a Rb, -S0 2 R 6 , -NR a Rb , -NR a C(0)R 6 and -OR 6 .
  • ring system A and substituent R 4 together form a structure selected from (b), (d), (e), (g) and (i):
  • Ri a is selected fromhalogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, - C(0)R 6 , -C(0)NR a R b , -S0 2 NR a R b , -S0 2 R 6 , -NR a R b , -NR a C(0)R 6 , -NR a S(0) 2 R 6 and -OR 6 ;
  • Ri b is selected from hydrogen, halogen and substituted or unsubstituted alkyl; R a and R are independently hydrogen or substituted or unsubstituted alkyl;
  • R 4 is selected from:
  • L 2 , L3 and L 4 are each independently selected from -C(O)- and -S(0) 2 -; wherein R is selected from hydrogen, cyano, halo and substituted and unsubstituted Ci-C 4 -alkyl; Rg and Rgare each independently selected from hydrogen, -CH 2 -N(CH 3 ) 2 , substituted and unsubstituted Ci-C 4 -alkyl, C 3 -C 6 cycloalkyl and Rio is independently selected from hydrogen and substituted and unsubstituted Ci-C 4 -alkyl; Rn is independently selected from hydrogen and substituted and unsubstituted Ci-C 4 -alkyl; and W is halogen; and at each occurrence, R 6 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted aryl,
  • the invention provides a pharmaceutical composition comprising at least one compound of Formula (I), Formula (la), Formula (II), and/or Formula (III) and at least one pharmaceutically acceptable excipient.
  • the invention provides a pharmaceutical composition of compound of Formula (I), Formula (la), Formula (II), and/or Formula (III) for use in treating, managing or lessening the severity of the diseases disorders, syndromes or conditions associated with BTK in a subject, in need thereof by administering to the subject, one or more compounds described herein in a therapeutically effective amount to cause inhibition of such enzyme.
  • the disease, disorders, syndromes or conditions associated with BTK is selected from cancer, proliferative disorders, autoimmune diseases, hetero-immune diseases, and inflammatory diseases.
  • alkyl refers to an alkane derived hydrocarbon radical that includes solely carbon and hydrogen atoms in the backbone, contains no unsaturation, has from 1 to 10, 1 to 6, or from 1 to 4 carbon atoms, and is attached to the remainder of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1 -methylethyl (isopropyl), n-butyl, n-pentyl, 1, 1- dimethylethyl (t-butyl) and the like. Unless set forth or recited to the contrary, all alkyl groups described or claimed herein may be straight chain or branched.
  • alkenyl refers to a hydrocarbon radical containing from 2 to 10 carbon atoms and including at least one carbon-carbon double bond.
  • alkenyl groups include ethenyl, 1-propenyl, 2-propenyl (allyl), zso-propenyl, 2-methyl-l- propenyl, 1-butenyl, 2-butenyl and the like. Unless set forth or recited to the contrary, all alkenyl groups described or claimed herein may be straight chain or branched.
  • alkynyl refers to a hydrocarbon radical containing 2 to 10 carbon atoms and including at least one carbon- carbon triple bond.
  • Non- limiting examples of alkynyl groups include ethynyl, propynyl, butynyl and the like. Unless set forth or recited to the contrary, all alkynyl groups described or claimed herein may be straight chain or branched.
  • alkoxy denotes an alkyl group attached via an oxygen linkage to the rest of the molecule. Representative examples of such groups are -OCH 3 and -OC 2 H 5 . Unless set forth or recited to the contrary, all alkoxy groups described or claimed herein may be straight chain or branched.
  • alkoxyalkyl refers to an alkoxy group as defined above directly bonded to an alkyl group as defined above, e.g., -CH 2 -0-CH 3 , -CH 2 -0-CH 2 CH 3 , -CH 2 CH 2 -0-CH 3 and the like.
  • haloalkyl refers to an alkyl group as defined above that is substituted by one or more halogen atoms as defined above.
  • the haloalkyl may be monohaloalkyl, dihaloalkyl or polyhaloalkyl including perhaloalkyl.
  • a monohaloalkyl can have one iodine, bromine, chlorine or fluorine atom.
  • Dihaloalkyl and polyhaloalkyl groups can be substituted with two or more of the same halogen atoms or a combination of different halogen atoms.
  • a polyhaloalkyl is substituted with up to 12 halogen atoms.
  • Non- limiting examples of a haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl and the like.
  • a perhaloalkyl refers to an alkyl having all hydrogen atoms replaced with halogen atoms. Unless set forth or recited to the contrary, all haloalkyl groups described or claimed herein may be straight chain or branche
  • haloalkoxy refers to a haloalkyl, defined herein, group attached via an oxygen linkage.
  • Non-limiting examples of such groups are monohaloalkoxy, dihaloalkoxy or polyhaloalkoxy including perhaloalkoxy. Unless set forth or recited to the contrary, all haloalkoxy group described or claimed herein may be straight chain or branched.
  • cycloalkyl refers to a non-aromatic mono or multicyclic ring system having 3 to 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • multicyclic cycloalkyl groups include, but are not limited to, perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups or spirobicyclic groups, e.g., spiro(4,4)non-2-yl and the like.
  • aryl refers to an aromatic radical having 6- to 14- carbon atoms, including monocyclic, bicyclic and tricyclic aromatic systems, such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, and biphenyl and the like.
  • arylalkyl refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH 2 C 6 H 5 and -C 2 H 4 C 6 H 5 .
  • heterocyclic ring or “heterocyclyl ring” or “heterocyclyl”, unless otherwise specified, refers to substituted or unsubstituted non-aromatic 3- to 15- membered ring which consists of carbon atoms and with one or more heteroatom(s) independently selected from N, O or S.
  • the heterocyclic ring may be a mono-, bi- or tricyclic ring system, which may include fused, bridged or spiro ring systems and the nitrogen, carbon, oxygen or sulfur atoms in the heterocyclic ring may be optionally oxidized to various oxidation states.
  • heterocyclic ring may also be fused with aromatic ring.
  • heterocyclic rings include azetidinyl, tetrahydro-2H-pyran,benzopyranyl, chromanyl, decahydroisoquinolyl, indanyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2- oxoazepinyl, octahydroindolyl, octahydroisoindolyl, perhydroazepinyl, piperazinyl, 4- piperidonyl, pyrrolidinyl, piperidinyl, phenothiazinyl, phenoxazinyl, quinuclidinyl, te
  • the heterocyclic ring may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
  • heteroaryl refers to a substituted or unsubstituted 5- to 14- membered aromatic heterocyclic ring with one or more heteroatom(s) independently selected from N, O or S.
  • the heteroaryl may be a mono-, bi- or tricyclic ring system.
  • the heteroaryl ring may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
  • Non-limiting examples of a heteroaryl ring include oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazolyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, isoquinolyl, thiadiazolyl, indolizinyl, acridinyl
  • heterocyclylalkyl refers to a heterocyclic ring radical directly bonded to an alkyl group.
  • the heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • heteroarylalkyl refers to a heteroaryl ring radical directly bonded to an alkyl group.
  • the heteroarylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • stereoisomer refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures which are not interchangeable. The three-dimensional structures are called configurations.
  • enantiomer refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another.
  • chiral center refers to a carbon atom to which four different groups are attached.
  • diastereomers refers to stereoisomers which are not enantiomers.
  • racemate or “racemic mixture” refer to a mixture of equal parts of enantiomers.
  • treating or “treatment” of a state, disease, disorder, condition or syndrome includes: (a) preventing or delaying the appearance of clinical symptoms of the state, disease, disorder, condition or syndrome developing in a subject that may be afflicted with or predisposed to the state, disease, disorder, condition or syndrome but does not yet experience or display clinical or subclinical symptoms of the state, disease, disorder, condition or syndrome; (b) inhibiting the state, disease, disorder, condition or syndrome, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; c) lessening the severity of a disease disorder or condition or at least one of its clinical or subclinical symptoms thereof; and/or (d) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
  • subject includes mammals, preferably humans and other animals, such as domestic animals; e.g., household pets including cats and dogs.
  • a “therapeutically effective amount” refers to the amount of a compound that, when administered to a subject in need thereof, is sufficient to cause a desired effect.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity, age, weight, physical condition and responsiveness of the subject to be treated.
  • Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, malic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benzenesulphonic, salicylic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids.
  • pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, n
  • the invention relates to pharmaceutical compositions containing the compounds of the Formula (I) disclosed herein.
  • pharmaceutical compositions containing a therapeutically effective amount of at least one compound of Formula (I) described herein and at least one pharmaceutically acceptable excipient (such as a carrier or diluent).
  • the contemplated pharmaceutical compositions include the compound(s) described herein in an amount sufficient to inhibit BTK associated diseases described herein when administered to a subject.
  • the subjects contemplated include, for example, a living cell and a mammal, including human mammal.
  • the compound of the invention may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
  • a pharmaceutically acceptable excipient includes pharmaceutical agent that does not itself induce the production of antibodies harmful to the individual receiving the composition, and which may be administered without undue toxicity.
  • suitable carriers or excipients include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatine, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatine, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, salicylic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, salts for influencing osmotic pressure, buffers, sweetening agents, flavouring agents, colorants, or any combination of the foregoing.
  • the pharmaceutical composition of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the subject by employing procedures known in the art.
  • the pharmaceutical compositions described herein may be prepared by conventional techniques known in the art.
  • the active compound can be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampoule, capsule, sachet, paper, or other container.
  • the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound.
  • compositions may be in conventional forms, for example, capsules, tablets, caplets, orally disintegrating tablets, aerosols, solutions, suspensions or products for topical application.
  • the route of administration may be any route which effectively transports the active compound of the invention to the appropriate or desired site of action.
  • Suitable routes of administration include, but are not limited to, oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic (such as with an ophthalmic solution) or topical (such as with a topical ointment).
  • Solid oral formulations include, but are not limited to, tablets, caplets, capsules (soft or hard gelatine), orally disintegrating tablets, dragees (containing the active ingredient in powder or pellet form), troches and lozenges. Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application.
  • Liquid formulations include, but are not limited to, syrups, emulsions, suspensions, solutions, soft gelatine and sterile injectable liquids, such as aqueous or non-aqueous liquid suspensions or solutions.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • the pharmaceutical preparation is preferably in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as pocketed tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, caplet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • the total daily dose of the compounds of the invention depends, of course, on the mode of administration.
  • oral administration may require a higher total daily dose, than an intravenous (direct into blood).
  • the quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 1000 mg according to the potency of the active component or mode of administration.
  • Suitable doses of the compounds for use in treating the diseases and disorders described herein can be determined by those skilled in the relevant art.
  • Therapeutic doses are generally identified through a dose ranging study in subject based on preliminary evidence derived from the animal studies. Doses must be sufficient to result in a desired therapeutic benefit without causing unwanted side effects for the patient.
  • Mode of administration, dosage forms, suitable pharmaceutical excipients, diluents or carriers can also be well used and adjusted by those skilled in the art. All changes and modifications are envisioned within the scope of the invention.
  • the compounds and compositions, according to the method of invention may be administered using any amount and any route of administration effective for treating or lessening the severity of cancer, autoimmune disorders, inflammatory diseases, neurodegenerative or neurological disorders, bone and joints related disorders.
  • the exact amount required will vary from subject to subject, depending on the age, and general condition of the subject, the severity of the disease, the particular agent, its mode of administration, depends on treatment disease, and the like.
  • the specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder, the activity of the compound, the specific composition employed, the age, body weight, general health, sex and diet of the patient, the time of administration, route of administration, and rate of excretion of the compound administered, the duration of the treatment, and like factors well known in the medical arts.
  • the compounds of the invention are useful in treating, managing and/or lessening the diseases, disorders, syndromes or conditions associated with the inhibition of Bruton's tyrosine kinase (BTK).
  • BTK Bruton's tyrosine kinase
  • the compounds of the invention are useful in treating, managing and/or lessening the severity of diseases, disorders, syndromes or conditions associated with the inhibition of Bruton's tyrosine kinase (BTK) such as but not limited to cancer, proliferative disorders, autoimmune diseases, hetero-immune diseases and inflammatory diseases.
  • BTK Bruton's tyrosine kinase
  • the invention relates to a method of treating, managing and/or lessening the severity of one or more diseases selected from a proliferative disorder, cancers or an autoimmune disorder hetero-immune diseases, and inflammatory diseases, wherein said method comprises administering to a patient in need thereof a compound or composition of compound of Formula (I).
  • the invention provides a method of treating, managing and/or lessening the severity of BTK associated disease or condition such as cancer.
  • the cancer is a B-cell proliferative disorders including but not limited to, diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, multiple myeloma (also known as plasma cell myeloma), non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmacytoma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, mantle cell lymphoma,
  • the cancer is breast cancer, bone cancer, prostate cancer or cancer of the mast cells (e.g., mastocytoma, mast cell leukemia, mast cell sarcoma, systemic mastocytosis).
  • the invention provides a method of treating, managing and/or lessening the severity of BTK associated disease or condition, namely, an autoimmune disease such as, but not limited to, inflammatory bowel disease, arthritis, lupus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, Sjogren's syndrome, multiple sclerosis, Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, systemic lupus erythematosis (SLE), autoimmune thyroiditissome
  • an autoimmune disease such
  • the invention provides a method of treating, managing and/or lessening the severity of BTK associated disease or condition such as heteroimmune conditions or diseases, which include, but are not limited to, allergies (e.g., allergies to plant pollens, latex, drugs, foods, insect poisons, animal hair, animal dander, dust mites, or cockroach calyx), allergic conjunctivitis, allergic rhinitis, atopic dermatitis, graft versus host disease, transplantation, transfusion, anaphylaxis and type I hypersensitivity.
  • allergies e.g., allergies to plant pollens, latex, drugs, foods, insect poisons, animal hair, animal dander, dust mites, or cockroach calyx
  • allergic conjunctivitis e.g., allergies to plant pollens, latex, drugs, foods, insect poisons, animal hair, animal dander, dust mites, or cockroach calyx
  • allergic conjunctivitis e.g.,
  • the invention provides a method of treating, managing and/or lessening the severity of BTK associated disease or condition such as inflammatory diseases which include, but are not limited to, asthma, chronic obstructive pulmonary disease (COPD), appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, Crohn's and ulcerative colitis, conjunctivitis, cystitis, dacryo adenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis, myelitis myocarditis
  • COPD
  • the invention provides a method of treating, managing and/or lessening the severity of BTK associated disease or condition such as thromboembolic disorder, including, but not limited to, myocardial infarct, angina pectoris, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after aortocoronary bypass, restenosis after aortocoronary bypass, stroke, transitory ischemia, a peripheral arterial occlusive disorder, pulmonary embolism, or deep venous thrombosis.
  • thromboembolic disorder including, but not limited to, myocardial infarct, angina pectoris, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after aortocoronary bypass, restenosis after aortocoronary bypass, stroke, transitory ischemia, a peripheral arterial occlusive disorder, pulmonary embolism, or deep venous thrombos
  • BTK-inhibition As used herein, the term "BTK-inhibition" "BTK-inhibition associated" diseases, disorders and/or conditions mean any disease or other disturbed condition in which BTK, or a mutant thereof, is known to play a role.
  • the diseases or disorders associated with BTK can be treated by compounds of Formulae (I) to (III) or pharmaceutically acceptable salts thereof.
  • the screening of compounds of Formulae (I) to (III) for BTK activity were achieved by using various in vitro protocols mentioned herein below.
  • the compounds described herein may be prepared by techniques known in the art.
  • the compounds described herein may be prepared by following the reaction sequence as depicted in Schemes- 1 & 2. Further, in the following schemes, where specific bases, acids, reagents, solvents, coupling agents, etc., are mentioned, it is understood that other bases, acids, reagents, solvents, coupling agents etc., known in the art may also be used and are therefore included within the scope of the present invention. Variations in reaction conditions, for example, temperature and/or duration of the reaction, which may be used as known in the art, are also within the scope of the present invention. All the isomers of the compounds described in these schemes, unless otherwise specified, are also encompassed within the scope of this invention.
  • This compounds of Formula (2) is reacted with compounds of Formula (3) in presence of a suitable base such as 2,6-lutidine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), K 2 C0 3 , Cs 2 C0 3 , NaH, KH, n-BuLi, lithium bis(trimethylsilyl)amide (LiHMDS) etc., in a suitable solvent to give compounds of Formula (4). Further, this compound of Formula (4) undergoes deprotection (removing the N protecting group of the ring A) reaction to give compounds of Formula (lb).
  • a suitable base such as 2,6-lutidine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), K 2 C0 3 , Cs 2 C0 3 , NaH, KH, n-BuLi, lithium bis(trimethylsilyl)amide (LiHMDS) etc.
  • Nomenclature of the compounds of the invention is according to ChemBioDraw version 12. Structures of the Intermediates as well as the final compounds were confirmed by spectral data.
  • Step-1 tert-Butyl 6'-nitrospiro[cyclopropane- 1 ,3'-indoline]- 1 '-carboxylate
  • Step-2 tert-Buty ⁇ 6'-aminospiro[cyclopropane-l,3'-indoline]-l'-carboxylate
  • Step-1 l-(6'-Nitrospiro[cyclopropane-l,3'-indolin]-l'-yl)propan-l-one
  • a solution of 6'-nitrospiro[cyclopropane-l,3'-indoline] (2.0 g, 10.52 mmol) and triethylamine (2.9 ml, 21.03 mmol) in DCM (30 ml) was added propionyl chloride (0.97 g, 10.52 mmol) at 0°C. Resulting mixture was stirred under N 2 atmosphere for 2 h. The solvent was evaporated in vacuo and the residue was partitioned between Ethyl acetate and water. The organic phase was separated and washed with aqueous NaHC0 3 solution and dried over sodium sulphate. The solvent was evaporated in vacuo to afford the title compound (2.4 g); which was used in the next step without further purification.
  • Step-2 l-(6'-Aminospiro[cyclopropane-l,3'-indolin]-l'-yl)propan-l-one
  • Step-3 l-(6'-((2-Chloro-5-fluoropyrimidin-4-yl)amino)spiro[cyclopropane-l,3'-indolin]-r- yl)propan-l-one
  • Step-1 l'-(2-Chloro-5-fluoropyrimidin-4-yl)-6'-nitrospiro[cyclopropane-l, 3'-indoline]
  • Step-2 5-Fluoro-N-(4-(2-methoxyethoxy)phenyl)-4-(6'-nitrospiro[cyclopropane- 1 ,3'- indolin] - 1 '-yl)pyrimidin-2-amine
  • Step-3 l'-(5-Fluoro-2-((4-(2-methoxyethoxy) phenyl) amino) pyrimidin-4-yl) spiro [cyclopropane- l,3'-indolin]-6'-amine
  • Step-1 tert-Eutyl 6'-nitrospiro[cyclobutane-l,3'-indoline]-l'-carboxylate
  • Step-2 tert-Buty ⁇ 6'-aminospiro[cyclobutane- 1 ,3'-indoline]- 1 '-carboxylate
  • Step-1 7'-Bromo-rH-spiro[cyclopropane-l,3'-quinolin]-2'(4'H)-one
  • Step-2 7'-Bromo-2',4'-dihydro- 1 'H-spiro[cyclopropane- 1 ,3'-quinoline]
  • Step-3 tert-Butyl 7'-bromo-2',4'-dihydro-rH-spiro[cyclopropane- l,3'-quinoline]-r- carboxylate
  • Step-4 tert-Butyl 7'-amino-2',4'-dihydro-rH-spiro[cyclopropane-l,3'-quinoline]-r- carboxylate
  • Bis(tri-teri-butylphosphine)palladium(0) (0.181 g, 0.36 mmol) was added to a solution of tert-butyl 7'-bromo-2',4'-dihydro-rH-spiro[cyclopropane-l,3'-quinoline]-r-carboxylate (2 g, 5.91 mmol) and LiHMDS (12 ml, 12 mmol) in THF. Resulting mixture was purged with N 2 for 5 min. and heated in a sealed tube at 90 °C for 1 h. After cooling to RT, 8 ml of 1 M TBAF solution in THF was added.
  • Step-1 l-(2,4-Dinitrophenyl)cyclopropanecarboxylic acid
  • Step-2 teri-Butyl 2-(l-(2,4-dinitrophenyl)cyclopropyl)acetate
  • Step-3 7'-Amino-rH-spiro[cyclopropane- l ,4'-quinolin]-2'(3'H)-one
  • Step-2 teri-Butyl 7'-((2-chloro-5-fluoropyrimidin-4-yl)amino)-2',3'-dihydro-rH- spiro[cyclopropane- 1 ,4'-quinoline] - l'-carboxylate
  • Step-3 tert-Buty ⁇ 7'-((5-fluoro-2-((4-(4-methylpiperazin- 1 -yl)phenyl)amino)pyrimidin-4- yl)amino)-2',3'-dihydro- 1 'H-spiro[cyclopropane- 1 ,4'-quinoline] - 1 '-carboxylate
  • Step-4 N-4-(2',3'-Dihydro-rH-spiro[cyclopropane-l,4'-quinolin]-7'-yl)-5-fluoro-N2-(4-(4- methylpiperazin- 1 -yl)phenyl)pyrimidine-2,4-diamine
  • Example-1 5-Fluoro-N2-(4-(2-methoxyethoxy)phenyl)-N4-(spiro[cyclopropane- 1 ,3'- indolin]-6'-yl)pyrimidine-2,4-diamine
  • Step-1 tert-Butyl 6'-((2-chloro-5-fluoropyrimidin-4-yl)amino)spiro[cyclopropane-l ,3'- indoline]- l'-carboxylate
  • Intermediate- 1 0.6 g, 2.31 mmol
  • 2,4-dichloro-5-fluoropyrimidine 0.462 g, 2.77 mmol
  • DIPEA 0.80 ml, 4.61 mmol
  • Step-2 teri-Butyl 6'-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4- yl)amino)spiro[cyclopropane- 1 ,3'-indoline]- 1 '-carboxylate
  • Step-3 5-Fluoro-N2-(4-(2-methoxyethoxy)phenyl)-N4-(spiro[cyclopropane- 1 ,3'-indolin]-6'- yl)pyrimidine-2,4-diamine
  • Example-2 l-(6'-((5-Fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino) spiro[cyclopropane- 1 ,3'-indolin]- l'-yl)prop-2-en- 1-one
  • reaction mixture was partitioned between water (25 ml) and Ethyl acetate (25 ml). The organic phase was separated and the aqueous phase was re-extracted with Ethyl acetate (25 ml). Combined organic phase was washed with water (50 ml), brine (25 ml) and dried over sodium sulphate. The solvent was evaporated in vacuo. Purification of the residue by flash chromatography afforded the title compound (60 mg).
  • Example-3 2-Chloro-l-(6'-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4- yl)amino)spiro[cyclopropane- 1 ,3'-indolin] - l'-yl)ethanone
  • Example-4 5-Fluoro-N2-(4-(2-methoxyethoxy)phenyl)-N4-(spiro[cyclobutane- 1 ,3'-indolin]- 6'-yl)pyrimidine-2,4-diamine
  • Step-1 tert-Buty ⁇ 6'-((2-chloro-5-fluoropyrimidin-4-yl)amino)spiro[cyclobutane-l ,3'- indoline]- l'-carboxylate
  • Step-2 5-Fluoro-N-2-(4-(2-methoxyethoxy)phenyl)-N4-(spiro[cyclobutane-l,3'-indolin]-6'- yl)pyrimidine-2,4-diamine
  • Example-7 5-Fluoro-N2-(4-(4-methylpiperazin-l-yl)phenyl)-N4-(spiro[cyclopropane-l ,3'- indolin]-6'-yl)pyrimidine-2,4-diamine
  • Step-1 tert-Buty ⁇ 6'-((5-fluoro-2-((4-(4-methylpiperazin-l-yl)phenyl)amino) pyrimidin-4- yl)amino)spiro[cyclopropane- 1 ,3'-indoline]- 1 '-carboxylate
  • Step-2 5-Fluoro-N2-(4-(4-methylpiperazin- 1 -yl)phenyl)-N4-(spiro[cyclo propane- 1 ,3'- indolin]-6'-yl)pyrimidine-2,4-diamine
  • Example-8 2-Chloro-l-(6'-((5-fluoro-2-((4-(4-methylpiperazin-l-yl)phenyl)amino) pyrimidin-4-yl)amino)spiro[cyclopropane-l ,3'-indolin]-l'-yl)propan-l-one
  • the chiral analysis conditions are:Column: Chiralpak-IB;Column size: 250 x 4.6 mm, 5 ⁇ ; injection: 5 ul; mobile phase: A: n-hexane + 0.1% DEA; B: EtOH: DCM (1: 1); flow rate: 1 ml/min;wave length: 225 nm; temperature: 25 °C
  • Example-8A 2-Chloro-l-(6'-((5-fluoro-2-((4-(4-methylpiperazin-l-yl) phenyl) amino) pyrimidin-4-yl)amino)spiro[cyclopropane-l,3'-indolin]-l'-yl)propan-l-one
  • Example-8B 2-Chloro-l-(6'-((5-fluoro-2-((4-(4-methylpiperazin-l-yl)phenyl) amino) pyrimidin-4-yl)amino)spiro[cyclopropane-l,3'-indolin]-l'-yl)propan-l-one
  • Example-9 l-(7'-((5-Fluoro-2-((4-morpholinophenyl)amino)pyrimidin-4-yl)amino)-2',3'- dihydro- 1 ⁇ -spiro [cyclopropane- 1 ,4'-quinolin] - 1 '-yl)prop-2-en- 1 -one
  • Step-1 7'-((2-Chloro-5-fluoropyrimidin-4-yl)amino)-rH-spiro[cyclopropane-l ,4'-quinolin]- 2'(3'H)-one
  • Step-2 7'-((5-Fluoro-2-((4-morpholinophenyl)amino)pyrimidin-4-yl)amino)-l'H-spiro [cyclopropane- l,4'-quinolin]-2'(3'H)-one
  • Step-3 N4-(2',3'-Dihydro-rH-spiro[cyclopropane-l ,4'-quinolin]-7'-yl)-5-fluoro-N2-(4- morpholinophenyl)pyrimidine-2,4-diamine
  • Step-4 l-(7'-((5-Fluoro-2-((4-morpholinophenyl)amino)pyrimidin-4-yl)amino)-2',3'-dihydro- 1 'H-spiro[cyclopropane- 1 ,4'-quinolin] - l'-yl)prop-2-en- 1 -one
  • reaction mixture was partitioned between water (25 ml) and ethyl acetate (25 ml). The organic phase was separated and the aqueous phase was re-extracted with Ethyl acetate (25 ml). Combined organic phase was washed with water (50 ml), brine (25 ml) and dried over sodium sulphate. The solvent was evaporated in vacuo. Purification of the residue by flash chromatography afforded the title compound (40 mg).
  • reaction mixture was partitioned between water (25 ml) and Ethyl acetate (25 ml). The organic phase was separated and the aqueous phase was re-extracted with Ethyl acetate (25 ml). Combined organic phase was washed with water (50 ml), brine (25 ml) and dried over sodium sulphate. The solvent was evaporated in vacuo. Purification of the residue by flash chromatography afforded the title compound (45 mg).
  • reaction mixture was partitioned between water (25 ml) and Ethyl acetate (25 ml). The organic phase was separated and the aqueous phase was re-extracted with Ethyl acetate (25 ml). Combined organic phase was washed with water (50 ml), brine (25 ml) and dried over sodium sulphate. The solvent was evaporated in vacuo. Purification of the residue by flash chromatography afforded the title compound (38 mg).
  • Example-12 N-(l'-(5-Fluoro-2-((4-phenoxyphenyl) amino) pyrimidin-4-yl) spiro [cyclo propane- 1 ,3'-indolin] -6'-yl)acrylamide
  • Step-1 5-Fluoro-4-(6'-nitrospiro [cyclopropane- l,3'-indolin]-l'-yl)-N-(4-phenoxy phenyl)pyrimidin-2-amine
  • Step-2 r-(5-Fluoro-2-((4-phenoxyphenyl)amino)pyrimidin-4-yl)spiro[cyclopropane-l,3'- indolin] -6'-amine
  • Step-3 N-(l'-(5-Fluoro-2-((4-phenoxyphenyl) amino) pyrimidin-4-yl) spiro[cyclopropane- l,3'-indolin]-6'-yl)acrylamide
  • Example-13 l-(6'-((5-Fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino) spiro[cyclopropane- 1 ,3'-indolin]- l'-yl)propan- 1 -one
  • Example-14 l-(6'-((5-Fluoro-2-((4-phenoxyphenyl)amino)pyrimidin-4-yl)amino)spiro [cyclo propane- 1 ,3'-indolin]- 1 '-yl)propan- 1 -one
  • Example-15 N-( 1 '-(5-Fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)spiro [cyclobutane-l,3'-indolin]-6'-yl)acrylamide
  • Step-1 r-(2-Chloro-5-fluoropyrimidin-4-yl)-6'-nitrospiro[cyclobutane-l,3'-indoline
  • Step-2 5-Fluoro-N-(4-(2-methoxyethoxy)phenyl)-4-(6'-nitrospiro [cyclobutane- 1 ,3'- indolin] - 1 '-yl)pyrimidin-2-amine
  • Step-3 r-(5-Fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)spiro [cyclo butane- l ,3'-indolin]-6'-amine
  • Step-4 N-( 1 '-(5-Fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)spiro [cyclo butane- l ,3'-indolin]-6'-yl)acrylamide
  • Example-16 N-(2-(6'-((5-Fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4- yl)amino)spiro[cyclobutane- 1 ,3'-indolin] - l'-yl)-2-oxoethyl)acrylamide
  • Step-1 tert-Butyl (2-(6'-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4- yl)amino)spiro[cyclobutane- 1 ,3'-indolin] - l'-yl)-2-oxoethyl)carbamate
  • Step-2 2-Amino- l-(6'-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4- yl)amino)spiro[cyclobutane- 1 ,3'-indolin] - l'-yl)ethanone
  • Step-3 N-(2-(6'-((5-Fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino) spiro[cyclobutane- 1 ,3'-indolin] - l'-yl)-2-oxoethyl)acrylamide
  • Example-17 (E)-4-(Dimethylamino)-l-(6'-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl) amino )pyrimidin-4-yl)amino)spiro[cyclopropane-l ,3'-indolin]-l'-yl)but-2-en-l -one
  • the biochemical assay uses ADP-GloTM Kinase Assay (Promega) to measure the ADP formed from a kinase reaction.
  • the assay carries three steps. First, the kinase enzyme reaction is carried out in presence or absence of test and reference compounds. ADP-GloTM Reagent is added to terminate the kinase reaction and deplete the remaining ATP. The Kinase detection reagent converts back the ADP formed during the kinase reaction to ATP, which is converted into light by Ultra-GloTM Luciferase, which is measure using BioTek Synergy 2 multimode plate reader. The luminescent signal positively correlates with kinase activity.
  • ADP-GloTM Kinase Assay Promega
  • test and reference compounds Desired concentration of test and reference compounds are pre incubated for 30 min with 1.5 ng/ml BTK kinase enzyme in 96 half area white opaque plate, followed by addition of 0.2 ⁇ g/ml substrate and 100 ⁇ ultra-pure ATP.
  • the reaction mixture is incubated in a shaking incubator for 30 min at room temperature at 250 rpm.
  • Equal volumes of ADP-GloTM Reagent is added and incubated in shaking for 40 min. Next, double the volume of Kinase detection reagent is added and the luminescence is measured after 30 min. Percentage incubation is calculated against positive control value.
  • This ELISA based assay measures tyrosine -phosphorylated Epidermal Growth Factor Receptor (phospho-EGF R) in cell lysates.
  • An immobilized capture antibody specific for EGFR binds both phosphorylated and unphosphorylated EGF R.
  • HRP-conjugated detection antibody specific for phosphorylated tyrosine is used to detect only phosphorylated protein, utilizing a standard HRP format.
  • A431 cells are pre incubated with desired concentration of test and reference compounds in serum free media for 30 min, followed by stimulation with 400 ng/ml EGF.
  • Spend media is removed after 6 to 8 min and cells lysed in ice cold IX lysis buffer containing protease and phosphatase inhibitor cocktails.
  • Phosphorylated EGFR in the lysate supernatant is measured by ELISA. Inhibition of EGFR Phosphorylation is calculated by comparing OD values of test against positive control values.
  • the biochemical assay uses ADP-GloTM Kinase Assay (Promega) to measure the ADP formed from a kinase reaction.
  • the assay carries three steps. First, the kinase enzyme reaction is carried out in presence or absence of test and reference compounds. ADP-GloTM Reagent is added to terminate the kinase reaction and deplete the remaining ATP. The Kinase detection reagent converts back the ADP formed during the kinase reaction to ATP, which is converted into light by Ultra-GloTM Luciferase, which is measure using BioTek Synergy 2 multimode plate reader. The luminescent signal positively correlates with kinase activity.
  • ADP-GloTM Kinase Assay Promega
  • test and reference compounds Desired concentration of test and reference compounds are pre incubated for 30 min with 1.5 ng/ml BTK kinase enzyme in 96 half area white opaque plate, followed by addition of 0.2 ⁇ g/ml substrate and 30 ⁇ ultra-pure ATP.
  • the reaction mixture is incubated in a shaking incubator for 30 min at room temperature at 250 rpm.
  • Equal volumes of ADP-GloTM Reagent is added and incubated in shaking for 40 min. Next, double the volume of Kinase detection reagent is added and the luminescence is measured after 30 min. Percentage incubation is calculated against positive control value.
  • Example BTK ICso ICso (nM) EGFR pEGFR inhibition (% No. nM Inhibition inhibition @10 ⁇ )
  • Inhibitory effect of compounds was assessed using recombinant JAK3 (Cat #J03-11G-10, SignalChem) as a source of kinase.
  • the kinase activity was measured using TR-FRET detection technology. Briefly, compounds and other reagents were diluted to desired concentrations in assay buffer (20 mM HEPES , pH 7.4, 10 mM MgC12, 2 mM DTT, 1 mM EGTA and 0.01% Tween-20). The enzyme at a concentration of 0.3nM was incubated with different concentrations of the test compound at room temperature for 30 minutes with shaking at 250rpm.
  • Kinase reaction was initiated by a freshly prepared mixture containing the substrate U Light polyGT Lance ultra (Cat# TRF 0100-M, Perkin Elmer) and Km concentration of ATP followed by incubation for 2 hours with shaking at 250rpm. lOmM EDTA was added to terminate the kinase reaction, followed by 2nM Anti-phosphotyrosine antibody (Cat # AD 0068, Perkin Elmer), and incubated at room temperature for 1 hour with shaking at 250rpm. FRET signal was measured in PHERAStar FS. The ratio of signals obtained at 620 nm and 665 nm were used to compute percent inhibition.
  • Table-8 BTK, EGFR, hoshoEGFR and JAK3 activity data for representative compounds.

Abstract

La présente invention concerne des composés pyrimidine de formule (I) dans laquelle les substituants sont tels que décrits dans la description, et leur utilisation dans un médicament destiné au traitement de maladies, de troubles associés à l'inhibition de la tyrosine kinase de Bruton (BTK). Elle concerne en outre les composés selon l'invention et leurs sels pharmaceutiquement acceptables, des compositions pharmaceutiques de ces derniers utiles dans le traitement de maladies, de troubles, de syndromes et/ou d'états associés à l'inhibition de la BTK.
PCT/IB2015/053306 2014-05-07 2015-05-06 Composés pyrimidine substitués en tant qu'inhibiteurs de la tyrosine kinase de bruton (btk) WO2015170266A1 (fr)

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CN107922405A (zh) * 2015-12-31 2018-04-17 中国科学院上海药物研究所 具有erk激酶抑制活性的化合物、其制备方法和用途
WO2020011731A1 (fr) * 2018-07-12 2020-01-16 UCB Biopharma SRL Analogues d'indanes spirocycliques utilisés comme modulateurs d'il-17
WO2022140246A1 (fr) 2020-12-21 2022-06-30 Hangzhou Jijing Pharmaceutical Technology Limited Procédés et composés destinés à l'autophagie ciblée
AU2021201532B2 (en) * 2015-07-09 2022-11-24 Merck Patent Gmbh Pyrimidine derivatives as BTK inhibitors and uses thereof
EP4079306A4 (fr) * 2019-12-19 2024-01-10 Taiho Pharmaceutical Co Ltd Agent thérapeutique contenant un composé de pyrimidine en tant que principe actif

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AU2021201532B2 (en) * 2015-07-09 2022-11-24 Merck Patent Gmbh Pyrimidine derivatives as BTK inhibitors and uses thereof
CN107922405A (zh) * 2015-12-31 2018-04-17 中国科学院上海药物研究所 具有erk激酶抑制活性的化合物、其制备方法和用途
CN107922405B (zh) * 2015-12-31 2021-02-19 中国科学院上海药物研究所 具有erk激酶抑制活性的化合物、其制备方法和用途
WO2018019204A1 (fr) * 2016-07-26 2018-02-01 深圳市塔吉瑞生物医药有限公司 Composé amino pyrimidine pour inhiber l'activité de la protéine tyrosine kinase
US11111233B2 (en) 2016-07-26 2021-09-07 Shenzhen Targetrx, Inc. Amino pyrimidine compound for inhibiting protein tyrosine kinase activity
WO2020011731A1 (fr) * 2018-07-12 2020-01-16 UCB Biopharma SRL Analogues d'indanes spirocycliques utilisés comme modulateurs d'il-17
JP2021531257A (ja) * 2018-07-12 2021-11-18 ユーシービー バイオファルマ エスアールエル Ｉｌ−１７モジュレーターとしてのスピロ環状インダン類似体
US11458124B2 (en) 2018-07-12 2022-10-04 UCBBiopharma Srl Spirocyclic indane analogues as IL-17 modulators
JP7349491B2 (ja) 2018-07-12 2023-09-22 ユーシービー バイオファルマ エスアールエル Ｉｌ－１７モジュレーターとしてのスピロ環状インダン類似体
EP4079306A4 (fr) * 2019-12-19 2024-01-10 Taiho Pharmaceutical Co Ltd Agent thérapeutique contenant un composé de pyrimidine en tant que principe actif
WO2022140246A1 (fr) 2020-12-21 2022-06-30 Hangzhou Jijing Pharmaceutical Technology Limited Procédés et composés destinés à l'autophagie ciblée

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