WO2015170266A1

WO2015170266A1 - Substituted pyrimidine compounds as btk inhibitors

Info

Publication number: WO2015170266A1
Application number: PCT/IB2015/053306
Authority: WO
Inventors: Bhavesh Dave; Milind Dattatraya Sindkhedkar; Abhijit Datta Khoje; Jitendra Sambhaji Jadhav; Venkata P. Palle; Rajender Kumar Kamboj
Original assignee: Lupin Limited
Priority date: 2014-05-07
Filing date: 2015-05-06
Publication date: 2015-11-12

Abstract

The present invention relates to pyrimidine compounds of Formula (I) wherein the substituents are as described herein, and their use in a medicine for the treatment of diseases, disorders associated with the inhibition of Bruton's tyrosine kinase (BTK). It further relates to the compounds herein and their pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof useful in treating diseases, disorders, syndromes and/or conditions associated with the inhibition of BTK.

Description

SUBSTITUTED PYRIMIDINE COMPOUNDS AS BTK INHIBITORS

Related applications

The present application claims the benefit of priority to Indian Provisional Patent Application No. 1591 MUM/2014 filed on May 7, 2014 and the entire provisional specification is incorporated herein by reference.

Field of the Invention

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). 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).

Background of the invention

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].

Bruton's Tyrosine Kinase (BTK), a member of 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. For instance, BTK has been found to be an important enzyme for the survival of BCR-Abl-positive B-cell acute lymphoblastic and leukemia cells. Thus, the inhibition of BTK enzyme activity can treat B-cell lymphoma and Leukemia [Quek et al. Current Biology (1998), 8, 1137-1140].

Additionally, 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. It has been further shown that selective BTK inhibitor has demonstrated dose-dependent efficacy in a mouse arthritis model [Lichuan Liu, Journal of Pharmacology and Experimental Therapeutics (2011) 338, 154-163 and Z. Pan et al., Chem. Med. Chem. 2007, 2, 58-61].

Several compounds have been reported in the art as BTK inhibitors. For example, patent application publications WO2015000949A1, WO2015002894A1, CN103864792A, WO2014040555A1, WO2013010380A1, WO2013148603A1, WO2009039397A2, WO2013185082A2, WO2013185084A1, WO2009158571A1, WO2013084216A2, WO2013173518A1, WO2010068806A1, WO2013067277A1, WO2013083666A1, and WO2011019780A1 disclose the compounds for inhibiting BTK. Some of the reported compounds are reversible or irreversible 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.

Summary of the Invention

In accordance with one aspect, the invention provides compounds having the structure of Formula (I),

wherein, ring system A and substituent R₄ together form a structure selected from (a) to (i):

wherein the substituent R5 is directly attached to the rest of the molecule at any chemically allowable position on the ring system A tricycle;

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)R₆, -C(0)NR_aR_b, - S0₂NR_aR_b, -S0₂R₆, -NR_aR_b , -NR_aC(0)R₆, -NR_aS(0)₂R₆and -OR₆;

R₂ is selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl and -C(0)NR_aRt,;

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;

R₄, which may be same or different at each occurrence, is independently selected from hydrogen, substituted or unsubstituted -C(0)-alkyl, substituted or unsubstituted -S(0)₂- alkyl, substituted or unsubstituted -C(0)-haloalkyl, substituted or unsubstituted -S(0)₂- haloalkyl, substituted or unsubstituted -S(0)₂- alkenyl, substituted or unsubstituted -S(0)₂- alkynyl, substituted or unsubstituted -C(0)-alkenyl, -C(0)-(CN)C=CH-C(CH₃)₂-morpholine, 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 -OR₆; at each occurrence, R₆ 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, -CH₂-OR^x, -C(0)NR^xR^y, -NR^xC(0)NR^yR^z, - N(R^x)S(0)₂R^y, -NR^xR^y, -CH₂NR^xR^y, -NR^xC(0)R^y, -S(0)₂NR^xR^y, -OR^x, -OC(0)R^x, - OC(0)NR^xR^y, -alkylene-C(0)R^yand -S(0)₂R^x wherein each occurrence of R^x, R^y and R^z are independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl and cycloalkyl; or pharmaceutically acceptable salt thereof.

In accordance with one aspect, the invention provides compounds having the structure of Formula (la),

(la) (Ri )_n wherein, ring A is selected from (a) to (i):

Li is bond or -NR₃;

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 -OR₆;

R_a and R are each independently hydrogen or substituted or unsubstituted alkyl; at each occurrence, R₃ is hydrogen or substituted or unsubstituted alkyl; R₄, 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 OR₆; at each occurrence, R₆ 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.

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_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 -NR₃- 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.

According to one embodiment wherein Li is -NR_3a- where R_3a is H.

According to another embodiment wherein Li is a bond.

According to another embodiment wherein ring system A and substituent R4 together form a group selected from:

; Inthis embodiment Li is -

NR3a-where R_3a is hydrogen.

According to another embodiment whereinring system A and substituent R₄ together form a group selected from:

embodiment Li is a bond.

According to another embodiment wherein R₂ is F. According to another embodiment wherein R₃ is H. According to another embodiment wherein R5 is H.

According to another embodiment whereinR₄ 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; Thus, R₄ may be selected from:

and ; wherein L₂ and L₃ are each independently selected from -C(O)- and -S(0)₂-; wherein R is selected from hydrogen, cyano, halo and substituted and unsubstituted Ci-C₄-alkyl; R 8 and R 9 are each independently selected from hydrogen, -CH₂- N(CH₃)₂, substituted and unsubstituted Ci-C₄-alkyl, C₃-C₆cycloalkyl and ^ ^— f and Rio is hydrogen or substituted and unsubstituted Ci-C₄-alkyl.

According to another embodiment wherein R₄ is hydrogen.

According to another embodiment wherein R₄ is substituted -C(0)-alkyl or substituted- S(0)₂-alkyl, where the alkyl is preferably substituted with a halogen (e.g. chloro) or -

NHC(0)alkenyl; Thus, R₄ may be: W , wherein L₄ 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.

In certain embodiments, R₄ is selected from (i) to (xxiii):

According to another embodiment wherein n is 1 ; in this embodiment Ri is situated para to the -NR₃- group.

According to another embodiment whereinRiis selected fromhalogen (e.g. CI or F.,) cyano, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, -C(0)NR_aR_b, -S0₂R₆, -NR_aR_b, -NR_aC(0)R₆, - and -OR₆; wherein each of R₆ isindependently selectedfrom substituted or unsubstituted alkyl (e.g. methyl), substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl (e.g. phenyl), substituted or unsubstituted heteroaryl (e.g. pyridyl) and substituted or unsubstituted heterocyclyl (e.g.a heteocyclyl group comprising an oxygen atom) andRa and Rbare each independently hydrogen or substituted or unsubstituted alkyl. In one embodiment Riis heterocyclyl, e.g. an N-heterocyclyl group attached to the rest of the molecule via a nitrogen atom. Thus, Ri may be morpholine or piperazine (e.g. N- methyl piperazine) attached to the rest of the molecule via a nitrogen atom.

In one embodiment Ri is -S0₂R₆ where R₆is alkyl or cycloalkyl.

In one embodiment Riis-NR_aR_bOr -NR_aC(0)R₆where R₆ is alkyl and Ra and Rbeach independently alkyl (e.g. methyl). iment Riis -OR₆ whereR₆isselected from alkyl,heterocyclyl(e.g.

), alkoxyalkyl, phenyl and heteroaryl.

According to another embodiment wherein n is 2. embodiment of the invention provides compounds having the structure of Formula

(II),

wherein, ring system A and substituent R₄ 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)R₆, -C(0)NR_aR_b, -S0₂NR_aR_b, -S0₂R₆, -NR_aR_b , -NR_aC(0)R₆, -NR_aS(0)₂R₆ and -OR₆;

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;

R₄ is selected from:

; wherein L₂, L3 and L₄ are each independently selected from -C(O)- and -S(0)₂-; wherein R is selected from hydrogen, cyano, halo and substituted and unsubstituted Ci-C₄-alkyl; Rg and Rgare each independently selected from hydrogen, -

CH₂-N(CH₃)₂, substituted and unsubstituted Ci-C₄-alkyl, C₃-C₆cycloalkyl and^ ^— / ; Rio is hydrogen and substituted or unsubstituted Ci-C₄-alkyl; Rn is hydrogen and substituted or unsubstituted Ci-C₄-alkyl; and W is halogen or -NHC(0)alkenyl; and at each occurrence, R₆ 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. According to another embodiment, there are provided compounds of Formula (II),whereinRi_ais selected fromhalogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, -C(0)NR_aRb, -S0₂R₆, -NR_aRb , -NR_aC(0)R₆and -OR₆. embodiment of the invention provides compounds having the structure of Formula

wherein, ring system A and substituent R₄ together form a structure selected from (b), (d), (e), (g) and (i):

Ri_b is selected from hydrogen, halogen and substituted or unsubstituted alkyl; R_a and R are independently hydrogen or substituted or unsubstituted alkyl;

R₄ is selected from:

; wherein L₂, L3 and L₄ are each independently selected from -C(O)- and -S(0)₂-; wherein R is selected from hydrogen, cyano, halo and substituted and unsubstituted Ci-C₄-alkyl; Rg and Rgare each independently selected from hydrogen, -CH₂-N(CH₃)₂, substituted and unsubstituted Ci-C₄-alkyl, C₃-C₆cycloalkyl and

Rio is independently selected from hydrogen and substituted and unsubstituted Ci-C₄-alkyl; Rn is independently selected from hydrogen and substituted and unsubstituted Ci-C₄-alkyl; and W is halogen; and at each occurrence, R₆ is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocyclyl; or pharmaceutically acceptable salt thereof.

Below are the representative compounds, which are illustrative in nature only and are not intended to limit to the scope of the invention:

5-Fluoro-N2-(4-(2-methoxyethoxy)phenyl)-N4-(spiro[cyclopropane-l,3'-indolin]-6'- yl)pyrimidine-2,4-diamine,

1- (6'-((5-Fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino) spiro[cyclopropane- 1 ,3'-indolin]- 1 '-yl)prop-2-en- 1-one,

2- Chloro-l-(6'-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4- yl)amino)spiro[cyclopropane- 1 ,3'-indolin] - l'-yl)ethanone, 5-Fluoro-N2-(4-(2-methoxyethoxy)phenyl)-N4-(spiro[cyclobutane-l,3'-indolin]-6'- yl)pyrimidine-2,4-diamine,

1- (6'-((5-Fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino) spiro[cyclobutane- 1 ,3'-indolin] - 1 '-yl)prop-2-en- 1 -one,

2- Chloro- l-(6'-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4- yl)amino)spiro[cyclobutane- 1 ,3'-indolin] - l'-yl)ethanone,

5-Fluoro-N2-(4-(4-methylpiperazin-l-yl)phenyl)-N4-(spiro[cyclopropane- l,3'-indolin]-6'- yl)pyrimidine-2,4-diamine,

2-Chloro- l-(6'-((5-fluoro-2-((4-(4-methylpiperazin-l-yl)phenyl)amino) pyrimidin-4- yl)amino)spiro[cyclopropane- 1 ,3'-indolin] - l'-yl)propan- 1 -one,

2-Chloro- l-(6'-((5-fluoro-2-((4-(4-methylpiperazin-l-yl) phenyl) amino) pyrimidin-4- yl)amino)spiro[cyclopropane- 1 ,3'-indolin] - l'-yl)propan- 1 -one,

2-Chloro- l-(6'-((5-fluoro-2-((4-(4-methylpiperazin-l-yl)phenyl) amino) pyrimidin-4- yl)amino)spiro[cyclopropane- 1 ,3'-indolin] - l'-yl)propan- 1 -one,

1- (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,

N-(l'-(5-Fluoro-2-((4-(2-methoxyethoxy) phenyl) amino) pyrimidin-4-yl) spiro

[cyclopropane- l,3'-indolin]-6'-yl)acrylamide,

2- Chloro-N-(l'-(5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4- yl)spiro[cyclopropane-l,3'-indolin]-6'-yl)acetamide,

N-(l'-(5-Fluoro-2-((4-phenoxyphenyl) amino) pyrimidin-4-yl) spiro [cyclo propane- 1,3'- indolin] -6'-yl)acrylamide, l-(6'-((5-Fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino) spiro[cyclopropane- 1 ,3'-indolin]- 1 '-yl)propan- 1-one, l-(6'-((5-Fluoro-2-((4-phenoxyphenyl)amino)pyrimidin-4-yl)amino)spiro [cyclo propane- 1 ,3 '-indolin] - l'-yl)propan- 1 -one,

N-(r-(5-Fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)spiro

[cyclobutane-l,3'-indolin]-6'-yl)acrylamide,

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,

(E)-4-(Dimethylamino)-l-(6'-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)

amino )pyrimidin-4-yl)amino)spiro[cyclopropane- 1 ,3'-indolin]- 1 '-yl)but-2-en- 1 -one,

5-Fluoro-N2-(4-(2-methoxyethoxy)phenyl)-N4-( 1 '-(vinylsulfonyl)spiro [cyclopropane- l,3'-indolin]-6'-yl)pyrimidine-2,4-diamine,

5-Fluoro-N2-(4-phenoxyphenyl)-N4-(spiro[cyclobutane-l,3'-indolin]-6'-yl)pyrimidine- 2,4-diamine,

5-Fluoro-N2-(4-morpholinophenyl)-N4-(spiro[cyclobutane-l,3'-indolin]-6'-yl)pyrimidine- 2,4-diamine,

N4-(2',4'-Dihydro-l'H-spiro[cyclo propane- 1, 3'-quinolin]-7'-yl)-5-fluoro-N2-(4-(2- methoxyethoxy)phenyl)pyrimidine-2,4-diamine, l-(6'-((5-Fluoro-2-((4-methoxyphenyl)amino) pyrimidin-4-yl)amino) spirofcyclopropane- 1 ,3'-indolin] - l'-yl)prop-2-en- 1 -one, l-(6'-((2-((4-Ethoxyphenyl)amino)-5-fluoropyrimidin-4-yl)amino)spiro [cyclo propane - 1 ,3'-indolin] - l'-yl)prop-2-en- 1 -one, l-(6'-((2-([ l, l'-Biphenyl]-4-ylamino)-5-fluoropyrimidin-4-yl)amino)spiro [cyclo propane- 1 ,3'-indolin] - 1 '-yl)prop-2-en- 1 -one, l-(6'-((2-((4-Chlorophenyl)amino)-5-fluoropyrimidin-4-yl)amino)spiro [cyclo propane - 1 ,3'-indolin] - l'-yl)prop-2-en- 1 -one, l-(6'-((5-Fluoro-2-((4-(pyridin-3-yloxy)phenyl)amino)pyrimidin-4- yl)amino)spiro[cyclopropane- 1 ,3'-indolin] - l'-yl)prop-2-en- 1 -one, l-(6'-((5-Fluoro-2-((4-(methylsulfonyl) phenyl)amino)pyrimidin-4-yl)amino)

spiro[cyclopropane- 1 ,3'-indolin]- 1 '-yl)prop-2-en- 1-one, l-(6'-((2-((4-(Cyclopropylsulfonyl) phenyl)amino)-5-fluoropyrimidin-4-yl)

amino)spiro [cyclopropane- 1 ,3'-indolin] - l'-yl)prop-2-en- 1 -one, l-(6'-((5-Fluoro-2-((4-fluorophenyl) amino )pyrimidin-4-yl)amino)spiro [cyclopropane- 1 ,3'-indolin] - l'-yl)prop-2-en- 1 -one, l-(6'-((5-Fluoro-2-((4-((tetrahydrofuran-3-yl)oxy)phenyl)amino)pyrimidin-4- yl)amino)spiro[cyclopropane- 1 ,3'-indolin] - l'-yl)prop-2-en- 1 -one, l-(6'-((5-Fluoro-2-(p-tolylamino)pyrimidin-4-yl)amino)spiro[cyclopropane-l,3'-indolin]- l'-yl)prop-2-en- 1 -one, l-(6'-((5-Fluoro-2-((4-(4-methylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)amino) spiro[cyclopropane- 1 ,3'-indolin]- 1 '-yl)prop-2-en- 1-one, l-(6'-((5-Fluoro-2-((4-(pyridin-4-yloxy)phenyl)amino)pyrimidin-4- yl)amino)spiro[cyclopropane- 1 ,3'-indolin] - l'-yl)prop-2-en- 1 -one, l-(6'-((5-Fluoro-2-((4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)amino) pyrimidin-4- yl)amino)spiro [cyclopropane- 1 ,3'-indolin]- l'-yl)prop-2-en- 1 -one, l-(6'-((5-Fluoro-2-((4-phenoxyphenyl) amino)pyrimidin-4-yl)amino)spiro [cyclopropane- 1 ,3'-indolin] - l'-yl)prop-2-en- 1 -one, l-(6'-((5-Fluoro-2-((4-morpholinophenyl)amino)pyrimidin-4-yl)amino)spiro [cyclo propane- 1 ,3'-indolin] - 1 '-yl)prop-2-en- 1 -one,

4-((4-(( Γ- Aery loylspiro [cyclopropane- 1 ,3'-indolin]-6'-yl)amino)-5-fluoropyrimidin-2- yl)amino)benzonitrile, N-(4-((4-((l'-Acryloylspiro[cyclopropane-l,3'-indolin]-6'-yl)amino)-5-fluoropyrimidin-2- yl)amino)phenyl)acetamide, l-(6'-((2-((4-(Dimethylamino)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)spiro

[cyclopropane- 1 ,3'-indolin]- 1 '-yl)prop-2-en- 1 -one, l-(6'-((5-Fluoro-2-((4-phenoxyphenyl) amino)pyrimidin-4-yl)amino)spiro [cyclobutane- 1 ,3'-indolin] - l'-yl)prop-2-en- 1 -one, l-(6'-((5-Fluoro-2-((4-fluorophenyl)amino) pyrimidin-4-yl)amino)spiro[cyclobutane-l,3'- indolin] - 1 '-yl)prop-2-en- 1 -one, l-(6'-((5-Fluoro-2-((4-((tetrahydrofuran-3-yl)oxy)phenyl)amino)pyrimidin-4- yl)amino)spiro[cyclobutane- 1 ,3'-indolin] - 1 '-yl)prop-2-en- 1 -one, l-(6'-((2-((4-Chlorophenyl)amino)-5-fluoropyrimidin-4-yl)amino)spiro[cyclobutane-l,3'- indolin] - 1 '-yl)prop-2-en- 1 -one, l-(6'-((2-((4-Ethoxyphenyl)amino)-5-fluoropyrimidin-4-yl)amino)spiro cyclo butane- 1 ,3'-indolin] - l'-yl)prop-2-en- 1 -one, l-(6'-((5-Fluoro-2-((4-morpholino phenyl) amino)pyrimidin-4-yl)amino)spiro [cyclo butane- l,3'-indolin]-l'-yl)prop-2-en-l-one, l-(6'-((5-Fluoro-2-((4-methoxyphenyl) amino)pyrimidin-4-yl)amino)spiro [cyclobutane- 1 ,3'-indolin] - l'-yl)prop-2-en- 1 -one, l-(6'-((2-([l,l'-Biphenyl]-4-ylamino)-5-fluoropyrimidin-4-yl)amino)spiro [cyclo butane - 1 ,3'-indolin] - l'-yl)prop-2-en- 1 -one, l-(6'-((5-Fluoro-2-((4-(methylsulfonyl) phenyl) amino)pyrimidin-4-yl)amino)spiro [cyclo butane- l,3'-indolin]-l'-yl)prop-2-en-l-one, l-(6'-((5-Fluoro-2-((4-(pyridin-3-yloxy)phenyl amino)pyrimidin-4-yl)amino)spiro[cyclo butane- l,3'-indolin]-l'-yl)prop-2-en-l-one, l-(6'-((2-((4-(Cyclopropylsulfonyl) phenyl)amino)-5-fluoropyrimidin-4- yl)amino)spiro[cyclobutane- 1 ,3'-indolin] - 1 '-yl)prop-2-en- 1 -one, l-(6'-((5-Fluoro-2-(p-tolylamino)pyrimidin-4-yl)amino)spiro[cyclobutane-l,3'-indolin]- l'-yl)prop-2-en- 1 -one,

4-((4-(( -Acryloylspko[cyclobutane-l,3'-indolin]-6'-yl)amino)-5-fluoropyrimidin-2- yl)amino)benzamide, l-(6'-((5-Fluoro-2-((4-(4-methylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)amino) spiro[cyclobutane- 1 ,3'-indolin] - 1 '-yl)prop-2-en- 1 -one, l-(7'-((5-Fluoro-2-((4-(2-methoxyethoxy) phenyl)amino)pyrimidin-4-yl)amino)-2',4'- dihydro- 1 Ή-spiro [cyclopropane- 1 ,3'-quinolin] - 1 '-yl)prop-2-en- 1 -one, l-(7'-((5-Fluoro-2-((4-morpholinophenyl) amino)pyrimidin-4-yl)amino)-2',4'-dihydro- rH-spiro[cyclopropane-l,3'-quinolin]-l'-yl)prop-2-en-l-one, l-(7'-((5-Fluoro-2-((4-(methylsulfonyl)phenyl) amino)pyrimidin-4-yl)amino)-2',4'- dihydro- 1 Ή-spiro [cyclopropane- 1 ,3'-quinolin] - 1 '-yl)prop-2-en- 1 -one, l-(7'-((5-Fluoro-2-((4-((tetrahydrofuran-3-yl)oxy)phenyl)amino)pyrimidin-4-yl)amino)- 2',4'-dihydro-rH-spiro[cyclopropane-l,3'-quinolin]-r-yl)prop-2-en-l-one,

(E)-l-(6'-((5-Fluoro-2-((4-(2-methoxyethoxy) phenyl)amino)pyrimidin-4-yl)amino)spiro [cyclopropane- 1 ,3'-indolin]- 1 '-yl)but-2-en- 1 -one,

(E)-l-(6'-((5-Fluoro-2-((4-(2-methoxyethoxy) phenyl)amino)pyrimidin-4-yl)amino)spiro [cyclobutane- 1 ,3'-indolin] - l'-yl)but-2-en- 1 -one,

1- (7'-((5-Fluoro-2-((4-(4-methylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)amino)- 2',3'-dihydro-rH-spiro[cyclopropane-l,4'-quinolin]-r-yl)prop-2-en-l-one,

2- Chloro-l-(6'-((5-fluoro-2-((4-methoxyphenyl)amino)pyrimidin-4- yl)amino)spiro[cyclopropane- 1 ,3'-indolin] - l'-yl)ethanone, 2-Chloro-l-(6'-((2-((4-ethoxyphenyl) amino)-5-fluoropyrimidin-4-yl)amino)

spiro[cyclopropane- 1 ,3'-indolin]- 1 '-yl)ethanone,

1- (6'-((2-([l,l'-Biphenyl]-4-ylamino)-5-fluoropyrimidin-4-yl)amino)spiro [cyclopropane- 1 ,3'-indolin] - l'-yl)-2-chloroethanone,

2- Chloro-l-(6'-((2-((4-chlorophenyl) amino)-5-fluoropyrimidin-4-yl)amino)

spiro[cyclopropane- 1 ,3'-indolin]- 1 '-yl)ethanone,

2-Chloro-l-(6'-((5-fluoro-2-((4-(pyridin-3-yloxy)phenyl)amino) pyrimidin-4- yl)amino)spiro [cyclopropane- 1 ,3'-indolin]- l'-yl)ethanone,

2-Chloro-l-(6'-((5-fluoro-2-((4-phenoxyphenyl) amino) pyrimidin-4-yl)amino) spiro [cyclopropane- 1 ,3'-indolin]- 1 '-yl)ethanone,

2-Chloro-l-(6'-((5-fluoro-2-((4-morpholinophenyl)amino)pyrimidin-4- yl)amino)spiro[cyclopropane- 1 ,3'-indolin] - l'-yl)ethanone,

2-Chloro-l-(6'-((5-fluoro-2-((4-((tetrahydrofuran-3-yl)oxy)phenyl) amino)pyrimidin-4- yl)amino)spiro [cyclopropane- 1 ,3'-indolin]- l'-yl)ethanone,

2-Chloro-l-(6'-((2-((4-(cyclopropyl sulfonyl) phenyl)amino)-5-fluoro pyrimidin-4- yl)amino)spiro [cyclo propane- l,3'-indolin]-l'-yl)ethanone,

2-Chloro- l-(6'-((5-fluoro-2-((4-fluorophenyl) amino) pyrimidin-4-yl)amino)spiro

[cyclopropane- 1 ,3'-indolin]- 1 '-yl)ethanone,

2-Chloro- l-(6'-((5-fluoro-2-((4-(methyl sulfonyl )phenyl) amino)pyrimidin-4-yl) amino)spiro [cyclopropane- 1 ,3'-indolin]- l'-yl)ethanone,

2-Chloro- l-(6'-((5-fluoro-2-(p-tolylamino)pyrimidin-4-yl)amino)spiro [cyclopropane- 1 ,3'-indolin] - l'-yl)ethanone,

2-Chloro- l-(6'-((5-fluoro-2-((3-fluoro-4-morpholino phenyl) amino) pyrimidin-4- yl)amino)spiro [cyclopropane -l,3'-indolin]-l'-yl)propan-l-one, 2-Chloro- l-(6'-((5-fluoro-2-((4-methoxyphenyl) amino) pyrimidin-4-yl)amino)spiro [cyclobutane- 1 ,3'-indolin] - l'-yl)ethanone,

2-Chloro- l-(6'-((5-fluoro-2-((4-((tetrahydrofuran-3-yl)oxy)phenyl) amino) pyrimidin-4- yl)amino)spiro [cyclobutane- l,3'-indolin]-l'-yl)ethanone,

2-Chloro- l-(6'-((2-((4-(cyclopropyl sulfonyl) phenyl)amino)-5-fluoro pyrimidin-4- yl)amino)spiro [cyclo butane-l,3'-indolin]-l'-yl)ethanone,

2-Chloro- l-(6'-((5-fluoro-2-((4-(pyridin-3-yloxy)phenyl)amino) pyrimidin-4- yl)amino)spiro [cyclobutane- l,3'-indolin]-l'-yl)ethanone,

2-Chloro- l-(6'-((5-fluoro-2-(p-tolyl amino)pyrimidin-4-yl)amino)spiro [cyclobutane- 1,3'- indolin]-l'-yl) ethanone,

2-Chloro- l-(6'-((5-fluoro-2-((4-(methylsulfonyl)phenyl)amino)pyrimidin-4- yl)amino)spiro [cyclobutane- l,3'-indolin]-l'-yl)ethanone,

2-Chloro- l-(6'-((5-fluoro-2-((4-fluorophenyl)amino)pyrimidin-4- yl)amino)spiro[cyclobutane- 1 ,3'-indolin] - l'-yl)ethanone,

1- (6'-((2-([l,l'-Biphenyl]-4-yl amino)-5-fluoropyrimidin-4-yl) amino)spiro [cyclobutane - 1 ,3'-indolin] - l'-yl)-2-chloroethanone,

2- Chloro- l-(6'-((2-((4-chlorophenyl) amino)-5-fluoro pyrimidin-4-yl)amino) spiro

[cyclobutane- 1 ,3'-indolin] - l'-yl) ethanone,

2-Chloro- l-(6'-((2-((4-ethoxyphenyl) amino)-5-fluoro pyrimidin-4-yl)amino) spiro

[cyclobutane- 1 ,3'-indolin] - l'-yl) ethanone,

2-Chloro- l-(6'-((5-fluoro-2-((4-morpholinophenyl)amino)pyrimidin-4- yl)amino)spiro[cyclobutane- 1 ,3'-indolin] - l'-yl)ethanone,

2-Chloro- l-(6'-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4- yl)amino)spiro [cyclobutane-l,3'-indolin]-l'-yl) ethanone, 2-Chloro-l-(6'-((5-fluoro-2-((4-phenoxyphenyl)amino)pyrimidin-4- yl)amino)spiro[cyclobutane- 1 ,3'-indolin] - l'-yl)ethanone,

2-Chloro-l-(7'-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)- 2',4'-dihydro-rH-spiro[cyclopropane-l,3'-quinolin]-r-yl)ethanone,

2-Chloro-l-(6'-((5-fluoro-2-((4-(pyridin-4-yloxy)phenyl)amino) pyrimidin-4- yl)amino)spiro [cyclopropane- 1 ,3'-indolin]- l'-yl)propan- 1 -one,

2-Chloro-l-(6'-((5-fluoro-2-((4-phenoxyphenyl)amino)pyrimidin-4- yl)amino)spiro[cyclopropane- 1 ,3'-indolin] - l'-yl)propan- 1 -one,

2-Chloro-l-(6'-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4- yl)amino)spiro[cyclopropane- 1 ,3'-indolin] - l'-yl)propan- 1 -one,

2-Chloro-l-(6'-((5-fluoro-2-((4-morpholinophenyl)amino)pyrimidin-4- yl)amino)spiro[cyclopropane- 1 ,3'-indolin] - l'-yl)propan- 1 -one,

2-Chloro-l-(6'-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4- yl)amino)spiro[cyclobutane- 1 ,3'-indolin] - 1 '-yl)propan- 1 -one,

2-Chloro-l-(6'-((5-fluoro-2-((4-morpholinophenyl)amino)pyrimidin-4- yl)amino)spiro[cyclobutane- 1 ,3'-indolin] - 1 '-yl)propan- 1 -one,

2-chloro-l-(6'-((2-((3,5-difluoro-4-morpholinophenyl)amino)-5-fluoropyrimidin-4- yl)amino)spiro[cyclopropane- 1 ,3'-indolin] - l'-yl)propan- 1 -one,

2-Chloro-l-(7'-((5-fluoro-2-((4-(4-methylpiperazin-l-yl)phenyl)amino) pyrimidin-4- yl)amino)-2',3'-dihydro- 1 'H-spiro[cyclopropane- 1 ,4'-quinolin]- 1 '-yl)propan- 1 -one, l-(7'-((5-Fluoro-2-((4-(2-methoxyethoxy) phenyl)amino) pyrimidin-4-yl)amino)-2',3'- dihydro- 1 Ή-spiro [cyclopropane- 1 ,4'-quinolin] - 1 '-yl)prop-2-en- 1 -one, l-(7'-((5-Fluoro-2-((3-fluoro-4-morpholinophenyl)amino)pyrimidin-4-yl)amino)-2',3'- dihydro- 1 Ή-spiro [cyclopropane- 1 ,4'-quinolin] - 1 '-yl)prop-2-en- 1 -one, 1- (7'-((2-((3,5-Difluoro-4-morpholino phenyl)amino)-5-fluoropyrimidin-4-yl)amino)- 2',3'-dihydro-l'H-spiro [cyclopropane- l,4'-quinolin]-l'-yl)prop-2-en-l-one,

2- Chloro-l-(7'-((5-fluoro-2-((4-morpholinophenyl)amino)pyrimidin-4-yl)amino)-2',3'- dihydro- 1 Ή-spiro [cyclopropane- 1 ,4'-quinolin] - l'-yl)propan- 1 -one,

2-Chloro-l-(7'-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)- 2',3'-dihydro-rH-spiro[cyclopropane-l,4'-quinolin]-r-yl)propan-l-one,

2-Chloro-l-(7'-((5-fluoro-2-((3-fluoro-4-morpholinophenyl)amino)pyrimidin-4- yl)amino)-2',3'-dihydro- 1 'H-spiro[cyclopropane- 1 ,4'-quinolin]- 1 '-yl)propan- 1 -one,

(E)-4-(Dimethylamino)-l-(6'-((5-fluoro-2-((4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl) amino) pyrimidin-4-yl)amino)spiro [cyclopropane- 1 ,3'-indolin]- 1 '-yl)but-2-en- 1-one,

(E)-4-(Dimethylamino)- 1 -(6'-((5-fluoro-2-((4-morpholinophenyl) amino)pyrimidin-4-yl) amino) spiro [cyclopropane- 1 ,3'-indolin]- l'-yl)but-2-en- 1 -one,

(E)-4-(Dimethylamino)- 1 -(6'-((5-fluoro-2-((4-morpholinophenyl) amino)pyrimidin-4- yl)amino spiro [cyclobutane-l,3'-indolin]-l'-yl)but-2-en-l-one,

(E)-4-(Dimethylamino)- 1 -(6'-((2-((4-(dimethylamino)phenyl) amino)-5-fluoropyrimidin- 4-yl) amino)spiro [cyclopropane- l,3'-indolin]-l'-yl)but-2-en- 1-one,

(E)-4-(Dimethylamino)- 1 -(6'-((5-fluoro-2-((4-(2-methoxyethoxy)

phenyl)amino)pyrimidin-4-yl)amino) spiro[cyclobutane-l,3'-indolin]-l'-yl)but-2-en-l- one,

(E)-4-((4-((r-(4-(dimethylamino)but-2-enoyl)spiro[cyclopropane-l,3'-indolin]-6'- yl)amino)-5-fluoropyrimidin-2-yl)amino)benzonitrile,

(E)-4-(Dimethylamino)- 1 -(6'-((5-fluoro-2-((4-(4-methylpiperazin- 1 - yl)phenyl)amino)pyrimidin-4-yl)amino)spiro[cyclopropane- 1 ,3'-indolin]- l'-yl)but-2-en- 1-one, l-(6'-((5-Fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)spiro

[cyclopropane- 1 ,3'-indolin]- 1 '-yl)-2-methylprop-2-en- 1 -one, l-(6'-((5-Fluoro-2-((4-(2-methoxy ethoxy)phenyl) amino)pyrimidin-4-yl)amino) spirofcyclobutane- 1 ,3'-indolin] - 1 '-yl)-2-methylprop-2-en- 1 -one, l-(6'-((5-Fluoro-2-((4-(4-methyl piperazin- l-yl)phenyl)amino) pyrimidin-4- yl)amino)spiro [cyclo propane- 1 ,3'-indolin]- 1 '-yl)but-2-yn- 1 -one, l-(6'-((5-Fluoro-2-((4-morpholinophenyl)amino)pyrimidin-4-yl)amino) spiro

[cyclopropane- 1 ,3'-indolin]- 1 '-yl)but-2-yn- 1 -one,

(E)-2-(6'-((5-Fluoro-2-((4-(4-methylpiperazin- l-yl) phenyl)amino) pyrimidin-4- yl)amino)spiro[cyclo propane- l ,3'-indolin]-r-ylcarbonyl)-4,4-dimethylpent-2-enenitrile,

N2-(4-(Dimethylamino)phenyl)-5-fluoro-N4-( 1 '-(vinylsulfonyl) spiro [cyclopropane- 1 ,3'- indolin]-6'-yl)pyrimidine-2,4-diamine,

4- ((5-Fluoro-4-(( l'-(vinylsulfonyl) spiro [cyclopropane- l ,3'-indolin]-6'- yl)amino)pyrimidin-2-yl) amino) benzonitrile,

5- Fluoro-N2-(4-fluorophenyl)-N4-( 1 '-(vinylsulfonyl) spiro [cyclopropane- 1 ,3'-indolin]-6'- yl) pyrimidine-2,4-diamine,

5-Fluoro-N2-(p-tolyl)-N4-( l '-(vinylsulfonyl)spiro[cyclopropane- l ,3'-indolin]-6'- yl)pyrimidine-2,4-diamine,

5-Fluoro-N2-(4-(methylsulfonyl) phenyl)-N4-( 1 '-(vinylsulfonyl) spiro [cyclopropane- 1 ,3'- indolin]-6'-yl)pyrimidine-2,4-diamine,

5-Fluoro-N2-(4-methoxyphenyl)-N4-( 1 '-(vinylsulfonyl) spiro [cyclopropane- 1 ,3'- indolin]-6'-yl)pyrimidine-2,4-diamine,

5-Fluoro-N2-(4-(4-methylpiperazin- l-yl)phenyl)-N4-( l'-(vinylsulfonyl)spiro

[cyclopropane- l ,3'-indolin]-6'-yl)pyrimidine-2,4-diamine, 5-Fluoro-N2-(4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-N4-( l'-(vinylsulfonyl)spiro [cyclopropane- l ,3'-indolin]-6'-yl)pyrimidine-2,4-diamine,

5-Fluoro-N2-(4-(2-methoxyethoxy) phenyl)-N4-( l '-(vinylsulfonyl)spiro [cyclo butane - l ,3'-indolin]-6'-yl)pyrimidine-2,4-diamine,

5-Fluoro-N2-(4-((tetrahydrofuran-3-yl)oxy)phenyl)-N4-( l '-(vinylsulfonyl)

spiro[cyclobutane- l ,3'-indolin]-6'-yl)pyrimidine-2,4-diamine,

5-Fluoro-N2-(4-(methylsulfonyl) phenyl)-N4-( 1 '-(vinylsulfonyl) spirofcyclobutane- 1 ,3'- indolin]-6'-yl)pyrimidine-2,4-diamine,

N2-(4-(Cyclopropylsulfonyl) phenyl)-5-fluoro-N4-( l '-(vinylsulfonyl)spiro [cyclo butane - l ,3'-indolin]-6'-yl) pyrimidine-2,4-diamine,

5-Fluoro-N2-(p-tolyl)-N4-( l '-(vinylsulfonyl)spiro[cyclobutane- l ,3'-indolin]-6'- yl)pyrimidine-2,4-diamine,

5-Fluoro-N2-(4-methoxyphenyl)-N4-( l '-(vinylsulfonyl) spiro[cyclobutane- l ,3'-indolin]- 6'-yl)pyrimidine-2,4-diamine,

(E/Z)- 3-cyclopropyl-2-(6'-((5-fluoro-2-((4-(4-methylpiperazin- l- yl)phenyl)amino)pyrimidin-4-yl)amino)spiro[cyclopropane- 1 ,3'-indolin]- Γ- ylcarbonyl)acrylonitrile,

(E/Z)- 2-(6'-((5-fluoro-2-((4-(4-methylpiperazin- 1 -yl)phenyl)amino)pyrimidin-4- yl)amino)spiro[cyclopropane- l ,3'-indolin]- l'-ylcarbonyl)-4-methylpent-2-enenitrile and

(E/Z)-2-(6'-((5-fluoro-2-((4-(4-methylpiperazin- l-yl)phenyl)amino)pyrimidin-4- yl)amino)spiro[cyclopropane- l ,3'-indolin]-r-ylcarbonyl)-4-methyl-4-morpholinopent-2- enenitrile or stereoisomers thereof or a pharmaceutically acceptable salt thereof. In another aspect of the invention, there is provided a compound of Formula (I), Formula (la), Formula (II), and/or Formula (III) for medical use. The compound may be for use in treating, managing or lessening the severity of diseases, disorders, syndromes or conditions associated with BTK.

In another aspect of the invention, there is provided a method of treating, managing or lessening the severity of 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.

In another aspect, 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.

In another aspect, 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.

It may be that the disease, disorders, syndromes or conditions associated with BTK is selected from cancer, proliferative disorders, autoimmune diseases, hetero-immune diseases, and inflammatory diseases.

Detailed description of the invention

Definitions and Abbreviations:

Unless otherwise stated, the following terms used in the specification and claims have the meanings given below.

For purposes of interpreting the specification, the following definitions will apply and whenever appropriate, terms used in the singular will also include the plural and vice versa.

The terms "halogen" or "halo" means fluorine, chlorine, bromine, or iodine. Unless otherwise stated, in the present application "oxo" means C(=0) group. Such an oxo group may be a part of either a cycle or a chain in the compounds of the present invention.

The term "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.

The term "alkenyl" refers to a hydrocarbon radical containing from 2 to 10 carbon atoms and including at least one carbon-carbon double bond. Non-limiting examples of 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.

The term "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.

The term "alkoxy" denotes an alkyl group attached via an oxygen linkage to the rest of the molecule. Representative examples of such groups are -OCH₃ and -OC₂H₅. Unless set forth or recited to the contrary, all alkoxy groups described or claimed herein may be straight chain or branched.

The term "alkoxyalkyl" refers to an alkoxy group as defined above directly bonded to an alkyl group as defined above, e.g., -CH₂-0-CH₃, -CH₂-0-CH₂CH₃, -CH₂CH₂-0-CH₃ and the like. The term "haloalkyl" refers to an alkyl group as defined above that is substituted by one or more halogen atoms as defined above. Preferably, 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. Preferably, 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 branched.

The term "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.

The term "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. Examples of 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.

The term "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.

The term "arylalkyl" refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH₂C₆H₅ and -C₂H₄C₆H₅. The term "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. In addition, the nitrogen atom may be optionally quaternized, the heterocyclic ring or heterocyclyl may optionally contain one or more olefinic bond(s), and one or two carbon atoms(s) in the heterocyclic ring or heterocyclyl may be interrupted with -CF₂-, -C(O)-, - S(O)-, S(0)₂, -C(=N-alkyl)-, or -C(=N-cycloalkyl), etc. In addition heterocyclic ring may also be fused with aromatic ring. Non-limiting examples of 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, tetrahydroisquinolyl, tetrahydrofuryl, tetrahydropyranyl, thiazolinyl, thiazolidinyl, 3- azabicyclo[3.1.0]hexane, l',6'-dimethylspiro[cyclopropane-l,3'-indoline, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone indoline, benzodioxole, tetrahydroquinoline, tetrahydrobenzopyran and the like.

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.

The term "heteroaryl" unless otherwise specified, 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, phenazinyl, phthalazinyl and the like.

The term "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.

The term "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.

The term "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. As used herein, the term "enantiomer" refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another. The term "chiral center" refers to a carbon atom to which four different groups are attached. As used herein, the term "diastereomers" refers to stereoisomers which are not enantiomers. The terms "racemate" or "racemic mixture" refer to a mixture of equal parts of enantiomers.

The term "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.

The term "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.

The compounds of the invention may be obtained, stored and/or administered in the form of a pharmaceutically acceptable salt. 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. Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. Also included are acid addition or base salts wherein the counter ion is optically active, for example, d-lactate or 1-lysine, or racemic, for example, dl-tartrate or dl-arginine. Pharmaceutical Compositions

The invention relates to pharmaceutical compositions containing the compounds of the Formula (I) disclosed herein. In particular, 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). Preferably, 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. The 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.

Examples of 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. For example, 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. When 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.

The pharmaceutical 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. For parenteral application, particularly suitable are 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. In such 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. Also, 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.

For administration to subject patients, the total daily dose of the compounds of the invention depends, of course, on the mode of administration. For example, 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. Methods of Treatment

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).

In one embodiment, 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.

In another embodiment, 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).

In another embodiment, the invention provides a method of treating, managing and/or lessening the severity of BTK associated disease or condition such as cancer. In this embodiment, wherein 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, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, Burkitt lymphoma/leukemia, or lymphomatoid granulomatosis. In some embodiments, 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). In some embodiments, 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 forms of diabetes, Reynaud's syndrome,ankylosing spondylosis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behcet's disease, chronic fatigue, dysautonomia, endometriosis, interstitial cystitis, neuromyotonia, scleroderma, or vulvodynia, a hyperproliferative disease or immunologically-mediated diseases including organ/tissue transplant rejection, transplant rejection disorders such as GVHD and allograft rejection; chronic glomerulonephritis and acquired Immunodeficiency Syndrome (AIDS, also known as HIV).

In some embodiments, 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.

In some embodiments, 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, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, or vulvitis.

In some embodiments, 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.

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.

As mentioned herein above, the diseases or disorders associated with BTK can be treated by compounds of Formulae (I) to (III) or pharmaceutically acceptable salts thereof. Thus the screening of compounds of Formulae (I) to (III) for BTK activity were achieved by using various in vitro protocols mentioned herein below.

It is to be understood that the invention encompasses any of the compounds of Formulae (I) to (III) or pharmaceutically acceptable salts thereof for use in the treatment of any of the conditions disclosed herein.

It is to be understood that the invention encompasses the use of any of the compounds of Formulae (I) to (III) or pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment of any of the conditions disclosed herein. General Methods of Preparation

The compounds described herein may be prepared by techniques known in the art. In addition, 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.

Scheme-1

Compounds of Formula (lb) and Formula (Ic), wherein ring A, R_1; R₂, R₃, R₄, R₅ and 'n' are defined herein above, are prepared from sequential transformations as depicted in scheme-1. Thus, compounds of Formula (1) wherein X is any suitable leaving group like CI, Br, I, -0(SO)₂(4-MePh), -0(SO)₂CH₃, -0(SO)₂CF₃ etc., is reacted with ring A where nitrogen is protected with suitable protecting group, in presence of a suitable base such as 2,6-lutidine, l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), K₂C0₃, Cs₂C0₃, NaH, KH, n-BuLi, lithium bis(trimethylsilyl)amide (LiHMDS) etc., in a suitable solvent to give compounds of Formula(2). Compounds of Formula (2) is also prepared from compounds of Formula (1) and ring A under standard Buchwald coupling reactions or standard Ullman coupling reactions.

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), K₂C0₃, Cs₂C0₃, 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). Finally, this -NH compound of Formula (lb) is reacted with R4- X' (where X' is halo or -COOH (acid or acid chloride)) in presence of base and in suitable solvent to give compounds of Formula (Ic).

Scheme-2

Compound of Formula (Id), wherein ring A, R_1; R₂, R3, R₄, R5 and 'n' herein above, are prepared from sequential transformations as depicted in scheme-2. Thus, compounds of Formula (1) wherein X is suitable leaving group like CI, Br, I, -0(SO)₂(4-MePh), - 0(SO)₂CH₃, -0(SO)₂CF₃ etc., is reacted with ring A in presence of a suitable base such as 2,6-Lutidine, l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), K₂C0₃, Cs₂C0₃, NaH, KH, n- BuLi, lithium bis(trimethylsilyl)amide (LiHMDS) etc., in a suitable solvent to give compounds of Formula (5). A compound of Formula (5) is obtained using compounds of Formula (1) and ring A under standard Buchwald coupling reactions or standard Ullman coupling reactions.

Compounds of Formula (5) 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), K₂C0₃, Cs₂C0₃, NaH, KH, n-BuLi, lithium bis(trimethylsilyl)amide (LiHMDS) etc., in a suitable solvent to give compounds of Formula (6). Further, this compound of Formula (6) undergoes reduction reaction under suitable reduction conditions to give compounds of Formula (7). Finally, this amino compound of Formula (7) is reacted with R₄-X' (where X' is halo or -COOH (acid or acid chloride)) in presence of base and in suitable solvent to give compounds of Formula (Id).

EXPERIMENTAL

Some of the representative examples of the present invention were prepared by following one or more reaction schemes as described above.

The invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. The examples set forth below demonstrate the synthetic procedures for the preparation of the relative compounds. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention. The aforementioned patents and patent applications are incorporated herein by reference.

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.

INTERMEDIATES

Intermediate-1: tert-Butyl 6'-aminospiro[cyclopropane-l ,3'-indoline]-l'-carboxylate

Step-1: tert-Butyl 6'-nitrospiro[cyclopropane- 1 ,3'-indoline]- 1 '-carboxylate

A mixture of 6'-nitrospiro[cyclopropane-l,3'-indoline] (synthesised as per procedure given in US2003225106) (0.750 g, 3.94 mmol), BOC-anhydride (1.1 ml, 4.73 mmol) and pyridine (0.8 ml, 9.86 mmol) in DCM (10 ml) was stirred at room temperature for 5 min before DMAP (0.120 g, 0.986 mmol) was added. Resulting mixture was stirred overnight at room temperature under N₂ atmosphere. Another portion of dimethyl amino pyridine (DMAP) (0.120 g, 0.986 mmol) and BOC-anhydride (0.90 ml, 3.94 mmol) was added. The reaction mixture was stirred further for 1 h and diluted with DCM (100 ml). The reaction mixture was washed with 20% aqueous citric acid solution (100 ml). The organic phase was separated and dried over sodium sulphate. The solvent was evaporated in vacuo and the residue was purified by flash chromatography to afford the title compound (0.70 g).¾ NMR (400 MHz, Chloroform-i δ 8.31- 8.67 (m, 1H), 7.83 (dd, / = 8.2, 2.1 Hz, 1H), 6.68 (d, / = 8.2 Hz, 1H), 4.05 (s, 2H), 1.40 - 1.81 (m, 9H), 1.19 (s, 4H). GCMS = 290.04 [M+].

Step-2: tert-Buty\ 6'-aminospiro[cyclopropane-l,3'-indoline]-l'-carboxylate

A suspension of tert-Buty\ 6'-nitrospiro[cyclopropane-l,3'-indoline]-l'-carboxylate (0.750 g, 2.58 mmol) , Fe (0.721 g, 12.92 mmol) and NH₄CI (1.4 g, 25.8 mmol) in ethanol (40 ml) and water (5 ml) was heated at 75-80°C for 2 h. After cooling to room temperature, the reaction mixture was filtered through a celite bed. The filtrate was evaporated in vacuo. The residual oil was partitioned between Ethyl acetate (50 ml) and water (30 ml). Organic phase was separated and dried over sodium sulphate. The solvent was evaporated in vacuo to give the crude product (0.62 g) which was used for the next step without further purification.

1H NMR (400 MHz, DMSO-J₆) δ 7.11 (s, 1H), 6.38 (d, = 7.9 Hz, 1H), 6.12 (dd, / = 8.0, 2.0 Hz, 1H), 5.02 (s, 2H), 3.81 (s, 2H), 1.49 (brs, 9H), 0.77 - 0.97 (m, 4H).GCMS = 260.13 M+].

Intermediate-2: 1 -(6'-((2-Chloro-5-fluoropyrimidin-4-yl)amino)spiro [cyclopropane- 1 ,3'- indolin] - 1 '-yl)propan- 1 -one

Step-1: l-(6'-Nitrospiro[cyclopropane-l,3'-indolin]-l'-yl)propan-l-one To 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 N₂ 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 NaHC0₃ 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.

1H NMR (400 MHz, DMSO-J₆) δ 8.83 (d, 7 = 2.3 Hz, 1H), 7.88 (dd, 7 = 8.3, 2.3 Hz, 1H), 7.05 (d, 7 = 8.3 Hz, 1H), 4.22 (s, 2H), 2.46 (t, 7 = 7.2 Hz, 2H), 1.24 (dt, 7 = 10.1, 2.6 Hz, 4H), 1.07 (t, 7 = 7.3 Hz, 3H). MS (ESI) = 246.98 [M+ 1]

Step-2: l-(6'-Aminospiro[cyclopropane-l,3'-indolin]-l'-yl)propan-l-one

A suspension of l-(6'-nitrospiro[cyclopropane-l,3'-indolin]-l'-yl)propan-l-one (2 g, 8.12 mmol), Fe (2.27 g, 40.6 mmol) and NH₄C1 (4.34 g, 81 mmol) in ethanol (50 ml) was heated at 80 °C for 2 h. After cooling to room temperature, the reaction mixture was filtered through a celite bed. The filtrate was evaporated in vacuo. The residue was partitioned between Ethyl acetate (50 ml) and water (30 ml). Organic phase was separated and dried over sodium sulphate. The solvent was evaporated in vacuo to give title compound (1.2 g). ¹H NMR (400 MHz, DMSO-J₆) δ 7.46 (d, 7 = 2.0 Hz, 1H), 6.40 (d, 7 = 8.0 Hz, 1H), 6.16 (dd, 7 = 8.0, 2.1 Hz, 1H), 4.93 (s, 2H), 3.99 (s, 2H), 2.37 (q, 7 = 7.3 Hz, 2H), 1.03 (t, 7 = 7.3 Hz, 3H), 0.94 (t, 7 = 3.2 Hz, 2H), 0.79 - 0.88 (m, 2H). MS (ESI)= 217.58 [M+ 1].

Step-3: l-(6'-((2-Chloro-5-fluoropyrimidin-4-yl)amino)spiro[cyclopropane-l,3'-indolin]-r- yl)propan-l-one

A mixture of l-(6'-aminospiro[cyclopropane-l,3'-indolin]-l'-yl)propan-l-one (0.78 g, 3.62 mmol), 2,4-dichloro-5-fluoropyrimidine (0.55 g, 3.29 mmol) and DIPEA (1.2 ml, 6.59 mmol) in ethanol (20 ml) was heated at 60°C under N₂ atmosphere for 18 h. After cooling to room temperature, the solvent was evaporated in vacuo and the residue was partitioned between Ethyl acetate (100 ml) and water (100 ml). Organic phase was separated, dried over sodium sulphate and evaporated in vacuo. The residue was triturated in ether and pentane to afford the title compound (1.1 g). 1H NMR (400 MHz, DMSO-J₆) δ 9.98 (s, 1H), 8.29 (dd, = 17.4, 2.7 Hz, 2H), 7.30 (dd, 7 = 8.1, 2.0 Hz, 1H), 6.79 (d, = 8.1 Hz, 1H), 4.12 (s, 2H), 2.43 (q, J = 7.2 Hz, 2H), 1.07 (ddd, J = 14.9, 5.5, 2.1 Hz, 7H). MS (ESI): 347.11 [M+ 1] Intermediate-3: 6'-Nitrospiro[cyclobutane- 1 ,3'-indoline

Spiro[cyclobutane-l,3'-indoline] (3.4 g, 21.35 mmol) was added drop-wise over a period of 10 min to a cooled (-15 °C) solution of sodium nitrate (1.8 g, 21.35 mmol) in H₂SO₄ (35 ml). After the addition, the reaction was stirred for another 50 min., then the mixture was poured onto crushed ice (400 g) and the resulting mixture was basified with aqueous NH₄OH with cooling. The basified mixture was extracted with ethyl acetate twice and the organic layer was washed with brine then dried over Na₂S04. After concentration in vacuo, the compound was isolated as a dark grey solid, 3.4 g. The crude material was carried forward for the next step. 1H NMR (400 MHz, Chloroform- d) δ 7.66 (dd, = 8.1, 2.0 Hz, 1H), 7.32 - 7.44 (m, 2H), 3.74 (s, 2H), 2.34 - 2.42 (m, 2H), 2.27 (ddt, = 15.7, 12.3, 6.5 Hz, 2H), 2.02 - 2.09 (m,

2H).

Intermediate-4: l'-(5-Fluoro-2-((4-(2-methoxyethoxy) phenyl) amino) pyrimidin-4-yl) spiro [cyclopropane- l,3'-indolin]-6'-amine

Step-1: l'-(2-Chloro-5-fluoropyrimidin-4-yl)-6'-nitrospiro[cyclopropane-l, 3'-indoline]

A mixture of 6'-nitrospiro [cyclopropane- l,3'-indoline] (1.0 g, 5.26 mmol), 2,4-dichloro-5- fluoropyrimidine (1.0 g, 6.31 mmol) and DIPEA (1.8 ml, 10.52 mmol) in ethanol (15 ml) was heated at 80 °C in a sealed tube for 18 h. After cooling to room temperature, the solvent was evaporated in vacuo and the residue was partitioned between Ethyl acetate (100 ml) and water (100 ml). Organic phase was separated, dried over sodium sulphate and evaporated in vacuo. The residue was purified by flash chromatography to afford the title compound (0.60 g). 1H NMR (400 MHz, DMSO-J₆) δ 8.97 (d, = 2.2 Hz, 1H), 8.53 (d, = 5.5 Hz, 1H), 7.94 (dd, / = 8.3, 2.2 Hz, 1H), 7.12 (d, = 8.3 Hz, 1H), 4.50 (d, = 5.3 Hz, 2H), 1.32 - 1.37 (m, 2H), 1.26 (p, J = 2.3 Hz, 2H). MS (ESI) = 321.05 [M+ 1]

Step-2: 5-Fluoro-N-(4-(2-methoxyethoxy)phenyl)-4-(6'-nitrospiro[cyclopropane- 1 ,3'- indolin] - 1 '-yl)pyrimidin-2-amine

To a solution of r-(2-Chloro-5-fluoropyrimidin-4-yl)-6'-nitrospiro [cyclopropane- 1,3'- indoline] (0.600 g, 1.871 mmol) and 4-(2-methoxyethoxy)aniline (0.375 g, 2.245 mmol) in dioxane (15 ml) was added p-TsOH (0.285 g, 1.497 mmol). Resulting mixture was stirred at 110 °C for 18 h. After cooling to room temperature, the solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate (100 ml) and aqueous saturated NaHC0₃ solution (50 ml). Organic phase was separated, dried over Na₂S0₄ and evaporated in vacuo. The residue was purified by flash chromatography to afford the title compound (0.720 g). 1H NMR (400 MHz, DMSO-J₆) δ 9.26 (s, 1H), 8.52 (d, J = 2.1 Hz, 1H), 8.29 (d, = 5.3 Hz, 1H), 7.81 (dd, / = 8.3, 2.2 Hz, 1H), 7.41 - 7.54 (m, 2H), 7.05 (d, = 8.3 Hz, 1H), 6.73 - 6.83 (m, 2H), 4.37 (d, = 4.5 Hz, 2H), 3.94 - 4.06 (m, 2H), 3.57 - 3.68 (m, 2H), 3.30 (s, 3H), 1.22 - 1.31 (m, 4H). MS (ESI) = 451.86 [M+ 1]

Step-3: l'-(5-Fluoro-2-((4-(2-methoxyethoxy) phenyl) amino) pyrimidin-4-yl) spiro [cyclopropane- l,3'-indolin]-6'-amine

A suspension of 5-Fluoro-N-(4-(2-methoxyethoxy)phenyl)-4-(6'-nitrospiro[cyclopropane- l,3'-indolin]-r-yl)pyrimidin-2-amine (0.6 g, 1.33 mmol) , Fe (0.37 g, 6.65 mmol) and NH₄C1 (0.71 g, 13.29 mmol) in ethanol (20 ml) and water (4 ml) was heated at 80 °C for 30 min. After cooling to room temperature, the reaction mixture was filtered through a celite bed. The filtrate was evaporated in vacuo. The residue was partitioned between Ethyl acetate (50 ml) and water (30 ml). Organic phase was separated and dried over sodium sulphate. The solvent was evaporated in vacuo to give title compound (0.52 g). 1H NMR (400 MHz, DMSO-J₆) δ 8.97 (s, 1H), 8.14 (d, / = 5.7 Hz, 1H), 7.51 - 7.66 (m, 2H), 7.41 (s, 1H), 6.81 - 6.94 (m, 2H), 6.47 (d, / = 7.9 Hz, 1H), 6.20 (dd, / = 8.0, 2.0 Hz, 1H), 4.82 (s, 2H), 4.18 (d, / = 4.6 Hz, 2H), 4.04 (dd, = 5.6, 3.6 Hz, 2H), 3.59 - 3.70 (m, 2H), 3.31 (s, 3H), 0.71 - 1.09 (m, 4H). MS (ESI) = 422.1 [M+ 1]

Intermediate-5: tert-Eutyl 6'-aminospiro[cyclobutane- 1 ,3'-indoline]- 1 '-carboxylate

Step-1: tert-Eutyl 6'-nitrospiro[cyclobutane-l,3'-indoline]-l'-carboxylate

A mixture of 6'-nitrospiro[cyclobutane-l,3'-indoline] (3.4 g, 16.65 mmol), BOC-anhydride (3.9 ml, 16.65 mmol) and pyridine (6.7 ml, 83 mmol) in DCM (40 ml) was stirred at RT under N₂ atm. for 18 h. The reaction mixture was diluted with DCM and washed with aqueous citric acid solution. The organic phase was separated and dried over sodium sulphate, concentrated in vacuo. The resulting residue was purified by column chromatography to afford the title compound (3.0 g). 1H NMR (400 MHz, Chloroform-J) δ 7.92 (dd, = 8.2, 2.2 Hz, 1H), 7.49 (d, = 8.2 Hz, 1H), 4.13 (s, 2H), 2.40 - 2.49 (m, 2H), 2.33 (tdd, = 8.1 , 6.8, 3.7 Hz, 2H), 2.06 - 2.15 (m, 2H), 1.61 (s, 9H).

Step-2: tert-Buty\ 6'-aminospiro[cyclobutane- 1 ,3'-indoline]- 1 '-carboxylate

A mixture of tert-Buty\ 6'-nitrospiro[cyclobutane-l ,3'-indoline]-l'-carboxylate (3.0 g, 9.86 mmol) , Fe (2.75 g, 49.3 mmol) and NH₄C1 (5.27 g, 99 mmol) in ethanol (30 ml) and water (5 ml) was heated to reflux at 75-80°C for 2 h. After cooling to Room temperature (RT), the reaction mixture was filtered through a celite bed and the filtrate was evaporated in vacuo. The residue was partitioned between Ethyl acetate and water .Organic phase was separated, dried over sodium sulphate and evaporated in vacuo to give 2.5 g of the title compound which was used in the next step without further purification. ^XH NMR (400 MHz, Chloroform- d) δ 7.29 (d, = 6.1 Hz, 1H), 7.17 (d, = 7.9 Hz, 1H), 6.40 (dd, = 7.7, 2.1 Hz, 1H), 4.01 (s, 2H), 2.35 (dt, = 12.0, 8.6 Hz, 2H), 2.11 - 2.27 (m, 2H), 1.90 - 2.05 (m, 2H), 1.57 (s, 9H).

Intermediate-6: tert-Butyl 7'-amino-2',4'-dihydro- l'H-spiro[cyclopropane- 1 ,3'-quinoline]- 1 '- carboxylate

Step-1: 7'-Bromo-rH-spiro[cyclopropane-l,3'-quinolin]-2'(4'H)-one

To a solution of 6'-bromospiro[cyclopropane-l ,2'-inden]-l'(3'H)-one (14.00 g, 59.0 mmol) in CHCI₃ (140 ml) was added methanesulfonicacid (38 ml, 590 mmol) followed by sodium azide (11.5 g, 177 mmol) under ice cooling. Resulting mixture was heated to reflux for 3 hr. After cooling to RT, the reaction mixture was diluted with water and basified with aqueous ammonia (pH 9). The organic phase was separated and the aqueous phase was re-extracted with CHCI₃ several times. The combined organic phase was washed with brine, dried over sodium sulphate and concentrated in vacuo. The residue was purified by flash chromatography to give title compound (2.5 g). ^XH NMR (400 MHz, DMSO-Je) δ 10.26 (s, 1H), 6.98-7.15 (m, 3H), 2.80 (s, 2H), 1.07 (q, = 3.7 Hz, 2H), 0.72 (q, = 3.8 Hz, 2H).

GCMS = 252.94 [M+l]

Step-2: 7'-Bromo-2',4'-dihydro- 1 'H-spiro[cyclopropane- 1 ,3'-quinoline]

A solution of 7'-bromo-rH-spiro[cyclopropane-l,3'-quinolin]-2'(4'H)-one (0.8 g, 3.17 mmol) in THF (10 ml) was added slowly to a slurry of LAH (0.241 g, 6.35 mmol)in THF (25 ml) at 0 °C. Resulting suspension was heated at 70 °C for 1 h under N₂ atm. After cooling to RT, the reaction mixture was quenched by adding 10% NaOH solution and extracted with EtOAc. Organic phase was dried over sodium sulphate. The solvent was removed in vacuo to afford title compound (0.7g) which was used in the next step without purification. ¹H NMR (400 MHz, DMSO-J₆) δ 6.71 (d, = 7.9 Hz, 1H), 6.62 (d, = 2.0 Hz, 1H), 6.51 (dd, = 7.9, 2.0 Hz, 1H), 6.06 (s, 1H), 2.92 (d, = 2.3 Hz, 2H), 2.46 (s, 2H), 0.36-0.52 (m, 4H). GCMS = 239.03 [M+l]

Step-3: tert-Butyl 7'-bromo-2',4'-dihydro-rH-spiro[cyclopropane- l,3'-quinoline]-r- carboxylate

BOC-anhydride (2.5 ml, 10.71 mmol) was added to a solution of 1M LiHMDS (8.6 ml, 8.6 mmol) and 7'-bromo-2',4'-dihydro-rH-spiro[cyclopropane-l,3'-quinoline] (1.7 g, 7.14 mmol) in THF (20 ml) at RT. Resulting mixture was stirred at RT under N₂ atm. for 3 h and quenched by addition of aqueous NH₄C1. The mixture was partitoned between EtOAC and water (1 : 1 200 ml). Organic phase was separated and dried over sodium sulphate. The solvent was removed in vacuo and the residue was purified by flash chromatography to give title compound (2.0 g). 1H NMR (400 MHz, Chloroform-JJ δ 7.92 (s, 1H), 7.12 (dd, = 8.2, 2.0 Hz, 1H), 6.89 (dd, = 8.2, 1.0 Hz, 1H), 3.52 (s, 2H), 2.64 (s, 2H), 1.54 (s, 9H), 0.57 - 0.66 (m, 2H), 0.51 - 0.42 (m, 2H). LCMS (ESI) = 339.1 [M+l]

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 N₂ 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. Resulting solution was stirred at RT for 30 min and partitioned between EtOAc and water. Organic phase was separated, dried over sodium sulphate and concentrated in vacuo. Residue was purified by flash chromatography to give title compound (0.750 g). 1H NMR (400 MHz, DMSO-J₆) δ 6.85 (d, = 2.3 Hz, 1H), 6.68 (d, = 8.1 Hz, 1H), 6.26 (dd, = 8.1, 2.3 Hz, 1H), 3.39 (s, 2H), 3.35 (s, 2H), 1.99 (s, 2H), 1.44 (s, 9H), 0.48-0.56 (m, 2H), 0.35-0.43 (m, 2H). GCMS = 274.18 [M+l]

Intermediate-7: 7'-Amino-rH-spiro[cyclopropane-l,4'-quinolin]-2'(3'H)-one

Step-1: l-(2,4-Dinitrophenyl)cyclopropanecarboxylic acid

1-phenylcyclopropanecarboxylic acid (15 g, 92 mmol) was added in portions to cone. H₂SO₄ (50 ml) at 0 °C. The resulting mixture was allowed to stir at 0 °C until a clear solution was obtained. A mixture of cone. H₂SO₄ (34.5 ml, 647 mmol) and fuming HNO₃ (16.5 ml, 370 mmol) was added drop wise to the reaction mixture. Resulting solution was stirred for 18 h at ambient temperature and poured on to ice. A pale yellow precipitate was obtained which was filtered and washed with water. The solid was dissolved in DCM and washed with water. The organic phase was dried over Na₂S0₄. The solvent was removed in vacuo to give l-(2,4- dinitrophenyl)cyclopropanecarboxylic acid (15 g). 1H NMR (400 MHz, DMSO-Je) δ 12.78 (s, 1H), 8.75 (d, = 2.4 Hz, 1H), 8.49 (dd, = 8.6, 2.5 Hz, 1H), 7.91 (d, = 8.6 Hz, 1H), 1.58-1.60 (m, 2H), 1.31-1.34 (m, 2H).

Step-2 :teri-Butyl 2-(l-(2,4-dinitrophenyl)cyclopropyl)acetate

A stirred suspension ofl-(2,4-dinitrophenyl)cyclopropanecarboxylic acid (11 g, 43.6 mmol) in dry dichloromethane (100 mL) was treated with oxalyl chloride (5.7 ml, 65.4 mmol) and catalytic amount dry dimethylformamide (5 drops). The mixture was stirred at room temperature, under anhydrous conditions, for 18 hours then evaporated in vacuo to give crude l-(2,4-dinitrophenyl)cyclopropanecarbonyl chloride . A stirred solution of (trimethylsilyl) diazomethane in hexanes (25 mL, 2.0 M) in dry acetonitrile (75 mL), at 0 °C and under N2 , was treated drop wise with a solution of l-(2,4- dinitrophenyl)cyclopropanecarbonyl chloride ( 10 g, 37.0 mmol) obtained above in dry acetonitrile (50 mL) . The cooling bath was removed and the solution was stirred at room temperature for 2 hours and then evaporated. The residue was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer washed with brine, then dried over sodium sulphate and then evaporated. The resulting amber coloured oil was dissolved in t-butanol ( 100 mL) and this solution was stirred, heated to gentle reflux and then treated drop wise with a solution of silver benzoate (5.0 g) in triethylamine (36.0 ml, 259 mmol) (nitrogen was evolved). The resulting dark coloured mixture was stirred at gentle reflux for 2.5 hours and then the hot mixture was filtered through celite. The filtrate was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was washed sequentially with aqueous sodium bicarbonate solution, water, 1M aqueous hydrochloric acid solution, water, aqueous sodium bicarbonate solution, and with brine, then dried over sodium sulphate and then evaporated. The residual black oil was subjected to flash chromatography on silica to afford the title compound (0.8 g). 1H NMR (400 MHz, DMSO- de) δ 8.69 (d, = 2.5 Hz, 1H), 8.49 (dd, = 8.6, 2.5 Hz, 1H), 7.93 (d, = 8.6 Hz, 1H), 2.61 (s, 2H), 1.34 (s, 9H), 0.95- 1.08 (m, 2H), 0.81-0.92 (m, 2H). MS (ESI) = 345.05 [M+23]

Step-3: 7'-Amino-rH-spiro[cyclopropane- l ,4'-quinolin]-2'(3'H)-one

A mixture of cone. HC1 (3 ml) and water (2 ml) was added drop wise to a suspension of tert- butyl 2-( 1 -(2,4-dinitrophenyl)cyclopropyl)acetate (0.8 g, 2.48 mmol) and Zinc (4 g, 62 mmol) in ethanol (20 ml)and water (5 ml). The resulting mixture was stirred briefly at RT and then refluxed at 74 °C for 3 h. After cooling to RT the suspension was decanted such that most of the zinc could be removed and then the mixture was basified using aqueous ammonia. The resulting mixture was concentrated in vacuo to remove most of ethanol and then water 50 ml was added. The mixture was extracted several times with ethyl acetate. Combined organic phase was dried over sodium sulphate and concentrated in vacuo. Residue was purified by flash chromatography to give the title compound, (0.32 g). ^XH NMR (400 MHz, DMSO-Je) δ 9.98 (s, 1H), 6.54 (d, = 7.9 Hz, 1H), 6.11 (d, J = 8.0 Hz, 2H), 4.97 (s, 2H), 2.28 (s, 2H), 0.71-0.82 (m, 2H), 0.60-0.70 (m, 2H). GCMS = 187.89 [M+]

Intermediate-8: N4-(2',3'-Dihydro-rH-spiro[cyclopropane-l,4'-quinolin]-7'-yl)-5-fluoro- N2-(4-(4-methylpiperazin- 1 -yl)phenyl)pyrimidine-2,4-diamine

Step-l:N-(2-Chloro-5-fluoropyrimidin-4-yl)-2',3'-dihydro-rH-spiro[cyclopropane-l ,4'- quinolin]-7'-amine

7'-((2-Chloro-5-fluoropyrimidin-4-yl)amino)-rH-spiro[cyclopropane-l,4'-quinolin]-2'(3'H)- one (0.200 g, 0.627 mmol) was added to an ice cold slurry of LAH (0.095 g, 2.51 mmol) in THF (5 ml). Resulting mixture was heated at 70 °C for 1 hr. The reaction mixture was cooled to RT and quenched by addition of aqueous NaOH. The resulting mixture was extracted several times with EtOAc. Combined organic phase was dried over sodium sulphate and evaporated in vacuo. Purification of the residue by flash chromatography afforded the title compound (0.101 g). 1H NMR (400 MHz, DMSO-J₆) δ 9.68 (s, 1H), 8.23 (d, 7 = 3.5 Hz, 1H), 6.63-6.77 (m, 2H), 6.52 (d, 7 = 8.2 Hz, 1H), 5.91 (s, 1H), 3.18 - 3.29 (m, 2H), 1.63 (t, 7 = 5.4 Hz, 2H), 0.92 (q, 7 = 4.1 Hz, 2H), 0.68 (q, 7 = 4.1 Hz, 2H). GCMS = 305.34 [M+l]

Step-2:teri-Butyl 7'-((2-chloro-5-fluoropyrimidin-4-yl)amino)-2',3'-dihydro-rH- spiro[cyclopropane- 1 ,4'-quinoline] - l'-carboxylate

A mixture of N-(2-Chloro-5-fluoropyrimidin-4-yl)-2',3'-dihydro-l'H-spiro[cyclopropane- l,4'-quinolin]-7'-amine (0.5 g, 1.641 mmol), and TEA (0.69 ml, 4.92 mmol) in DCM (15 ml) was stirred at RT for 5 min before DMAP (0.200 g, 1.641 mmol) was added slowly portion wise. Resulting mixture was stirred at RT for 18 hr. The reaction was diluted with DCM (150 ml). The organic phase was washed with brine, separated, dried over sodium sulphate. The solvent was removed in vacuo and the residue was purified by flash chromatography to give title compound (0.518g). 1H NMR (400 MHz, DMSO-J₆) δ 8.93 (d, 7 = 2.4 Hz, 1H), 6.53 (d, 7 = 8.3 Hz, 1H), 6.31 (d, 7 = 2.2 Hz, 1H), 6.22 (dd, 7 = 8.2, 2.2 Hz, 1H), 5.97 (d, 7 = 2.3 Hz, 1H), 3.23 (dt, 7 = 6.0, 3.0 Hz, 2H), 1.64 (t, 7 = 5.4 Hz, 2H), 1.41 (s, 9H), 0.94 (q, 7 = 4.2 Hz, 2H), 0.71 (q, 7 = 4.1 Hz, 2H). LCMS (ESI) = 405.05 [M+l]

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

To a stirred solution tert-Butyl 7'-((2-chloro-5-fluoropyrimidin-4-yl)amino)-2',3'-dihydro- rH-spiro[cyclopropane- l,4'-quinoline]-l'-carboxylate (0.400 g, 0.988 mmol) in 1 ,4-Dioxane (30 ml) was added 4-(4-methylpiperazin-l-yl)aniline (0.208 g, 1.087 mmol) , xantphos (0.114 g, 0.198 mmol), Pd₂(dba)₃ (0.090 g, 0.099 mmol) and Cs₂C0₃ (0.644 g, 1.976 mmol). Resulting suspension was heated in sealed tube at 110 °C for 1 h. After cooling to RT, the reaction mixture was adsorbed on silica and purified by flash chromatography to give title compound (0.419 g) ^XH NMR (400 MHz, DMSO-J₆) δ 9.42 (s, 1H), 8.48 (d, = 2.8 Hz, 1H), 7.34 - 7. 46 (m, 2H), 7.29 (d, = 8.6 Hz, 2H), 6.75 (d, = 8.7 Hz, 2H), 6.55 (d, = 8.3 Hz, 1H), 6.33 (d, = 2.3 Hz, 1H), 6.25 (dd, = 8.2, 2.2 Hz, 1H), 5.96 (s, 1H), 3.24 (s, 2H), 3.02 (t, = 5.0 Hz, 3H), 2.39 - 2.49 (m, 5H), 1.65 (s, 2H), 1.42 (s, 9H), 0.94 (q, = 4.2 Hz, 2H), 0.71 (q, = 4.1 Hz, 2H). MS (ESI) = 559.95 [M+l]

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

TFA (lml, 13.40 mmol) was added to a solution of te -Butyl 7'-((5-fluoro-2-((4-(4- methylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)amino)-2',3'-dihydro-rH-spiro[cyclo propane- l,4'-quinoline]- l'-carboxylate (0.500 g, 0.893 mmol) in DCM (10 ml). Resulting mixture was stirred at room temperature for 18 h. The solvent was removed in vacuo. The residue was basified by addition of aqueous Ammonia. Resulting precipitate was filtered and dried under vacuum to give title compound (0.374g). The crude material was used in the next step without further purification. MS (ESI) = 460 [M+l].

EXAMPLES

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 A mixture of Intermediate- 1(0.6 g, 2.31 mmol), 2,4-dichloro-5-fluoropyrimidine (0.462 g, 2.77 mmol) and DIPEA (0.80 ml, 4.61 mmol) in ethanol (15 ml) was heated at 80°C in a sealed tube for 18 h. After cooling to room temperature, the solvent was evaporated in vacuo and the residue was partitioned between Ethyl acetate (100 ml) and water (100 ml). Organic phase was separated, dried over sodium sulphate and evaporated in vacuo. The residue was purified by flash chromatography to afford the title compound (0.860 g). 1H NMR (400 MHz, DMSO-J₆) 9.97 (s, 1H), 8.27 (d, = 3.4 Hz, 1H), 7.94 (brs, 1H), 7.27 (brs, 1H), 6.75 (d, = 8.1 Hz, 1H), 3.93 (s, 2H), 1.51 (s, 9H), 0.95 - 1.11 (m, 4H). GCMS= 267.12 [M+]

Step-2: teri-Butyl 6'-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4- yl)amino)spiro[cyclopropane- 1 ,3'-indoline]- 1 '-carboxylate

To a solution of tert-butyl 6'-((2-chloro-5-fluoropyrimidin-4-yl)amino)spiro[cyclopropane- l,3'-indoline]-l'-carboxylate (0.850 g, 2.175 mmol) and 4-(2-methoxyethoxy)aniline (0.44 g, 2.61 mmol)in dioxane (20 ml) was added p-TsOH (0.33 g, 1.74 mmol). Resulting mixture was stirred at 110 °C for 18 h. After cooling to room temperature, the solvent was evaporated in vacuo and the residue was partitioned between Ethyl acetate (100 ml) and aqueous saturated NaHC0₃ solution (50 ml). Organic phase was separated, dried over Na₂S0₄ and evaporated in vacuo. The residue was purified by flash chromatography to afford the title compound (0.650 g). 1H NMR (400 MHz, DMSO-J₆) δ 9.31 (s, 1H), 8.98 (s, 1H), 8.03 (d, = 3.7 Hz, 1H), 7.90 (brs, 1H), 7.53 (brs, 3H), 7.35 (brs, 1H), 6.71 (d, = 8.0 Hz, 2H), 3.99 - 4.01 (m, 2H), 3.94 (s, 2H), 3.58 - 3.66 (m, 2H), 3.30 (s, 3H), 1.29 - 1.56 (m, 9H), 1.06 - 1.13 (m, 2H), 0.96 - 1.03 (m, 2H). MS (ESI) = 521.82 [M+l]

Step-3: 5-Fluoro-N2-(4-(2-methoxyethoxy)phenyl)-N4-(spiro[cyclopropane- 1 ,3'-indolin]-6'- yl)pyrimidine-2,4-diamine

TFA (0.886 ml, 11.50 mmol) was added to a solution of tert-butyl 6'-((5-fluoro-2-((4-(2- methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)spiro[cyclopropane-l,3'-indoline]-r- carboxylate (0.6 g, 1.150 mmol) in DCM (10 ml). Resulting mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with DCM (50 ml) and basified by addition of aqueous saturated NaHC0₃ solution. The organic phase was separated, dried over sodium sulphate and evaporated in vacuo. The residue was triturated in n-pentane and dried under vacuum to afford the title compound (0.390 g). 1H NMR (400 MHz, DMSO-J₆) δ 8.98 (d, = 1.8 Hz, 1H), 8.92 (s, 1H), 7.98 (d, = 3.8 Hz, 1H), 7.47 - 7.61 (m, 2H), 6.76 - 6.92 (m, 4H), 6.51 (d, = 7.9 Hz, 1H), 5.55 (t, = 2.1 Hz, 1H), 4.07 - 3.95 (m, 2H), 3.67 - 3.58 (m, 2H), 3.52 - 3.41 (m, 2H), 3.31 (s, 3H), 0.89 (brs, 4H). MS (ESI) = 422.2 [M+l]

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

A mixture of 5-Fluoro-N2-(4-(2-methoxyethoxy)phenyl)-N4-(spiro[cyclopropane-l,3'- indolin]-6'-yl)pyrimidine-2,4-diamine (0.2 g, 0.475 mmol) and K₂C0₃ (0.131 g, 0.949 mmol) in NMP (1.5 ml) was stirred at 0°C for 5 min. before a solution of acryloyl chloride (0.034 g, 0.380 mmol) in NMP (0.5 ml) was added. Resulting mixture was stirred at 0 °C for 1 h. The 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). 1H NMR (400 MHz, DMSO-J₆) δ 9.34 (brs, 1H), 8.93 (s, 1H), 8.30 (brs, 1H), 8.03 (d, = 3.6 Hz, 1H), 7.46-7.5 l(m, 3H), 6.64 - 6.79 (m, 4H), 6.30 (d, = 17.0 Hz, 1H), 5.83 (d, = 9.9 Hz, 1H), 4.27 (s, 2H), 3.99 (t, = 4.6 Hz, 2H), 3.63 (dd, = 5.7, 3.4 Hz, 2H), 3.30 (s, 3H), 0.95 - 1.18 (m, 4H). MS (ESI) = 476

[M+l].

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

A mixture of 5-Fluoro-N2-(4-(2-methoxyethoxy)phenyl)-N4-(spiro[cyclopropane-l ,3'- indolin]-6'-yl)pyrimidine-2,4-diamine (0.11 g, 0.261 mmol) and K₂C0₃ (0.072 g, 0.522 mmol) in NMP (1.5 ml) was stirred at 0°C for 5 min. before a solution of chloroacetyl chloride (0.021 ml, 0.261 mmol) in NMP (0.5 ml) was added. Resulting mixture was stirred at 0°C for 1 h. The 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 (20 mg). 1H NMR (400 MHz, DMSO- d₆) 5 9.35 (d, = 1.7 Hz, 1H), 8.94 (s, 1H), 8.18 (d, = 2.0 Hz, 1H), 8.03 (d, = 3.6 Hz, 1H), 7.42 - 7.62 (m, 3H), 6.67 - 6.85 (m, 3H), 4.51 (s, 2H), 4.19 (s, 2H), 3.94 - 4.05 (m, 2H), 3.57 - 3.68 (m, 2H), 3.30 (s, 3H), 1.07-1.23 (m, 4H). MS (ESI) = 497.94 [M+]

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

A mixture of tert-Buty\ 6'-aminospiro[cyclobutane-l ,3'-indoline]- l'-carboxylate (2.53 g, 9.22 mmol), 2,4-dichloro-5-fluoropyrimidine (1.4 g, 8.38 mmol) and DIPEA (4.39 ml, 25.2 mmol) in ethanol (15 ml) was heated in a sealed tube at 80°C for 18 h. After cooling to RT, the solvent was evaporated in vacuo and residue was partitioned between Ethyl acetate and water. Organic phase was separated, dried over sodium sulphate and evaporated in vacuo. Trituration of the residue in diethyl ether and pentane afforded the title compound (2.8 g).

1H NMR (400 MHz, DMSO-J6) δ 10.00 (d, = 2.2 Hz, 1H), 8.29 (d, = 3.4 Hz, 1H), 7.87 (s, 1H), 7.47 (d, = 8.0 Hz, 2H), 4.03 (s, 2H), 2.17 - 2.37 (m, 4H), 1.98 (dtd, = 8.5, 7.3, 6.2, 4.7 Hz, 2H), 1.51 (s, 9H). ). MS (ESI) = 405.10 [M+l]

Step-2: 5-Fluoro-N-2-(4-(2-methoxyethoxy)phenyl)-N4-(spiro[cyclobutane-l,3'-indolin]-6'- yl)pyrimidine-2,4-diamine

To a solution of tert-Buty\ 6'-((2-chloro-5-fluoropyrimidin-4-yl)amino)spiro[cyclobutane- l,3'-indoline]- l'-carboxylate (1.8 g, 4.45 mmol) and 4-(2-methoxyethoxy)aniline (0.818 g, 4.89 mmol) in dioxane (10 ml) was added pTsOH (0.68 g, 3.56 mmol). Resulting mixture was stirred at 110°C for 18 h. The solvent was evaporated in vacuo and the residue was partitoned between Ethyl acetate and aqueous saturated NaHC0₃ solution. The organic phase was separated, dried over Na2S04 and evaporated in vacuo to afford crude 1.0 g of crude compound which was used in the next step without further purification. MS (ESI)

[M+l]

Example-5: l-(6'-((5-Fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin

spiro[cyclobutane- 1 ,3'-indolin] - 1 '-yl)prop-2-en- 1 -one

A mixture of 5-Fluoro-N2-(4-(2-methoxyethoxy)phenyl)-N4-(spiro[cyclobutane-l ,3'- indolin]-6'-yl)pyrimidine-2,4-diamine (300 mg, 0.689 mmol) and K₂C0₃ (190 mg, 1.378 mmol) in NMP (3.0 ml) was stirred at 0°C. Acryloyl chloride (62 mg, 0.689 mmol) was added and the resulting mixture was stirred under N₂ atmosphere allowed to RT over 1.5 h. The reaction mixture was partitioned between water (30 ml) and Ethyl acetate (50 ml). Organic phase was removed and aqueous phase was re-extracted with Ethyl acetate (50 ml x 3). Combined organic phase was washed with water and dried over sodium sulphate. Solvent was evaporated in vacuo and the residue was purified by Prep HPLC to give the title compound (40 mg). ^XH NMR (400 MHz, DMSO-J₆) δ 9.37 (s, 1H), 8.95 (s, 1H), 8.01 - 8.26 (m, 2H), 7.37 - 7.66 (m, 4H), 6.67 - 6.90 (m, 3H), 6.29 (d, = 16.6 Hz, 1H), 5.70 - 5.94 (m, 1H), 4.38 (s, 2H), 3.99 (dd, = 5.8, 3.6 Hz, 2H), 3.55 - 3.70 (m, 2H), 3.30 (s, 3H), 2.34 (tt, = 15.4, 8.1 Hz, 4H), 2.02 (p, = 7.7 Hz, 2H). MS (ESI)= 489.94 Example-6: 2-Chloro- l-(6'-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4- yl)amino)spiro[cyclobutane- 1 ,3'-indolin] - l'-yl)ethanone

A mixture of 5-Fluoro-N2-(4-(2-methoxyethoxy)phenyl)-N4-(spiro[cyclobutane-l ,3'- indolin]-6'-yl)pyrimidine-2,4-diamine (400 mg, 0.918 mmol) and K₂C0₃ (254 mg, 1.837 mmol)in NMP (2.5 ml) was stirred at 0°C for 5 min. before a solution of 2-chloroacetyl chloride (104 mg, 0.918 mmol) in NMP (0.5 ml) was added. Resulting mixture was stirred at 0°C for 1 h. The reaction mixture was partitioned between water and Ethyl acetate. The organic phase was separated and the aqueous phase was re-extracted with Ethyl acetate (25 ml). Combined organic phase was washed with water, brine (25 ml) and dried over sodium sulphate, filtered and concentrated in vacuo. Purification of the residue by preparative HPLC afforded the title compound. ^XH NMR (400 MHz, DMSO-J₆) δ 9.38 (d, = 1.6 Hz, 1H), 8.95 (s, 1H), 8.08 (dd, = 33.7, 2.8 Hz, 2H), 7.66 (dd, 7 = 8.1, 2.0 Hz, 1H), 7.50 (t, = 8.6 Hz, 3H), 6.68 - 6.84 (m, 2H), 4.57 (s, 2H), 4.29 (s, 2H), 3.88- 4.12 (m, 2H), 3.57 - 3.71 (m, 2H), 3.30 (s, 3H), 2.19 - 2.43 (m, 4H), 1.96 - 2.1 1 (m, 2H). MS (ESI) = 51 1.74

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

A mixture of tert-Butyl 6'-((2-chloro-5-fluoropyrimidin-4-yl)amino)spiro[cyclopropane-l ,3'- indoline]-l'-carboxylate (500 mg, 1.279 mmol) , 4-(4-methylpiperazin-l-yl)aniline (294 mg, 1.535 mmol), xantphos (148 mg, 0.256 mmol), Pd₂(dba)₃ (234 mg, 0.256 mmol) and Cs₂C0₃ (834 mg, 2.56 mmol) in 1,4-Dioxane (30 ml) was purged with N₂ for few min. The resulting suspension was heated in a sealed vial at 1 10 °C for 2 h. After cooling to RT the reaction mixture was adsorbed on silica and purified by flash chromatography to afford title compound (600 mg). 1H NMR (400 MHz, DMSO-J₆) δ 9.27 (s, 1H), 8.88 (s, 1H), 8.01 (d, = 3.7 Hz, 1H), 7.88 (s, 1H), 7.46(s, 3H), 6.83 - 6.59 (m, 3H), 3.94 (s, 2H), 3.00 (s, 4H), 2.44 (t, = 5.0 Hz, 4H), 2.21 (s, 3H), 1.28 - 1.5 l(m, 9H), 0.97- 1.13 (m, 4H).MS (ESI)= 546.25 [M+].

Step-2: 5-Fluoro-N2-(4-(4-methylpiperazin- 1 -yl)phenyl)-N4-(spiro[cyclo propane- 1 ,3'- indolin]-6'-yl)pyrimidine-2,4-diamine

To a stirred solution of tert-butyl 6'-((5-fluoro-2-((4-(4-methylpiperazin-l-yl)phenyl)amino) pyrimidin-4-yl)amino)spiro[cyclopropane-l ,3'-indoline]-l'-carboxylate (600 mg, 1.100 mmol) in DCM (10 ml) was added TFA (0.85 ml, 11.00 mmol) and stirred reaction mass at room temp for 1 hr. The solvent was evaporated under reduced pressure, diluted with DCM (50 ml) and basified by addition of saturated NaHC0₃ solution. The organic phase was separated, dried over sodium sulphate and evaporated in vacuo. The residue was triturated in n-pentane and dried under vacuum to afford the title compound (450 mg). ¹H NMR (400 MHz, Chloroform-J) δ 7.89 (d, / = 3.3 Hz, 1H), 7.50 - 7.39 (m, 2H), 7.14 (d, = 1.9 Ηζ, ΙΗ), 6.97 - 6.87 (m, 2H), 6.69 (dd, = 8.0, 2.0 Hz, 2H), 6.55 (d, = 7.9 Hz, 1H), 3.63 (s, 2H), 3.35 (d, = 5.3 Hz, 4H), 3.03 (s, 4H), 2.66 (s, 3H), 0.85- 1.07 (m, 4H).MS (ESI)= 446.17 [M+l].

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

A mixture of 5-Fluoro-N2-(4-(4-methylpiperazin-l-yl)phenyl)-N4-(spiro[cyclopropane-l ,3'- indolin]-6'-yl)pyrimidine-2,4-diamine (200 mg, 0.449 mmol) and K₂C0₃ (186 mg, 1.347 mmol) in NMP (1ml) was stirred at 0°C for 5 min. 2-chloropropanoyl chloride (85 mg, 0.673 mmol) in NMP (0.5 ml) was added. Resulting mixture was stirred at 0 °C for 30 min. The reaction mixture was partitioned between water (25 ml) and EtOAc (100 ml). The organic phase was separated and the aqueous phase was re-extracted with EtOAc (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 (100 mg). ^XH NMR (400 MHz, DMSO-J₆) δ 9.32 (s, 1H), 8.86 (s, 1H), 8.23 (d, = 1.9 Hz, 1H), 8.17 (s, 1H), 7.58 - 7.50 (m, 1H), 7.50 - 7.36 (m, 2H), 6.89 - 6.63 (m, 3H), 4.91 (q, =6.4 Hz, 1H), 4.40 - 4.21 (m, 2H), 3.03 (t, = 4.9 Hz, 4H), 2.77- 2.65 (m, 4H), 2.27 (s, 3H), 1.60 (d, = 6.4 Hz, 3H), 1.21 - 1.01 (m, 4H) MS (ESI)= 536.17 [M+].

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 was separated in to two enantiomeric stereoisomers - Example-8A (peak 1, R or S; retention time at 3.99 min. in chiral analysis), and Example-8B (peak 2, R or S; retention time at 5.69 min. in chiral analysis) by chiral preparative HPLC.

Column: Chiral-IB; Column size: 30 x 250 mm, 5 μ; Injection: 1 ml;Mobile phase: A: n- hexane + 0.1% DEA; B: EtOH: DCM (1 : 1); flow rate: 40 ml/min; wave length: 225 nm; temperature: 25 °C; sample solution: 10 mg/ml.

The chiral analysis conditions are:Column: Chiralpak-IB;Column size: 250 x 4.6 mm, 5 μ; 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

1H NMR (400 MHz, DMSO-J₆) δ 9.31 (s, 1H), 8.86 (s, 1H), 8.23 (d, = 1.9 Hz, 1H), 8.02 (d, = 3.7 Hz, 1H), 7.53 (t, J = 10.2 Hz, 1H), 7.43 (d, = 8.6 Hz, 2H), 6.77 (dd, = 19.0, 8.4 Hz, 3H), 4.85-4.95 (m, 1H), 4.36 (d, = 10.3 Hz, 1H), 4.25 (d, = 10.4 Hz, 1H), 2.94 - 3.11 (m, 4H), 2.46 (d, / = 5.2 Hz, 4H), 2.23 (s, 3H), 1.60 (d, = 6.4 Hz, 3H), 1.06 - 1.17 (m, 4H). MS (ESI) = 536.15[M+1]. Specific Optical Rotation (SOR)= - 43.20, 0.1 % in MeOH, 20 °C.

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

1H NMR (400 MHz, DMSO-d₆)5 9.31 (s, IH), 8.86 (s, IH), 8.23 (d, = 2.0 Hz, IH), 8.01 (d, = 3.7 Hz, IH), 7.48 - 7.55 (m, IH), 7.40 - 7.48 (m, 2H), 6.77 (dd, = 18.0, 8.6 Hz, 3H), 4.85-4.95 (m, IH), 4.36 (d, = 10.3 Hz, IH), 4.25 (d, = 10.4 Hz, IH), 3.02 (s, 4H), 2.41 - 2.49 (m, 4H), 2.25 (s, 3H), 1.60 (d, = 6.4 Hz, 3H), 1.05 - 1.19 (m, 4H). MS (ESI) = 537.82[M+1]. SOR = +52.00, 0.1 % in MeOH, 20 °C.

Example-9: l-(7'-((5-Fluoro-2-((4-morpholinophenyl)amino)pyrimidin-4-yl)amino)-2',3'- dihydro- 1 Ή-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

A mixture of 7'-amino-rH-spiro[cyclopropane-l ,4'-quinolin]-2'(3'H)-one (0.3 g, 1.59 mmol), 2,4-dichloro-5-fluoropyrimidine (0.346 g, 2.072 mmol) and Hunig's base (0.7ml, 3.98 mmol) in ethanol (15 ml) was heated in a sealed vial at 60 °C for 18 h. Solvent was evaporated in vacuo and the residue was purified by flash chromatography to afford the title compound (0.425 g). 1H NMR (400 MHz, DMSO-J₆) δ 10.40 (s, 1H), 9.99 (d, = 1.7 Hz, 1H), 8.30 (d, = 3.5 Hz, 1H), 7.14 - 7.27 (m, 2H), 6.93 (d, = 8.3 Hz, 1H), 2.39 (s, 2H), 0.91- 1.02 (m, 2H), 0.75 - 0.83 (m, 2H). MS (ESI) = 319.28 [M+l]

Step-2: 7'-((5-Fluoro-2-((4-morpholinophenyl)amino)pyrimidin-4-yl)amino)-l'H-spiro [cyclopropane- l,4'-quinolin]-2'(3'H)-one

A mixture of 7'-((2-Chloro-5-fluoropyrimidin-4-yl)amino)-rH-spiro[cyclopropane-l ,4'- quinolin]-2'(3'H)-one (0.4 g, 1.255 mmol), 4-morpholinoaniline (0.246 g, 1.380 mmol) and cone. HCl (0.1 ml) in 2-Propanol (40 ml) was heated in a sealed vial for 24 h at 90 °C. After cooling to RT, solvent was evaporated in vacuo and residue was basified by addition of aqueous ammonia solution. The resulting mixture was extracted several times with ethyl acetate. The combined organic phase was dried over sodium sulphate and concentrated in vacuo. The residue was purified by flash chromatography to afford the title compound (0.450 g). 1H NMR (400 MHz, DMSO-J₆) δ 10.16 (s, 1H), 9.32 (d, = 1.5 Hz, 1H), 8.79 (s, 1H), 8.03 (d, = 3.8 Hz, 1H), 7.45 - 7.57 (m, 2H), 7.38 (s, 1H), 7.19 (dd, = 8.3, 2.1 Hz, 1H), 6.68 - 6.98 (m, 3H), 3.55 - 3.90 (m, 4H), 2.85- 3.12 (m, 4H), 2.41 (s, 2H), 0.88- 1.03 (m, 2H), 0.71 - 0.86 (m, 2H). MS (ESI) = 461.14 [M+l]

Step-3:N4-(2',3'-Dihydro-rH-spiro[cyclopropane-l ,4'-quinolin]-7'-yl)-5-fluoro-N2-(4- morpholinophenyl)pyrimidine-2,4-diamine

7'-((5-Fluoro-2-((4-morpholinophenyl)amino)pyrimidin-4-yl)amino)-l'H- spiro[cyclopropane-l,4'-quinolin]-2'(3'H)-one (0.260 g, 0.565 mmol) was added to an ice cold slurry of LAH (0.086 g, 2.258 mmol) in THF (10 ml). Resulting mixture was heated at 70 °C for 1.5 h. The reaction mixture was cooled to RT and quenched by addition of aqueous NaOH. The resulting mixture was extracted several times with EtOAc. Combined organic phase was dried over sodium sulphate and concentrated in vacuo to give the title compound

(0.230 g).1H NMR (400 MHz, DMSO-J₆) δ 8.96 (s, 1H), 8.80 (s, 1H), 7.97 (d, J = 3.8 Hz, 1H), 7.45 - 7.57 (m, 2H), 6.68 - 6.92 (m, 4H), 6.47 (d, J = 8.4 Hz, 1H), 5.58 (s, 1H), 3.68 - 3.82 (m, 4H), 3.25 (dd, = 6.9, 3.1 Hz, 2H), 2.91- 3.09 (m, 4H), 1.66 (t, = 5.4 Hz, 2H), 0.81 - 0.98 (m, 3H), 0.61 - 0.75 (m, 2H). MS (ESI) = 447.17 [M+l].

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

A mixture of N4-(2',3'-Dihydro-rH-spiro[cyclopropane-l,4'-quinolin]-7'-yl)-5-fluoro-N2-(4- morpholinophenyl)pyrimidine-2,4-diamine (0.2 g, 0.448 mmol) and K₂CO₃ (0.155 g, 1.120 mmol) in NMP (3 ml)was stirred at 0°C for 5 min. before a solution of acryloyl chloride (0.04 ml, 0.45 mmol) in NMP (0.5 ml) was added. Resulting mixture was stirred at 0 °C for 20 min. The 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). ^XH NMR (400 MHz, DMSO- d₆) δ 9.32 (s, 1H), 8.88 (s, 1H), 8.04 (d, = 3.7 Hz, 1H), 7.54 (d, = 8.0 Hz, 2H), 7.36 - 7.46 (m, 2H), 6.76 - 6.86 (m, 2H), 6.75 (d, = 8.7 Hz, 1H), 6.66 (dd, / = 16.6, 10.3 Hz, 1H), 6.19 (dd, = 16.7, 2.4 Hz, 1H), 5.68 (dd, = 10.3, 2.3 Hz, 1H), 3.93 (dd, = 6.7, 4.8 Hz, 2H), 3.66 - 3.81 (m, 4H), 2.97- 3.08(m, 4H), 1.72 - 1.83 (m, 2H), 0.95- 1.03(m, 2H), 0.85- 0.94(m, 2H). MS (ESI) = 501.21 [M+l]. Example-10: N-(l'-(5-Fluoro-2-((4-(2-methoxyethoxy) phenyl) amino) pyrimidin-4-yl) spiro [cyclopropane- l,3'-indolin]-6'-yl)acrylamide

A mixture l'-(5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)spiro [cyclo propane-l,3'-indolin]-6'-amine (Intermediate-4) (0.25 g, 0.59 mmol) and K₂CO₃ (0.164 g, 1.18 mmol) in NMP (1.5 ml) was stirred at 0°C for 5 min. before a solution of acryloyl chloride (43 mg, 0.475 mmol) in NMP (0.5 ml) was added. Resulting mixture was stirred at 0°C for 1 h. The 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). 1H NMR (400 MHz, DMSO- d₆) δ 9.95 (s, 1H), 9.03 (s, 1H), 8.23 (d, = 5.2 Hz, 1H), 8.00 (s, 1H), 7.50 - 7.66 (m, 2H), 7.36 (dd, 7 = 8.1, 1.8 Hz, 1H), 6.70 - 6.87 (m, 3H), 6.42 (dd, = 16.9, 10.1 Hz, 1H), 6.22 (dd, / = 17.0, 2.1 Hz, 1H), 5.73 (dd, = 10.1, 2.1 Hz, 1H), 4.23 (d, = 3.9 Hz, 2H), 3.91 - 4.05 (m, 2H), 3.53 - 3.71 (m, 2H), 3.30 (s, 2H), 1.08 - 1.19 (m, 2H), 1.01-1.04 (m, 2H). MS (ESI) = 476.17 [M+ 1].

Example-11: 2-Chloro-N-(r-(5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4- yl)spiro[cyclopropane-l,3'-indolin]-6'-yl)acetamide

A mixture of r-(5-Fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)spiro [cyclopropane- l,3'-indolin]-6'-amine (0.2 g, 0.47 mmol) and K₂CO₃ (0.13 g, 0.95 mmol) in NMP (2.0 ml) was stirred at 0 °C for 5 min. before a solution of chloroacetyl chloride (0.04 ml, 0.47 mmol) in NMP (0.5 ml) was added. Resulting mixture was stirred at 0 °C for 1 h. The 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). 1H NMR (400 MHz, DMSO-J₆) δ 10.08 (s, 1H), 9.06 (s, 1H), 8.24 (d, = 5.3 Hz, 1H), 7.92 (s, 1H), 7.49 - 7.60 (m, 2H), 7.24 (dd, = 8.1, 1.8 Hz, 1H), 6.70 - 6.89 (m, 3H), 4.24 (d, = 3.9 Hz, 2H), 4.21 (s, 2H), 3.98 - 4.05 (m, 2H), 3.57 - 3.68 (m, 2H), 3.31 (s, 3H), 1.08 - 1.24 (m, 2H), 0.95 - 1.07 (m, 2H). MS (ESI) = 498.17 [M+ 1].

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

To a solution of r-(2-Chloro-5-fluoropyrimidin-4-yl)-6'-nitrospiro [cyclopropane- 1,3'- indoline] (0.500 g, 1.559 mmol) and 4-phenoxyaniline (0.35 g, 1.871 mmol)in dioxane (15.0 ml) was added pTsOH.H₂0 (0.24 g, 1.25 mmol). Resulting mixture was stirred at 110 °C for 18 h. The solvent was evaporated in vacuo and the residue was partitioned between Ethyl acetate (100 ml) and aqueous saturated NaHC0₃ solution (50 ml). Organic phase was separated, dried over Na₂S0₄ and evaporated in vacuo. The residue was purified by flash chromatography to afford title compound (0.55 g). 1H NMR (400 MHz, DMSO-J₆) δ 9.49 (s, 1H), 8.59 (d, = 2.1 Hz, 1H), 8.34 (d, = 5.3 Hz, 1H), 7.82 (dd, = 8.3, 2.2 Hz, 1H), 7.57 - 7.70 (m, 2H), 7.35 (dd, / = 8.6, 7.3 Hz, 2H), 7.03 - 7.14 (m, 2H), 6.92 - 7.00 (m, 2H), 6.85 - 6.93 (m, 2H), 4.39 (d, = 4.5 Hz, 2H), 1.20 - 1.38 (m, 4H). MS (ESI) = 470.10 [M+ 1].

Step-2: r-(5-Fluoro-2-((4-phenoxyphenyl)amino)pyrimidin-4-yl)spiro[cyclopropane-l,3'- indolin] -6'-amine

A suspension of 5-Fluoro-4-(6'-nitrospiro[cyclopropane-l,3'-indolin]-l'-yl)-N-(4-phenoxy phenyl)pyrimidin-2-amine (500 mg, 1.07 mmol) , Fe (0.29 g, 5.33 mmol) and NH₄C1 (0.57 g, 10.65 mmol) in ethanol (20 ml) and water (4 ml) was heated at 80°C for 18 h. After cooling to room temperature, the reaction mixture was filtered through a celite bed. The filtrate was evaporated in vacuo. The residue was partitioned between Ethyl acetate (50 ml) and water (30 ml). Organic phase was separated and dried over sodium sulphate. The solvent was evaporated in vacuo to give title compound (0.38 g). 1H NMR (400 MHz, DMSO-J₆) δ 9.20 (s, 1H), 8.19 (d, 7 = 5.7 Hz, 1H), 7.65 - 7.81 (m, 2H), 7.27 - 7.46 (m, 3H), 7.07 (t, 7 = 7.4 Hz, 1H), 6.90 - 7.03 (m, 4H), 6.47 (d, 7 = 7.9 Hz, 1H), 6.20 (dd, 7 = 8.0, 2.0 Hz, 1H), 4.80 (s, 2H), 4.19 (d, 7 = 4.4 Hz, 2H), 0.81 - 1.06 (m, 4H). MS (ESI) = 440.11 [M+ 1].

Step-3: N-(l'-(5-Fluoro-2-((4-phenoxyphenyl) amino) pyrimidin-4-yl) spiro[cyclopropane- l,3'-indolin]-6'-yl)acrylamide

A mixture r-(5-Fluoro-2-((4-phenoxyphenyl)amino)pyrimidin-4-yl)spiro[cyclopropane-l,3'- indolin]-6'-amine (0.2 g, 0.45 mmol) and K₂C0₃ (0.126 g, 0.91 mmol) in NMP (1.5 ml) was stirred at 0°C for 5 min. before a solution of acryloyl chloride (33.0 mg, 0.36 mmol) in NMP (0.5 ml) was added. Resulting mixture was stirred at 0°C for lhr. The 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 preparative HPLC afforded the title compound (18 mg). 1H NMR (400 MHz, DMSO-J₆) δ 9.96 (s, 1H), 9.31 (s, 1H), 8.28 (d, 7 = 5.3 Hz, 1H), 7.96 - 8.09 (m, 1H), 7.66 - 7.75 (m, 2H), 7.27 - 7.41 (m, 3H), 7.01 - 7.12 (m, 1H), 6.84 - 6.99 (m, 4H), 6.77 (d, 7 = 8.2 Hz, 1H), 6.33 (d, 7 = 10.1 Hz, 1H), 6.09 - 6.25 (m, 1H), 5.63 (dd, 7 = 10.1, 2.1 Hz, 1H), 4.25 (d, 7 = 3.9 Hz, 2H), 0.95 - 1.17 (m, 4H). MS (ESI) = 493.94 [M+ 1].

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

To a solution of l-(6'-((2-chloro-5-fluoropyrimidin-4-yl)amino)spiro[cyclopropane-l,3'- indolin]-l'-yl)propan-l-one (Intermediate-2) (300 mg, 0.865 mmol) and 4-(2- methoxyethoxy)aniline (145 mg, 0.865 mmol) in dioxane (8.0 ml) was added pTsOH (0.13 g, 0.692 mmol). Resulting mixture was stirred at 110 °C for 18 h. The solvent was evaporated in vacuo and the residue was partitioned between Ethyl acetate (50 ml) and aqueous saturated NaHC0₃ solution (50 ml). Organic phase was separated, dried over Na₂S0₄ and evaporated in vacuo. The residue was purified preparative HPLC to afford title compound (49 mg). ¹H

NMR (400 MHz, Chloroform-JJ δ 8.25 (d, = 2.1 Hz, 1H), 7.88 (d, = 3.4 Hz, 1H), 7.64 (dd, = 8.2, 2.1 Hz, 1H), 7.47 - 7.37 (m, 2H), 6.81 - 6.99 (m, 3H), 6.62 (d, = 8.2 Hz, 1H), 4.16 - 4.09 (m, 2H),4.08 (s, 2H), 3.73 - 3.81 (m, 2H), 3.48 (s, 3H), 2.43 (q, / = 7.3 Hz, 2H), 1.24 (t, = 7.3 Hz, 3H), 1.04 -1.17 (m, 4H). MS (ESI) = 478.18 [M+ 1].

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

To a solution of l-(6'-((2-Chloro-5-fluoropyrimidin-4-yl)amino)spiro[cyclopropane-l,3'- indolin]-l'-yl)propan-l-one (0.3 g, 0.87 mmol) and 4-phenoxyaniline (0.16 g, 0.87 mmol) in dioxane (8.0 ml) was added pTsOH (0.13 g, 0.692 mmol). Resulting mixture was stirred at 110°C for 18 h. The solvent was evaporated in vacuo and the residue was partitioned between Ethyl acetate (50 ml) and aqueous saturated NaHC0₃ solution (50 ml). Organic phase was separated, dried over Na₂S0₄ and evaporated in vacuo. The residue was purified preparative HPLC to afford title compound (54 mg). 1H NMR (400 MHz, Chloroform-J) δ

8.29 (d, = 2.1 Hz, 1H), 7.90 (d, = 3.4 Hz, 1H), 7.43 - 7.62 (m, 4H), 7.30 - 7.39 (m, 2H), 7.06 - 7.13 (m, 1H), 6.87 - 7.05 (m, 5H), 6.60 (d, = 8.1 Hz, 1H), 4.05 (s, 2H),2.40 (q, = 7.3 Hz, 2H), 1.23 (t, = 7.3 Hz, 3H), 1.09 (dt, = 6.5, 2.1 Hz, 4H). MS (ESI) = 496.17 [M+

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

A mixture of 6'-nitrospiro[cyclobutane-l,3'-indoline] (Intermediate-3) (400 mg, 1.959 mmol), 2,4-dichloro-5-fluoropyrimidine (0.39 g, 2.4 mmol) and DIPEA 0.7 ml, 3.92 mmol) in acetonitrile (20 ml) was heated at 70°C under N₂ atmosphere for 18 h. After cooling to room temperature, the solvent was evaporated in vacuo and the residue was partitioned between Ethyl acetate (100 ml) and water (100 ml). Organic phase was separated, dried over sodium sulphate and evaporated in vacuo. The residue was purified by column chromatography to afford the title compound (0.3 g). 1H NMR (400 MHz, Chloroform-J) δ 9.00 (d, / = 2.1 Hz, 1H), 8.23 (d, J = 4.9 Hz, 1H), 8.06 (dd, / = 8.3, 2.1 Hz, 1H), 7.60 (d, = 8.3 Hz, 1H), 4.53 (d, = 4.7 Hz, 2H), 2.47 - 2.56 (m, 2H), 2.35 - 2.44 (m, 2H), 2.1 1 - 2.20 (m, 2H). MS (ESI) = 335.0 [M+ 1].

Step-2: 5-Fluoro-N-(4-(2-methoxyethoxy)phenyl)-4-(6'-nitrospiro [cyclobutane- 1 ,3'- indolin] - 1 '-yl)pyrimidin-2-amine

To a solution of r-(2-chloro-5-fluoropyrimidin-4-yl)-6'-nitrospiro[cyclobutane-l ,3'-indoline] (400 mg, 1.195 mmol) and 4-(2-methoxyethoxy)aniline (240 mg, 1.434 mmol) in dioxane (5.0 ml) was added pTsOH.H₂0 (0.18 g, 0.96 mmol). Resulting mixture was stirred at 1 10 °C for 18 h. The solvent was evaporated in vacuo and the residue was partitoned between Ethyl acetate and aqueous saturated NaHC0₃ solution. Organic phase was separated, dried over Na2S04 and evaporated in vacuo. The residue was purified by column chromatography to afford title compound. (450 mg^H NMR (400 MHz, DMSO-J₆) δ 9.36 (d, = 7.8 Hz, 1H), 8.48 (d, = 2.1 Hz, 1H), 8.31 (d, = 5.4 Hz, 1H), 7.87 - 7.97 (m, 1H), 7.74 - 7.85 (m, 1H), 7.42 - 7.52 (m, 2H), 7.11 (d, = 7.8 Hz, 1H), 6.79 - 6.85 (m, 1H), 4.47 (d, = 4.5 Hz, 2H), 3.95 - 4.07 (m, 2H), 3.59 - 3.70 (m, 2H), 3.31 (s, 3H), 2.38 (tt, = 13.2, 10.6, 5.1 Hz, 4H), 2.02 - 2.10 (m, 2H). MS (ESI) = 466.11 [M+ 1 ] .

Step-3: r-(5-Fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)spiro [cyclo butane- l ,3'-indolin]-6'-amine

A mixture of 5-fluoro-N-(4-(2-methoxyethoxy)phenyl)-4-(6'-nitrospiro[cyclobutane-l ,3'- indolin]-l'-yl)pyrimidin-2-amine (0.45 g, 0.967 mmol), Fe (0.27 g, 4.83 mmol) and NH₄C1 (0.52 g, 9.67 mmol) in ethanol (5.0 ml) and water (1.0 ml) was heated to reflux at 75-80°C for 2 h. after cooling to RT, the reaction mixture was filtered through celite and the filtrate was evaporated in vacuo. Residue was partitioned between ethyl acetate and water. Organic phase was separated, dried over sodium sulphate and evaporated in vacuo to give the crude product (0.3 g), which was used in the next step without further purification. MS (ESI) = 436.20 [M+ 1]. Step-4: N-( 1 '-(5-Fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)spiro [cyclo butane- l ,3'-indolin]-6'-yl)acrylamide

A mixture of r-(5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)spiro [cyclobutane-l,3'-indolin]-6'-amine (0.150 g, 0.344 mmol) and K₂C0₃ (0. 95 g, 0.69 mmol) in NMP (3.0 ml) was stirred at 0°C. Acryloyl chloride (31 mg, 0.34 mmol) was added and the resulting mixture was stirred under N₂ atmosphere, allowed to room temperature over 1.5 h. The reaction mixture was partitioned between water (30 ml) and Ethyl acetate (50 ml). Organic phase was removed and aqueous phase was re-extracted with Ethyl acetate (50 ml x 3). Combined organic phase was washed with water and dried over sodium sulphate. Solvent was evaporated in vacuo and the residue was purified by column chromatography to afford the title compound (42 mg). 1H NMR (400 MHz, DMSO-J₆) δ 10.01 (s, 1H), 9.05 (s, 1H), 8.24 (d, J = 5.1 Hz, 1H), 7.90 (s, 1H), 7.53 - 7.63 (m, 2H), 7.39 - 7.49 (m, 2H), 6.75 - 6.86 (m, 2H), 6.43 (dd, J = 16.9, 10.1 Hz, 1H), 6.23 (dd, J = 16.9, 2.1 Hz, 1H), 5.74 (dd, J = 10.1, 2.1 Hz, 1H), 4.30 (d, = 3.6 Hz, 2H), 3.90 - 4.05 (m, 2H), 3.56 - 3.66 (m, 2H), 3.30 (s, 3H), 2.21 - 2.37 (m, 4H), 1.95 - 2.05 (m, 2H). MS (ESI) = 490.0 [M+ 1].

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

To a stirred solution of 5-fluoro-N2-(4-(2-methoxyethoxy)phenyl)-N4-(spiro[cyclobutane- l ,3'-indolin]-6'-yl)pyrimidine-2,4-diamine (0.250 g, 0.574 mmol) was added 2-((tert- butoxycarbonyl)amino)acetic acid (0.151 g, 0.861 mmol), HATU (0.437 g, 1.148 mmol) and DIPEA (0.20 ml, 1.148 mmol) at 0°C, resulting reaction mixture was stirred at room temperature for 2 h. The reaction mixture was partitoned between water and EtOAc. Organic layer was separated, dried over sodium sulphate and concentrated in vacuo. Purification of the residue by flash chromatography afforded the title compound (0.3 lOg). MS (ESI) 592.83 [M+] .

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

TFA (0.390 ml, 5.06 mmol) was added to a solution of tert-butyl (2-(6'-((5-fluoro-2-((4-(2- methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)spiro[cyclobutane-l,3'-indolin]-r-yl)- 2-oxoethyl)carbamate (0.300 g, 0.506 mmol) in DCM (10 ml). Resulting mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with DCM and basified by addition of aqueous NaHC0₃. The organic phase was separated, dried over Na₂S0₄. Removal of solvent under reduced pressure afforded crude product (0.167g) which was used in the next step without further purification. MS (ESI) = 493 [M+l]

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

A mixture of K₂C0₃ (0.084 g, 0.609 mmol) and 2-amino-l-(6'-((5-fluoro-2-((4-(2- methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)spiro[cyclobutane-l,3'-indolin]-r- yl)ethanone (0.150 g, 0.305 mmol) in NMP (2 ml) was stirred at 0 °C for 5 min. before acryloyl chloride (0.034 g, 0.365 mmol) in NMP (0.5 ml) was added. Resulting mixture was stirred for 50 min. The mixture was partitioned between water 50 ml and EtOAc 50 ml. Organic phase was separated, and washed repeatedly with water. Organic phase was dried over Na₂S0₄. The solvent was removed in vacuo and the residue was purified by flash chromatography to give the title compound (31 mg). ^XH NMR (400 MHz, DMSO-Je) δ 9.36 (s, 1H), 8.93 (s, 1H), 8.42 (t, = 5.5 Hz, 1H), 8.07 (dd, / = 31.9, 2.8 Hz, 2H), 7.81 - 7.58 (m, 1H), 7.59 - 7.38 (m, 3H), 6.92 - 6.71 (m, 2H), 6.41 (dd, / = 17.1, 10.2 Hz, 1H), 6.13 (dd, / = 17.1, 2.2 Hz, 1H), 5.63 (dd, = 10.2, 2.2 Hz, 1H), 4.31 (s, 2H), 4.19 (d, = 5.5 Hz, 2H), 4.08 - 3.94 (m, 2H), 3.71 - 3.57 (m, 2H), 3.30 (s, 3H), 2.35 (tt, / = 11.6, 6.5 Hz, 4H), 2.04 (h, = 8.8, 8.2 Hz, 2H). MS (ESI) = 547.23 [M+l].

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

To stirred solution of 5-Fluoro-N2-(4-(2-methoxyethoxy)phenyl)-N4-(spiro[cyclopropane- l,3'-indolin]-6'-yl)pyrimidine-2,4-diamine (0.150 g, 0.356 mmol) in DCM (5 ml) was added (E)-4-(dimethylamino)but-2-enoic acid (0.055 g, 0.427 mmol), HATU (0.203 g, 0.534 mmol) and triethylamine (0.1 ml, 0.712 mmol), resulting mixture was stirred at room temperature for 2 h. The reaction mixture was poured in water and extracted with DCM (2X 50 ml). Combined organic layer was washed with aqueous NaHC0₃ and dried over sodium sulphate. The solvent was evaporated in vacuo. The residue was purified by flash chromatography to give title compound (30 mg). 1H NMR (400 MHz, DMSO-J6) δ 9.34 (s, 1H), 8.95 (s, 1H), 8.32 (d, = 7.9 Hz, 1H), 8.05 (d, = 12.3Hz, 1H), 7.72 - 7.37 (m, 3H), 7.09 - 6.62 (m, 4H), 6.48 (d, = 16.4 Hz, 1H), 4.27 (s, 2H), 4.00 (s, 2H),3.63 (s, 2H), 3.31 (S, 3H), 3.22 - 2.91 (m, 2H), 2.50 (s, 3H), 2.18 (s, 3H), 1.10 (d, J = 33.6 Hz, 4H). MS (ESI)= 533.28 [M+l]. Example-18: 5-Fluoro-N2-(4-(2-methoxyethoxy)phenyl)-N4-( 1 '-(vinylsulfonyl)spiro

[cyclopropane- l,3'-indolin]-6'-yl)pyrimidine-2,4-diamine

To a cooled solution of 5-Fluoro-N2-(4-(2-methoxyethoxy)phenyl)-N4-(spiro[cyclopropane- l,3'-indolin]-6'-yl)pyrimidine-2,4-diamine (0.150 g, 0.356 mmol) and triefhylamine (0.1 ml, 0.712 mmol) in DCM (5.0 ml)was added 2-chloroefhanesulfonyl chloride (0.070 g, 0.427 mmol) at 0°C. Resulting mixture was stirred at 0°C for 1 h. The reaction mixture was diluted with CHCI₃ and 1M HCl was added. The organic layer was separated, washed with water and dried over sodium sulphate. The solvent was removed in vacuo and the residue was purified by flash chromatography to give the title compound (27 mg). 1H NMR (400 MHz, DMSO- d6) 5 9.37 (s, 1H), 8.94 (s, 1H), 8.05 (d, 7 = 3.7 Hz, 1H), 7.66 (dd, 7 = 8.1 , 1.9 Hz, 1H), 7.60 - 7.36 (m, 3H), 6.99 - 6.70 (m, 4H), 6.30 (d, 7 = 16.4 Hz, 1H), 6.20 (d, 7 = 9.9 Hz, 1H), 4.17 - 3.98 (m, 2H), 3.94 (s, 2H), 3.64 (t, 7 = 4.6 Hz, 2H), 3.31 (s, 3H), 1.19 - 0.91 (m, 4H). MS (ESI) = 511.94 [M+l].

Example-19:5-Fluoro-N2-(4-phenoxyphenyl)-N4-(spiro[cyclobutane-l,3'-indolin]-6'- yl)pyrimidine-2,4-diamine

The title compound was prepared by following the similar procedure as described in Example-4 using suitable Intermediate. 1H NMR (400 MHz, DMSO-J₆) δ 9.16 (s, 1H), 9.08 (d, = 1.7 Hz, 1H), 8.03 (d, = 3.8 Hz, 1H), 7.65 -7.72 (m, 2H), 7.31 - 7.39 (m, 2H), 7.15 (d, = 7.9 Hz, 1H), 7.12-7.06 (m, 1H), 6.93 - 6.98 (m,3H), 6.86 - 6.92 (m, 2H), 6.76 (d, = 1.9 Hz, 1H), 5.41 (t, = 2.0 Hz, 1H), 3.46 (d, = 1.9 Hz, 2H), 2.20-2.15 (m, 2H), 2.10-2.05 (m, 2H), 1.86 - 1.96 (m, 2H). MS (ESI): 454.0.

Example-20:5-Fluoro-N2-(4-morpholinophenyl)-N4-(spiro[cyclobutane-l,3'-indolin]-6'- yl)pyrimidine-2,4-diamine

The title compound was prepared by following the similar procedure as described in Example-4 using suitable Intermediate. 1H NMR (400 MHz, DMSO-J₆) δ 9.00 (d, = 1.7 Hz, 1H), 8.86 (s, 1H), 7.98 (d, = 3.8 Hz, 1H), 7.45 -7.57 (m, 2H), 7.17 (d, = 7.9 Hz, 1H), 6.98 (dd, = 8.0, 1.9 Hz, 1H), 6.72 - 6.88 (m, 3H), 5.38 (t, = 1.9 Hz, 1H), 3.65 - 3.78 (m, 4H), 3.51 (d, = 2.0 Hz, 2H), 2.94 - 3.07 (m, 4H), 2.22-2.26 (m, 2H), 2.07 - 2.15 (m, 2H), 1.89-1.95 (m, 2H). MS (ESI): 447.0.

Example-21:N4-(2',4'-Dihydro-rH-spiro[cyclo propane- l,3'-quinolin]-7'-yl)-5-fluoro-N2-(4- (2-methoxyethoxy)phenyl)pyrimidine-2,4-diamine

The title compound was prepared by following the similar procedure as described in Example-7 using suitable Intermediate. 1H NMR (400 MHz, DMSO-J₆) δ 8.99 (d, = 1.7 Hz, 1H), 8.88 (s, 1H), 7.99 (d, J = 3.8 Hz, 1H), 7.51 - 7.60 (m, 2H), 6.69 - 6.92 (m, 5H), 5.59 (s, 1H), 4.08 - 3.92 (m, 2H), 3.54 - 3.71 (m, 2H), 3.30 (s, 3H), 2.94 (s, 2H), 0.37 - 0.52 (m, 4H). Mass: 436.2 [M+l].

The below Examples 22 to 60 were prepared by following the similar procedure as described in Example-2 or Example-5 using appropriate Intermediates

Table- 1

MS

Example Structure and Name 1H NMR

(ESI)

The below Examples 61 to 94 were prepared by following the similar procedure as described in Example-6 or Example-8 using appropriate Intermediates

Table-2

MS

Example Structure and Name 1H NMR

(ESI)

yl)amino)spiro[cyclopropane- 1 ,3'- indolin] - 1 '-yl)propan- 1 -one

The below Examples 95 to 101 were prepared by following the similar procedure as described in Example-9 using appropriate Intermediates

Table-3

spiro [cyclopropane- 1 ,4' -quinolin] - Γ - 3H), 1.01 (s, 2H), 0.92 (s,

yl)propan- 1 -one 2H).

The below Examples 102 to 113 were prepared by following the similar procedure as described in Example- 17 using appropriate Intermediates

Table-4

4,4-dimethylpent-2-enenitrile

The below Examples 1 14 to 127 were prepared by following the similar procedure as described in Example- 18 using appropriate Intermediates

Table-5

(s, 3H), 2.16-2.38 (m, 4H),

1.97-2.09 (m, 2H)

125 ^XH NMR (400 MHz, 556.00

DMSO-Je)

δ 9.79 (brs, 1H), 9.64 (brs,

1H), 8.20 (d, 7=3.6 Hz,

l N A NH 1H), 7.83 - 7.96 (m, 2H),

7.57-7.76 (m, 3H), 7.51

(d, 7 =8.2 Hz, 1H), 7.36 (d,

o*^s*o 7= 1.9 Hz, 1H), 6.82 (dd, 7

N2-(4-(Cyclopropylsulfonyl) phenyl)- = 16.4, 10.0 Hz, 1H), 6.29 5-fluoro-N4-(l'-(vinylsulfonyl)spiro (d,7= 16.4 Hz, 1H), 6.16 [cyclo butane- 1 ,3'-indolin] -6'-yl) (d,7= 10.0 Hz, 1H), 4.02 pyrimidine-2,4-diamine (s, 2H), 2.71-2.75 (m, 1H),

2.22-2.42 (m, 4H), 1.94- 2.08 (m, 2H), 0.94- 1.13

(m, 4H).

126 ^XH NMR (400 MHz, 466.10

DMSO-J₆)

δ 9.42 (brs, 1H), 9.03 (brs,

1H), 8.08 (d,7=3.6 Hz,

N NH 1H), 7.79 (dd, 7=8.3, 1.9

Hz, 1H), 7.49 - 7.57 (m,

2H), 7.45 (d,7=8.2 Hz,

1H), 7.37 (d,7= 1.9 Hz,

5-Fluoro-N2-(p-tolyl)-N4-( 1 '- 1H), 7.02 (d,7=8.3 Hz,

(vinylsulfonyl)spiro[cyclobutane-l,3'- 2H), 6.82 (dd, 7= 16.4, 10.0 indolin]-6'-yl)pyrimidine-2,4-diamine

Hz, 1H), 6.30 (d, 7= 16.5

Hz, 1H), 6.17 (d, 7= 10.0

Below Examples 128-130were prepared by following the similar procedure as described in Example- 17 using appropriate Intermediates.

Table-6

Example Structure Name MS (ESI)

Pharmacological activity BTK Kinase Assay

The biochemical assay uses ADP-Glo™ 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-Glo™ 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-Glo™ Luciferase, which is measure using BioTek Synergy 2 multimode plate reader. The luminescent signal positively correlates with kinase activity.

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 μg/ml substrate and 100 μΜ 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-Glo™ 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.

RLU positive - negative " RLU test - negative

% Inhibition = X 100

RLU positive - negative

Phospho EGFR Assay (ELISA)

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. After washing away unbound material, 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.

OD positive - negative - OD test - negative

% Inhibition = X 100

OD positive - negative

EGFR Kinase Assay

The biochemical assay uses ADP-Glo™ 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-Glo™ 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-Glo™ Luciferase, which is measure using BioTek Synergy 2 multimode plate reader. The luminescent signal positively correlates with kinase activity.

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 μg/ml substrate and 30 μΜ ultra-pure ATP. The reaction mixture is incubated in a shaking incubator for 30 min at room temperature at 250 rpm.

RLU positive - negative - RLU test - negative

% Inhibition = X 100

RLU positive - negative

The compounds of the present invention were screened in assay methods mentioned herein to obtain the activity. Table-7: In vitro activity of BTK (IC₅₀), EGFR (IC₅₀) and % inhibition of phosho EGFR

Example BTK ICso ICso (nM) EGFR pEGFR inhibition (% No. nM Inhibition inhibition @10 μΜ)

1 126 Not Active —

2 22 1030 —

3 13 41 —

4 Not Active —

-

5 51 69% at 10 μΜ 40

6 19 38 31

7 175.6 —

-

8 17 — 36

8A 5 > 250 49

8B -171 — -

9 23.3 — 47

10 Not Active — -

11 Not Active —

-

12 Not Active — -

13 Not Active —

-

14 Not Active — -

15 Not Active —

-

16 1886 —

-

17 21 447 69

18 43 — 28

19 Not Active —

- 20 >625 —

—

21 800 —

—

22 10 1564 72.32

23 122 —

—

24 72 >250 11

25 198 —

—

26 101 —

—

27 17 — Not active

28 22 — Not active

29 63 —

—

30 25 — 13

31 75 — —

32 4.6 — 67

33 7.8 — 3

34 21 — 52

35 152 —

—

36 13 — Not Active

37 24 — 19

38 10 —

—

39 14 — 38

40 86 30% at 10 uM 10

41 177 —

—

42 60 -542 11

43 253 —

— 44 70 Not Active Not Active

45 12 -1385 42

46 20 Not active 13.8

47 150 —

—

48 19 — 10

49 210 —

—

50 43 —

—

51 45 — —

52 18 — 109

53 5 — 87

54 31 Not Active Not Active

55 16 — 18

56 18.6 — 50

57 44 —

—

58 Not Active —

—

59 748 —

—

60 12 —

—

61 9 112 46.12

62 58 75 80

63 53 89 12

64 104 —

—

65 86 —

—

66 54 99 39

67 16 — 100 68 30 — 95

69 24 — -404

70 38 — 68

71 17 — 105

72 54 — 69

73 29 —

—

74 9 156 59.92

75 29 27 79

76 46 — 95

77 172 —

—

78 201 — —

79 18 — 100

80 156 —

—

81 240 —

—

82 127 —

—

83 35 184 Not Active

75

84 13 37

85 19 38 31

86 81 59% at 2.5 uM

87 52 1121 30.07

88 15 — Not Active

89 Not Active —

—

90 160 —

— 91 19 — 26

92 12 Not Active Not Active

93 27 — Not Active

94 53 —

—

95 Inactive —

—

96 43.3 —

—

97 14.6 Not Active 32.79

98 22,45 Not Active —

99 Not Active —

—

100 Not Active —

—

101 Not Active —

—

102 59 —

—

103 8.2 — 30

104 7 — 83

105 15.8 — 71

106 45 414 73

107 36 —

—

108 8.1 — 71

109 Not Active — —

110 Not Active — —

111 21 — 21.82

112 49 —

—

113 >250 —

—

114 19.2 — 61 115 25 — 47

116 96 — —

117 83 — —

118 83 — —

119 16 — 69

120 5 — 100

121 16 Not Active Not Active

122 65 —

—

123 19 — Not Active

124 225 — —

125 36 — —

126 >1000 — —

127 55 — —

Protocol for Biochemical assay against JAK3 kinase:

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.

Claims

1. A compound having the structur

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)R₆, -C(0)NR_aR_b, - S0₂NR_aR_b, -S0₂R₆, -NR_aR_b , -NR_aC(0)R₆, -NR_aS(0)₂R₆ and -OR₆;

R₂ is selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl and -C(0)NR_aR_t,;

R_a and R are independently hydrogen or substituted or unsubstituted alkyl;

R₃ and R_3a are each independently selected from hydrogen or substituted or unsubstituted alkyl;

R₄, which may be same or different at each occurrence, is independently selected from hydrogen, substituted or unsubstituted -C(0)-alkyl, substituted or unsubstituted -S(0)₂- alkyl, substituted or unsubstituted -C(0)-haloalkyl, substituted or unsubstituted -S(0)₂- haloalkyl, substituted or unsubstituted -S(0)₂- alkenyl, substituted or unsubstituted -S(0)₂- alkynyl, substituted or unsubstituted -C(0)-alkenyl, -C(0)-(CN)C=CH-C(CH₃)₂-morpholine, substituted or unsubstituted -C(0)-alkynyl, substituted or unsubstituted -C(0)-cycloalkyl and substituted or unsubstituted -S(0)₂-cycloalkyl;

'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, -CH₂-OR^x, -C(0)NR^xR^y, -NR^xC(0)NR^yR^z, - N(R^x)S(0)₂R^y, -NR^xR^y, -CH₂NR^xR^y, -NR^xC(0)R^y, -S(0)₂NR^xR^y, -OR^x, -OC(0)R^x, - OC(0)NR^xR^y, -alkylene-C(0)R^y and -S(0)₂R^x wherein each occurrence of R^x, R^y and R^z are independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl and cycloalkyl; or pharmaceutically acceptable salt thereof.

2. The compound of claim 1, having the Formula (II),

R₄ is selected from:

Rio is hydrogen or substituted and unsubstituted Ci-C₄-alkyl; Rn is hydrogen and substituted or unsubstituted Ci-C₄-alkyl; and W is halogen or -NHC(0)alkenyl; and at each occurrence, R₆ 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.

3. The compound of claim- 1 having the Formula (III):

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;

R₄ is selected from:

; wherein L₂, L₃ and L₄ are each independently selected from -C(O)- and -S(0)₂-; wherein R is selected from hydrogen, cyano, halo and substituted and unsubstituted Ci-C₄-alkyl; R$ and Rgare each independently selected from hydrogen, -CH₂-N(CH₃)₂, substituted and unsubstituted Ci-C₄-alkyl, C₃-C₆cycloalkyl and

^ ^N— ' ; Rio is independently selected from hydrogen and substituted and unsubstituted Ci-C₄-alkyl; Rn is independently selected from hydrogen and substituted and unsubstituted Ci-C₄-alkyl; and W is halogen; and at each occurrence, R₆ is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocyclyl; or pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein ring system A and substituent R₄ together form a group selected from:

R_3a is hydrogen

5. The compound of claim 1, wherein ring system A and substituent R₄ together form a group selected from:

is a bond.

6. The compound of claim 1 , wherein R₂ is F.

7. The compound of claim 1, wherein R₃ is hydrogen.

8. The compound of claim 1, wherein R5 is hydrogen.

9. The compound of claim 1, wherein R4 is selected from:

0 ; wherein L₂ and L₃ are each independently selected from

-C(O)- and -S(0)₂-; wherein R is selected from hydrogen, cyano, halo and

8 9

substituted and unsubstituted Ci-C₄-alkyl; R and R are each independently selected from hydrogen, -CH₂-N(CH₃)₂, substituted and unsubstituted Ci-C₄-alkyl, C₃-

C₆cycloalkyl and <- ^— f ; Rio is hydrogen or substituted and unsubstituted C1-C₄- alkyl.

10. The compound of claim 1 , wherein R₄ is: W wherein L4 is -C(O)- or -S(0)₂-;

R11 is H or substituted and unsubstituted Ci-C₄-alkyl; and W is halogen or -NH- C(0)alkenyl.

1 1. The compound of claim 1 , wherein R₄ is hydrogen.

12. The compound of any one of claims 1 , wherein n is 1.

13. A compound of claim 1 , wherein Ri is selected fromhalogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, -C(0)NR_aR_b, -S0₂R₆, -NR_aR_b , -NR_aC(0)R₆, - and -OR₆.

14. The compound of claim- 1 which is selected from:

5-Fluoro-N2-(4-(2-methoxyethoxy)phenyl)-N4-(spiro[cyclopropane- l ,3'-indolin]-6'- yl)pyrimidine-2,4-diamine,

2- Chloro- l-(6'-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4- yl)amino)spiro[cyclopropane- 1 ,3'-indolin] - l'-yl)ethanone,

5-Fluoro-N2-(4-(2-methoxyethoxy)phenyl)-N4-(spiro[cyclobutane- l ,3'-indolin]-6'- yl)pyrimidine-2,4-diamine, 1- (6'-((5-Fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino) spiro[cyclobutane- 1 ,3'-indolin] - 1 '-yl)prop-2-en- 1 -one,

N-(l'-(5-Fluoro-2-((4-(2-methoxyethoxy) phenyl) amino) pyrimidin-4-yl) spiro

[cyclopropane- l,3'-indolin]-6'-yl)acrylamide,

N-(l'-(5-Fluoro-2-((4-phenoxyphenyl) amino) pyrimidin-4-yl) spiro [cyclo propane- 1,3'- indolin] -6'-yl)acrylamide, l-(6'-((5-Fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino) spiro[cyclopropane- 1 ,3'-indolin]- 1 '-yl)propan- 1-one, l-(6'-((5-Fluoro-2-((4-phenoxyphenyl)amino)pyrimidin-4-yl)amino)spiro [cyclo propane- 1 ,3 '-indolin] - l'-yl)propan- 1 -one, N-(r-(5-Fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)spiro

[cyclobutane-l,3'-indolin]-6'-yl)acrylamide,

(E)-4-(Dimethylamino)-l-(6'-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)

4-((4-(( Γ- Aery loylspiro [cyclopropane- 1 ,3'-indolin]-6'-yl)amino)-5-fluoropyrimidin-2- yl)amino)benzonitrile,

N-(4-((4-((r-Acryloylspiro[cyclopropane-l,3'-indolin]-6'-yl)amino)-5-fluoropyrimidin-2- yl)amino)phenyl)acetamide, l-(6'-((2-((4-(Dimethylamino)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)spiro

2- Chloro-l-(6'-((5-fluoro-2-((4-methoxyphenyl)amino)pyrimidin-4- yl)amino)spiro[cyclopropane- 1 ,3'-indolin] - l'-yl)ethanone,

2-Chloro-l-(6'-((2-((4-ethoxyphenyl) amino)-5-fluoropyrimidin-4-yl)amino) spirofcyclopropane- 1 ,3'-indolin]- 1 '-yl)ethanone, 1- (6'-((2-([l,l'-Biphenyl]-4-ylamino)-5-fluoropyrimidin-4-yl)amino)spiro [cyclopropane- 1 ,3'-indolin] - l'-yl)-2-chloroethanone,

2- Chloro-l-(6'-((2-((4-chlorophenyl) amino)-5-fluoropyrimidin-4-yl)amino)

spiro[cyclopropane- 1 ,3'-indolin]- 1 '-yl)ethanone,

[cyclopropane- 1 ,3'-indolin]- 1 '-yl)ethanone,

2-Chloro- l-(6'-((5-fluoro-2-((3-fluoro-4-morpholino phenyl) amino) pyrimidin-4- yl)amino)spiro [cyclopropane -l,3'-indolin]-l'-yl)propan-l-one,

2-Chloro- l-(6'-((5-fluoro-2-((4-methoxyphenyl) amino) pyrimidin-4-yl)amino)spiro [cyclobutane- 1 ,3'-indolin] - l'-yl)ethanone, 2-Chloro- l-(6'-((5-fluoro-2-((4-((tetrahydrofuran-3-yl)oxy)phenyl) amino) pyrimidin-4- yl)amino)spiro [cyclobutane-l,3'-indolin]-l'-yl)ethanone,

2-Chloro- l-(6'-((5-fluoro-2-((4-(pyridin-3-yloxy)phenyl)amino) pyrimidin-4- yl)amino)spiro [cyclobutane-l,3'-indolin]-l'-yl)ethanone,

2-Chloro- l-(6'-((5-fluoro-2-((4-(methylsulfonyl)phenyl)amino)pyrimidin-4- yl)amino)spiro [cyclobutane-l,3'-indolin]-l'-yl)ethanone,

[cyclobutane- 1 ,3'-indolin] - l'-yl) ethanone,

2-Chloro- l-(6'-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4- yl)amino)spiro [cyclobutane-l,3'-indolin]-l'-yl) ethanone,

2-Chloro- l-(6'-((5-fluoro-2-((4-phenoxyphenyl)amino)pyrimidin-4- yl)amino)spiro[cyclobutane- 1 ,3'-indolin] - l'-yl)ethanone, 2-Chloro-l-(7'-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)- 2',4'-dihydro-rH-spiro[cyclopropane-l,3'-quinolin]-r-yl)ethanone,

2-Chloro-l-(7'-((5-fluoro-2-((4-(4-methylpiperazin-l-yl)phenyl)amino) pyrimidin-4- yl)amino)-2',3'-dihydro- 1 'H-spiro[cyclopropane- 1 ,4'-quinolin]- 1 '-yl)propan- 1 -one, l-(7'-((5-Fluoro-2-((4-(2-methoxyethoxy) phenyl)amino) pyrimidin-4-yl)amino)-2',3'- dihydro- 1 Ή-spiro [cyclopropane- 1 ,4'-quinolin] - 1 '-yl)prop-2-en- 1 -one, l-(7'-((5-Fluoro-2-((3-fluoro-4-morpholinophenyl)amino)pyrimidin-4-yl)amino)-2',3'- dihydro- 1 Ή-spiro [cyclopropane- 1 ,4'-quinolin] - 1 '-yl)prop-2-en- 1 -one, l-(7'-((2-((3,5-Difluoro-4-morpholino phenyl)amino)-5-fluoropyrimidin-4-yl)amino)- 2',3'-dihydro-l'H-spiro [cyclopropane- l,4'-quinolin]-l'-yl)prop-2-en-l-one, 2-Chloro-l-(7'-((5-fluoro-2-((4-morpholinophenyl)amino)pyrimidin-4-yl)amino)-2',3'- dihydro- 1 Ή-spiro [cyclopropane- 1 ,4'-quinolin] - l'-yl)propan- 1 -one,

(E)-4-(Dimethylamino)- 1 -(6'-((5-fluoro-2-((4-(2-methoxyethoxy)

(E)-4-(Dimethylamino)- 1 -(6'-((5-fluoro-2-((4-(4-methylpiperazin- 1 - yl)phenyl)amino)pyrimidin-4-yl)amino)spiro[cyclopropane- 1 ,3'-indolin]- l'-yl)but-2-en- 1-one, l-(6'-((5-Fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)spiro [cyclopropane- 1 ,3'-indolin]- 1 '-yl)-2-methylprop-2-en- 1 -one, l-(6'-((5-Fluoro-2-((4-(2-methoxy ethoxy)phenyl) amino)pyrimidin-4-yl)amino) spiro[cyclobutane- 1 ,3'-indolin] - 1 '-yl)-2-methylprop-2-en- 1 -one, l-(6'-((5-Fluoro-2-((4-(4-methyl piperazin- l-yl)phenyl)amino) pyrimidin-4- yl)amino)spiro [cyclo propane- 1 ,3'-indolin]- 1 '-yl)but-2-yn- 1 -one, l-(6'-((5-Fluoro-2-((4-morpholinophenyl)amino)pyrimidin-4-yl)amino) spiro

[cyclopropane- 1 ,3'-indolin]- 1 '-yl)but-2-yn- 1 -one,

5-Fluoro-N2-(4-(4-methylpiperazin- l-yl)phenyl)-N4-( l'-(vinylsulfonyl)spiro

[cyclopropane- l ,3'-indolin]-6'-yl)pyrimidine-2,4-diamine,

5-Fluoro-N2-(4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-N4-( l'-(vinylsulfonyl)spiro [cyclopropane- l ,3'-indolin]-6'-yl)pyrimidine-2,4-diamine, 5-Fluoro-N2-(4-(2-methoxyethoxy) phenyl)-N4-( l '-(vinylsulfonyl)spiro [cyclo butane - l ,3'-indolin]-6'-yl)pyrimidine-2,4-diamine,

5-Fluoro-N2-(4-((tetrahydrofuran-3-yl)oxy)phenyl)-N4-( l '-(vinylsulfonyl)

spiro[cyclobutane- l ,3'-indolin]-6'-yl)pyrimidine-2,4-diamine,

5-Fluoro-N2-(4-(methylsulfonyl) phenyl)-N4-( 1 '-(vinylsulfonyl) spiro[cyclobutane- 1 ,3'- indolin]-6'-yl)pyrimidine-2,4-diamine,

5-Fluoro-N2-(4-methoxyphenyl)-N4-( 1 '-(vinylsulfonyl) spirofcyclobutane- 1 ,3'-indolin]- 6'-yl)pyrimidine-2,4-diamine,

(E/Z)-2-(6'-((5-fluoro-2-((4-(4-methylpiperazin- l-yl)phenyl)amino)pyrimidin-4- yl)amino)spiro[cyclopropane- l ,3'-indolin]- l'-ylcarbonyl)-4-methyl-4-morpholinopent-2- enenitrile or stereoisomers thereof or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition comprising one or more compounds according to any one of the preceding claims, and one or more pharmaceutically acceptable excipients.

16. Use of a compound for the manufacture of a medicament for treating, managing and/or lessening diseases or disorders, syndromes or conditions associated with the inhibition of BTK in a subject in need thereof wherein the method comprises administering to the subject a therapeutically effective amount of a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

17. The use of claim 16, wherein the diseases, disorders, syndromes or conditions associated with the inhibition of BTK are selected from the group consisting of cancer, proliferative disorders, autoimmune diseases, hetero-immune diseases and inflammatory diseases.

18. The use of claim 17, wherein the cancer disease associated with the inhibition of BTKare selected from: 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, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, Burkitt lymphoma/leukemia, or lymphomatoid granulomatosis. In some embodiments, 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).

19. The use of claim 17, wherein the autoimmune disease associated with the inhibition of BTK is rheumatoid arthritis.

20. The use of claim 17, wherein the autoimmune disease which is associated with the inhibition of BTK are selected from: inflammatory bowel disease, arthritis, lupus, 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 forms of diabetes, Reynaud's syndrome, ankylosing spondylosis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behcet's disease, chronic fatigue, dysautonomia, endometriosis, interstitial cystitis, neuromyotonia, scleroderma, or vulvodynia, a hyperproliferative disease or immunologically-mediated diseases including organ/tissue transplant rejection, transplant rejection disorders such as GVHD and allograft rejection; chronic glomerulonephritis and acquired Immunodeficiency Syndrome (AIDS, also known as HIV).