NEW BROMODOMAIN INHIBITORS

Technical field The present invention relates to novel spiro[cycloalkyl-1,3’-indolin]-2’-one derivatives of formula (I) which are useful as bromodomain inhibitors and to

pharmaceutical compositions thereof.

( ) The invention relates also to the use of compounds of formula (I) for the treatment or prevention of diseases or disorders, in particular those where bromodomain inhibition is desired. Background of the invention The acetylation of histone lysine is central for providing the dynamic regulation of chromatin-based gene transcription. The bromodomain (BRD), which is the conserved structural module in chromatin-associated proteins and histone acetyltranferases, is the sole protein domain known to recognize acetyl-lysine residues on proteins. The BET family of bromodomain containing proteins comprises 4 proteins (BRD2, BRD3, BRD4 and BRDT) which contain tandem bromodomains capable of binding to two acetylated lysine residues in close proximity, increasing the specificity of the interaction. BRD2 and BRD3 are reported to associate with histones along actively transcribed genes and may be involved in facilitating transcriptional elongation (Leroy et al., Mol. Cell., 2008, 30(1):51 -60), while BRD4 appears to be involved in the recruitment of the pTEF-[beta] complex to inducible genes, resulting in phosphorylation of RNA polymerase and increased transcriptional output (Hargreaves et al., Cell, 2009, 138(1): 129-145). It has also been reported that BRD4 or BRD3 may fuse with NUT (nuclear protein in testis) forming novel fusion oncogenes, BRD4-NUT or BRD3-NUT, in a highly malignant form of epithelial neoplasia (French et al., Cancer Research, 2003, 63, 304-307 and French et al., Journal of Clinical Oncology, 2004, 22 (20), 4135-4139). Data suggests that BRD-NUT fusion proteins contribute to carcinogenesis (Oncogene, 2008, 27, 2237-2242). BRD-t is uniquely expressed in the testes and ovary. All family members have been reported to have some function in controlling or executing aspects of the cell cycle, and have been shown to remain in complex with chromosomes during cell division suggesting a role in the maintenance of epigenetic memory. In addition some viruses make use of these proteins to tether their genomes to the host cell chromatin, as part of the process of viral replication (You et al., Cell, 2004, 1, 17(3), 349-60). Japanese patent application JP 2008-156311 discloses a benzimidazole derivative which is said to be a BRD2 bromodomain binding agent which has utility with respect to virus infection / proliferation. International patent application WO 2009/084693 discloses a series of thienotriazolodiazepiene derivatives that are said to inhibit the binding between an acetylated histone and a bromodomain containing protein and are said to be useful as anti-cancer agents. International patent application WO 2011/054846 discloses a series of quinoline derivatives that inhibit the binding of BET family bromodomains with acetylated lysine residues. International patent application WO 2015/092118 discloses spiro[cyclobutane- 1,3’-indolin]-2’-one derivatives which are useful as bromodomain inhibitors. Bromodomain and Extra-Terminal motif (BET) proteins BRD2, BRD3, BRD4, and BRDT consists of tandem bromodomains. These domains are frequently referred to as BD1 (first bromodomain) and BD2 (second bromodomain) respectively and they share a high sequence homology. Lack of availability of potent and selective inhibitors have hindered the progress of dissecting biology of such bromodomain selective BET inhibitors. Selective targeting of either of these BD domains might pose different therapeutic profile over the pan BET inhibitors. There remains a need for potent bromodomain inhibitors with desirable selectivity and pharmaceutical properties. Summary of the invention The present invention provides novel spiro[cycloalkyl-1,3’-indolin]-2’-one derivatives which are able to inhibit the binding of BET family bromodomains to acetylated lysine residues. Such compounds will hereafter be referred to as

"bromodomain inhibitors". The compounds exhibit significant selectivity for BRD4 BD1 inhibition over BRD4 BD2 inhibition. The compounds of the present invention are represented by formula (I):

wherein

ring Cy ₁ and ring Cy ₂ are selected, independently, from a 4-12 membered monocyclic or bicyclic ring containing 0-4 heteroatoms independently selected form N, O or S;

R ₁ is hydrogen or C _1-7 alkyl;

R ₂ is -NHR ₅ , -C(O)NHR ₆ , -NHC(O)R ₇ , -OR ₈ , -C(O)R ₉ , or -OC(O)R ₁₀ , C _3-7 cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl C1-7 alkyl, optionally substitutedC _5-12 spiroheterocyclyl, optionally substituted aryl, optionally substituted aryl C _1-7 alkyl, wherein the optional substitution at each occurrence is independently selected from 1-3 substituents selected from halogen, hydroxy, oxo, amino, C _1-7 alkyl, C _3-7 cycloalkyl or C _3-7 spirocycloalkyl;

L is absent or is selected from -O-, -NH- or C _1-7 alkylene; R ₃ at each occurrence is independently selected from halogen, C _1-7 alkyl, C _1-7 alkoxy, C1-7 alkoxy C1-7 alkyl, C3-7 cycloalkyl C1-7 alkyl, halo C1-7 alkyl, hydroxy, hydroxy C _1-7 alkyl, nitro, oxo, -NR ₁₁ R _12, -SO ₂ (C _1-7 alkyl) or heterocyclyl;

R ₄ at each occurrence is independently selected from halogen, C _1-7 alkyl, C _1-7 alkoxy, halo C _1-7 alkyl, hydroxy, hydroxy C _1-7 alkyl, nitro, oxo, -NHSO ₂ -C _1-7 alkyl, heterocyclyl optionally substituted by C _1-7 alkyl or -O-heterocyclyl optionally substituted by C _1-7 alkyl;

R ₅ and R ₆ are, independently, selected from hydrogen, halogen, halo C _1-7 alkyl, optionally substituted C _1-7 alkyl, optionally substituted C _3-7 cycloalkyl, optionally substituted heterocyclyl or optionally substituted aryl; wherein the optional substitution at each occurrence is independently selected from 1-3 substituents selected from halogen, hydroxy, oxo, amino, C _1-7 alkyl, C _3-7 cycloalkyl, C _3-7 spirocycloalkyl or heterocyclyl optionally substituted by halogen, hydroxy, C1-7 alkyl or C1-7 alkoxy;

R _7, R _8, R ₉ and R ₁₀ are, independently, selected from hydrogen, halo C _1-7 alkyl, C _{1- 7} alkyl amino C _1-7 alkyl, optionally substituted C _1-7 alkyl, optionally substituted C _3-7 cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl C1-7 alkyl, optionally substituted C _5-12 spiroheterocyclyl or optionally substituted aryl; wherein the optional substitution at each occurrence is independently selected from 1-3 substituents selected from halogen, hydroxy, oxo, amino, C _1-7 alkyl, C _3-7 cycloalkyl, imino, C _3-7 spirocycloalkyl or heterocyclyl optionally substituted by halogen, hydroxy, C _{1- 7} alkyl or C _1-7 alkoxy,

R ₁₁ and R ₁₂ are selected, independently, from hydrogen, C _1-7 alkyl,

C _1-7 hydroxyalkyl or -SO ₂ (C _1-7 alkyl);

m and n are selected, independently, from 0, 1, 2 or 3;

q is 1 or 2;

or a pharmaceutically acceptable salt thereof. In a further aspect, the present invention provides a pharmaceutical

composition comprising spiro[cycloalkyl-1,3’-indolin]-2’-one derivative of formula (I) or a pharmaceutically acceptable salt thereof. In yet further aspect of the present invention, it provides spiro[cycloalkyl-1,3’- indolin]-2’-one derivatives of formula (I) or a pharmaceutically acceptable thereof for use in the treatment or prevention of diseases or disorders where bromodomain inhibition is desired, in particular for the treatment or prevention of an autoimmune disease, inflammatory disease or cancer. Detailed description of the invention An embodiment of the present application provides novel spiro[cycloalkyl-1,3’- indolin]-2’-one derivatives of formula (I) or pharmaceutically acceptable salts thereof which are useful as bromodomain inhibitors. One of the embodiments of the present invention provides a compound of formula (I) :

wherein

ring Cy ₁ and ring Cy ₂ are selected, independently, from a 4-12 membered monocyclic or bicyclic ring containing 0-4 heteroatoms independently selected form N, O or S;

R ₁ is hydrogen or C _1-7 alkyl;

R ₂ is -NHR ₅ , -C(O)NHR ₆ , -NHC(O)R ₇ , -OR ₈ , -C(O)R ₉ , or -OC(O)R ₁₀ , C _3-7 cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl C _1-7 alkyl, optionally substituted aryl, optionally substituted aryl C _1-7 alkyl, wherein the optional substitution at each occurrence is independently selected from 1-3 substituents selected from halogen, hydroxy, oxo, amino, C1-7 alkyl, C3-7 cycloalkyl, C3-7 spiro- cycloalkyl, or C _3-7 spiroheterocyclyl optionally substituted by C _1-7 alkyl;

L is absent or is selected from -O-, -NH- or C _1-7 alkylene;

R ₃ at each occurrence is independently selected from halogen, C _1-7 alkyl, C _1-7 alkoxy, C _1-7 alkoxy C _1-7 alkyl, C _3-7 cycloalkyl C _1-7 alkyl, halo C _1-7 alkyl, hydroxy, hydroxy C _1-7 alkyl, amino, nitro, oxo, -NR ₁₁ R _12, -SO ₂ (C _1-7 alkyl) or heterocyclyl; R ₄ at each occurrence is independently selected from halogen, C _1-7 alkyl, C _1-7 alkoxy, halo C1-7 alkyl, hydroxy, hydroxy C1-7 alkyl, nitro, oxo, -NHSO2-C1-7 alkyl, heterocyclyl optionally substituted by C _1-7 alkyl or -O-heterocyclyl optionally substituted by C _1-7 alkyl;

R ₅ and R ₆ are, independently, selected from hydrogen, halogen, halo C _1-7 alkyl, optionally substituted C _1-7 alkyl, optionally substituted C _3-7 cycloalkyl, optionally substituted heterocyclyl or optionally substituted aryl; wherein the optional substitution at each occurrence is independently selected from 1-3 substituents selected from halogen, hydroxy, oxo, amino, C _1-7 alkyl, C _3-7 cycloalkyl, C _3-7 spirocycloalkyl or heterocyclyl optionally substituted by halogen, hydroxy, C _1-7 alkyl or C _1-7 alkoxy;

R _7, R _8, R ₉ and R ₁₀ are, independently, selected from hydrogen, halo C _1-7 alkyl, C _{1- 7} alkyl amino C _1-7 alkyl, optionally substituted C _1-7 alkyl, optionally substituted C _3-7 cycloalkyl, optionally substituted heterocyclyl or optionally substituted aryl; wherein the optional substitution at each occurrence is independently selected from 1-3 substituents selected from halogen, hydroxy, oxo, amino, C _1-7 alkyl, C _3-7 cycloalkyl, halo C _1-7 alkyl, imino, C3-7 spirocycloalkyl, heterocyclyl optionally substituted by halogen, hydroxy, C1-7 alkyl or C _1-7 alkoxy, or C _3-7 spiroheterocyclyl optionally substituted by C _1-7 alkyl;

R ₁₁ and R ₁₂ are selected, independently, from hydrogen, C _1-7 alkyl,

C _1-7 hydroxyalkyl or -SO ₂ (C _1-7 alkyl);

m and n are selected, independently, from 0, 1, 2 or 3;

q is 1 or 2;

or a pharmaceutically acceptable salt thereof. The embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. According to one embodiment of the present invention, the compound of formula (I) is a compound of formula (I’)

wherein

ring Cy ₁ and ring Cy ₂ are selected, independently, from a 4-12 membered monocyclic or bicyclic ring containing 0-4 heteroatoms independently selected form N, O or S;

R ₁ is hydrogen or C _1-7 alkyl;

R ₂ is -NHR ₅ , -C(O)NHR ₆ , -NHC(O)R ₇ , -OR ₈ , -C(O)R ₉ , or -OC(O)R ₁₀ , C _3-7 cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl C1-7 alkyl, optionally substituted aryl, optionally substituted aryl C _1-7 alkyl, wherein the optional substitution at each occurrence is independently selected from 1-3 substituents selected from halogen, hydroxy, oxo, amino, C _1-7 alkyl, C _3-7 cycloalkyl or C _3-7 spiro- cycloalkyl;

L is absent or is selected from -O-, -NH- or C _1-7 alkylene;

R ₃ at each occurrence is independently selected from halogen, C _1-7 alkyl, C _1-7 alkoxy, halo C _1-7 alkyl, hydroxy, hydroxy C _1-7 alkyl, amino, nitro, oxo, or -NHSO ₂ -C _1-7 alkyl;

R ₄ at each occurrence is independently selected from halogen, C _1-7 alkyl, C _1-7 alkoxy, halo C _1-7 alkyl, hydroxy, hydroxy C _1-7 alkyl, amino, nitro, oxo, or -NHSO ₂ -C _1-7 alkyl;

R ₅ and R ₆ are, independently, selected from hydrogen, halogen, halo C _1-7 alkyl, optionally substituted C _1-7 alkyl, optionally substituted C _3-7 cycloalkyl, optionally substituted heterocyclyl or optionally substituted aryl; wherein the optional substitution at each occurrence is independently selected from 1-3 substituents selected from halogen, hydroxy, oxo, amino, C _1-7 alkyl, C _3-7 cycloalkyl, C _3-7 spirocycloalkyl or heterocyclyl optionally substituted by halogen, hydroxy, C _1-7 alkyl or C _1-7 alkoxy;

R _7, R _8, R ₉ and R ₁₀ are, independently, selected from hydrogen, halo C _1-7 alkyl, C _{1- 7} alkyl amino C _1-7 alkyl, optionally substituted C _1-7 alkyl, optionally substituted C _3-7 cycloalkyl, optionally substituted heterocyclyl or optionally substituted aryl; wherein the optional substitution at each occurrence is independently selected from 1-3 substituents selected from halogen, hydroxy, oxo, amino, C1-7 alkyl, C3-7 cycloalkyl, C3-7 spirocyclo- alkyl or heterocyclyl optionally substituted by halogen, hydroxy, C _1-7 alkyl or C _1-7 alkoxy; m and n are selected, independently, from 0, 1, 2 or 3;

or a pharmaceutically acceptable salt thereof. According to one embodiment of the present invention, the compound of formula (I) is a compound of formula (IA)

wherein Cy ₁ , Cy ₂ , R ₂ , R ₃ , R ₄ , L, m, n and q are as defined in claim 1, or a pharmaceutically acceptable salt thereof. According to yet another embodiment of the present invention, the compound of formula (I) is a compound of formula (IB)

wherein Cy1, Cy2, R1, R3, R4, R5, L, m, n and q are same as defined in any of the above embodiments for formula (I), or a pharmaceutically acceptable salt thereof. According to yet another embodiment of the present invention, the compound of formula (I) is a compound of formula (IC)

wherein Cy ₁ , Cy ₂ , R ₁ , R ₃ , R ₄ , R ₈ , L, m, n and q are same as defined in any of the above embodiments for formula (I), or a pharmaceutically acceptable salt thereof. According to yet another embodiment of the present invention, the compound of formula (I) is a compound of formula (ID)

wherein Cy ₁ , Cy ₂ , R ₁ , R ₂ , R ₃ , R ₄ , m, n and q are same as defined in any of the above embodiments for formula (I), or a pharmaceutically acceptable salt thereof. According to one embodiment, specifically provided is a compound of formula (I) wherein

ring Cy ₁ and ring Cy ₂ are selected, independently, from a 4-12 membered monocyclic or bicyclic ring containing 0-4 heteroatoms independently selected form N, O or S;

R ₁ is hydrogen;

R ₂ is -NHR ₅ , -C(O)NHR ₆ , -NHC(O)R ₇ , -OR ₈ , -C(O)R ₉ , -OC(O)R ₁₀ or optionally substituted C _5-12 spiroheterocyclyl;

L is absent or is selected from -O-, -NH- or C _1-7 alkylene;

R ₃ at each occurrence is independently selected from halogen, C _1-7 alkyl, C _1-7 alkoxy, C _1-7 alkoxy C _1-7 alkyl, C _3-7 cycloalkyl C _1-7 alkyl, halo C _1-7 alkyl, hydroxy, hydroxy C _1-7 alkyl, nitro, oxo, or -NR ₁₁ R ₁₂ or heterocyclyl; R ₄ at each occurrence is independently selected from halogen, C _1-7 alkyl, C _1-7 alkoxy, halo C1-7 alkyl, hydroxy, hydroxy C1-7 alkyl, amino, nitro, oxo, or -NHSO2-C1-7 alkyl;

R ₅ and R ₆ are, independently, selected from hydrogen, halogen, halo C _1-7 alkyl, optionally substituted C _1-7 alkyl, optionally substituted C _3-7 cycloalkyl, optionally substituted heterocyclyl or optionally substituted aryl; wherein the optional substitution at each occurrence is independently selected from 1-3 substituents independently selected from halogen, hydroxy, oxo, amino, C _1-7 alkyl, C _3-7 cycloalkyl, C _3-7 spirocycloalkyl or heterocyclyl optionally substituted by halogen, hydroxy, C _1-7 alkyl or C _1-7 alkoxy;

R _7, R _8, R ₉ and R ₁₀ are, independently, selected from hydrogen, halo C _1-7 alkyl, C _{1- 7} alkyl amino C _1-7 alkyl, optionally substituted C _1-7 alkyl, optionally substituted C _3-7 cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl C _1-7 alkyl, optionally substituted C5-12 spiroheterocyclyl or optionally substituted aryl; wherein the optional substitution at each occurrence is independently selected from 1-3 substituents selected from halogen, hydroxy, oxo, amino, C _1-7 alkyl, C _3-7 cycloalkyl, C _3-7 spirocycloalkyl or heterocyclyl optionally substituted by halogen, hydroxy, C1-7 alkyl or C _1-7 alkoxy;

m and n are selected, independently, from 0, 1, 2 or 3;

q is 1 or 2;

or a pharmaceutically acceptable salt thereof. According to one further embodiment, specifically provided is a compound of formula (I) wherein

ring Cy ₁ and ring Cy ₂ are selected, independently, from a 4-12 membered monocyclic or bicyclic ring containing 0-4 heteroatoms independently selected form N, O or S;

R1 is hydrogen;

R ₂ is -NHR ₅ , -C(O)NHR ₆ , -NHC(O)R ₇ , -OR ₈ , -C(O)R ₉ , or -OC(O)R ₁₀ ;

L is absent or is selected from -O-, -NH- or C _1-7 alkylene;

R ₃ at each occurrence is independently selected from halogen, C _1-7 alkyl, C _1-7 alkoxy, halo C _1-7 alkyl, hydroxy, hydroxy C _1-7 alkyl, amino, nitro, oxo, or -NHSO ₂ -C _1-7 alkyl; R ₄ at each occurrence is independently selected from halogen, C _1-7 alkyl, C _1-7 alkoxy, halo C1-7 alkyl, hydroxy, hydroxy C1-7 alkyl, amino, nitro, oxo, or -NHSO2-C1-7 alkyl;

R ₅ and R ₆ are, independently, selected from hydrogen, halogen, halo C _1-7 alkyl, optionally substituted C _1-7 alkyl, optionally substituted C _3-7 cycloalkyl, optionally substituted heterocyclyl or optionally substituted aryl; wherein the optional substitution at each occurrence is independently selected from 1-3 substituents independently selected from halogen, hydroxy, oxo, amino, C _1-7 alkyl, C _3-7 cycloalkyl, C _3-7 spirocycloalkyl or heterocyclyl optionally substituted by halogen, hydroxy, C _1-7 alkyl or C _1-7 alkoxy;

R _7, R _8, R ₉ and R ₁₀ are, independently, selected from hydrogen, halo C _1-7 alkyl, C _{1- 7} alkyl amino C _1-7 alkyl, optionally substituted C _1-7 alkyl, optionally substituted C _3-7 cycloalkyl, optionally substituted heterocyclyl or optionally substituted aryl; wherein the optional substitution at each occurrence is independently selected from 1-3 substituents selected from halogen, hydroxy, oxo, amino, C _1-7 alkyl, C _3-7 cycloalkyl, C _3-7 spirocyclo- alkyl or heterocyclyl optionally substituted by halogen, hydroxy, C _1-7 alkyl or C _1-7 alkoxy; m and n are selected, independently, from 0, 1, 2 or 3;

q is 1;

or a pharmaceutically acceptable salt thereof. According to one embodiment, specifically provided are compounds of formula (I), (I’), (IA), (IB), (IC) or (ID), wherein ring Cy ₁ is selected from a 4-12 membered monocyclic or bicyclic ring containing 1-4 heteroatoms independently selected form N, O or S. In a subclass of the above embodiment are compounds wherein Cy ₁ is selected from a 4-6 membered ring containing 1-4 heteroatoms N. In still another subclass of the above embodiment are compounds wherein ring Cy1 is selected from the following groups In still another subclass of the above embodiment are compounds wherein ring Cy ₁ is selected from the following groups ,

wherein the wavy line means site of attachment to Cy ₁ , L or spiro[cycloalkyl-1,3’- indolin]-2’-one ring. In still another subclass of the above embodiment are compounds wherein ring C ₁ is selected from the followin rou s

,

wherein * means site of attachment to the spiro[cycloalkyl-1,3’-indolin]-2’-one ring. According to one embodiment, specifically provided are compounds of formula (I), (I’), (IA), (IB), (IC) or (ID), or according to any other embodiment or subclass referred to above, wherein R ₃ is selected from C _1-7 alkyl, C _1-7 alkoxy, C _1-7 alkoxy C _1-7 alkyl, C _3-7 cycloalkyl C _1-7 alkyl, halo C _1-7 alkyl, NR ₁₁ R ₁₂ or heterocyclyl , and m is 0, 1 or 2. According to one embodiment, specifically provided are compounds of formula (I), (I’), (IA), (IB), (IC) or (ID), or according to any other embodiment or subclass referred to above, wherein heterocyclyl, at each occurrence, is a monocyclic or polycyclic ring with 5 to 10 ring atoms of which 1-4 are heteroatoms independently selected from the group consisting of N, O and S. According to one embodiment, specifically provided are compounds of formula (I), (I’), (IA), (IB), (IC) or (ID), or according to any other embodiment or subclass referred to above, wherein L is absent, -CH ₂ - or -O-. According to one embodiment, specifically provided are compounds of formula (I), (I’), (IA), (IB), (IC) or (ID), or according to any other embodiment or subclass referred to above, wherein R ₅ is hydrogen or an optionally substituted heterocyclyl, wherein the heterocyclyl is a monocyclic or polycyclic ring with 5 to 10 ring atoms of which 1-4 are heteroatoms independently selected from the group consisting of N, O and S, and the optional substitution is selected from 1-3 substituents independently selected from C _1-7 alkyl, C _3-7 cycloalkyl, halogen, amino or oxo. In a subclass of the above embodiment are compounds wherein R ₅ is an optionally substituted piperidinyl, pyridinyl, piperazinyl, pyrrolidinyl, tetrahydro-2H-pyranyl or 1,1-dioxidotetrahydro-2H-thiopyranyl ring the optional substitution at each occurrence being independently selected from 1-3 substituents independently selected from C _1-7 alkyl, C _3-7 cycloalkyl, halogen, amino or oxo. In still another subclass of the above embodiment are compounds wherein R5 is optionally substituted piperidine ring optionally substituted by 1-3 substituents independently selected from C _1-7 alkyl or C _3-7 cycloalkyl. According to one embodiment, specifically provided are compounds of formula (I), (I’), (IA), (IC) or (ID), or according to any other embodiment or subclass referred to above, wherein R ₈ is hydrogen, C _1-7 alkyl amino C _1-7 alkyl, optionally substituted C _3-7 cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl C _1-7 alkyl, optionally substituted C _5-12 spiroheterocyclyl, the optional substitution, at each occurrence, being independently selected from 1-3 substituents selected independently from halogen, hydroxy, oxo, amino, C _1-7 alkyl, C _3-7 cycloalkyl, C _3-7 spirocycloalkyl or heterocyclyl optionally substituted by halogen, hydroxy, C1-7 alkyl or C1-7 alkoxy. In a subclass of the above embodiment are compounds wherein R ₈ is hydrogen, optionally substituted heterocyclyl or optionally substituted heterocyclyl C _1-7 alkyl or optionally substituted C _5-12 spiroheterocyclyl, the optional substitution at each occurrence being independently selected from 1-3 substituents independently selected from C _1-7 alkyl, C _3-7 cycloalkyl, C _1-7 alkoxy, amino or oxo. In still another subclass of the above embodiment are compounds wherein heterocyclyl, at each occurrence, is a monocyclic or polycyclic ring with 5 to 10 ring atoms of which 1-4 are heteroatoms independently selected from the group consisting of N, O and S. In still another subclass of the above embodiment are compounds wherein the optionally substituted heterocyclyl is piperidinyl, pyridinyl, piperazinyl, pyrrolidinyl, tetrahydro-2H-pyranyl or 1,1-dioxidotetrahydro-2H-thiopyranyl ring the optional substitution at each occurrence being independently selected from 1-3 substituents independently selected from C _1-7 alkyl, C _3-7 cycloalkyl, C _1-7 alkoxy, halogen, amino or oxo. In still another subclass of the above embodiment are compounds wherein the optionally substituted heterocyclyl ring is piperidinyl or pyrrolidinyl, optionally substituted by 1-3 substituents independently selected from C _1-7 alkyl or halogen. According to one embodiment, specifically provided are compounds of formula (I), (I’), (IA), (IB), (IC) or (ID), or according to any other embodiment or subclass referred to above, wherein ring Cy2 is selected from phenyl, cyclohexyl, pyridinyl, piperidinyl, or tetrahydropyranyl ring. According to one embodiment, specifically provided are compounds of formula (I), (I’), (IA), (IB), (IC) or (ID), or according to any other embodiment or subclass referred to above, wherein R ₄ is selected from halogen, halo C _1-7 alkyl, C _1-7 alkyl, or C _1-7 alkoxy, and n is 0, 1 or 2. According to still one embodiment, specifically provided is a compound of formula I or I’ wherein

ring Cy ₂ is phenyl; R ₁ is hydrogen; R ₂ is -OR ₈ or -NHR ₅ ; L is absent or -O-; R ₈ and R ₅ are, independently, optionally substituted piperidinyl or optionally substituted pyrrolidinyl wherein the optional substitution at each occurrence is independently selected from 1-3 substituents independently selected from C _1-7 alkyl or C _{3- 7} cycloalkyl; R ₃ at each occurrence is independently selected from halo C _1-7 alkyl, amino, or C _1-7 alkyl; R ₄ at each occurrence is independently selected from halogen, C _1-7 alkyl or C _1-7 alkoxy; m is 0 or 1; n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof. In a subclass of the above embodiment are compounds wherein R2 is -OR8. In another subclass of the above embodiment are compounds wherein R ₂ is -NHR _5. According to one embodiment, specifically provided are compounds of formula (I), (IA), (IB), (IC) or (ID), or according to any other embodiment or subclass referred to above, wherein q is 1. According to another embodiment, specifically provided are compounds of formula (I), (IA), (IB), (IC) or (ID), or according to any other embodiment or subclass referred to above, wherein q is 2. In yet another particular embodiment of the present invention, the compound of formula (I) is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof. In yet another embodiment according to the present patent application, it provides a pharmaceutical composition comprising a compound of formula (I), (I’), (IA), (IB), (IC) or (ID) of the present invention and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent). Preferably, the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein. It should be understood that formulas (I), (I’), (IA), (IB), (IC) and (ID) encompass all stereoisomers, enantiomers, diastereomers and isotopes that may be contemplated from the chemical structure of the compounds according to above formulas. The present compounds may also exist as tautomers or equilibrium mixtures thereof wherein a proton of a compound shifts from one atom to another. Examples of tautomers include, but are not limited to, amido-imido, keto-enol, phenol-keto, oxime- nitroso, nitro-aci, imine-enamine and the like. All tautomeric forms of the compounds are intended to be encompassed by their structural formula even though only one tautomeric form may be depicted. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in art to which the subject matter herein belongs. As used herein, the following definitions are supplied in order to facilitate the understanding of the present invention. The term“C _1-7 alkyl”, as employed herein as such or as part of another group, refers to a straight or branched chain saturated hydrocarbon group having 1, 2, 3, 4, 5, 6 or 7 carbon atom(s). Representative examples of C _1-7 alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl and n-hexyl. The term“C _1-3 alkyl” refers to a preferred embodiment of“C _1-7 alkyl” having 1, 2 or 3 carbon atoms. The term“C2-7 alkenyl”, as employed herein as such or as part of another group, refers to an aliphatic hydrocarbon group having 2 to 7 carbon atoms and containing one or several double bonds. Representative examples include, but are not limited to, ethy- lene, prop-1-ene, but-1-ene, but-2-ene, pent-1-ene, pent-2-ene, hex-1-ene and hex-2-ene. The term“C _1-7 alkylene” as employed herein refers to a divalent moiety by removing two hydrogen atoms from one or two carbon atoms from a C _1-7 alkyl group. Representative examples of“C _1-7 alkylene” groups include, but are not limited, to -CH ₂ -, -CH ₂ -CH ₂ - and -CH ₂ -CH ₂ - CH ₂ - groups. The term“C _3-10 cycloalkyl", as employed herein as such or as part of another group, refers to a saturated or partially saturated, monocyclic, bicyclic or polycyclic hydrocarbon ring system having 3 to 10 carbon atoms. Examples of C _3-10 cycloalkyl groups include those where saturated 5 or 6 membered cycloalkyl ring is fused to a phenyl ring. The term“C3-7 cycloalkyl”, as employed herein as such or as part of another group, refers to a saturated or partially saturated monocyclic hydrocarbon ring containing 3, 4, 5, 6 or 7 carbon atoms. Representative examples of C _3-10 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term“C _3-7 spirocycloalkyl” as employed herein as such or as part of another group, refers to a saturated or partially saturated, monocyclic hydrocarbon ring having 3 to 7 carbon atoms which ring is attached to another group via spiro configuration. The term“C _5-10 spirocycloalkyl” as employed herein as such or as part of another group, refers to a bicyclic saturated hydrocarbon ring system having 5-10 carbon ring atoms wherein one carbon atom is common to both rings.

The term“halo” or“halogen”, as employed herein as such or as part of another group, refers to chlorine, bromine, fluorine or iodine. The term“C _1-7 alkoxy”, as employed herein as such or as part of another group, refers to C1-7 alkyl, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of C _1-7 alkoxy include, but are not limited to methoxy, ethoxy, propoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy. The term“hydroxy”, as employed herein as such or as part of another group, refers to an–OH group. The term“amino”, as employed herein as such or as part of another group, refers to an–NH ₂ group. The term“cyano”, as employed herein as such or as part of another group, refers to a–CN group. The term“carboxy”, as employed herein as such or as part of another group, refers to–COOH group. The term “carbonyl”, as employed herein as such or as part of another group, refers to a carbon atom double-bonded to an oxygen atom (C=O). The term“oxo”, as employed herein as such or as part of another group, refers to oxygen atom linked to another atom by a double bond (=O). The term“imino”, as employed herein as such or as part of another group, refers to =NH group. The term“hydroxy C _1-7 alkyl”, as employed herein, refers to at least one hydroxy group, as defined herein, appended to the parent molecular moiety through a C _1-7 alkyl group, as defined herein. Representative examples of hydroxyl C _1-7 alkyl include, but are not limited to, hydroxymethyl, 2,2-dihydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 1- hydroxypropyl, 1-methyl-1-hydroxyethyl and 1-methyl-1-hydroxypropyl. The term“halo C _1-7 alkyl”, as employed herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through a C _1-7 alkyl group, as defined herein. Representative examples of halo C _1-7 alkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-chloroethyl and 3-bromopropyl. The term“amino C _1-7 alkyl”, as employed herein, refers to at least one amino group, as defined herein, appended to the parent molecular moiety through a C _1-7 alkyl group, as defined herein. The term“C _1-7 alkyl amino C _1-7 alkyl”, as employed herein, refers to at least one C1-7 alkyl group, as defined herein, appended to the parent molecular moiety through amino C _1-7 alkyl group, as defined herein. The term“C _3-10 cycloalkyl C _1-7 alkyl”, as employed herein refers to a C _3-10 cyclo- alkyl group, as defined herein, appended to the parent molecular moiety through a C _1-7 alkyl group, as defined herein. The term“phenyl C _1-7 alkyl”, as employed herein, refers to at least one phenyl group appended to the parent molecular moiety through a C _1-7 alkyl group, as defined herein. The term“halo phenyl C _1-7 alkyl”, as employed herein, refers to at least one halo group appended to the parent molecular moiety through a phenyl C _1-7 alkyl group, as defined herein. The term“aryl”, as employed herein, refers to a monocyclic, bicyclic or polycyclic aromatic hydrocarbon ring system of 6 to 14 carbon atoms. Examples of aryl groups include, but are not limited to phenyl, naphthyl, biphenyl, anthryl, biphenylenyl, and acenaphthyl. Preferred aryl group is phenyl. The term "aryl C _1-7 alkyl", as employed herein, refers to at least one aryl group appended to the parent molecular moiety through a C _1-7 alkyl group, as defined herein. Examples of aryl C _1-7 alkyl groups include, but are not limited to benzyl, benzhydryl, 1- phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1-naphthylmethyl and 2- naphthylmethyl. Preferred aryl C _1-7 alkyl group is phenyl C _1-7 alkyl. The term "aryl C _2-7 alkenyl", as employed herein, refers to an aryl group appended to the parent molecular moiety through a C _2-7 alkenyl group, as defined herein. Examples of aryl C _1-7 alkenyl groups include, but are not limited to 1-phenylethenyl, 2-phenylethenyl and 2- phenylprop-1-enyl. The term“aryl halo C _1-7 alkyl”, as employed herein, refers to at least one aryl group, as defined herein, appended to the parent molecular moiety through a halo C _1-7 alkyl group, as defined herein. Examples of aryl halo C _1-7 alkyl groups include, but are not limited to phenyl fluoro methyl and 1-phenyl 2-chloro ethyl. The term“monocyclic or bicyclic ring”, as employed herein, refers to saturated, partially saturated or aromatic monocyclic or bicyclic ring system. The term“heterocyclyl” includes the definitions of“heterocycloalkyl” and “heteroaryl”. The term“heterocycloalkyl” refers to a non-aromatic, saturated or partially saturated, monocyclic or polycyclic ring system with 3 to 10 ring atoms of which at least one, preferably 1-4, is a heteroatom selected from the group consisting of O, N, and S. One particular embodiment of“heterocycloalkyl” is a non-aromatic, saturated or partially saturated, monocyclic or polycyclic ring system with 5 to 10 ring atoms of which 1-4 are heteroatoms selected from the group consisting of N, O and S.

Examples of heterocycloalkyl groups include piperdinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,3-dioxolanyl and 1,4-dioxanyl. The term“heteroaryl” refers to a monocyclic, bicyclic, or polycyclic aromatic ring system of 6-14 ring atoms containing at least one, preferably 1 to 4, heteroatom selected from the group consisting of N, O and S. One particular embodiment of“heteroaryl” is a monocyclic, bicyclic, or polycyclic aromatic ring with 5-10 ring atoms of which 1-4 are heteroatoms selected from the group consisting of N, O and S. Examples of 5-10 membered heteroaryl groups include furan, thiophene, indole, azaindole, oxazole, thiazole, thiadiazole, isoxazole, isothiazole, imidazole, 1H-indazole N-methylimidazole, pyridine, pyrimidine, pyrazine, pyrrole, N-methylpyrrole, pyrazole, N-methylpyrazole, 1,3,4-oxadiazole, 1,2,4-triazole, 1-methyl-1,2,4-triazole, 1H-tetrazole, 1,2,3,4- tetrahydroisoquinoline 1-methyltetrazole, benzoxazole, benzothiazole, benzofuran, benzisoxazole, benzimidazole, 3-quinuclidine, 3,4-dihydroisoquinolin-1(2H)-one, N- methylbenzimidazole, azabenzimidazole, indazole, quinazoline, quinoline, and isoquinoline. Examples of bicyclic heteroaryl groups include those where a phenyl, pyridine, pyrimidine or pyridazine ring is fused to a 5 or 6-membered monocyclic heterocyclyl ring having one or two nitrogen atoms in the ring, one nitrogen atom together with either one oxygen or one sulfur atom in the ring, or one O or S ring atom. The term“C _5-12 spiroheterocyclyl” as employed herein as such or as part of another group, refers to bicyclic ring system having 5-12 ring atoms of which at least one, preferably 1-4, is a heteroatom selected from the group consisting of O, N, and S and wherein one ring atom is common to both rings. The term heterocyclyl C _1-7 alkyl refers to at least one heterocyclyl group, as defined herein, appended to the parent molecular moiety through a C _1-7 alkyl group. The term heterocyclyl C _2-7 alkenyl refers to at least one heterocyclyl group, as defined herein, appended to the parent molecular moiety through a C _2-7 alkenyl group. The term heterocyclyl C _3-7 cycloalkyl refers to at least one heterocyclyl group, as defined herein, appended to the parent molecular moiety through a C3-7 cycloalkyl group, wherein the heterocyclyl group is attached to C _3-7 cycloalkyl group via spiro

configuration or via single bond. The term "4-12 membered monocyclic or bicyclic ring containing 0-4 hetero- atoms” refers to a 4-12 membered monocyclic or bicyclic aromatic or non-aromatic cyclic ring in which 0-4 of the ring carbon atoms have been independently replaced with N, O or S. Representative examples of such rings include, but are not limited to phenyl, pyridine, pyrimidine, morpholine, piperidine, piperazine, imidazole, pyrazole, pyrrole, thiophene, cyclopropyl, 2,3dihydrobenzo[b][1,4]dioxine, 1,2,3,4-tetrahydroisoquinoline, quinoline, indazole, [1,2,4]triazolo[4,3-a]pyridine and tetrahydroisoquinoline. A particular embodiment of "4-12 membered monocyclic or bicyclic ring containing 0-4 heteroatoms” are a monocyclic or bicyclic aromatic or non-aromatic cyclic ring with 5- 10 ring atoms of which 0-4 are heteroatoms selected from a group consisting of N, O and S. The term“4-10 membered heterocyclic ring having 1-4 heteroatoms selected from O, N, or S” refers to aromatic, saturated or partially saturated monocyclic, bicyclic or polycyclic ring which have 4 to 10 ring member atoms of which 1 to 4 are

heteroatoms selected from a group consisting of O, N, and S. The term“9-12 membered heterocyclic ring having 1-3 heteroatoms selected from N or O” refers to aromatic, saturated or partially saturated monocyclic, bicyclic or polycyclic ring which have 9 to 12 ring member atoms of which 1 to 3 are heteroatoms selected from a group consisting of N and O. The term“optionally substituted or substituted”, if not otherwise specified, means that at least one hydrogen atom of the optionally substituted group has been substituted with suitable groups as exemplified but not limited to halogen, nitro, cyano, hydroxy, oxo (=O), thio (=S), -N(C ₁ - ₃ alkyl)C(O)(C ₁ - ₇ alkyl), -NHC(O)(C ₁ - ₇ alkyl),

-NHC(O)(cycloalkyl), -NHC(O)(aryl), -NHC(O)(heterocyclyl), -NHC(O)(heteroaryl), -NHC(O)H, -C(O)NH ₂ , -C(O)NH(C ₁ - ₇ alkyl), -C(O)NH(cycloalkyl),

-C(O)NH(heterocyclyl), -C(O)NH(heteroaryl), -C(O)N(C ₁ - ₇ alkyl)(C ₁ - ₇ alkyl),

-S(O)NH(C1-7 alkyl), -S(O)2NH(C1-7 alkyl), -S(O)NH(cycloalkyl),

-S(O) ₂ NH(cycloalkyl), carboxy, -C(O)O(C ₁ - ₇ alkyl), -C(O)(C ₁ - ₇ alkyl), =N-OH, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl- alkyl, cycloalkenyl, amino, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclic ring. One particular embodiment of“optionally substituted or substituted” is 1-3 substituents selected from the group consisting of C ₁ - ₇ alkyl, C ₃ - ₇ cycloalkyl, halogen, nitro, cyano, amino, hydroxy, halo C ₁ - ₇ alkyl, hydroxy C ₁ - ₇ alkyl, C ₁ - ₇ alkoxy and halo C ₁ - ₇ alkoxy substituents. As used herein, the terms“treat”, "treating" or "treatment" encompass either or both responsive and prophylaxis measures, e.g. measures designed to inhibit or delay the onset of the disease or disorder, achieve a full or partial reduction of the symptoms or disease state, and/or to alleviate, ameliorate, lessen, or cure the disease or disorder and/or its symptoms. The terms“treat,”“treating” or“treatment”, include, but are not limited to, prophylactic and/or therapeutic treatments. As used herein the terms "subject" or "patient" are well-recognized in the art, and, are used interchangeably herein to refer to a mammal, including dog, cat, rat, mouse, monkey, cow, horse, goat, sheep, pig, camel, and, most preferably, a human. In some embodiments, the subject is a subject in need of treatment or a subject with a disease or disorder. However, in other embodiments, the subject can be a normal subject. The term does not denote a particular age or sex. Thus, adult and new-born subjects, whether male or female, are intended to be covered. As used herein the term“therapeutically effective amount,” refers to a sufficient amount of a compound or a composition being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. The term“therapeutically effective amount” includes, for example, a prophylactically effective amount. "Pharmaceutically acceptable" means that, which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use. “Pharmaceutically acceptable salt” refers to the salts of the compounds, that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Such salts include: acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4- hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methane sulfonic acid, ethane sulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzene sulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluene- sulfonic acid, camphor sulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxyl naphthoic acid, salicylic acid, stearic acid, muconic acid, and the like. The term“stereoisomers” refers to any enantiomers, diastereomers, or geometrical isomers of the compounds of formula (I) wherever they are chiral or when they bear one or more double bond. When the compounds of the formula (I) and related formulae are chiral, they can exist in racemic or in optically active form. Since the pharmaceutical activity of the racemates or stereoisomers of the compounds according to the invention may differ, it may be desirable to use the enantiomers. In these cases, the end product or even the intermediates can be separated into enantiomeric compounds by chemical or physical measures known to the person skilled in the art or even employed as such in the synthesis. In the case of racemic amines, diastereomers are formed from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as the R and S forms of tartaric acid, diacetyl tartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (for example N-benzoylproline or N- benzenesulfonylproline), or the various optically active camphorsulfonic acids. Also advantageous is chromatographic enantiomer resolution with the aid of an optically active resolving agent (for example dinitrobenzoylphenylglycine, cellulose triacetate or other derivatives of carbohydrates or chirally derivatised methacrylate polymers immobilised on silica gel). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, such as, for example, hexane/isopropanol/ acetonitrile, for example in the ratio 82:15:3. Bromodomain inhibitors are believed to be useful in the treatment of a variety of diseases or conditions related to systemic or tissue inflammation, inflammatory responses to infection or hypoxia, cellular activation and proliferation, lipid metabolism, fibrosis and in the prevention and treatment of viral infections. Bromodomain inhibitors may be useful in the treatment of a wide variety of chronic autoimmune and inflammatory conditions such as rheumatoid arthritis, osteoarthritis, acute gout, psoriasis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease (Crohn's disease and Ulcerative colitis), asthma, chronic obstructive airways disease, pneumonitis, myocarditis, pericarditis, myositis, eczema, dermatitis, alopecia, vitiligo, bullous skin diseases, nephritis, vasculitis, atherosclerosis, Alzheimer's disease, depression, retinitis, uveitis, scleritis, hepatitis, pancreatitis, primary biliary cirrhosis, sclerosing cholangitis, Addison's disease, hypophysitis, thyroiditis, type I diabetes and acute rejection of transplanted organs. Bromodomain inhibitors may be useful in the treatment of a wide variety of acute inflammatory conditions such as acute gout, giant cell arteritis, nephritis including lupus nephritis, vasculitis with organ involvement such as glomerulonephritis, vasculitis including giant cell arteritis, Wegener's granulomatosis, Polyarteritisnodosa, Behcet's disease, Kawasaki disease, Takayasu's Arteritis, vasculitis with organ involvement and acute rejection of transplanted organs. Bromodomain inhibitors may be useful in the prevention or treatment of diseases or conditions which involve inflammatory responses to infections with bacteria, viruses, fungi, parasites or their toxins, such as sepsis, sepsis syndrome, septic shock, endo- toxaemia, systemic inflammatory response syndrome (SIRS), multi-organ dysfunction syndrome, toxic shock syndrome, acute lung injury, ARDS (adult respiratory distress syndrome), acute renal failure, fulminant hepatitis, burns, acute pancreatitis, post-surgical syndromes, sarcoidosis, Herxheimer reactions, encephalitis, myelitis, meningitis, malaria and SIRS associated with viral infections such as influenza, herpes zoster, herpes simplex and coronavirus. Bromodomain inhibitors may be useful in the prevention or treatment of conditions associated with ischaemia-reperfusion injury such as myocardial infarction, cerebro- vascular ischaemia (stroke), acute coronary syndromes, renal reperfusion injury, organ transplantation, coronary artery bypass grafting, cardio-pulmonary bypass procedures, pulmonary, renal, hepatic, gastro-intestinal or peripheral limb embolism. Bromodomain inhibitors may be useful in the treatment of disorders of lipid metabolism via the regulation of APO-A1 such as hypercholesterolemia, atherosclerosis and Alzheimer's disease. Bromodomain inhibitors may be useful in the treatment of fibrotic conditions such as idiopathic pulmonary fibrosis, renal fibrosis, post-operative stricture, keloid formation, scleroderma and cardiac fibrosis. Bromodomain inhibitors may be useful in the prevention and treatment of viral infections such as herpes virus, human papilloma virus, adenovirus and poxvirus and other DNA viruses. Bromodomain inhibitors may be useful in the treatment of cancer, including hematological, epithelial including lung, breast and colon carcinomas, midline

carcinomas, mesenchymal, hepatic, renal and neurological tumours. In one embodiment the disease or condition for which a bromodomain inhibitor is indicated is selected from diseases associated with systemic inflammatory response syndrome, such as sepsis, burns, pancreatitis, major trauma, haemorrhage and ischaemia. In this embodiment the bromodomain inhibitor would be administered at the point of diagnosis to reduce the incidence of: SIRS, the onset of shock, multi-organ dysfunction syndrome, which includes the onset of acute lung injury, ARDS, acute renal, hepatic, cardiac and gastro-intestinal injury and mortality. In another embodiment the bromodomain inhibitor would be administered prior to surgical or other procedures associated with a high risk of sepsis, haemorrhage, extensive tissue damage, SIRS or MODS (multiple organ dysfunction syndrome). In a particular embodiment the disease or condition for which a bromodomain inhibitor is indicated is sepsis, sepsis syndrome, septic shock and endotoxaemia. In another embodiment, the bromodomain inhibitor is indicated for the treatment of acute or chronic pancreatitis. In another embodiment the bromodomain is indicated for the treatment of burns. In one embodiment the disease or condition for which a

bromodomain inhibitor is indicated is selected from herpes simplex infections and reactivations, cold sores, herpes zoster infections and reactivations, chickenpox, shingles, human papilloma virus, cervical neoplasia, adenovirus infections, including acute respiratory disease, poxvirus infections such as cowpox and smallpox and African swine fever virus. In one particular embodiment a bromodomain inhibitor is indicated for the treatment of Human papilloma virus infections of skin or cervical epithelia. The term "diseases or disorders where bromodomain inhibition is desired", is intended to include each of or all of the above disease states. While it is possible that for use in therapy, a compound of formula (I) as well as pharmaceutically acceptable salts thereof may be administered as such, it is common to present the active ingredient as a pharmaceutical composition. The compounds and pharmaceutically compositions of the present invention may be used in combination with other drugs that are used in the treatment/prevention/- suppression or amelioration of the diseases or conditions for which compounds of the present invention may be useful. Such other drugs may be administered, by a route and in an amount commonly used there for, simultaneously or sequentially with a compound of the present invention. When a compound of the present invention is used simultaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the present invention may also be preferred. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention. A pharmaceutical composition of the invention may be formulated as being compatible with its intended route of administration, which may preferably be an oral administration. For example the pharmaceutical compositions of the invention may be formulated for administration by inhalation, such as aerosols or dry powders; for oral administration, such in the form of tablets, capsules, gels, syrups, suspensions, emulsions, elixirs, solutions, powders or granules; for rectal or vaginal administration, such as suppositories; or for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular, or infusion) such as a sterile solution, suspension or emulsion. The compounds of the present invention may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethyl cellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980). In a further aspect, the compounds of the present invention can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the present invention also embraces isotopically-labeled variants of the present invention which are identical to those recited herein, but for the fact that one or more atoms of the compound are replaced by an atom having the atomic mass or mass number different from the predominant atomic mass or mass number usually found in nature for the atom. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention, and their uses. Exemplary isotopes that can be incorporated in to compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine, such as 2H (“D”), 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 32P, 33P, 35S, 18F, 36Cl, 123I and 125I. Isotopically labeled compounds of the present inventions can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. The abbreviations used in the entire specification may be summarized herein below with their particular meaning. MeOH– Methanol, EtOH– Ethanol, DCM– Dichloromethane, DMF– N, N- methylformamide, DMSO– Dimethyl sulfoxide, CDCl ₃ – Deuterated chloroform, CHCl ₃ - Chloroform, CCl4 - Carbon tetrachloride, EtOAc– Ethyl acetate, CH3CN - Acetonitrile, THF– Tetrahydrofuran, TFA - Trifluoroacetic acid, AcOH - Acetic acid, Ac ₂ O - Acetic anhydride, AlCl ₃ - Aluminium chloride, NBS - N-bromo succinimide, NIS - N-Iodo succinimide, DMAP-4 - Dimethylaminopyridine, TMSCl - Trimethyl silyl chloride, DIAD - Diisopropyl azodicarboxylate, PTSA - Para toluene sulfonic acid, DIBAL - Di isobutyl aluminum hydride, HATU - (1-[Bis(dimethylamino) methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluoro phosphate), DMF- DMA - N,N-Dimethylformamide dimethyl acetal, DCE– 1,2-Dichloro ethane, KOAc - Potassium acetate, Na ₂ SO ₄ - Sodium sulphate, H ₂ SO ₄ – Sulfuric acid, NaHCO ₃ - Sodiumbicarbonate, Na ₂ CO ₃ – Sodium carbonate, K ₂ CO ₃ – Potassium carbonate, Cs ₂ CO ₃ - Cesium carbonate, KI - Potassium iodide, NaH - Sodium hydride, NaBH ₄ - Sodiumborohydride, LiHMDS - Lithium bis(trimethylsilyl)amide, BOC - tert-Butyloxy- carbonyl, (BOC) ₂ O - Di-tert-butyl dicarbonate, AcCl - Acetyl chloride, NH ₄ Cl - Ammonium chloride, H ₂ O - water, H ₂ O ₂ - Hydrogen peroxide, NaOH– Sodium hydroxide, HCl– Hydrochloric acid, Pd ₂ (dba) ₃ - Tris(dibenzylideneacetone)- dipalladium(0), Pd(Amphos)Cl ₂ - Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine) dichloropalladium(II), t-BuXPhos - 2-Di-tert-butylphosphino-2′,4′,6′-triisopropyl- biphenyl, Pd(pph ₃ ) ₄ – Tetrakis (triphenylphosphine)palladium(0), Pd (dppf) Cl ₂ - [1,1′- Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane, Pd(OAc) ₂ - Palladium (II) acetate, Pd/C– Palladium on activated carbon, POBr ₃ - Phosphoryl bromide, Fe– Iron powder, mL– Milliliter, TLC– Thin layer

chromatography, RT - Room temperature, h - Hour, N– Normality, M - Molarity, s - Singlet, d - Doublet, t- Triplet, m - Multiplet, 1HNMR– Proton nuclear magnetic resonance, MS– Mass spectroscopy, HPLC - High-performance liquid chromatography, LC– Liquid chromatography, H– Proton, MHz– Mega hertz, Hz– Hertz, Ppm– Parts per million, Bs– Broad singlet, Conc– Concentrated, g - Gram, mmol– Milli mol.

Although the invention has been illustrated by following examples, it is not to be construed as being limited thereby. Various modifications and embodiments can be made without departing from the spirit and scope thereof. It will be appreciated that where typical or preferred experimental conditions (i.e. reaction temperatures, time, moles of reagents, solvents etc.) are given, other experimental conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by the person skilled in the art, using routine optimization procedures. The MS data provided in the examples described below were obtained as follows: Mass spectrum: LC/MS Agilent 6120 Quadrapole LC/MS. The NMR data provided in the examples described below were obtained as follows: 1H-NMR: Varian 400 MHz. The microwave chemistry was performed on a CEM Explorer.

The starting materials for the compounds of formula (I) are commercially available or they may be prepared using the general methods and procedures. The procedure for preparing the compounds of formula (I) are detailed below including the synthesis of various intermediates involved in process of preparing the compounds according to the present invention. Examples: Intermediate-1: 7'-Amino-5'-bromospiro[cyclobutane-1,3'-indolin]-2'-one

Step-a: N'-Phenylcyclobutanecarbohydrazide

To a solution of phenyl hydrazine hydrochloride (60 g, 416.6 mmol) in DMF (200 mL) at -30 oC were added pyridine (100 mL, 1249.8 mmol) followed by cyclobutanecarbonyl chloride (47.3 mL, 416.6 mmol) dropwise. The mixture was stirred at -30 oC for 2 h. TLC was monitored and the reaction mixture was poured into crushed ice. The solid formed was filtered off, washed with water and dried under reduced pressure to afford the title product as white solid 50.0 g (63 %).1H NMR (400 MHz, DMSO-d ₆ ): δ 9.47 (s, 1H), 7.13-7.09 (m, 2H), 6.70-6.63 (m, 3H), 3.12-3.08 (m, 1H), 2.20-2.06 (m, 4H), 1.96-1.77 (m, 2H ); LC-MS: m/z 191.2 (M+H).

Step-b: Spiro[cyclobutane-1,3'-indolin]-2'-one

To a solution of N'-phenylcyclobutanecarbohydrazide (15 g, 78.9 mmol) in quinoline (15 mL) was added calcium oxide (44.2 g, 789.0 mmol). The reaction mixture heated to 260 oC on preheated sand bath, and stirring was continued for 4 h. TLC was monitored and the reaction mixture was cooled to RT and quenched with 6 N HCl added dropwise. The mixture was extracted with EtOAc (250 ml x 2). The combined organic layer was washed with water (200 mL), brine (200 mL), dried over sodium sulphate and concentrated under reduced pressure. The residue was purified on silica gel (60-120 mesh) to afford the title product as yellow solid 8.0 g (58 %).1H NMR (400 MHz, DMSO-d ₆ ): δ 10.20 (s, 1H), 7.54 (d, J=7.4 Hz, 1H), 7.15 (t, J=7.3 Hz, 1H), 6.99 (t, J=7.4 Hz, 1H), 6.77 (d, J = 7.8 Hz, 1H), 2.44-2.38 (m, 2H), 2.30-2.22 (m, 4H); LC-MS: m/z 174.1 (M+H).

Step-c: 5'-Bromospiro[cyclobutane-1,3'-indolin]-2'-one

To an ice cold solution of spiro[cyclobutane-1,3'-indolin]-2'-one (5.0 g, 28.90 mmol) in acetonitrile (150 mL) was added NBS (5.65 g, 31.79 mmol) followed by stirring at RT for 16 h. TLC was monitored and the reaction mixture was poured into ice water. Solids were filtered off, washed with water and dried under reduced pressure to afford the title compound as brown solid (6.5 g).1H NMR (400 MHz, DMSO-d ₆ ): δ 10.34 (bs, 1H), 7.75 (d, J=2.0 Hz, 1H), 7.33 (dd, J=8.4 Hz & 2.0 Hz, 1H), 6.74 (d, J=7.8 Hz, 1H), 2.44-2.27 (m, 4H), 2.24-2.07 (m, 2H); LC-MS: m/z 254.0 (M+2H).

Step-d: 5'-Bromo-7'-nitrospiro[cyclobutane-1,3'-indolin]-2'-one

To a suspension of 5'-bromospiro[cyclobutane-1,3'-indolin]-2'-one (6.5 g, 25.79 mmol) in H ₂ SO ₄ at -10 ºC was added KNO ₃ (2.8 g, 28.37 mmol) portion wise followed by stirring at RT for 2 h. TLC was monitored and the reaction mixture was poured into ice water. Solids were filtered off, washed with water and dried under reduced pressure to afford the title compound as pale brown solid (10.0 g).1H NMR (400 MHz, DMSO- d ₆ ): δ 11.18 (bs, 1H), 8.23 (d, J=1.5 Hz, 1H), 8.10 (d, J=2.0 Hz, 1H), 2.47-2.41 (m, 4H), 2.26-2.09 (m, 2H); LC-MS: m/z 297.0 (M+2H).

Step-e: 7'-Amino-5'-bromospiro[cyclobutane-1,3'-indolin]-2'-one

To a stirred solution of 5'-bromo-7'-nitrospiro[cyclobutane-1,3'-indolin]-2'-one (0.5 g, 1.68 mmol) in a mixture of EtOH (10 mL) and water (5 mL) were added NH4Cl (0.44 g, 8.40 mmol) followed by iron powder (0.47 g, 8.40 mmol). The mixture was then heated to 100 ºC for 2 h. TLC was monitored, and the reaction mixture was cooled to RT, filtered through Celite® and washed with EtOAc. Combined filtrate was washed with water and brine. The organic layer was dried over sodium sulphate and

concentrated under reduced pressure and column purified to afford the title compound as pale yellow solid (0.49 g, 88 %).1H NMR (400 MHz, DMSO- d ₆ ): δ 9.81 (s, 1H), 6.96 (d, J = 1.5 Hz, 1H), 6.68 (d, J = 2.0 Hz, 1H), 5.08 (s, 2H), 2.41– 2.35 (m, 2H), 2.28– 2.22 (m, 2H), 2.19-2.11 (m, 2H); LCMS: m/z 267.0 (M + H). Intermediate-2: 5'-Aminospiro[cyclobutane-1,3'-indolin]-2'-one Step-a: 5'-Nitrospiro[cyclobutane-1,3'-indolin]-2'-one

To a stirred suspension of spiro[cyclobutane-1,3'-indolin]-2'-one (4.0 g, 23.12 mmol) in sulphuric acid (40 mL) at -20 oC was added potassium nitrate (2.3 g, 23.12 mmol) portion wise followed by stirring at -20 oC for 30 min. TLC was monitored, and the reaction mixture was poured into crushed ice. The solid formed was filtered off, washed with water and dried under reduced pressure and column purified to afford the title compound as yellow solid 2.0 g (40 %).1H NMR (400 MHz, DMSO-d ₆ ): δ 10.95 (s, 1H), 8.44 (d, J=2.5 Hz, 1H), 8.15(dd, J=2.1 Hz & 8.5 Hz, 1H), 6.97 (d, J=8.3 Hz, 1H), 2.46-2.38 (m, 4H), 2.27-2.17 (m, 2H ); LC-MS: m/z 217.1 (M-H).

Step-b: 5'-Aminospiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-e of

Intermediate-1. NMR (400 MHz, DMSO-d ₆ ): δ 9.77 (s, 1H), 6.82 (d, J=2.0 Hz, 1H), 6.47 (d, J=7.8 Hz, 1H), 6.39-6.36 (m, 1H), 4.69 (s, 2H), 2.44-2.37 (m, 2H), 2.20-2.00 (m, 4H); LC-MS: m/z 189.2 (M+1). Intermediate-3: 5'-Amino-7'-bromospiro[cyclobutane-1,3'-indolin]-2'-one Step-a: 7'-Bromo-5'-nitrospiro[cyclobutane-1,3'-indolin]-2'-one

To a stirred suspension of 5'-nitrospiro[cyclobutane-1,3'-indolin]-2'-one (3.0 g, 13.76 mmol) in sulphuric acid (20 mL) at RT was added N-bromosuccinimide (2.9 g, 16.51 mmol) portion wise followed by stirring at RT for 16 h. TLC was monitored, and the reaction mixture was poured into crushed ice. The solid formed was filtered off, washed with water and dried under reduced pressure to afford the title compound as pale brown solid 2.8 g (70 %).1H NMR (400 MHz, DMSO-d6) δ 11.27 (s, 1H), 8.46 (d, J=2.1 Hz, 1H), 8.30 (d, J=1.9 Hz, 1H), 2.48-2.41 (m, 4H), 2.25-2.19 (m, 2H); LC-MS: m/z 297 (M+H).

Step-b: 5'-Amino-7'-bromospiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-e of

Intermediate-1.1H NMR (400 MHz, DMSO-d ₆ ) δ 10.04 (s, 1H), 6.82 (d, J=2.0 Hz, 1H), 6.55 (d, J=2.0 Hz, 1H), 4.98 (s, 2H), 2.44-2.39 (m, 2H), 2.22-2.07 (m, 4H); LC-MS: m/z 267.5 (M+H). Intermediate-4: 4-(2,4-Difluorophenyl)-4-oxobutanal

Step-a: 5-(2,4-Difluorophenyl)furan-2(3H)-one

To a stirred solution of 4-(2,4-difluorophenyl)-4-oxobutanoic acid (1.0 g, 4.67 mmol) in AcOH (10 mL) were added acetic anhydride (1.3 mL, 14.01 mmol) and PTSA (1.3 g, 7.0 mmol) followed by stirring at RT for 4 h. TLC was monitored, and the reaction mixture was poured into ice water. Solids were filtered off and dried under reduced pressure to afford the title compound as orange solid (0.7 g, 79 %).1H NMR (400 MHz, DMSO–d ₆ ): δ 7.67– 7.61 (m, 1H), 7.49– 7.43 (m, 1H), 7.29– 7.19 (m, 1H), 6.07 (q, J=2.9 Hz.1H), 3.60 (d, J = 2.9 Hz, 2H).

Step-b: 4-(2,4-Difluorophenyl)-4-oxobutanal

To a stirred solution of 5-(2,4-difluorophenyl)furan-2(3H)-one (0.7 g, 3.57 mmol) in THF (10 mL) at -78 ºC was added DIBAL-H 1.0 M in hexane (4.3 mL) followed by stirring for 4 h. TLC was monitored, and the reaction mixture was quenched with 1 mL of EtOAc and a solution of sodium potassium tartrate at -78 ºC. The mixture was then allowed to stir at RT for 2 h. The mixture was extracted with EtOAc. The organic layer was dried over sodium sulphate and concentrated under pressure to afford the title compound as pale brown oil which was used in the further step without purification (0.5 g). LCMS: m/z 199.1 (M+H). Intermediate-5: 5'-Amino-7'-nitros iro c clobutane-13'-indolin -2'-one

Step-a: 2-(2'-Oxospiro[cyclobutane-1,3'-indolin]-5'-yl)isoindoline-1 ,3-dione To a solution of 5'-aminospiro[cyclobutane-1,3'-indolin]-2'-one (3.6 g, 18.99 mmol) in AcOH (35 mL) was added phthalic anhydride (4.2 g, 20.48 mmol) followed by heating the mixture to 100 oC for 2 h. TLC was monitored, and the reaction mixture was poured into crushed ice. The solid formed was filtered off, washed with water and dried under reduced pressure to afford the title product as brown solid 4.5 g (75 %).1HNMR (400 MHz, DMSO-d ₆ ): δ 10.43 (s, 1H), 7.98-7.90 (m, 4H), 7.33 (d, J=1.9 Hz, 1H), 7.24-7.21 (m, 1H), 6.92 (d, J=8.3 Hz, 1H), 2.48-2.43 (m, 2H), 2.32-2.14 (m, 4H); LC- MS: m/z 319.1 (M+1).

Step-b: 2-(7'-Nitro-2'-oxospiro[cyclobutane-1,3'-indolin]-5'-yl)isoi ndoline-1,3- dione

To a solution of 2-(2'-oxospiro[cyclobutane-1,3'-indolin]-5'-yl)isoindoline-1 ,3- dione (9.2 g, 28.93 mmol) in AcOH (100 mL) at RT was added nitric acid (9.0 mL) drop wise followed by heating to 110 oC for 2 h. TLC was monitored, and the reaction mixture was poured into crushed ice. The solids were filtered off, washed with water and dried under reduced pressure to afford the title compound as brown solid 10.5 g.1H NMR (400 MHz, DMSO-d ₆ ): δ 10.19 (s, 1H), 8.15 (d, J=1.5 Hz, 1H), 8.13 (d, J=1.5 Hz, 1H), 8.02-7.93 (m, 4H), 2.51-2.48 (m, 2H), 2.39-2.37 (m, 4H); LC-MS: m/z 364.1 (M+1).

Step-c: 5'-Amino-7'-nitrospiro[cyclobutane-1,3'-indolin]-2'-one

To a solution of 2-(7'-nitro-2'-oxospiro[cyclobutane-1,3'-indolin]-5'-yl)iso- indoline-1,3-dione (10.5 g, 28.92 mmol) in EtOH (100 mL) was added hydrazine hydrate (21 mL) followed by heating to 100 oC for 2 h. TLC was monitored, and the reaction mixture was poured into crushed ice. The solid formed was filtered off, washed with water and dried under reduced pressure to afford the title compound (5.5 g).1H NMR (400 MHz, DMSO-d ₆ ): δ 10.52 (s, 1H), 7.30 (d, J=2.0 Hz, 1H), 7.11 (d, J=1.9 Hz, 1H), 5.38 (s, 2H), 2.54-2.48 (m, 2H), 2.48-2.14 (m, 4H); LC-MS: m/z 234.1 (M+1). Intermediate-6: (E)-7'-Bromo-5'-(3-(dimethylamino)acryloyl)-1'-(4-methoxyben zyl)- spiro[cyclobutane-1,3'-indolin]-2'-one

Step-a: 5'-Acetylspiro[cyclobutane-1,3'-indolin]-2'-one

To a cold suspension of AlCl3 (4.6 g, 34.64 mmol) in DCE (50 mL) was added acetyl chloride (1.5 mL, 20.78 mmol) followed by stirring for 15 min. Then spiro[cyclo- butane-1,3'-indolin]-2'-one (3.0 g, 17.32 mmol) was added and the mixture was stirred at RT for 16 h. TLC was monitored, and the reaction mixture was quenched with ice and extracted with EtOAc. The organic layer was dried over sodium sulphate and

concentrated under reduced pressure. The residue was purified by combi flash to afford the title compound as brown solid (2.5 g, 67 %).1H NMR (400 MHz, DMSO-d ₆ ): δ 10.62 (s, 1H), 8.12 (s, 1H), 7.86 (dd, J=1.9 Hz, 7.8 Hz, 1H), 6.89 (d, J=7.9 Hz, 1H), 2.56 (s, 3H), 2.46-2.34 (m, 4H), 2.28-2.19 (m, 2H); LC-MS: m/z 216.2 (M+H)

Step-b: 5'-Acetyl-7'-bromospiro[cyclobutane-1,3'-indolin]-2'-one

To an ice cold solution of 5'-acetylspiro[cyclobutane-1,3'-indolin]-2'-one (4.0 g, 18.58 mmol) in H2SO4 (40 mL) was added NBS (5.0 g, 27.87 mmol) followed by stirring at RT for 3 h. TLC was monitored, and the reaction mixture was quenched with ice water and extracted with EtOAc. The combined organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by

CombiFlash® to afford the title compound as pale brown solid (2.5 g, 46 %).1H NMR (400 MHz, DMSO-d ₆ ): δ 10.94 (s, 1H), 8.12 (d, J=1.5 Hz, 1H), 7.97 (d, J=1.5 Hz, 1H), 2.58 (s, 3H), 2.44-2.38 (m, 4H), 2.28-2.18 (m, 2H); LC-MS: m/z 294.0 (M+H).

Step-c: 5'-Acetyl-7'-bromo-1'-(4-methoxybenzyl)spiro[cyclobutane-1,3 '-indolin]- 2'-one To an ice cold solution of 5'-acetyl-7'-bromospiro[cyclobutane-1,3'-indolin]-2'- one (6.5 g, 22.1 mmol) in DMF (100 mL) were added cesium carbonate (21.6 g, 66.3 mmol) followed by 1-(chloromethyl)-4-methoxybenzene (3.6 mL, 26.52 mmol). The mixture was stirred at RT for 6 h. TLC was monitored, and the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulphate, concentrated under reduced pressure and column purified to afford the title compound as brown solid (6.5 g, 71 %).1HNMR (400 MHz, DMSO–d ₆ ): δ 8.21 (d, J = 2 Hz, 1H),7.94 (d, J = 1.5 Hz, 1H),7.04 (d, J = 8.8 Hz, 2H),6.87 (d, J = 8.8 Hz, 2H),5.24 (s, 2H), 3.70 (s, 3H), 2.61 (s, 3H), 2.60–2.18 (m, 6H); LCMS: m/z

414.1(M+H).

Step-d: (E)-7'-Bromo-5'-(3-(dimethylamino)acryloyl)-1'-(4-methoxyben zyl)- spiro[cyclobutane-1,3'-indolin]-2'-one

A solution of 5'-acetyl-7'-bromo-1'-(4-methoxybenzyl)spiro[cyclobutane-1,3 '- indolin]-2'-one (2.6 g, 6.29 mmol) in DMF-DMA (10 mL) was heated to 100 ºC for 16 h. TLC was monitored, and the reaction mixture was concentrated under reduced pressure and column purified to afford the title compound as yellow solid (2.6 g, 89 %). 1HNMR (400 MHz, DMSO–d ₆ ): δ 8.17 (d, J = 1.5 Hz, 1H),7.91 (d, J = 1.5 Hz, 1H),7.73 (d, J = 12.2 Hz, 1H),7.05 (d, J = 8.8 Hz, 2H),6.87 (d, J = 8.3 Hz, 2H),5.91 (d, J = 12.2 Hz, 1H),5.22 (s, 2H), 3.70 (s, 3H), 3.16 (s, 3H), 2.96 (s, 3H), 2.59–2.18 (m, 6H); LCMS: m/z469.1 (M+H) . Intermediate-7: 7'-Nitro-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spi ro[cyclo- butane-1,3'-indolin]-2'-one

Step-a: 7'-Nitro-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spi ro[cyclo- butane-1,3'-indolin]-2'-one

To a solution of 5'-bromo-7'-nitrospiro[cyclobutane-1,3'-indolin]-2'-one (2.0 g, 6.73 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (3.4 g, 13.46 mmol) in 1,4-dioxane (50 mL) was added potassium acetate (2.0 g, 20.2 mmol) followed by degassing with nitrogen purging for 15 min. Then Pd(dppf) ₂ Cl ₂ (0.55 g, 0.67 mmol) was added and the mixture was again degassed with nitrogen purging for 15 min followed by heating to 100 ºC for 16 h. TLC was monitored, and the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as pale yellow solid (0.8 g, 34 %).1H NMR (400 MHz, DMSO-d6): δ 11.17 (bs, 1H), 8.21 (s, 1H), 8.08 (s, 1H), 2.47-2.42 (m, 4H), 2.25-2.10 (m, 2H), 1.33 (s, 12H); LC-MS: m/z 345.2 (M+H). Intermediate-8: 5-Bromo-1-(2,4-difluorophenyl)-1H-1,2,4-triazole Step-a: 1-(2,4-Difluorophenyl)-1H-1,2,4-triazole

A solution of (2,4-difluorophenyl)hydrazine hydrochloride (10.0 g, 55.37) in formamide (100 mL) was heated to 120 ºC for 16 h. TLC was monitored, and the reaction mixture was cooled to RT, diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as off white solid (5.0 g, 50 %).1H NMR (400 MHz, DMSO-d ₆ ): δ 9.00 (d, J=2.4 Hz, 1H), 8.30 (s, 1H), 7.89-7.83 (m, 1H), 7.68-7.62 (m, 1H), 7.36-7.30 (m, 1H); LC-MS: m/z 182.1 (M+H).

Step-b: 5-Bromo-1-(2,4-difluorophenyl)-1H-1,2,4-triazole

To a stirred solution of 1-(2,4-difluorophenyl)-1H-1,2,4-triazole (5.0 g, 27.60 mmol) in CCl ₄ (100 mL) were added NBS (9.8 g, 55.20 mmol) followed by benzoyl peroxide (0.67 g, 2.76 mmol). The mixture was then heated to 100 ºC under light for 16 h. TLC was monitored, and the reaction mixture was cooled to RT, diluted with DCM, filtered through Celite® pad and washed with DCM. The combined filtrate was concentrated under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as pale brown solid (3.0 g, 42 %).1H NMR (400 MHz, DMSO-d ₆ ): δ 8.35 (s, 1H), 7.86-7.81 (m, 1H), 7.72-7.67 (m, 1H), 7.40-7.36 (m, 1H); LC-MS: m/z 262.0 (M+2H). Intermediate-9: 2-Bromo-1-(2,4-difluorophenyl)-1H-imidazole

Step-a: 1-(2,4-Difluorophenyl)-1H-imidazole

To a stirred solution of 2,4-difluoroaniline (10.0 g, 77.45 mmol) in MeOH (80 mL) was added glyoxal 40 % in water (12 mL) followed by stirring at RT for 16 h. NH ₄ Cl (8.5 g, 154.9 mmol) and formaldehyde 37 % in water (15 mL) were added to the reaction mixture followed by heating to 85 ºC for 1 h. The reaction mixture was cooled to RT. H ₃ PO ₄ (12 mL) was added dropwise and the mixture was again heated to 85 ºC for 16 h. TLC was monitored, and the mixture was concentrated. The residue was basified with 40 % KOH solution and extracted with DCM. The organic layer was dried over sodium sulphate and concentrated under reduced pressure and column purified to afford the title compound as pale brown solid (12.0 g, 86 %).1H NMR (400 MHz, DMSO-d6): δ 8.00 (s, 1H), 7.75-7.69 (m, 1H), 7.61-7.55 (m, 1H), 7.54 (d, J=1.5 Hz, 1H), 7.30-7.25 (m, 1H), 7.13 (s, 1H); LC-MS: m/z 181.1 (M+H).

Step-b: 2-Bromo-1-(2,4-difluorophenyl)-1H-imidazole

The compound was prepared using the process described in step-b of

Intermediate-8.1H NMR (400 MHz, DMSO-d6): δ 7.75-7.61 (m, 2H), 7.58 (d, J=1.5 Hz, 1H), 7.34-7.29 (m, 1H), 7.14 (d, J=1.4 Hz, 1H); LC-MS: m/z 261.0 (M+2H). Intermediate-10: (E)-5'-(3-(Dimethylamino)acryloyl)-1'-(4-methoxybenzyl)-7'- nitrospiro[cyclobutane-1,3'-indolin]-2'-one

Step-a: 5'-Acetyl-7'-nitrospiro[cyclobutane-1,3'-indolin]-2'-one

To an ice cold solution of 5'-acetylspiro[cyclobutane-1,3'-indolin]-2'-one (1.5 g, 6.96 mmol) in H2SO4 (15 mL) was added KNO3 (0.77 g, 7.66 mmol) portion wise and the mixture was stirred at RT for 3 h. TLC was monitored, and the reaction mixture was poured into ice water. Solid was filtered off, washed with water and dried under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as off white solid (0.6 g, 33 %).1H NMR (400 MHz, DMSO-d ₆ ): δ 11.41 (s, 1H), 8.49 (d, J=1.4 Hz, 1H), 8.47 (s, 1H), 2.67 (s, 3H), 2.51-2.42 (m, 4H), 2.32-2.19 (m, 2H); LC- MS: m/z 261.1 (M+H).

Step-b: 5'-Acetyl-1'-(4-methoxybenzyl)-7'-nitrospiro[cyclobutane-1,3 '-indolin]-2'- one

The compound was prepared using the process described in step-c of

Intermediate-6.1H NMR (400 MHz, DMSO-d ₆ ): δ 8.48 (d, J=1.5 Hz, 1H), 8.14 (d, J=1.5 Hz, 1H), 6.85-6.79 (m, 4H), 4.97 (s, 2H), 3.68 (s, 3H), 2.62 (s, 3H), 2.68-2.54 (m, 4H), 2.43-2.23 (m, 2H); LC-MS: m/z 381.2 (M+H).

Step-c: (E)-5'-(3-(dimethylamino)acryloyl)-1'-(4-methoxybenzyl)-7'-n itrospiro- [cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-d of

Intermediate-6.1H NMR (400 MHz, DMSO-d6): δ 8.44 (d, J=1.4 Hz, 1H), 8.08 (d, J=1.4 Hz, 1H), 7.77 (d, J=12.2 Hz, 1H), 6.85-6.79 (m, 4H), 5.94 (d, J=12.2 Hz, 1H), 4.96 (s, 2H), 3.68 (s, 3H), 3.16 (s, 3H), 2.96 (s, 3H), 2.67-2.53 (m, 4H), 2.44-2.24 (m, 2H); LC-MS: m/z 436.2 (M+H). Intermediate-11: 5-Bromo-1-(2,4-difluorophenyl)-3-methyl-1H-pyrazole

Step-a: 2-(2,4-Difluorophenyl)-5-methyl-1,2-dihydro-3H-pyrazol-3-one

To an ice cold solution of (2,4-difluorophenyl)hydrazine hydrochloride (10.0 g, 55.55) in MeOH (200 mL) was added triethyl amine (10.0 mL) followed by ethyl 3- oxobutanoate (8.0 g) in MeOH dropwise. The mixture was then heated to 100 ºC for 4 h. TLC was monitored, and the reaction mixture was concentrated. The residue was diluted with water and extracted with DCM. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by

CombiFlash® to afford the title compound as yellow solid (8.5 g, 73 %).1H NMR (400 MHz, DMSO-d ₆ ): δ 11.25 (s, 1H), 7.55– 7.43 (m, 2H), 7.21– 7.16 (m, 1H), 5.32 (s, 1H), 2.07 (s, 3H);LC-MS: m/z 211.1 (M+H).

Step-b: 5-Bromo-1-(2,4-difluorophenyl)-3-methyl-1H-pyrazole

To a stirred solution of 2-(2,4-difluorophenyl)-5-methyl-1,2-dihydro-3H-pyrazol- 3-one (2.5 g, 11.90 mmol) in toluene (25 mL) was added POBr ₃ (1.8 mL, 17.85 mmol) and then the mixture was heated to 120 ºC for 16 h. TLC was monitored, and the reaction mixture was quenched with ice water and extracted with EtOAc. The organic layer was washed with saturated NaHCO ₃ solution, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as pale yellow solid (0.6 g, 17 %).1H NMR (400 MHz, DMSO-d ₆ ): δ 7.44– 7.38 (m, 1H), 6.99 (t, J = 7.8 Hz, 2H), 6.28 (s, 1H), 2.32 (s, 3H); LC-MS: m/z 273.0 (M+H). Intermediate-12: 1-(2,4-Difluorophenyl)-4-iodo-1H-pyrazole Step-a: 1-(2,4-Difluorophenyl)-1H-pyrazole

To a stirred solution of (2,4-difluorophenyl)hydrazine hydrochloride (10.0 g, 55.55 mmol) and 1,1,3,3-tetramethoxypropane (18.2 g, 111.1 mmol) in EtOH (100 mL) was added concentrated HCl (10 mL) followed by heating to 80 ºC for 16 h. TLC was monitored, and the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulphate and concentrated and purified by CombiFlash® to afford the title compound as colorless oil (5.0 g, 50 %).1H NMR (400 MHz, DMSO-d ₆ ): δ 8.19– 8.18 (m, 1H), 8.87– 8.82 (m, 2H), 7.59– 7.53 (m, 1H), 7.29 – 7.24 (m, 1H), 6.58– 6.57 (m, 1H); LCMS: m/z 181.1 (M+H).

Step-b: 1-(2,4-Difluorophenyl)-4-iodo-1H-pyrazole

To a stirred solution of 1-(2,4-difluorophenyl)-1H-pyrazole (1.0 g, 5.55 mmol) and iodine (0.7 g, 2.77 mmol) in water (1.0 mL) was added 30 % H ₂ O ₂ (0.38 mL) followed by stirring at RT for 16 h. The reaction mixture was quenched with aqueous NaHSO ₃ and extracted with EtOAc. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as white solid (0.4 g, 23 %). LCMS: m/z 307.1 (M+H). Intermediate-13: 2-Bromo-1-(2,4-difluorophenyl)-1H-pyrrole

To an ice cold solution of 1-(2,4-difluorophenyl)-1H-pyrrole (0.9 g, 5.02 mmol) in DMF (20 mL) was added NBS (0.98 g, 5.52 mmol) followed by stirring at RT for 16 h. TLC was monitored, and the reaction was mixture diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as colorless oil (1.0 g).1H NMR (400 MHz, DMSO-d ₆ ): δ 7.60– 7.54 (m, 2H), 7.29– 7.24 (m, 1H), 7.08 (s, 1H), 6.38– 6.37 (m, 1H), 6.31– 6.29 (m, 1H); LCMS: m/z 260.0 (M+2H).

Intermediate-14

Conditions: a) NBS, benzoyl peroxide, CCl ₄ , 80ºC, 16h

The compound was prepared using the process described in step-b of

Intermediate-8.1H NMR (400 MHz, DMSO-d ₆ ): δ 8.29 (s, 1H), 7.64-7.57 (m, 5H); LC- MS: m/z 224.1 (M+2H). Intermediate-15: tert-Butyl 4-hydroxy-2,6-dimethylpiperidine-1-carboxylate.

Step-a: 1-Benzyl-2,6-dimethylpiperidin-4-one

A solution of 3-oxopentanedioic acid (11.5 g, 78.76 mmol) and acetaldehyde (8.8 mL, 157.52 mmol) in water (25 mL) was stirred at RT for 10 min, then cooled to 0 ºC. Benzyl amine (8.2 mL, 78.76 mmol) was added dropwise over a period of 15 min (exothermic) followed by stirring at RT for 3 days. TLC was monitored, and the reaction mixture was stirred with 1 N HCl for 1 h, followed by addition of aqueous NaHCO ₃ . pH was adjusted to ~8-10. The mixture was then extracted with EtOAc. The organic layer was washed with water and brine, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as brown solid (5.0 g, 28 %). 1H NMR (400 MHz, DMSO-d6): δ 7.42-7.21 (m, 5H), 3.85-3.79 (m, 1H), 3.68-3.65 (m, 1H), 3.22-3.17 (m, 2H), 2.44-2.40 (m, 2H), 2.14-2.08 (m, 2H), 1.02 (d, J=6.4 Hz, 6H); ES-MS: m/z 218.2 (M+H).

Step-b: 2,6-Dimethylpiperidin-4-one

To a solution of 1-benzyl-2,6-dimethylpiperidin-4-one (1.4 g, 6.45 mmol) in MeOH (15 mL) was added 10 % Pd-C (0.7 g) followed by stirring at RT under hydrogen bladder pressure for 6 h. TLC was monitored, and the reaction mixture was filtered through Celite® and concentrated under reduced pressure to afford the title compound as brown oil (0.7 g).1H NMR (400 MHz, DMSO-d6): δ 3.36-3.29 (m, 2H), 2.35-2.31 (m, 2H), 2.00-1.959m, 2H), 1.01 (d, J=6.8 Hz, 6H); LC-MS: m/z 128.2 (M+H).

Step-c: tert-Butyl 2,6-dimethyl-4-oxopiperidine-1-carboxylate

To a solution of 2,6-dimethylpiperidin-4-one (0.7 g, 5.51 mmol) in DCM (10 mL) were added triethyl amine (1.5 mL, 11.02 mmol), DMAP (0.07 g, 0.55 mmol) and (Boc) ₂ O (1.9 mL, 8.26 mmol) followed by stirring at RT for 16 h. TLC was monitored, and the reaction mixture was diluted with DCM and washed with water. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as off white solid (0.34 g, 27 %).1H NMR (400 MHz, DMSO-d6): δ 4.23-4.20 (m, 2H), 2.95-2.89 (m, 2H), 2.28 (s, 1H), 2.24 (s, 1H), 1.43 (s, 9H), 1.16 (d, J=6.8 Hz, 6H); ES-MS: m/z 128.2 (M-Boc).

Step-d: tert-Butyl 4-hydroxy-2,6-dimethylpiperidine-1-carboxylate

To an ice cold solution of tert-butyl 2,6-dimethyl-4-oxopiperidine-1-carboxylate (2.0 g, 8.81 mmol) in MeOH (20 mL) was added sodium borohydride (0.67 g, 17.62 mmol) followed by stirring at RT for 2 h. TLC was monitored, and the reaction mixture was quenched with aqueous NH ₄ Cl and extracted with EtOAc. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as colour less oil (1.6 g, 79 % ). 1H NMR (400 MHz, DMSO-d6): δ 4.66 (bs, 1H), 4.03-3.94 (m, 2H), 3.75-3.70 (m, 1H), 2.07-1.98 (m, 1H), 1.91-1.85 (m, 1H), 1.66-1.59 (m, 1H), 1.45-1.41 (m, 1H), 1.39 (s, 9H), 1.26 (d, J=6.8 Hz, 3H), 1.07 (d, J=6.9 Hz, 3H). Intermediate-16: tert-Butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate

Step-a: tert-Butyl 4-((trimethylsilyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylat e To an ice cold solution of tert-butyl 4-oxopiperidine-1-carboxylate (5.0 g, 25.12 mmol) in DMF (30 mL) was added TMSCl (4.8 mL, 37.68 mmol) followed by triethyl amine (10.5 mL, 75.36 mmol). The mixture was then heated to 80 ºC for 16 h. TLC was monitored, and the reaction mixture was cooled to RT, diluted with water and extracted with EtOAc. The organic layer was washed with aqueous NaHCO3, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by

CombiFlash® to afford the title compound as pale yellow liquid (6.1 g, 90 %). 1H NMR (400 MHz, DMSO-d6): δ 4.80 (s, 1H), 3.77 (s, 2H), 3.42 (t, J = 5.9 Hz, 2H), 2.01 (t, J = 5.4 Hz, 2H), 1.39 (s, 9H), 0.16 (s, 9H).

Step-b: tert-Butyl 3-fluoro-4-oxopiperidine-1-carboxylate

To an ice cold solution of tert-butyl 4-((trimethylsilyl)oxy)-3,6-dihydropyridine- 1(2H)-carboxylate (6.1 g, 22.5 mmol) in acetonitrile (100 mL) was added Selectfluor® (9.55 g, 27.0 mmol) followed by stirring at RT for 2 h. TLC was monitored, and the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as white solid (3.2 g, 63 %). 1H NMR (400 MHz, DMSO-d6): δ 5.17– 5.01 (m, 1H), 4.36– 4.28 (m, 1H), 4.05– 3.99 (m, 1H), 3.26– 3.16 (m, 2H), 2.62– 2.54 (m, 1H), 2.40– 2.34 (m, 1H), 1.44 (s, 9H).

Step-c: tert-Butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate

To an ice cold solution of tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate (2.0 g, 9.21 mmol) in MeOH (20 mL) was added sodium borohydride (0.7 g, 18.42 mmol) followed by stirring at RT for 6 h. TLC was monitored, and the reaction mixture was quenched with aqueous NH ₄ Cl and extracted with EtOAc. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as white solid (two diastereomers) (0.9 g, 45 % and 0.6 g, 30 %).1H NMR (400 MHz, DMSO-d6): δ 5.27 (d, J=4.9 Hz, 1H), 4.36 – 4.15 (m, 1H), 3.69– 3.67 (m, 2H), 3.50– 3.28 (m, 1H), 3.22– 3.18 (m, 2H), 1.77– 1.74 (m, 1H), 1.40-1.38 (m, 10H). Intermediate-17: 2-(2-(2,4-Difluorophenoxy)-5-nitrophenyl)-4,4,5,5-tetramethy l-1,3,2- dioxaborolane

Step-a: 2-Bromo-1-(2,4-difluorophenoxy)-4-nitrobenzene

To a stirred solution of 2,4-difluorophenol (0.5 g, 2.28 mmol) and 2-bromo-1- fluoro-4-nitrobenzene (0.36 g, 2.74 mmol) in DMSO (25 mL) was added cesium carbonate (1.1 g, 3.42 mmol) followed by heated the mixture to 110 ºC for 1 h. TLC was monitored, and the reaction mixture poured into ice water. Solids were filtered off, washed with water and dried under reduced pressure to afford the title compound as pale brown solid (0.6 g).1H NMR (400 MHz, DMSO-d ₆ ): δ 8.58 (d, J = 2.7 Hz, 1H), 8.23– 8.20 (m, 1H), 7.62– 7.48 (m, 2H), 7.13– 7.07 (m, 2H); LCMS: m/z 329.0 (M+H).

Step-b: 2-(2-(2,4-Difluorophenoxy)-5-nitrophenyl)-4,4,5,5-tetramethy l-1,3,2- dioxaborolane

This compound was prepared using the process described for Intermediate-7.1H NMR (400 MHz, DMSO-d ₆ ): δ 8.46– 8.35 (m, 1H), 8.27– 8.25 (m, 1H), 7.60– 7.45 (m, 2H), 7.20– 7.18 (m, 1H), 7.09– 7.07 (m, 1H), 1.25 (s, 12H). Intermediate-18: 5'-Bromo-1'-(4-methoxybenzyl)-7'-((1-methylpiperidin-4-yl)ox y)spiro- c clobutane-13'-indolin -2'-one

Step-a: 5'-Bromo-7'-iodospiro[cyclobutane-1,3'-indolin]-2'-one

To an ice cold solution of 5'-bromospiro[cyclobutane-1,3'-indolin]-2'-one (4.0 g, 15.87 mmol) in AcOH (40 mL) was added NIS (4.3 g, 19.04 mmol) portion wise followed by stirring at RT for 16 h. The reaction mixture was cooled to 0 ºC. H ₂ SO ₄ (2.0 mL) was added dropwise followed by stirring at RT for 2 h. TLC was monitored, and the reaction mixture was poured into ice water. Solids were filtered off, washed with water and dried under vacuum to afford the title compound as pale brown solid (4.4 g, 73 %).1H NMR (400 MHz, DMSO-d ₆ ): δ 10.41 (s, 1H), 7.79 (d, J=1.4 Hz, 1H), 7.70 (d, J=2.0 Hz, 1H), 2.43-2.33 (m, 4H), 2.30-2.09 (m, 2H); LC-MS: m/z 377.7 (M-H).

Step-b: 5'-Bromo-7'-iodo-1'-(4-methoxybenzyl)spiro[cyclobutane-1,3'- indolin]-2'- one

The compound was prepared using the process described in step-c of

Intermediate-6.1H NMR (400 MHz, DMSO-d ₆ ): δ 7.94 (d, J=2.0 Hz, 1H), 7.80 (d, J=2.0 Hz, 1H), 6.98 (d, J=8.3 Hz, 2H), 6.87 (d, J=8.4 Hz, 2H), 5.22 (s, 2H), 3.70 (s, 3H), 2.52-2.41 (m, 4H), 2.33-2.03 (m, 2H); ES-MS: m/z 499.8 (M+H).

Step-c: 5'-Bromo-7'-hydroxy-1'-(4-methoxybenzyl)spiro[cyclobutane-1, 3'- indolin]-2'-one

To a solution of 5'-bromo-7'-iodo-1'-(4-methoxybenzyl)spiro[cyclobutane-1,3'- indolin]-2'-one (0.4 g, 0.80 mmol) in pyridine (2.5 mL) and water (5.0 mL) were added NaOH (0.16 g, 4.01 mmol) followed by copper(I) oxide (0.02 g, 0.12 mmol). The mixture was then heated to 110 ºC for 48 h. TLC was monitored, and the reaction mixture was diluted with EtOAc and washed with 1 N HCl. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as pale brown solid (0.1 g, 32 %).1H NMR (400 MHz, DMSO-d ₆ ): δ 10.18 (s, 1H), 7.32 (d, J=2.0 Hz, 1H), 7.15 (d, J=8.4 Hz, 2H), 6.86-6.84 (m, 3H), 4.97 (s, 2H), 3.69 (s, 3H), 2.45-2.30 (m, 4H), 2.25-2.15 (m, 2H); ES-MS: m/z 388.8 (M+H).

Step-d: 5'-Bromo-1'-(4-methoxybenzyl)-7'-((1-methylpiperidin-4-yl)ox y)spiro- [cyclobutane-1,3'-indolin]-2'-one

To an ice cold solution of 1-methylpiperidin-4-ol (0.72 ml, 6.18 mmol) in THF (10 mL) was added triphenyl phosphine (1.62 g, 6.18 mmol) followed by DIAD (1.2 mL, 6.18 mmol). The mixture was stirred at 0 ºC for 15 min. Then 5'-bromo-7'-hydroxy-1'- (4-methoxybenzyl)spiro[cyclobutane-1,3'-indolin]-2'-one (0.6 g, 1.54 mmol) was added followed by stirring at RT for 16 h. TLC was monitored, and the reaction mixture was diluted with EtOAc and washed with water. The organic layer dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by

CombiFlash® to afford the title compound as pale yellow oil (0.6 g, 80 %).1H NMR (400 MHz, DMSO-d ₆ ): δ 7.47 (d, J=1.5 Hz, 1H), 7.14 (d, J=1.5 Hz, 1H), 7.03 (d, J=8.8 Hz, 2H), 6.85 (d, J=8.8 Hz, 2H), 5.06 (s, 2H), 4.42-4.40 (m, 1H), 3.69 (s, 3H), 2.46- 2.35 (m, 6H), 2.27-2.08 (m, 7H), 1.79-1.76 (m, 2H), 1.48-1.41 (m, 2H); LC-MS: m/z 487.0 (M+2H). Intermediate-19: 5'-(3-(Dimethylamino)acryloyl)-7'-methoxy-1'-(4-methoxybenzy l)- s iro c clobutane-1 3’-indolin -2'-one

Intermediate-19 Step-a: 5'-Acetyl-7'-hydroxy-1'-(4-methoxybenzyl)spiro[cyclobutane-1 ,3'- indolin]-2'-one

To a solution of 5'-acetyl-7'-bromo-1'-(4-methoxybenzyl)spiro[cyclobutane-1,3 '- indolin]-2'-one (2.0 g, 4.48 mmol) in 1,4-dioxane (16 mL) and H ₂ O (4 mL) was added KOH (0.8 g, 14.52 mmol) followed by degassing the mixture with nitrogen purging for 20 min. Then t-BuXPhos (0.2 g, 0.48 mmol) and Pd ₂ (dba) ₃ (0.44 g, 0.48 mmol) were added followed by degassing the mixture again with nitrogen purging for 20 min. Then the mixture was heated at 100 °C for 16 h. TLC was monitored, and the mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over sodium sulphate and concentrated under reduced pressure and purified by CombiFlash® to afford the title compound as pale yellow solid (0.8 g, 47 %).1H NMR (400 MHz, DMSO–d ₆ ): δ 10.07 (s, 1H), 7.75 (d, J=1.4 Hz, 1H),7.33 (d, J=1.5 Hz, 1H), 7.17 (d, J=8.8 Hz, 2H), 6.85 (d, J=8.8 Hz, 2H), 5.04 (s, 2H), 3.69 (s, 3H), 2.53 (s, 3H), 2.67– 2.19 (m, 6H); LCMS: m/z 352.2(M+H).

Step-b: 5'-Acetyl-7'-methoxy-1'-(4-methoxybenzyl)spiro[cyclobutane-1 ,3'- indolin]-2'-one

To a solution of 5'-acetyl-7'-hydroxy-1'-(4-methoxybenzyl)spiro[cyclobutane- 1,3'-indolin]-2'-one (0.8 g, 2.27 mmol) in acetonitrile (10 mL) was added potassium carbonate (0.94 g, 6.83 mmol) and methyl iodide (0.28 mL, 4.55 mmol) followed by stirring at RT for 4 h. TLC was monitored and the mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as off white solid (0.7 g, 84 %).1H NMR (400 MHz, DMSO– d ₆ ): δ 7.90 (d, J=1.5 Hz, 1H), 7.46 (d, J=1.0 Hz, 1H), 7.13 (d, J=8.3 Hz, 2H), 6.85 (d, J=8.8 Hz, 2H), 5.00 (s, 2H), 3.79 (s, 3H), 3.69 (s, 3H), 2.59 (s, 3H), 2.47–2.23 (m, 6H); LCMS: m/z 366.2(M+H).

Step-c: 5'-(3-(Dimethylamino) acryloyl)-7'-methoxy-1'-(4-methoxybenzyl)spiro- [cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-d of

Intermediate-6.1H NMR (400 MHz, DMSO–d ₆ ): δ 7.80 (d, J=1.0 Hz, 1H), 7.69 (d, J=7.69 Hz, 1H), 7.44 (d, J=1.0 Hz, 1H), 7.14 (d, J=8.3 Hz, 2H), 6.86-6.84 (m, 2H), 5.89 (d, J=12.7 Hz, 1H), 4.99 (s, 2H), 3.77 (s, 3H), 3.69 (s, 3H), 3.15-3.13 (m, 3H), 2.96-2.94 (m, 3H), 2.46–2.23 (m, 6H); LCMS: m/z 421.2(M+H). Intermediate-20: tetrah dro-2H- ran-4- l h drazine trifluoroacetate

Intermediate 20

Step-a: tert-butyl 2-(Tetrahydro-4H-pyran-4-ylidene)hydrazine-1-carboxylate To a solution of tert-butyl hydrazine carboxylate (6.6 g, 5.0 mmol) in n-hexane (100 mL) was added tetrahydro-4H-pyran-4-one (5.0 g, 5.0 mmol) dropwise followed by stirring at RT for 30 min and then heating to 90ºC for 2 h. TLC was monitored and the mixture was cooled to RT. Solids were filtered off and dried under reduced pressure to afford the title compound as white solid (7.0 g, 70 %).1H NMR (400 MHz, DMSO–d ₆ ): δ 9.64 (s, 1H), 3.69 (t, J=5.7 Hz, 2H), 3.60 (t, J=5.7 Hz, 2H), 2.42 (t, J=5.8 Hz, 2H), 2.27 (t, J=5.6 Hz, 2H), 1.43 (s, 9H).

Step-b: tert-butyl 2-(tetrahydro-2H-pyran-4-yl)hydrazine-1-carboxylate

To a solution of tert-butyl 2-(tetrahydro-4H-pyran-4-ylidene) hydrazine-1- carboxylate (7.0 g, 32.71 mmol) in a mixture of AcOH: H ₂ O (35 mL: 35 mL) was added NaBH3CN (3.04 g, 49.06 mmol) followed by stirring at RT for 2 h. TLC was monitored and the reaction mixture was quenched with 1N NaOH and extracted with DCM. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as white solid (6.5 g).1H NMR (400 MHz, DMSO–d ₆ ): δ 8.18 (s, 1H), 3.82-3.77 (m, 2H), 3.29-3.23 (m, 2H), 2.91-2.87 (m, 1H), 1.65-1.62 (m, 2H), 1.38 (s, 9H), 1.33-1.20 (m, 2H). Step-c: (tetrahydro-2H-pyran-4-yl)hydrazine trifluoroacetate To a solution of tert-butyl 2-(tetrahydro-2H-pyran-4-yl) hydrazine-1-carboxylate (2.0 g, 9.25 mmol) in DCM (30 mL) was added trifluoro acetic acid (3.5 mL, 46.25 mmol) followed by stirring at RT for 2 h. TLC was monitored and the reaction mixture was concentrated under reduced pressure to afford title compound as pale green oil (2.0 g).1H NMR (400 MHz, DMSO–d ₆ ): δ 3.90-3.87 (m, 2H), 3.41-3.26 (m, 2H), 3.19-3.12 (m, 1H), 1.88-1.85 (m, 2H), 1.52-1.40 (m, 2H). Intermediate-21: 7'-Bromo-5'-(3-(dimethylamino)acryloyl)-1'-(4-methoxybenzyl) - s iro c clobutane-13'-indolin -2'-one

Step-a: 5'-Acetylspiro [cyclobutane-1,3'-indolin]-2'-one

To a cold suspension of AlCl ₃ (4.6 g, 34.64 mmol) in DCE (50 mL) was added acetyl chloride (1.5 mL, 20.78 mmol) followed by stirring for 15 min. Then spiro[cyclobutane- 1,3'-indolin]-2'-one (3.0 g, 17.32 mmol) was added and the mixture was stirred at RT for 16 h. The reaction mixture was quenched with ice and extracted with EtOAc. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by combi flash to afford the title compound as brown solid (2.5 g, 67 %).1H NMR (400 MHz, DMSO-d6): δ 10.62 (s, 1H), 8.12 (s, 1H), 7.86 (dd, J=1.9 Hz, 7.8 Hz, 1H), 6.89 (d, J=7.9 Hz, 1H), 2.56 (s, 3H), 2.46-2.34 (m, 4H), 2.28-2.19 (m, 2H); LC-MS: m/z 216.2 (M+H).

Step-b: 5'-Acetyl-7'-bromospiro[cyclobutane-1,3'-indolin]-2'-one

To an ice cold solution of 5'-acetylspiro[cyclobutane-1,3'-indolin]-2'-one (4.0 g, 18.58 mmol) in H ₂ SO ₄ (40 mL) was added NBS (5.0 g, 27.87 mmol) followed by stirring at RT for 3 h. The reaction mixture was quenched with ice water and extracted with EtOAc. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by combi-flash to afford the title compound as pale brown solid (2.5 g, 46 %).1H NMR (400 MHz, DMSO-d6): δ 10.94 (s, 1H), 8.12 (d, J=1.5 Hz, 1H), 7.97 (d, J=1.5 Hz, 1H), 2.58 (s, 3H), 2.44-2.38 (m, 4H), 2.28- 2.18 (m, 2H); LC-MS: m/z 294.0 (M+H).

Step-c: 5'-Acetyl-7'-bromo-1'-(4-methoxybenzyl)spiro[cyclobutane-1,3 '-indolin]- 2'-one

To an ice cold solution of 5'-acetyl-7'-bromospiro[cyclobutane-1,3'-indolin]-2'- one (6.5 g, 22.1 mmol) in DMF (100 mL) were added cesium carbonate (21.6 g, 66.3 mmol) and 1-(chloromethyl)-4-methoxybenzene (3.6 mL, 26.52 mmol) followed by stirring at RT for 6 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulphate and concentrated under reduced pressure and column purified to afford the title compound as brown solid (6.5 g, 71 %). 1H NMR (400 MHz, DMSO–d ₆ ): δ 8.21 (d, J = 2 Hz, 1H),7.94 (d, J = 1.5 Hz, 1H), 7.04 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 5.24 (s, 2H), 3.70 (s, 3H), 2.61 (s, 3H), 2.60–2.18 (m, 6H); LCMS: m/z 414.1(M+H).

Step-d: 7'-Bromo-5'-(3-(dimethylamino)acryloyl)-1'-(4-methoxybenzyl) spiro- [cyclobutane-1,3'-indolin]-2'-one

A solution of 5'-acetyl-7'-bromo-1'-(4-methoxybenzyl)spiro[cyclobutane-1,3 '- indolin]-2'-one (2.6 g, 6.29 mmol) in DMF.DMA (10 mL) was heated in 100 ºC for 16 h. The mixture was concentrated under reduced pressure and column purified to afford the title compound as yellow solid (2.6 g, 89 %).1H NMR (400 MHz, DMSO–d ₆ ): δ 8.17 (d, J = 1.5 Hz, 1H),7.91 (d, J = 1.5 Hz, 1H), 7.73 (d, J = 12.2 Hz, 1H), 7.05 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.3 Hz, 2H), 5.91 (d, J = 12.2 Hz, 1H),5.22 (s, 2H), 3.70 (s, 3H), 3.16 (s, 3H), 2.96 (s, 3H), 2.59–2.18 (m, 6H); LCMS: m/z 469.1 (M+H). Intermediate-22: tert-butyl 6-((Methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2- carboxylate

To a solution of tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (0.1 g, 0.47 mmol) in DCM (2 mL) at 0 ºC was added triethyl amine (0.2 mL, 1.41 mmol) and methanesulfonyl chloride (0.07 mL, 0.94 mmol) followed by stirring at RT for 3 h. TLC was monitored and the reaction mixture was quenched with aqueous NaHCO ₃ and extracted with DCM. The organic was layer dried over sodium sulphate and

concentrated to afford the title compound as off-white solid (0.1 g).1H NMR (400 MHz, DMSO–d ₆ ): δ 4.89-4.86 (m, 1H), 3.85-3.81 (m, 4H), 3.13 (s, 3H), 2.65–2.60 (m, 2H), 2.39-2.34 (m, 2H), 1.36 (s, 9H). Intermediate-23: 2-methyl-2,6-diazaspiro[3.3]heptane trifluoroacetate

To an ice cold solution of tert-butyl 6-methyl-2,6-diazaspiro[3.3]heptane-2- carboxylate (0.18 g, 0.85 mmol) in DCM (5.0 mL) was added TFA (1.0 mL) dropwise followed by stirring at RT for 5 h. The mixture was concentrated under reduced pressure to afford the title compound as pale yellow oil (0.2 g). LCMS: m/z 113.2 (M+H free base). Intermediate-24: 2-((tert-butyldimethylsilyl)oxy)-N-methylethan-1-amine

To a solution of 2-(methylamino)ethan-1-ol (6.0 g, 80.0 mmol) in DCM (100 mL) was added imidazole (8.2 g, 120.0 mmol) and TBSCl (14.5 g, 96.0 mmol) followed by stirring at RT for 16 h. The mixture was concentrated under reduced pressure and purified by CombiFlash® to afford the title compound as colourless liquid (8.0 g, 52 %). 1H NMR (400 MHz, DMSO–d ₆ ): δ 3.61 (t, J=5.9 Hz, 2H), 2.54 (t, J=5.9 Hz, 2H), 2.28 (s, 3H), 0.86 (s, 9H), 0.03 (s, 6H). Intermediate-25: 5-ethox -3-iodo-1- hen l-1H- razole

To a solution of 3-ethoxy-5-iodo-1H-pyrazole (0.37 g, 1.55 mmol) and phenyl- boronic acid (0.21 g, 1.71 mmol) in DCM (20 mL) were added pyridine (0.25 mL, 3.11 mmol) and 4Ao molecular sieves (0.5 g) and copper acetate mono hydrate (0.46 g, 2.33 mmol) followed by stirring in open air at RT for 16 h. The mixture was filtered, concentrated under reduced pressure and purified by CombiFlash® to afford the title compound as colourless oil (0.3 g, 61 %).1HNMR (400 MHz, DMSO–d6): δ 7.62–7.59 (m, 2H), 7.49–7.45 (m, 2H), 7.35-7.32 (m 1H), 6.18 (s, 1H), 4.20 (q, J =6.9 Hz, 2H), 1.34 (t, J=7.3 Hz, 3H); LCMS: m/z 314.5(M+1H). Example-I: 7'-Amino-5'-(1-(2,4-difluorophenyl)-1H-pyrazol-5-yl)spiro[cy clobutane- 1,3'-indolin]-2'-one (Compound-1)

Step-i: 5'-Acetyl-7'-nitrospiro[cyclobutane-1,3'-indolin]-2'-one

To an ice cold solution of 5'-acetylspiro[cyclobutane-1,3'-indolin]-2'-one (1.5 g, 6.96 mmol) in H ₂ SO ₄ (15 mL) was added KNO ₃ (0.77 g, 7.66 mmol) portion wise followed by stirring at RT for 3 h. TLC was monitored, and the reaction mixture was poured into ice water. Solids were filtered off, washed with water and dried under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as off white solid (0.6 g, 33 %).1H NMR (400 MHz, DMSO-d6): δ 11.41 (s, 1H), 8.49 (d, J=1.4 Hz, 1H), 8.47 (s, 1H), 2.67 (s, 3H), 2.51-2.42 (m, 4H), 2.32-2.19 (m, 2H); LC-MS: m/z 261.1 (M+H).

Step-ii (A) : (E)-5'-(3-(Dimethylamino)acryloyl)-7'-nitrospiro[cyclobutane -1,3'- indolin]-2'-one

To a solution of 5'-acetyl-7'-nitrospiro[cyclobutane-1,3'-indolin]-2'-one (0.6 g, 2.30 mmol) in THF (20 mL) was added DMF-DMA (0.92 mL, 6.92 mmol) followed by stirring at 80 ºC for 16 h. TLC was monitored, and the reaction mixture was

concentrated under reduced pressure and purified by CombiFlash® to afford the title compound as yellow solid (0.25 g, 34 %).1H NMR (400 MHz, DMSO-d ₆ ): δ 11.15 (s, 1H), 8.44 (d, J=1.5 Hz, 1H), 8.42 (s, 1H), 7.79-7.75 (m, 1H), 5.98-5.93 (m, 1H), 3.16 (s, 3H), 2.97 (s, 3H), 2.50-2.39 (m, 4H), 2.29-2.16 (m, 2H); LC-MS: m/z 316.2 (M+H). Step-iii: 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-5-yl)-7'-nitrospiro[cy clobutane- 1,3'-indolin]-2'-one

To a solution of (E)-5'-(3-(dimethylamino)acryloyl)-7'-nitrospiro[cyclobutane - 1,3'-indolin]-2'-one (0.25 g, 0.79 mmol) and (2,4-difluorophenyl)hydrazine hydrochloride (0.17 g, 0.95 mmol) in EtOH (10 mL) was added AcOH (1 mL) followed by stirring at 100 ºC for 16 h. TLC was monitored, and the reaction mixture was concentrated under reduced pressure and purified by CombiFlash® to afford the title compound as yellow solid (0.15 g, 47%).1H NMR (400 MHz, DMSO-d ₆ ): δ 11.14 (s, 1H), 7.87 (d, J=1.4 Hz, 1H), 7.81 (d, J=1.5 Hz, 1H), 7.78-7.74 (m, 1H), 7.75 (d, J=1.5 Hz, 1H), 7.51-7.45 (m, 1H), 7.34-7.29 (m, 1H), 6.95 (d, J=2.0 Hz, 1H), 2.46-2.39 (m, 2H), 2.33-2.17 (m, 3H), 2.08-1.98 (m, 1H); LC-MS: m/z 397.2 (M+H).

Step-iv: 7'-Amino-5'-(1-(2,4-difluorophenyl)-1H-pyrazol-5-yl)spiro[cy clobutane- 1,3'-indolin]-2'-one

To a solution of 5'-(1-(2,4-difluorophenyl)-1H-pyrazol-5-yl)-7'-nitrospiro[cy clo- butane-1,3'-indolin]-2'-one (0.2 g, 0.51 mmol) in EtOH (15 mL) and H ₂ O (5 mL) were added iron powder (0.14 g, 2.52 mmol) and NH4Cl (0.14 g, 2.52 mmol) followed by heating to 100 oC for 3 h. TLC was monitored, and the reaction mixture was cooled to RT, filtered through Celite® and washed with EtOAc. The combined filtrate was concentrated. The residue was diluted with water and extracted with EtOAc (100 mL), washed with brine (100 mL), dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as yellow solid (0.12 g,65 %).1H NMR (400 MHz, DMSO-d ₆ ): δ 9.83 (s, 1H), 7.74 (d, J=1.9 Hz, 1H), 7.65-7.59 (m, 1H), 7.46-7.41 (m, 1H), 7.27-7.22 (m, 1H), 6.56 (d, J=1.9 Hz, 1H), 6.50 (d, J=1.5 Hz, 1H), 6.48 (d, J=1.5 Hz, 1H), 4.92 (s, 2H), 2.38-2.32 (m, 2H), 2.11-2.06 (m, 1H), 1.99-1.90 (m, 3H); LC-MS: m/z 367.1 (M+H). The below compound was prepared by procedure similar to the one described in Example-I with appropriate variations in reactants, quantities of reagents and reaction conditions. The physiochemical characteristics of the compounds are also summarized in the table below.

Example-II: 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-5-yl)-7'-((1-methylpip eridin-4-yl)- amino)spiro[cyclobutane-1,3'-indolin]-2'-one (Compound-3)

Compound-3 To a suspension of 7'-amino-5'-(1-(2,4-difluorophenyl)-1H-pyrazol-5-yl)spiro- [cyclobutane-1,3'-indolin]-2'-one (0.1 g, 0.27 mmol) in titanium isopropoxide (2.0 mL) was added 1-methylpiperidine-4-one (0.05 mL, 0.41 mmol) followed by stirring at RT for 16h . The reaction mixture was cooled to 0 oC. MeOH (5 mL) was added followed by sodium borohydride (0.02 g, 0.55 mmol). The mixture was stirred at RT for 1 h. TLC was monitored, and the reaction mixture was diluted with EtOAc and washed with aqueous ammonia and water. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by CombiFlash® followed by preparative HPLC to afford the title compound as pale yellow solid (0.018 g, 14 %).1H NMR (400 MHz, DMSO-d6): δ 9.90 (s, 1H), 7.75 (d, J=2.0 Hz, 1H), 7.69- 7.63 (m, 1H), 7.49-7.43 (m, 1H), 7.28-7.24 (m, 1H), 6.84 (s, 1H), 6.67 (d, J=1.9 Hz, 1H), 6.13 (s, 1H), 4.74 (d, J=5.4 Hz, 1H), 2.89-2.82 (m, 1H), 2.73-2.66 (m, 2H), 2.40- 2.33 (m, 2H), 2.21-2.14 (m, 3H), 2.16 (s, 3H), 2.09-2.06 (m, 1H), 2.05-1.90 (m, 2H), 1.61-1.58 (m, 2H), 1.23-1.18 (m, 2H); LC-MS: m/z 464.3 (M+H). The below compound was prepared by procedure similar to the one described in Example-II with appropriate variations in reactants, quantities of reagents and reaction conditions. The physiochemical characteristics of the compounds are summarized also in the table below.

Example-III: 7'-Benzyl-5'-(1-(2,4-difluorophenyl)-1H-pyrazol-5-yl)spiro[c yclo- butane-13'-indolin -2'-one Com ound-5

Step-i: 7'-Bromo-5'-(1-(2,4-difluorophenyl)-1H-pyrazol-5-yl)spiro[cy clobutane- 1,3'-indolin]-2'-one

To an ice cold solution of 7'-amino-5'-(1-(2,4-difluorophenyl)-1H-pyrazol-5- yl)spiro[cyclobutane-1,3'-indolin]-2'-one (0.1 g, 0.27 mmol) in acetonitrile (10 mL) were added CuBr ₂ (0.12 g, 0.54 mmol) followed by tert-butyl nitrite (0.065 mL, 0.54 mmol) dropwise. The mixture was then heated to 60 ºC for 1 h. TLC was monitored, and the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulphate and concentrated. The residue was purified by

CombiFlash® to afford the title compound as pale brown solid (0.08 g, 68 %).1H NMR (400 MHz, DMSO-d ₆ ): δ 10.97 (s, 1H), 8.04 (d, J=1.5 Hz, 2H), 7.64 (s, 1H), 7.62-7.56 (m, 1H), 7.51 (s, 1H), 7.48-7.40 (m, 1H), 7.22-7.17 (m, 1H), 2.41-2.37 (m, 2H), 2.32- 2.27 (m, 4H).

Step-ii: 7'-Benzyl-5'-(1-(2,4-difluorophenyl)-1H-pyrazol-5-yl)spiro[c yclobutane- 1,3'-indolin]-2'-one

To a solution of 7'-bromo-5'-(1-(2,4-difluorophenyl)-1H-pyrazol-5-yl)spiro- [cyclobutane-1,3'-indolin]-2'-one (0.08 g, 0.18 mmol) in 1,4-dioxane (7 mL) and H ₂ O (3 mL) were added 2-benzyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.06 g, 0.27 mmol) and potassium phosphate (0.12 g, 0.55 mmol) followed by degassing with nitrogen purging for 20 min. Then Pd (Amphos)Cl ₂ (0.013 g, 0.018 mmol) was added followed by heating the mixture to 110 °C for 16 h. TLC was monitored, and the reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc and washed with water and brine. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by CombiFlash® followed by preparative HPLC to afford the title compound as white solid (0.015 g, 18 %).1H NMR (400 MHz, DMSO-d ₆ ): δ 10.55 (s, 1H), 7.76 (d, J=2.0 Hz, 1H), 7.59-7.53 (m, 1H), 7.38-7.32 (m, 2H), 7.24-7.15 (m, 4H), 7.03-7.00 (m, 2H), 6.70 (d, J=1.9 Hz, 1H), 6.66 (d, J=2.0 Hz, 1H), 3.77 (s, 2H), 2.44-2.32 (m, 2H), 2.20-2.15 (m, 3H), 2.09- 2.03 (m, 1H); LC-MS: m/z 442.2 (M+H). Example-IV: 7'-Amino-5'-(2-(2,4-difluorophenyl)-1H-pyrrol-1-yl)spiro[cyc lobutane- 1,3'-indolin]-2'-one (Compound-6)

Step-i: 5'-(2-(2,4-Difluorophenyl)-1H-pyrrol-1-yl)-7'-nitrospiro[cyc lobutane-1,3'- indolin]-2'-one

To a stirred solution of 4-(2,4-difluorophenyl)-4-oxobutanal (0.5 g, 2.52 mmol) and 5'-amino-7'-nitrospiro[cyclobutane-1,3'-indolin]-2'-one (0.7 g, 3.02 mmol) in EtOH was added AcOH followed by heating the mixture to 90 ºC for 5 h. TLC was monitored, and the reaction mixture was diluted with cold water and extracted with EtOAc. The organic layer was dried over sodium sulphate and concentrated under pressure. The residue was purified by CombiFlash® to afford the title compound as yellow solid (0.09 g, 9 %).1HNMR (400 MHz, DMSO–d ₆ ): δ 11.11 (s, 1H), 7.74 (s, 1H), 7.68 (s, 1H), 7.42– 7.36 (m, 2H), 7.21 (t, J = 9.8 Hz, 1H), 7.11 (t, J = 8.3 Hz, 1H), 6.47– 6.46 (m, 1H), 6.40 (t, J = 2.9 Hz, 1H), 2.46– 2.33 (m, 2H), 2.23– 2.12 (m, 3H), 2.04– 1.99 (m, 1H); LCMS: m/z 396.1 (M+H). Step-ii: 7'-Amino-5'-(2-(2,4-difluorophenyl)-1H-pyrrol-1-yl)spiro[cyc lobutane- 1,3'-indolin]-2'-one

The compound was prepared using the process described in step-iv of Example-I. 1H NMR (400 MHz, DMSO–d ₆ ): δ 9.78 (s, 1H), 7.27– 7.16 (m, 2H), 7.07– 7.02 (m, 2H), 6.45 (d, J = 1.9 Hz, 1H), 6.36– 6.34 (m, 2H), 6.29– 6.28 (m, 1H), 4.99 (s, 2H), 2.38– 2.33 (m, 2H), 2.11– 1.92 (m, 4H); LCMS: m/z 366.1 (M+H). Example-V: N-(5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-5-yl)-2'-oxospiro[c yclobutane- 1,3'-indolin]-7'-yl)-1-methylpiperidine-4-carboxamide (Compound-7)

To a solution of 7'-amino-5'-(1-(2,4-difluorophenyl)-1H-pyrazol-5-yl)spiro- [cyclobutane-1,3'-indolin]-2'-one (0.05 g, 0.13 mmol) in DCM (3 mL) were added HATU (0.15 g, 0.41 mmol) and pyridine (0.03 mL, 0.41 mmol). After 5 min 1-methyl- piperidine-4-carboxylic acid (0.03 g, 0.2 mmol) was added followed by stirring at RT for 16 h. TLC was monitored, and the reaction mixture was diluted with DCM, washed with aqueous NaHCO ₃ and brine. The organic layer was dried over sodium sulphate and concentrated under reduced pressure and purified by CombiFlash® to afford the title compound as pale brown solid (0.02 g, 30 %).1H NMR (400 MHz, DMSO-d ₆ ): δ 10.03 (s, 1H), 9.18 (s, 1H), 7.79 (d, J=1.4 Hz, 1H), 7.71-7.65 (m, 1H), 7.50 (d, J=1.5 Hz, 1H), 7.47-7.41 (m, 1H), 7.29-7.25 (m, 1H), 7.05 (d, J=1.0 Hz, 1H), 6.67 (d, J=0.9 Hz, 1H), 2.82-2.79 (m, 2H), 2.41-2.37 (m, 2H), 2.21-2.16 (m, 5H), 2.13-1.95 (m, 3H), 1.89- 1.83 (m, 2H), 1.76-1.74 (m, 2H), 1.65-1.59 (m, 2H); LC-MS: m/z 491.9 (M+H). Example-VI: 5'-(2-(2,4-Difluorophenyl)-1H-pyrrol-1-yl)-7'-((1-methylpipe ridin-4- yl)amino)spiro[cyclobutane-1,3'-indolin]-2'-one (Compound-8)

This compound was prepared using the process described in Example-II.1HNMR (400 MHz, DMSO–d ₆ ): δ 9.84 (s, 1H), 7.32– 7.26 (m, 1H), 7.22– 7.16 (m, 2H), 7.08– 7.05 (m, 1H), 6.71 (s, 1H), 6.35– 6.34 (m, 1H), 6.30– 6.29 (m, 1H), 6.03 (s, 1H), 4.79 (d,J = 7.8 Hz, 1H), 2.87– 2.85 (m, 1H), 2.67– 2.61 (m, 2H), 2.43–2.34 (m, 2H), 2.16– 2.05 (m, 7H), 1.87-1.82 (m, 2H), 1.57– 1.54 (m, 2H), 1.23–1.15 (m,2H); LCMS: m/z463.2 (M+H). Example-VII: 7'-Amino-5'-(1-(2,4-difluorophenyl)-1H-pyrazol-5-yl)-1'-meth yl- s iro c clobutane-13'-indolin -2'-one Com ound-9

Step-i: 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-5-yl)-1'-methyl-7'-nit rospiro[cyclo- butane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-iii of Example-I. 1H NMR (400 MHz, DMSO-d6): δ 7.86 (d, J=2.0 Hz, 1H), 7.81-7.75 (m, 1H), 7.71 (d, J=1.5 Hz, 1H), 7.63 (d, J=1.5 Hz, 1H), 7.52-7.46 (m, 1H), 7.35-7.31 (m, 1H), 6.93 (d, J=2.0 Hz, 1H), 3.07 (s, 3H), 2.46-2.40 (m, 2H), 2.23-2.15 (m, 3H), 2.08-2.00 (m, 1H); LC-MS: m/z 411.2 (M+H).

Step-ii: 7'-Amino-5'-(1-(2,4-difluorophenyl)-1H-pyrazol-5-yl)-1'-meth ylspiro- [cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-iv of Example-I. 1H NMR (400 MHz, DMSO-d ₆ ): δ 7.76 (d, J=1.5 Hz, 1H), 7.67-7.61 (m, 1H), 7.47- 7.41 (m, 1H), 7.28-7.23 (m, 1H), 6.66 (d, J=1.5 Hz, 1H), 6.59 (d, J=1.9 Hz, 2H), 4.86 (s, 2H), 3.36 (s, 3H), 2.37-2.29 (m, 2H), 2.14-2.05 (m, 1H), 1.97-1.87 (m, 3H); LC-MS: m/z 381.2 (M+H). Example-VIII: 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-5-yl)-1'-methyl-7'-((1 -methyl- i eridin-4- l amino s iro c clobutane-13'-indolin -2'-one Com ound-10

To a solution of 7'-amino-5'-(1-(2,4-difluorophenyl)-1H-pyrazol-5-yl)-1'-meth yl- spiro[cyclobutane-1,3'-indolin]-2'-one (0.16 g, 0.42 mmol) in THF (2.0 mL) were added titanium isopropoxide (2.0 mL) and 1-methylpiperidine-4-one (0.07 g, 0.63 mmol) followed by stirring at RT for 16 h. The reaction mixture was cooled to 0 oC. MeOH (10 mL) was added followed by sodium borohydride (0.03 g, 0.84 mmol) and stirring at RT for 1 h. TLC was monitored, and the reaction mixture was diluted with EtOAc and washed with aqueous ammonia and water. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford title compound as off white solid (0.015 g, 8 %).1H NMR (400 MHz, DMSO-d ₆ ): δ 7.78 (d, J=2.0 Hz, 1H), 7.71-7.65 (m, 1H), 7.50-7.45 (m, 1H), 7.30-7.26 (m, 1H), 7.04 (s, 1H), 6.72 (d, J=1.4 Hz, 1H), 6.33 (s, 1H), 4.48 (d, J=6.4 Hz, 1H), 3.40 (s, 3H), 2.73-2.71 (m, 1H), 2.67-2.59 (m, 2H), 2.38-2.32 (m, 2H), 2.24- 1.98 (m, 7H), 1.91-1.85 (m, 2H), 1.56-1.47 (m, 2H), 1.35-1.23 (m, 2H); LC-MS: m/z 478.3 (M+H). Example-IX: 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-5-yl)-7'-hydroxyspiro[ cyclobutane- 1,3'-indolin]-2'-one (Compound-11) & 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-5-yl)-7'- ((1-methylpiperidin-4-yl)oxy)spiro[cyclobutane-1,3'-indolin] -2'-one (Compound-12) _p ^p

Step-i: 7'-Bromo-5'-(1-(2,4-difluorophenyl)-1H-pyrazol-5-yl)spiro[cy clobutane- 1,3'-indolin]-2'-one

To a cold solution of 7'-bromo-5'-(1-(2,4-difluorophenyl)-1H-pyrazol-5-yl)-1'-(4- methoxybenzyl)spiro[cyclobutane-1,3'-indolin]-2'-one (0.8 g, 1.46 mmol) in DCM (10 mL) was added TFA (3.0 mL) followed by trifluoromethanesulfonic acid (1.0 mL). The reaction mixture stirred at RT for 8 h. TLC was monitored, and the reaction mixture was slowly poured in aqueous NaHCO ₃ followed by extracting the mixture with DCM. The organic layer dried over Na ₂ SO ₄ , concentrated under reduced pressure and purified by CombiFlash® to afford the title compound as pale yellow solid (0.5 g, 80 %).1HNMR (400 MHz, DMSO–d ₆ ): δ 10.70 (s, 1H), 7.81 (d, J = 1.9 Hz, 1H), 7.76– 7.70 (m, 1H), 7.50– 7.45 (m, 1H), 7.33– 7.28 (m, 3H), 6.79 (d, J =2.0 Hz, 1H), 2.41– 2.36 (m, 2H), 2.14– 1.96 (m, 4H); LCMS: m/z 432.1 (M+2H).

Step-ii: 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-5-yl)-7'-(4,4,5,5-tetr amethyl- 1,3,2-dioxaborolan-2-yl)spiro[cyclobutane-1,3'-indolin]-2'-o ne

To a solution of 7'-bromo-5'-(1-(2,4-difluorophenyl)-1H-pyrazol-5-yl)spiro- [cyclobutane-1,3'-indolin]-2'-one (0.5 g, 1.16 mmol) and 4,4,4',4',5,5,5',5'-octamethyl- 2,2'-bi(1,3,2-dioxaborolane) (0.59 g, 2.33 mmol) in 1,4-dioxane (15 mL) was added potassium acetate (0.34 g, 3.49 mmol) followed by degassing the mixture with nitrogen purging for 15 min. Pd(dppf) ₂ Cl ₂ (0.1 g, 0.116 mmol) was then added and the mixture was again degassed with nitrogen purging for 15 min followed by heating to 100 ºC for 16 h. TLC was monitored, and the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as yellow solid (0.6 g).1HNMR (400 MHz, DMSO–d ₆ ): δ 9.13 (s, 1H), 7.79 (d, J = 2.0 Hz, 1H), 7.72– 7.66 (m, 1H), 7.47– 7.41 (m, 2H), 7.28– 7.26 (m, 2H), 6.76 (d, J =1.9 Hz, 1H), 2.40– 2.35 (m, 2H), 2.15– 1.91 (m, 4H), 1.27 (s, 12H); LCMS: m/z 478.2 (M+H).

Step-iii: 5'-(1-(2,4-difluorophenyl)-1H-pyrazol-5-yl)-7'-hydroxyspiro[ cyclo- butane-1,3'-indolin]-2'-one

To a cold solution of 5'-(1-(2,4-difluorophenyl)-1H-pyrazol-5-yl)-7'-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclobutane-1,3'-i ndolin]-2'-one (0.6 g, 1.25 mmol) in THF (5 mL) was added 30 % H ₂ O ₂ (2 mL) followed by stirring at RT for 3 h. TLC was monitored, and the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as white solid (0.18 g, 39 %).1HNMR (400 MHz, DMSO–d ₆ ): δ 10.10 (s, 1H), 9.62 (s, 1H), 7.77 (d, J = 2.0 Hz, 1H), 7.67– 7.61 (m, 1H), 7.48– 7.43 (m, 1H), 7.29– 7.24 (m, 1H), 6.81 (d, J = 1.5 Hz, 1H), 6.63 (d, J = 2.0 Hz, 1H), 6.59 (d, J = 1.4 Hz, 1H), 2.40– 2.31 (m, 2H), 2.15– 1.94 (m, 4H); LCMS: m/z 368.2 (M+H).

Step-iv: 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-5-yl)-7'-((1-methylpip eridin-4- yl)oxy)spiro[cyclobutane-1,3'-indolin]-2'-one

To a stirred solution of 5'-(1-(2,4-difluorophenyl)-1H-pyrazol-5-yl)-7'-hydroxy- spiro[cyclobutane-1,3'-indolin]-2'-one (0.13 g, 0.35 mmol) and 4-chloro-1-methyl piperidine (0.09 g, 0.71 mmol) in DMF was added potassium carbonate (0.14 g, 1.06 mmol) followed by heating to 120 ºC for 48 h. TLC was monitored, and the reaction mixture was cooled to RT, diluted with water and extracted with DCM. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as white solid (0.01 g, 6 %).1HNMR (400 MHz, DMSO–d ₆ ): δ 10.35 (s, 1H), 7.78 (d, J = 1.5 Hz, 1H), 7.71– 7.69 (m, 1H), 7.47 (t, J =8.4 Hz, 1H), 7.28 (t, J =7.6 Hz, 1H), 7.14 (s, 1H), 6.74 (d, J =1.5 Hz, 1H), 6.58 (s, 1H), 4.01– 3.98 (m, 1H), 2.58– 2.57 (m, 2H), 2.41– 2.33 (m, 2H), 2.21– 1.98 (m, 9H), 1.62– 1.60 (m, 2H), 1.46– 1.42 (m, 2H); LCMS: m/z 465.2 (M+H). Example-X: 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-5-yl)-7'-(4-methylpipe razin-1- yl)spiro[cyclobutane-1,3'-indolin]-2'-one (Compound-13)

Step-i: 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-5-yl)-1'-(4-methoxyben zyl)-7'-(4- methylpiperazin-1-yl)spiro[cyclobutane-1,3'-indolin]-2'-one

To a solution of 7'-bromo-5'-(1-(2,4-difluorophenyl)-1H-pyrazol-5-yl)-1'-(4- methoxybenzyl)spiro[cyclobutane-1,3'-indolin]-2'-one (0.2 g, 0.36 mmol) and 1-methyl- piperazine (0.07 g, 0.72 mmol) in toluene (1 mL) was added K ₃ PO ₄ (0.23 g, 1.09 mmol) followed by degassing the mixture with nitrogen purging for 15 min. Pd ₂ (dba) ₃ (0.03 g, 0.04 mmol) and xantphos (0.04g, 0.07 mmol) were added and the mixture was again degassed with nitrogen purging for 15 min followed by heating to 110 ºC for 16 h. TLC was monitored, and the reaction mixture was diluted with EtOAc and washed with water. The organic layer dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as pale brown oil (0.05g, 25 %).1HNMR (400 MHz, DMSO–d6): δ 7.80 (d, J = 2.0 Hz, 1H), 7.74– 7.69 (m, 1H), 7.50– 7.45 (m, 1H), 7.38 (d, J =1.5 Hz, 1H), 7.32– 7.23 (m, 1H), 7.01 (d, J =8.8 Hz, 2H), 6.85– 6.79 (m, 4H), 5.11 (s, 2H), 3.68 (s, 3H), 2.45– 2.38 (m, 7H), 2.28– 2.19 (m, 4H), 2.12 (s, 3H), 2.10– 1.86 (m, 3H); LCMS: m/z 570.3 (M+H).

Step-ii: 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-5-yl)-7'-(4-methylpipe razin-1-yl)- spiro[cyclobutane-1,3'-indolin]-2'-one

To a cold solution of 5'-(1-(2,4-difluorophenyl)-1H-pyrazol-5-yl)-1'-(4-methoxy- benzyl)-7'-(4-methylpiperazin-1-yl)spiro[cyclobutane-1,3'-in dolin]-2'-one (0.05 g, 0.09 mmol) in DCM (2 mL) was added TFA (1.0 mL) followed by trifluoromethanesulfonic acid (0.2 mL). The reaction mixture was stirred at RT for 4 h. TLC was monitored, and the reaction mixture was slowly poured in aqueous NaHCO ₃ and extracted with DCM. The organic layer was dried over Na2SO4, concentrated under reduced pressure and purified by CombiFlash® to afford the title compound as white solid (0.01 g, 25 %). 1HNMR (400 MHz, DMSO–d ₆ ): δ 10.22 (s, 1H), 7.78 (d, J = 1.4 Hz, 1H), 7.72– 7.66 (m, 1H), 7.50– 7.45 (m, 1H), 7.28 (t, J =8.5 Hz, 1H), 7.12 (d, J =1 Hz, 1H), 6.74 (d, J =1.5 Hz, 1H), 6.59 (d, J =1.0 Hz, 1H), 2.66– 2.64 (m, 4H), 2.41– 2.33 (m, 6H), 2.19– 2.00 (m, 7H); LCMS: m/z 450.3 (M+H). Example-XI: 7'-Amino-5'-(1-(2,4-difluorophenyl)-1H-1,2,4-triazol-5-yl)sp iro[cyclo- butane-1,3'-indolin]-2'-one (Compound-14) & 5’-(1-(2,4-Difluorophenyl)-1H-1,2,4- triazol-5-yl)-7'-((1-methylpiperidin-4-yl)amino)spiro[cyclob utane-1,3'-indolin]-2'-one Com ound-15

Step-i: 5'-(1-(2,4-Difluorophenyl)-1H-1,2,4-triazol-5-yl)-7'-nitrosp iro[cyclo- butane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-ii of Example- III.1H NMR (400 MHz, DMSO-d ₆ ): δ 11.29 (s, 1H), 8.40 (s, 1H), 7.99 (d, J=1.4 Hz, 1H), 7.97 (s, 1H), 7.94-7.88 (m, 1H), 7.66-7.61 (m, 1H), 7.43-7.39 (m, 1H), 2.46-2.32 (m, 2H), 2.26-2.17 (m, 3H), 2.08-1.98 (m, 1H); LC-MS: m/z 398.1 (M+H).

Step-ii: 7'-Amino-5'-(1-(2,4-difluorophenyl)-1H-1,2,4-triazol-5-yl)sp iro[cyclo- butane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-iv of Example-I. 1H NMR (400 MHz, DMSO-d6): δ 9.95 (s, 1H), 8.23 (s, 1H), 7.82-7.76 (m, 1H), 7.61- 7.55 (m, 1H), 7.37-7.32 (m, 1H), 6.81 (d, J=1.4 Hz, 1H), 6.69 (d, J=1.5 Hz, 1H), 5.06 (s, 2H), 2.41-2.32 (m, 2H), 2.13-2.06 (m, 1H), 2.00-1.87 (m, 3H); LC-MS: m/z 368.2 (M+H).

Step-iii: 5’-(1-(2,4-Difluorophenyl)-1H-1,2,4-triazol-5-yl)-7'-((1-m ethylpiperidin- 4-yl)amino)spiro[cyclobutane-1,3'-indolin]-2'-one The compound was prepared using the process described in Example-VIII.1H NMR (400 MHz, DMSO-d6): δ 10.05 (s, 1H), 8.25 (s, 1H), 7.86-7.80 (m, 1H), 7.64- 7.58 (m, 1H), 7.39-7.35 (m, 1H), 7.12 (s, 1H), 6.35 (s, 1H), 4.87 (d, J=7.3 Hz, 1H), 2.81-2.70 (m, 3H), 2.45-2.38 (m, 2H), 2.20-2.11 (m, 6H), 2.08-1.94 (m, 3H), 1.63-1.60 (m, 2H), 1.33-1.23 (m, 2H); LC-MS: m/z 465.3 (M+H). Example-XII: 5'-(1-(2,4-Difluorophenyl)-1H-imidazol-2-yl)-7'-((1-methylpi peridin-4- l amino s iro c clobutane-13'-indolin -2'-one Com ound-16

Step-i: 5'-(1-(2,4-Difluorophenyl)-1H-imidazol-2-yl)-7'-nitrospiro[c yclobutane- 1,3'-indolin]-2'-one

The compound was prepared using the process described in step-ii of Example- III.1H NMR (400 MHz, DMSO-d ₆ ): δ 11.19 (s, 1H), 7.85 (s, 1H), 7.80-7.68 (m, 1H), 7.64-7.53 (m, 3H), 7.37-7.31 (m, 1H), 7.28 (s, 1H), 2.47-2.41 (m, 2H), 2.27-2.12 (m, 3H), 2.08-1.91 (m, 1H); LC-MS: m/z 395.1 (M-H).

Step-ii: 7'-Amino-5'-(1-(2,4-difluorophenyl)-1H-imidazol-2-yl)spiro[c yclobutane- 1,3'-indolin]-2'-one

The compound was prepared using the process described in step-iv of Example-I. 1H NMR (400 MHz, DMSO-d ₆ ): δ 10.23 (s, 1H), 7.88-7.77 (m, 3H), 7.66-7.62 (m, 1H), 7.39-7.31 (m, 1H), 6.77 (s, 1H), 6.62 (s, 1H), 2.46-2.38 (m, 2H), 2.26-2.12 (m, 1H), 2.08-1.97 (m, 3H); LC-MS: m/z 367.2 (M+H).

Step-iii: 5'-(1-(2,4-Difluorophenyl)-1H-imidazol-2-yl)-7'-((1-methylpi peridin-4- yl)amino)spiro[cyclobutane-1,3'-indolin]-2'-one The compound was prepared using the process described in Example-VIII.1H NMR (400 MHz, DMSO-d6): δ 9.99 (bs, 1H), 7.70-7.64 (m, 1H), 7.58-7.53 (m, 1H), 7.42 (s, 1H), 7.32-7.28 (m, 1H), 7.16 (s, 1H), 6.83 (s, 1H), 6.40 (s, 1H), 4.96-4.91 (m, 1H), 3.17-3.01 (m, 3H), 2.59-2.54 (m, 2H), 2.41-2.33 (m, 3H), 2.20-1.91 (m, 4H), 1.78- 1.71 (m, 2H), 1.51-1.47 (m, 2H), 1.35-1.29 (m, 2H); LC-MS: m/z 464.3 (M+H). Example-XIII: 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-5-yl)-N-(1-methylpiper idin-4-yl)- 2'-oxospiro[cyclobutane-1,3'-indoline]-7'-carboxamide (Compound-17)

Step-i: 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-5-yl)-1'-(4-methoxyben zyl)-N-(1- methylpiperidin-4-yl)-2'-oxospiro[cyclobutane-1,3'-indoline] -7'-carboxamide

To a solution of 7'-bromo-5'-(1-(2,4-difluorophenyl)-1H-pyrazol-5-yl)-1'-(4- methoxybenzyl)spiro[cyclobutane-1,3'-indolin]-2'-one (0.15 g, 0.27 mmol) and 1-methyl- piperidin-4-amine (0.04 g, 0.32 mmol) in toluene (6.0 mL) was added K ₃ PO ₄ (0.17 g, 0.81 mmol). The reaction mixture was purged with carbon monoxide gas for 20 min. Then xantphos (0.02g, 0.027 mmol) and Pd(OAc)2 (0.015 g, 0.05 mmol) were added, and the reaction mixture was again purged with carbon monoxide gas for 20 min followed by heating to 100 oC for 16 h under carbon monoxide atmosphere. TLC was monitored, and the reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as off white solid (0.08 g, 48 %).1H NMR (400 MHz, DMSO-d ₆ ): δ 8.13 (d, J = 6.8 Hz, 1H), 7.82 (d, J = 1.0 Hz, 1H), 7.79– 7.66 (m, 1H), 7.51– 7.46 (m, 2H), 7.31-7.27 (m, 2H), 7.00 (s, 1H), 6.92 (d, J=8.3 Hz, 2H), 6.81-6.77 (m, 3H), 4.99 (s, 2H), 3.68 (s, 3H), 3.50 – 3.46 (m, 1H), 2.78– 2.70 (m, 2H), 2.50– 2.41 (m, 2H), 2.33-2.19 (m, 7H), 2.09-1.99 (m, 3H), 1.53-1.48 (m, 2H); LCMS: m/z 612.3 (M+H).

Step-ii: 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-5-yl)-N-(1-methylpiper idin-4-yl)- 2'-oxospiro[cyclobutane-1,3'-indoline]-7'-carboxamide The compound was prepared using the process described in step-ii of Example-X. 1H NMR (400 MHz, DMSO-d6): δ 9.90 (s, 1H), 8.41 (d, J = 7.4 Hz, 1H), 7.85 (d, J = 1.9 Hz, 1H), 7.75– 7.71 (m, 1H), 7.69 (s, 1H), 7.49– 7.43 (m, 1H), 7.34 (s, 1H), 7.34– 7.28 (m, 1H), 6.80 (d, J=1.5 Hz, 1H), 3.80– 3.78 (m, 1H), 3.01– 2.95 (m, 2H), 2.42– 2.00 (m, 11H), 1.84– 1.80 (m, 2H), 1.68– 1.58 (m, 2H); LCMS: m/z 492.3 (M+H). Example-XIV: 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-5-yl)-7'-(4-methyl- i erazine-1-carbon l s iro c clobutane-13'-indolin -2'-one Com ound-18

Step-i: 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-5-yl)-1'-(4-methoxyben zyl)-7'-(4- methylpiperazine-1-carbonyl)spiro[cyclobutane-1,3'-indolin]- 2'-one

The compound was prepared using the process described in step-i of Example- XIII. LCMS: m/z598.3 (M+H).

Step-ii: 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-5-yl)-7'-(4-methylpipe razine-1- carbonyl)spiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-ii of Example-X. 1H NMR (400 MHz, DMSO-d6): δ 10.48 (s, 1H), 7.82 (s, 1H), 7.73– 7.67 (m, 1H), 7.49 (s, 1H), 7.46– 7.43 (m, 1H), 7.28 (t, J = 8.3 Hz, 1H), 6.84 (s, 1H), 6.78 (s, 1H), 3.61– 3.40 (m, 2H), 3.20– 3.00 (m, 2H), 2.49– 2.40 (m, 3H), 2.36– 2.00 (m, 10H); LCMS: m/z 478.2 (M+H). Example-XV: 5'-(1-(4-Methoxyphenyl)-1H-pyrazol-5-yl)-7'-((1-methylpiperi din-4- yl)amino)spiro[cyclobutane-1,3'-indolin]-2'-one (Compound-19)

Step-i: 1'-(4-Methoxybenzyl)-5'-(1-(4-methoxyphenyl)-1H-pyrazol-5-yl )-7'-nitro- spiro[cyclobutane-1,3'-indolin]-2'-one

To a solution of (E)-5'-(3-(dimethylamino)acryloyl)-1'-(4-methoxybenzyl)-7'- nitrospiro[cyclobutane-1,3'-indolin]-2'-one (0.4 g, 0.92 mmol) and (4-methoxyphenyl)- hydrazine hydrochloride (0.24 g, 1.38 mmol) in EtOH (6 mL) was added AcOH (1 mL) followed by heating to 100 ºC for 16 h. TLC was monitored, and the reaction mixture was concentrated under reduced pressure and purified by CombiFlash® to afford the title compound as yellow solid (0.35 g, 76 %).1H NMR (400 MHz, DMSO-d ₆ ): δ 7.74 (d, J = 1.5 Hz, 1H), 7.61 (d, J = 1.5 Hz, 1H), 7.51 (d, J = 1.5 Hz, 1H), 7.25 (d, J = 8.3 Hz, 2H), 7.00 (d, J = 8.8 Hz, 2H), 6.83– 6.80 (m, 5H), 4.91 (s, 2H), 3.76 (s, 3H), 3.68 (s, 3H), 2.33– 2.14 (m, 4H), 2.08– 1.95 (m, 2H); LCMS: m/z511.2 (M+H).

Step-ii: 7'-Amino-1'-(4-methoxybenzyl)-5'-(1-(4-methoxyphenyl)-1H-pyr azol-5- yl)spiro[cyclobutane-1,3'-indolin]-2'-one

To a solution of 1'-(4-methoxybenzyl)-5'-(1-(4-methoxyphenyl)-1H-pyrazol-5- yl)-7'-nitrospiro[cyclobutane-1,3'-indolin]-2'-one (0.3 g, 0.59 mmol) in EtOH (6 mL) and H ₂ O (3 mL) were added iron powder (0.16 g, 2.94 mmol) and NH ₄ Cl (0.16 g, 2.94 mmol) followed by heating to 100 oC for 2 h. TLC was monitored, and the reaction mixture was cooled to RT, filtered through Celite® and washed with EtOAc. The combined filtrate was concentrated. The residue was diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as yellow solid (0.18 g, 64 %). LCMS: m/z481.3 (M+H). Step-iii: 1'-(4-Methoxybenzyl)-5'-(1-(4-methoxyphenyl)-1H-pyrazol-5-yl )-7'-((1- methylpiperidin-4-yl)amino)spiro[cyclobutane-1,3'-indolin]-2 '-one

To a solution of 7'-amino-1'-(4-methoxybenzyl)-5'-(1-(4-methoxyphenyl)-1H- pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one (0.2 g, 0.42 mmol) in THF (2.0 mL) were added titanium isopropoxide (2.0 mL) and 1-methylpiperidine-4-one (0.07 g, 0.63 mmol) followed by stirring at RT for 16 h. The reaction mixture was cooled to 0 oC, MeOH (5 mL) was added followed by sodium borohydride (0.03 g, 0.84 mmol). The mixture was stirred at RT for 1 h. TLC was monitored, and the reaction mixture was diluted with EtOAc and washed with aqueous ammonia and water. The organic layer dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as off white solid (0.1 g, 41 %). This material was as such taken to next step without further characterization.

Step-iv: 5'-(1-(4-Methoxyphenyl)-1H-pyrazol-5-yl)-7'-((1-methylpiperi din-4- yl)amino)spiro[cyclobutane-1,3'-indolin]-2'-one

To a cold solution of 1'-(4-methoxybenzyl)-5'-(1-(4-methoxyphenyl)-1H-pyrazol- 5-yl)-7'-((1-methylpiperidin-4-yl)amino)spiro[cyclobutane-1, 3'-indolin]-2'-one (0.1 g, 0.17 mmol) in DCM (2 mL) was added TFA (2.0 mL) followed by

trifluoromethanesulfonic acid (0.2 mL). The reaction mixture stirred at RT for 16 h. TLC was monitored, and the reaction mixture was slowly poured in aqueous NaHCO ₃ and extracted with DCM. The organic layer was dried over Na ₂ SO ₄ , concentrated under reduced pressure and purified by CombiFlash® to afford the title compound as pale yellow solid (0.01 g, 12 %).1H NMR (400 MHz, DMSO-d ₆ ): δ 9.88 (s, 1H), 7.65 (d, J = 2.0 Hz, 2H), 7.21 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 6.87 (s, 1H), 6.61 (s, 1H), 6.11 (s, 1H), 4.72 (d, J = 6.8 Hz, 1H), 3.77 (s, 3H), 2.96– 2.65 (m, 2H), 2.45-2.30 (m, 3H), 2.32– 2.04 (m, 10H), 1.59– 1.55 (m, 2H); LCMS: m/z 458.3 (M+H). The below compound was prepared by procedure similar to the one described in Example-XV with appropriate variations in reactants, quantities of reagents and reaction conditions. The physiochemical characteristics of the compounds are also summarized in the table below. Example-XVI: 7'-Amino-5'-(1-(2,4-difluorophenyl)-1H-pyrazol-3-yl)spiro[cy clo- butane-1,3'-indolin]-2'-one (Compound-21) & 5’-(1-(2,4-Difluorophenyl)-1H-pyrazol-3- yl)-7'-((1-methylpiperidin-4-yl)amino)spiro[cyclobutane-1,3' -indolin]-2'-one (Compound-

Step-i: 1'-(4-Methoxybenzyl)-7'-nitro-5'-(1H-pyrazol-5-yl)spiro[cycl obutane-1,3'- indolin]-2'-one

To a solution of (E)-5'-(3-(dimethylamino)acryloyl)-1'-(4-methoxybenzyl)-7'- nitrospiro[cyclobutane-1,3'-indolin]-2'-one (3.0 g, 6.90 mmol) and hydrazine hydro- chloride (1.90 g, 27.59 mmol) in EtOH (40 mL) was added AcOH (3 mL) followed by heating to 100 ºC for 2 h. TLC was monitored, and the reaction mixture was poured into ice water. Solids were filtered off and dried under reduced pressure to afford the title compound as yellow solid (2.7 g).1H NMR (400 MHz, DMSO-d ₆ ): δ 13.04 (s, 1H), 8.41 (d, J = 1.5 Hz, 1H), 7.96 (s, 1H), 7.83 (s, 1H), 6.89– 6.80 (m, 5H), 4.96 (s, 2H), 3.68 (s, 3H), 2.62– 2.58 (m, 4H), 2.45– 2.33 (m, 2H); LCMS: m/z 405.2 (M+H). Step-ii: 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-3-yl)-1'-(4-methoxyben zyl)-7'- nitrospiro[cyclobutane-1,3'-indolin]-2'-one

In a sealed tube, to a solution of 1'-(4-methoxybenzyl)-7'-nitro-5'-(1H-pyrazol-5- yl)spiro[cyclobutane-1,3'-indolin]-2'-one (0.4 g, 0.99 mmol) and 2,4-difluoro-1-iodo- benzene (0.72 g, 2.97 mmol) in DMSO (6 mL) were added CuI (0.02 g, 0.1 mmol), L- proline (0.02 g, 0.2 mmol) and K ₂ CO ₃ (0.28 g, 1.98 mmol) followed by heating to 100 ºC for 16 h. TLC was monitored, and the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as brown solid (0.35 g, 68 %). LCMS: m/z 517.2 (M+H).

Step-iii: 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-3-yl)-7'-nitrospiro[cy clobutane- 1,3'-indolin]-2'-one

To a cold solution of 5'-(1-(2,4-difluorophenyl)-1H-pyrazol-3-yl)-1'-(4-methoxy- benzyl)-7'-nitrospiro[cyclobutane-1,3'-indolin]-2'-one (0.35 g, 0.60 mmol) in DCM (3 mL) was added TFA (1.0 mL) followed by trifluoromethanesulfonic acid (0.3 mL). The reaction mixture was stirred at RT for 2 h. TLC was monitored, and the reaction mixture was slowly poured in aqueous NaHCO ₃ and extracted with DCM. The organic layer was dried over Na ₂ SO ₄ , concentrated under reduced pressure and purified by CombiFlash® to afford the title compound as yellow solid (0.25 g, 93 %).1H NMR (400 MHz, DMSO-d ₆ ): δ 11.17 (s, 1H), 8.48 (s, 1H), 8.45 (s, 1H), 8.31 (s, 1H), 8.01– 7.95 (m, 1H), 7.67-7.60 (m, 1H), 7.34– 7.27 (m, 2H), 2.55– 2.50 (m, 4H), 2.36– 2.18 (m, 2H); LCMS: m/z 397.1 (M+H).

Step-iv: 7'-Amino-5'-(1-(2,4-difluorophenyl)-1H-pyrazol-3-yl)spiro[cy clobutane- 1,3'-indolin]-2'-one

To a solution of 5'-(1-(2,4-difluorophenyl)-1H-pyrazol-3-yl)-7'-nitrospiro[cy clo- butane-1,3'-indolin]-2'-one (0.25 g, 0.63 mmol) in MeOH (10 mL) was added 10 % Pd- C (0.03 g) followed by stirring at RT under hydrogen bladder pressure for 4 h. TLC was monitored, and the reaction mixture was filtered through Celite® pad and concentrated under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as off white solid (0.2 g, 87 %).1H NMR (400 MHz, DMSO-d ₆ ): δ 9.86 (s, 1H), 8.18 (t, J = 3.5 Hz, 1H), 7.94– 7.88 (m, 1H), 7.60– 7.55 (m, 1H), 7.35 (d, J = 1.5 Hz, 1H), 7.31– 7.26 (m, 1H), 7.13 (d, J 1.0 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 4.94 (s, 2H), 2.47– 2.40 (m, 2H), 2.35– 2.18 (m, 4H); LCMS: m/z 367.1 (M+H). Step-v: 5’-(1-(2,4-Difluorophenyl)-1H-pyrazol-3-yl)-7'-((1-methylp iperidin-4-yl)- amino)spiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in Example-VIII.1H NMR (400 MHz, DMSO-d ₆ ): δ 9.98 (s, 1H), 8.18 (d, J = 2.9 Hz, 1H), 7.96– 7.90 (m, 1H), 7.61– 7.55 (m, 1H), 7.40 (s, 1H), 7.31– 7.27 (m, 1H), 7.03 (s, 1H), 7.00 (d, J = 2.5 Hz, 1H), 4.89 (d, J = 7.8 Hz, 1H), 3.64– 3.58 (m, 1H), 2.98– 2.96 (m, 2H), 2.82– 2.77 (m, 2H), 2.56 (s, 3H), 2.47– 2.40 (m, 2H), 2.36– 2.30 (m, 2H), 2.26– 2.18 (m, 2H), 1.92– 1.90 (m, 4H); LCMS: m/z 464.3 (M+H). Example-XVII: 5'-(1-Benzyl-1H-pyrazol-5-yl)-7'-((1-methylpiperidin-4-yl)am ino)- s iro c clobutane-13'-indolin -2'-one Com ound-23

Step-i: 5'-(1-Benzyl-1H-pyrazol-5-yl)-7'-bromo-1'-(4-methoxybenzyl)s piro[cyclo- butane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-i of Example- XV.1H NMR (400 MHz, DMSO-d ₆ ): δ 7.61 (d, J = 1.5 Hz, 1H), 7.57 (d, J = 1.5 Hz, 1H), 7.38– 7.24 (m, 4H), 7.06– 7.03 (m, 4H), 6.87 (d, J = 8.8 Hz, 2H), 6.54 (d, J = 1.9 Hz, 1H), 5.43 (s, 2H), 5.19 (s, 2H), 3.71 (s, 3H), 2.48– 2.44 (m, 2H), 2.37– 2.32 (m, 2H), 2.30– 2.16 (m, 1H), 2.04– 1.96 (m, 1H); LCMS: m/z 528.1 (M+H).

Step-ii: 5'-(1-Benzyl-1H-pyrazol-5-yl)-1'-(4-methoxybenzyl)-7'-((1-me thyl- piperidin-4-yl)amino)spiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-i of Example-X. 1H NMR (400 MHz, DMSO-d ₆ ): δ 7.58 (d, J = 2.0 Hz, 1H), 7.39– 7.26 (m, 5H), 7.08 (d, J = 8.3 Hz, 2H), 7.00 (s, 1H), 6.91 (d, J = 8.8 Hz, 2H), 6.46– 6.44 (m, 2H), 5.37 (s, 2H), 5.08 (s, 2H), 4.02 (d, J = 6.4 Hz, 1H), 3.70 (s, 3H), 2.78– 2.72 (m, 1H), 2.47– 2.43 (m, 3H), 2.38– 2.22 (m, 4H), 2.08– 2.00 (m, 4H), 1.91– 1.78 (m, 2H), 1.51– 1.46 (m, 2H), 1.06– 0.99 (m, 2H); LCMS: m/z 562.4 (M+H).

Step-iii: 5'-(1-Benzyl-1H-pyrazol-5-yl)-7'-((1-methylpiperidin-4-yl)am ino)spiro- [cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-ii of Example-X. 1H NMR (400 MHz, DMSO-d ₆ ): δ 9.95 (s, 1H), 7.57 (d, J = 1.9 Hz, 1H), 7.35– 7.27 (m, 3H), 7.04 (d, J=6.3 Hz, 2H), 6.79 (s, 1H), 6.40 (d, J = 1.5 Hz, 1H), 6.34 (s, 1H), 5.36 (s, 2H), 4.76 (d, J = 7.8 Hz, 1H), 2.93– 2.91 (m, 1H), 2.67– 2.61 (m, 2H), 2.42- 2.32 (m, 2H), 2.22– 2.14 (m, 6H), 2.10– 1.95 (m, 1H), 1.88– 1.82 (m, 2H), 1.73– 1.70 (m, 2H), 1.31-1.24 (m, 2H); LCMS: m/z 442.4 (M+H). The below compound was prepared by procedure similar to the one described in Example-XVII with appropriate variations in reactants, quantities of reagents and reaction conditions. The physiochemical characteristics of the compounds are also summarized in the table below.

Example-XVIII: 5'-(1-(2,4-Difluorobenzyl)-1H-pyrazol-3-yl)-7'-((1-methylpip eridin-4- yl)amino)spiro[cyclobutane-1,3'-indolin]-2'-one (Compound-25)

Step-i: 5'-(1-(2,4-Difluorobenzyl)-1H-pyrazol-3-yl)-1'-(4-methoxyben zyl)-7'- nitrospiro[cyclobutane-1,3'-indolin]-2'-one

To a stirred solution of 1'-(4-methoxybenzyl)-7'-nitro-5'-(1H-pyrazol-5-yl)spiro- [cyclobutane-1,3'-indolin]-2'-one (0.45 g, 0.85 mmol) in DMF (8 mL) was added Cs ₂ CO ₃ (0.55 g, 1.70 mmol) followed by 1-(bromomethyl)-2,4-difluorobenzene (0.16 mL, 1.27 mmol). The mixture was stirred at RT for 16 h. TLC was monitored, and the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as brown solid (0.45 g, 78%).1H NMR (400 MHz, DMSO-d ₆ ): δ 8.34 (d, J = 1.4 Hz, 1H), 7.91– 7.89 (m, 1H), 7.39– 7.04 (m, 4H), 6.93 (d, J = 2.0 Hz, 1H), 6.84– 6.78 (m, 4H), 5.43 (s, 2H), 4.91 (s, 2H), 3.67 (s, 3H), 2.64– 2.54 (m, 4H), 2.43– 2.28 (m, 2H); LCMS: m/z531.2 (M+H).

Step-ii: 5'-(1-(2,4-Difluorobenzyl)-1H-pyrazol-3-yl)-7'-nitrospiro[cy clobutane- 1,3'-indolin]-2'-one

The compound was prepared using the process described in step-ii of Example-X. 1H NMR (400 MHz, DMSO-d ₆ ): δ 11.05 (bs, 1H), 8.30 (s, 2H), 7.92 (d, J = 2.0 Hz, 1H), 7.35– 7.29 (m, 2H), 7.14– 7.09 (m, 1H), 6.96 (t, J = 2.4 Hz, 1H), 5.46 (s, 2H), 2.47-2.43 (m, 4H), 2.33– 2.21 (m, 2H); LCMS: m/z 411.2 (M+H).

Step-iii: 7'-Amino-5'-(1-(2,4-difluorobenzyl)-1H-pyrazol-3-yl)spiro[cy clobutane- 1,3'-indolin]-2'-one

To a stirred solution of 5'-(1-(2,4-difluorobenzyl)-1H-pyrazol-3-yl)-7'-nitro- spiro[cyclobutane-1,3'-indolin]-2'-one (0.22 g, 0.54 mmol) in AcOH (2 mL) was added iron powder (0.09 g, 1.62 mmol) followed by heating to 60 ºC for 2 h. The reaction mixture was filtered through Celite ® and washed with EtOAc. The combined filtrate was concentrated under reduced pressure and purified by CombiFlash® to afford the title compound as brown solid (0.18 g, 88 %).1H NMR (400 MHz, DMSO-d6): δ 9.82 (s, 1H), 7.84-7.80 (m, 1H), 7.29– 7.27 (m, 2H), 7.23 (s, 1H), 7.09 (t, J = 7.8 Hz, 1H), 7.02 (s, 1H), 6.61 (s, 1H), 5.41 (s, 2H), 5.20– 4.80 (m, 2H), 2.42– 2.40 (m, 2H), 2.29– 2.18 (m, 4H); LCMS: m/z 381.2 (M+H).

Step-iv: 5'-(1-(2,4-Difluorobenzyl)-1H-pyrazol-3-yl)-7'-((1-methylpip eridin-4- yl)amino)spiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in Example-VIII.1H NMR (400 MHz, DMSO-d ₆ ): δ 9.90 (s, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.32– 7.23 (m, 3H), 7.12– 7.07 (m, 1H), 6.91 (s, 1H), 6.69 (d, J = 1.9 Hz, 1H), 5.39 (s, 2H), 4.66 (d, J = 6.8 Hz, 1H), 2.79– 2.74 (m, 2H), 2.43– 2.37 (m, 2H), 2.32– 2.09 (m, 10H), 1.93– 1.90 (m, 2H), 1.43– 1.30 (m, 2H); LCMS: m/z 478.3 (M+H). Example-XIX: 5'-(1-(2,4-Difluorophenyl)-3-methyl-1H-pyrazol-5-yl)-7'-((1- methyl- piperidin-4-yl)amino)spiro[cyclobutane-1,3'-indolin]-2'-one (Compound-26)

Step-i: 5'-(1-(2,4-Difluorophenyl)-3-methyl-1H-pyrazol-5-yl)-7'-nitr ospiro[cyclo- butane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-ii of Example- III.1H NMR (400 MHz, DMSO-d ₆ ): δ 11.13 (s, 1H), 7.99 (d, J = 1.5 Hz, 2H), 7.76– 7.71 (m, 1H), 7.70 (d, J = 1.4 Hz, 1H), 7.49– 7.43 (m, 1H), 7.32– 7.27 (m, 1H), 6.75 (s, 1H), 2.50– 2.44 (m, 2H), 2.30 (s, 3H), 2.22– 2.17 (m, 3H), 2.08– 2.02 (m, 1H); LCMS: m/z 411.2 (M+H). Step-ii: 7'-Amino-5'-(1-(2,4-difluorophenyl)-3-methyl-1H-pyrazol-5- yl)spiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-iv of Example-I. 1H NMR (400 MHz, DMSO-d ₆ ): δ 9.82 (s, 1H), 7.61– 7.56 (m, 1H), 7.44– 7.37 (m, 1H), 7.24– 7.19 (m, 1H), 6.48 (d, J = 1.4 Hz, 1H), 6.44 (d, J = 1.4 Hz, 1H), 6.36 (s, 1H), 4.91 (s, 2H), 2.39– 2.33 (m, 2H), 2.25 (s, 3H), 2.12– 2.04 (m, 1H), 1.99– 1.91 (m, 3H); LCMS: m/z381.2 (M+H).

Step-iii: 5'-(1-(2,4-Difluorophenyl)-3-methyl-1H-pyrazol-5-yl)-7'-((1- methyl- piperidin-4-yl)amino)spiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in Example-VIII.1 _H NMR (400 MHz, DMSO-d ₆ ): δ 9.91 (s, 1H), 7.67– 7.61 (m, 1H), 7.48– 7.42 (m, 1H), 7.27– 7.22 (m, 1H), 6.82 (s, 1H), 6.43 (s, 1H), 6.10 (s, 1H), 4.73 (d, J = 7.3 Hz, 1H), 2.83– 2.79 (m, 1H), 2.65– 2.59 (m, 2H), 2.38– 2.33 (m, 2H), 2.25 (s, 3H), 2.18– 2.02 (m, 7H), 1.90– 1.80 (m, 2H), 1.59– 1.55 (m, 2H), 1.24– 1.17 (m, 2H); LCMS:

m/z478.3 (M+H). Example-XX: 7'-((1-Methylpiperidin-4-yl)oxy)-5'-(1-phenyl-1H-pyrazol-5-y l)spiro- c clobutane-13'-indolin -2'-one Com ound-27

Step-i: 7'-Bromo-1'-(4-methoxybenzyl)-5'-(1-phenyl-1H-pyrazol-5-yl)s piro- [cyclobutane-1,3'-indolin]-2'-one

To a solution of (E)-7'-bromo-5'-(3-(dimethylamino)acryloyl)-1'-(4-methoxy- benzyl)spiro[cyclobutane-1,3'-indolin]-2'-one (0.3 g, 0.64 mmol) in EtOH (10 mL) were added phenyl hydrazine hydrochloride (0.11 g, 0.77 mmol) and AcOH (0.2 mL) followed by heating the mixture to 100 ºC for 16 h. TLC was monitored, and the reaction mixture was concentrated under reduced pressure and purified by CombiFlash® to afford the title compound as off white solid (0.3 g, 90 %).1HNMR (400 MHz, DMSO–d6): δ 7.76 (d, J = 2.0 Hz, 1H), 7.49– 7.42 (m, 3H), 7.35– 7.33 (m, 3H), 7.29 (d, J =1.5 Hz, 1H), 7.04 (d, J =8.8 Hz, 2H), 6.87 (d, J =8.3 Hz, 2H), 6.78 (d, J =2.0 Hz, 1H), 5.16 (s, 2H), 3.70 (s, 3H), 2.44– 2.41 (m,2H), 2.21– 2.14 (m, 3H), 1.98– 1.96 (m, 1H) ; LCMS: m/z 516.1(M+2H).

Step-ii: 7'-Hydroxy-1'-(4-methoxybenzyl)-5'-(1-phenyl-1H-pyrazol-5- yl)spiro[cyclobutane-1,3'-indolin]-2'-one

To a solution of 7'-bromo-1'-(4-methoxybenzyl)-5'-(1-phenyl-1H-pyrazol-5-yl)- spiro[cyclobutane-1,3'-indolin]-2'-one (0.3 g, 0.58 mmol) in 1,4-dioxane (8 mL) and H ₂ O (2 mL) was added KOH (0.1 g, 1.74 mmol) followed by degassed the mixture with nitrogen purging for 20 min. Then t-BuXPhos (0.025 g, 0.058 mmol) and Pd ₂ (dba) ₃ (0.05 g, 0.058 mmol) were added followed by degassing the mixture again with nitrogen purging for 20 min. Then the reaction mixture was heated at 100 °C for 16 h. TLC was monitored, and the reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over sodium sulphate and concentrated under reduced pressure and purified by CombiFlash® to afford the title compound (0.22 g, 83 %). 1HNMR (400 MHz, DMSO–d ₆ ): δ 9.87 (s, 1H), 7.72 (s, 1H), 7.44– 7.37 (m, 3H), 7.31 – 7.29 (m, 2H), 7.19 (d, J =8.3 Hz, 2H), 6.84 (d, J =8.3 Hz, 2H), 6.79 (s, 1H), 6.68 (s, 1H), 6.57 (s, 1H), 4.97 (s, 2H), 3.70 (s, 3H), 2.38– 2.34 (m,2H), 2.00– 1.88 (m, 4H); LCMS: m/z 452.2 (M+H).

Step-iii: 1'-(4-Methoxybenzyl)-7'-((1-methylpiperidin-4-yl)oxy)-5'-(1- phenyl-1H- pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one

To an ice cold solution of 1-methylpiperidin-4-ol (0.22 g, 1.96 mmol) in THF (10 mL) was added triphenyl phosphine (0.51 g, 1.96 mmol) followed by DIAD (0.38 mL, 1.96 mmol). The mixture was stirred at 0 ºC for 15 min.7'-Hydroxy-1'-(4-methoxy- benzyl)-5'-(1-phenyl-1H-pyrazol-5-yl)spiro[cyclobutane-1,3'- indolin]-2'-one (0.22 g, 0.49 mmol) was then added followed by stirring the mixture at RT for 16 h. TLC was monitored, and the reaction mixture was diluted with EtOAc and washed with water. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as off white solid (0.21 g, 78 %).1HNMR (400 MHz, DMSO–d ₆ ): δ 7.74 (d, J = 1.5 Hz, 1H), 7.46– 7.40 (m, 3H), 7.39– 7.30 (m, 2H), 7.18 (s, 1H), 7.05 (d, J =8.8 Hz, 2H), 6.84 (d, J =8.8 Hz, 2H), 6.73 (d, J =1.4 Hz, 1H), 6.58 (s, 1H), 5.00 (s, 2H), 3.97– 3.96 (m, 1H), 3.69 (s, 3H), 2.46– 2.41 (m, 4H), 2.33– 2.19 (m, 3H), 2.15– 2.03 (m,4H), 1.89– 1.82 (m, 2H), 1.49– 1.42 (m, 2H), 1.39– 1.27(m, 2H); LCMS: m/z 549.3 (M+H).

Step-iv: 7'-((1-Methylpiperidin-4-yl)oxy)-5'-(1-phenyl-1H-pyrazol-5-y l)spiro- [cyclobutane-1,3'-indolin]-2'-one

To an ice cold solution of 1'-(4-methoxybenzyl)-7'-((1-methylpiperidin-4-yl)oxy)- 5'-(1-phenyl-1H-pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin] -2'-one (0.21 g, 0.38 mmol) in DCM (4 mL) was added TFA (4 mL) followed by trifluoromethanesulfonic acid (0.2 mL). The reaction mixture was stirred at RT for 6 h. TLC was monitored, and the reaction mixture was slowly poured in aqueous NaHCO ₃ and extracted with DCM. The organic layer was dried over Na ₂ SO ₄ , concentrated under reduced pressure and purified by preparative HPLC to afford the title compound as off white solid (0.03 g, 18 %). 1HNMR (400 MHz, DMSO–d6): δ 10.36 (s, 1H), 7.73 (d, J = 2.0 Hz, 1H), 7.46– 7.38 (m, 3H), 7.31– 7.29 (m, 2H), 7.12 (s, 1H), 6.70 (d, J =1.4 Hz, 1H), 6.56 (s, 1H), 3.98 – 3.97 (m, 1H), 2.68– 2.67 (m, 2H), 2.39– 2.32 (m, 2H), 2.20– 2.16 (m, 6H), 2.14– 1.87 (m, 3H), 1.60– 1.48 (m, 2H), 1.46– 1.40 (m, 2H); LCMS: m/z 429.3 (M+H). The below compounds were prepared by procedure similar to the one described in four steps of Example-XX with appropriate variations in reactants, quantities of reagents and reaction conditions. The physiochemical characteristics of the compounds are also summarized in the table below.

Example-XXI: 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-4-yl)-7'-((1-methylpip eridin-4- yl)amino)spiro[cyclobutane-1,3'-indolin]-2'-one (Compound-49)

Step-i: 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-4-yl)-7'-nitrospiro[cy clobutane- 1,3'-indolin]-2'-one

The compound was prepared using the process described in step-ii of Example- III.1H NMR (400 MHz, DMSO-d6): δ 11.06 (s, 1H), 8.89 (d, J = 1.9 Hz, 1H), 8.46 (s, 1H), 8.39 (d, J = 0.9 Hz, 1H), 8.27 (d, J = 1.5 Hz, 1H), 7.92– 7.86 (m, 1H), 7.67– 7.61 (m, 1H), 7.34– 7.30 (m, 1H), 2.50– 2.47 (m, 4H), 2.33– 2.28 (m, 2H); LCMS: m/z 397.1 (M+H).

Step-ii: 7'-Amino-5'-(1-(2,4-difluorophenyl)-1H-pyrazol-4-yl)spiro[cy clobutane- 1,3'-indolin]-2'-one

The compound was prepared using the process described in step-iv of Example-I. 1H NMR (400 MHz, DMSO-d ₆ ): δ 9.81 (s, 1H), 8.47 (d, J = 1.5 Hz, 1H), 8.11 (s, 1H), 7.90– 7.84 (m, 1H), 7.63– 7.57 (m, 1H), 7.31-7.26 (m, 1H), 7.20 (d, J = 1.0 Hz, 1H), 6.81 (d, J=1.5 Hz, 1H), 4.88 (bs, 2H), 2.46– 2.39 (m, 2H), 2.33– 2.21 (m, 4H); LCMS: m/z 367.2 (M+H).

Step-iii: 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-4-yl)-7'-((1-methylpip eridin-4- yl)amino)spiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in Example-VIII.

1HNMR (400 MHz, DMSO–d ₆ ): δ 9.88 (s, 1H), 8.55 (d, J=1.9 Hz, 1H), 8.22 (s, 1H), 7.88– 7.82 (m, 1H), 7.62-7.57 (m, 1H), 7.31-7.26 (m, 1H), 7.21 (s, 1H), 6.80 (s, 1H), 4.65 (d, J=8.3 Hz, 1H), 3.45-3.43 (m, 1H), 2.75– 2.67 (m, 2H), 2.45– 2.08 (m, 11H), 1.95-1.93 (m, 2H), 1.42-1.35 (m, 2H); LCMS: m/z 464.3 (M+H). Example-XXII: 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-5-yl)-7'-((1-methylpyr rolidin-3- yl)oxy)spiro[cyclobutane-1,3'-indolin]-2'-one (Compound-50)

Step-i: 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-5-yl)-7'-hydroxy-1'-(4 -methoxy- benzyl)spiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-ii of Example- XX.1H NMR (400 MHz, DMSO-d ₆ ): δ 9.91 (s, 1H), 7.78 (d, J = 2.0 Hz, 1H), 7.68– 7.63 (m, 1H), 7.50– 7.44 (m, 1H), 7.29– 7.25 (m, 1H), 7.18 (d, J = 8.4 Hz, 2H), 6.87– 6.85 (m, 3H), 6.65– 6.62 (m, 2H), 4.96 (s, 2H), 3.69 (m, 3H), 2.42– 2.37 (m, 2H), 2.20– 1.96 (m, 4H); LCMS: m/z 488.2 (M+H).

Step-ii: 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-5-yl)-1'-(4-methoxyben zyl)-7'-((1- methylpyrrolidin-3-yl)oxy)spiro[cyclobutane-1,3'-indolin]-2' -one

The compound was prepared using the process described in step-iii of Example- XX.1H NMR (400 MHz, DMSO-d ₆ ): δ 7.81 (d, J = 1.5 Hz, 1H), 7.72– 7.68 (m, 1H), 7.52– 7.46 (m, 1H), 7.30 (d, J = 8.8 Hz, 1H), 7.18 (s, 1H), 7.11 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.3 Hz, 2H), 6.77 (d, J = 1.5 Hz, 1H), 6.55 (s, 1H), 4.97 (s, 2H), 4.63– 4.60 (m, 1H), 3.69 (s, 3H), 2.45– 2.41 (m, 4H), 2.36– 2.06 (m, 9H), 2.09– 2.04 (m, 1H), 1.54– 1.50 (m, 1H); LCMS: m/z 571.3 (M+H).

Step-iii: 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-5-yl)-7'-((1-methylpyr rolidin-3- yl)oxy)spiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-ii of Example-X. 1H NMR (400 MHz, DMSO-d ₆ ): δ 10.34 (s, 1H), 7.80 (d, J = 2.0 Hz, 1H), 7.72– 7.67 (m, 1H), 7.50– 7.44 (m, 1H), 7.29 (t, J = 6.9 Hz, 1H), 7.11 (s, 1H), 6.74 (d, J = 1.5 Hz, 1H), 6.54 (s, 1H), 4.69– 4.67 (m, 1H), 2.80– 2.52 (m, 3H), 2.42– 2.35 (m, 5H), 2.17– 2.02 (m, 6H), 1.78– 1.75 (m, 1H); LCMS: m/z 451.2 (M+H). The below compound was prepared by procedure similar to the one described in three steps of Example-XXII with appropriate variations in reactants, quantities of reagents and reaction conditions. The physiochemical characteristics of the compounds are also summarized in the table below.

Example-XXIII: 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-5-yl)-2'-oxospiro- c clobutane-13'-indolin -7'- l 4-meth l i erazine-1-carbox late Com ound-52

Step-i: 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-5-yl)-1'-(4-methoxyben zyl)-2'- oxospiro[cyclobutane-1,3'-indolin]-7'-yl 4-methylpiperazine-1-carboxylate To an ice cold solution of 5'-(1-(2,4-difluorophenyl)-1H-pyrazol-5-yl)-7'- hydroxy-1'-(4-methoxybenzyl)spiro[cyclobutane-1,3'-indolin]- 2'-one (0.12 g, 0.25 mmol) in DMF (3.0 mL) were added potassium carbonate (0.1 g, 0.75 mmol) and DMAP (0.006 g, 0.05 mmol) followed by 4-methylpiperazine-1-carbonyl chloride hydrochloride (0.1 g, 0.5 mmol). The mixture was then stirred at RT for 2 h. TLC was monitored, and the reaction mixture was poured into ice water. Solids were filtered off, washed with water and dried under reduced pressure to afford the title compound as white solid (0.13 g).1H NMR (400 MHz, DMSO-d ₆ ): δ 7.81 (d, J = 2.0 Hz, 1H), 7.77– 7.71 (m, 1H), 7.50– 7.45 (m, 1H), 7.32– 7.28 (m, 2H), 6.97 (d, J = 8.8 Hz, 2H), 6.86– 6.83 (m, 3H), 6.78 (d, J = 1.5 Hz, 1H), 4.83 (s, 2H), 3.69 (s, 3H), 3.25– 3.18 (m, 4H), 2.50– 2.43 (m, 2H), 2.20– 2.15 (m, 10H), 2.06– 2.00 (m, 1H); LCMS: m/z614.3 (M+H).

Step-ii: 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-5-yl)-2'-oxospiro[cycl obutane- 1,3'-indolin]-7'-yl 4-methylpiperazine-1-carboxylate

The compound was prepared using the process described in step-ii of Example-X. 1H NMR (400 MHz, DMSO-d ₆ ): δ 10.74 (s, 1H), 7.79 (d, J = 0.9 Hz, 1H), 7.75– 7.68 (m, 1H), 7.48– 7.43 (m, 1H), 7.29 (t, J = 7.3 Hz, 1H), 7.11 (s, 1H), 6.94 (s, 1H), 6.74 (s, 1H), 3.53– 3.51 (m, 2H), 3.38– 3.36 (m, 2H), 2.40– 2.36 (m, 6H), 2.23 (s, 3H), 2.09– 1.96 (m, 4H); LCMS: m/z 494.2 (M+H). Example-XXIV: 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-5-yl)-7'-(pyridin-2-yl oxy)- s iro c clobutane-13'-indolin -2'-one Com ound-53

Step-i: 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-5-yl)-1'-(4-methoxyben zyl)-7'- (pyridin-2-yloxy)spiro[cyclobutane-1,3'-indolin]-2'-one

In a sealed tube, to a solution of 5'-(1-(2,4-difluorophenyl)-1H-pyrazol-5-yl)-7'- hydroxy-1'-(4-methoxybenzyl)spiro[cyclobutane-1,3'-indolin]- 2'-one (0.12 g, 0.25 mmol) in DMF (3.0 mL) was added potassium carbonate (0.1 g, 0.75 mmol) followed by 2- fluoropyridine (0.04mL, 0.5 mmol). The mixture was heated to 130 ºC for 16 h. TLC was monitored, and the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulphate and concentrated under pressure. The residue was purified by CombiFlash® to afford the title compound as off white solid (0.1 g, 72 %).1H NMR (400 MHz, DMSO-d ₆ ): δ 7.99 (d, J = 3.9 Hz, 1H), 7.78 (d, J = 2.0 Hz, 1H), 7.75– 7.73 (m, 1H), 7.65– 7.59 (m, 1H), 7.47 (d, J = 0.9 Hz, 1H), 7.40 (t, J = 7.8 Hz, 2H), 6.16 (t, J = 7.8 Hz, 1H), 7.08 - 7.05 (m, 1H), 6.94 (d, J = 8.8 Hz, 1H), 6.78– 6.69 (m, 4H), 6.60 (d, J = 1.0 Hz, 1H), 4.73 (s, 2H), 3.65 (s, 3H), 2.52– 2.50 (m, 2H), 2.40– 2.34 (m, 3H), 2.16– 2.07 (m, 1H); LCMS: m/z565.2 (M+H).

Step-ii: 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-5-yl)-7'-(pyridin-2-yl oxy)spiro- [cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-ii of Example-X. 1H NMR (400 MHz, DMSO-d ₆ ): δ 10.59 (s, 1H), 8.05 (d, J = 3.4 Hz, 1H), 7.83– 7.78 (m, 2H), 7.68– 7.62 (m, 1H), 7.46– 7.40 (m, 1H), 7.31 (s, 1H), 7.23– 7.19 (m, 1H), 7.11-7.09 (m, 1H), 6.95 (d, J = 8.5Hz, 1H), 6.76– 6.74 (m, 2H), 2.46– 2.39 (m, 2H), 2.23– 2.03 (m, 4H); LCMS: m/z 445.0 (M+H). Example-XXV: 7'-((1-Methylpiperidin-4-yl)oxy)-5'-(1-(pyridin-4-yl)-1H-pyr azol-3- yl)spiro[cyclobutane-1,3'-indolin]-2'-one (Compound-54)

Step-i: 7'-Bromo-1'-(4-methoxybenzyl)-5'-(1-(pyridin-4-yl)-1H-pyrazo l-3-yl)- spiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-i of Example- XV. LC-MS: m/z 515.2 (M+H).

Step-ii: 7'-Hydroxy-1'-(4-methoxybenzyl)-5'-(1-(pyridin-4-yl)-1H-pyra zol-3- yl)spiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-ii of Example- XX.1H NMR (400 MHz, DMSO-d ₆ ): δ 9.89 (s, 1H), 8.75 (d, J=2.9 Hz, 1H), 8.66 (d, J=5.8 Hz, 2H), 7.91-7.89 (m, 2H), 7.67 (d, J=1.5 Hz, 1H), 7.37 (d, J=1.5 Hz, 1H), 7.21 (d, J=8.8 Hz, 2H), 7.08 (d, J=2.4 Hz, 1H), 6.86 (d, J=8.8 Hz, 2H), 5.03 (s, 2H), 3.69 (s, 3H), 2.45-2.40 (m, 4H), 2.37-2.23 (m, 2H); LC-MS: m/z 453.2 (M+H).

Step-iii: 1'-(4-Methoxybenzyl)-7'-((1-methylpiperidin-4-yl)oxy)-5'-(1- (pyridin-4- yl)-1H-pyrazol-3-yl)spiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-iii of Example- XX. LC-MS: m/z 550.3 (M+H).

Step-iv: 7'-((1-Methylpiperidin-4-yl)oxy)-5'-(1-(pyridin-4-yl)-1H-pyr azol-3- yl)spiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-ii of Example-X. 1H NMR (400 MHz, DMSO-d ₆ ): δ 10.43 (s, 1H), 8.76 (d, J=3.0 Hz, 1H), 8.66 (d, J=6.3 Hz, 2H), 7.94 (d, J=6.4 Hz, 2H), 7.80 (s, 1H), 7.52 (m, 1H), 7.21 (d, J=2.5 Hz, 1H), 4.61-4.59 (m, 1H), 2.93-2.87 (m, 2H), 2.47-2.27 (m, 11H), 1.97-1.94 (m, 2H), 1.87- 1.84 (m, 2H); LC-MS: m/z 430.3 (M+H). Example-XXVI: 5'-(1-(2,4-Difluorophenyl)-1H-pyrrol-2-yl)-7'-((1-methylpipe ridin-4- yl)amino)spiro[cyclobutane-1,3'-indolin]-2'-one (Compound-55)

Step-i: 5'-(1-(2,4-Difluorophenyl)-1H-pyrrol-2-yl)-7'-nitrospiro[cyc lobutane-1,3'- indolin]-2'-one

The compound was prepared using the process described in step-ii of Example- III.1HNMR (400 MHz, DMSO–d ₆ ): δ 11.00 (s, 1H), 7.64– 7.58 (m, 3H), 7.48– 7.43 (m, 1H), 7.27-7.23 (m, 1H), 7.10 (s, 1H), 6.68-6.67 (m, 1H), 6.40-6.38 (m, 1H), 2.45– 2.40 (m, 2H), 2.18– 2.02 (m, 4H); LCMS: m/z396.1 (M+H).

Step-ii: 7'-Amino-5'-(1-(2,4-difluorophenyl)-1H-pyrrol-2-yl)spiro[cyc lobutane- 1,3'-indolin]-2'-one

The compound was prepared using the process described in step-iv of Example-I. 1HNMR (400 MHz, DMSO–d ₆ ): δ 9.73 (s, 1H), 7.48– 7.38 (m, 2H), 7.20– 7.16 (m, 1H), 6.94 (s, 1H), 6.44 (s, 1H), 6.31 (s, 1H), 6.29 (s, 1H), 6.28 (s, 1H), 5.75 (bs, 2H), 2.40– 2.30 (m, 2H), 2.21– 1.89 (m, 4H); LCMS: m/z 364.0 (M-H).

Step-iii: 5'-(1-(2,4-Difluorophenyl)-1H-pyrrol-2-yl)-7'-((1-methylpipe ridin-4-yl)- amino)spiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-ii of Example- VIII.1HNMR (400 MHz, DMSO–d ₆ ): δ 9.80 (s, 1H), 7.52– 7.40 (m, 2H), 7.21– 7.17 (m, 1H), 6.93 (s, 1H), 6.70 (s, 1H), 6.40-6.38 (m, 1H), 6.30 (s, 1H), 6.02 (s, 1H), 4.62 (d, J=7.4 Hz, 1H), 2.82– 2.56 (m, 3H), 2.43– 2.30 (m, 2H), 2.17– 2.01 (m, 7H), 1.99 – 1.87 (m, 2H), 1.61-1.58 (m, 2H), 1.34– 1.20 (m, 2H); LCMS: m/z 463.2 (M+H). Example-XXVII: 5'-(1-(2-Fluorophenyl)-1H-pyrazol-5-yl)-7'-(piperidin-4-ylox y)spiro- [cyclobutane-1,3'-indolin]-2'-one (Compound-56)

Step-i: tert-Butyl 4-((5'-(1-(2-fluorophenyl)-1H-pyrazol-5-yl)-1'-(4-methoxy- benzyl)-2'-oxospiro[cyclobutane-1,3'-indolin]-7'-yl)oxy)pipe ridine-1-carboxylate

The compound was prepared using the process described in step-iii of Example- XX.1HNMR (400 MHz, DMSO–d ₆ ): δ 7.79 (d, J = 2.0 Hz, 1H), 7.64– 7.60 (m, 1H), 7.56– 7.50 (m, 1H), 7.40– 7.36 (m, 2H), 7.16 (d, J =0.9 Hz, 1H), 7.00 (d, J =8.8 Hz, 2H), ), 6.84– 6.80 (m, 3H), 6.78 (d, J =2.0 Hz,1H), 4.97 (s, 2H), 4.21– 4.17 (m, 1H), 3.68 (s, 3H), 2.96– 2.85 (m, 4H), 2.45– 2.40 (m, 2H), 2.24– 2.01 (m, 4H), 1.55– 1.43 (m, 2H), 1.40 (s, 9H), 1.19– 1.09 (m, 2H); LCMS: m/z 653.1 (M+H).

Step-ii: 5'-(1-(2-Fluorophenyl)-1H-pyrazol-5-yl)-1'-(4-methoxybenzyl) -7'-(piperi- din-4-yloxy)spiro[cyclobutane-1,3'-indolin]-2'-one

To an ice cold solution of tert-butyl 4-((5'-(1-(2-fluorophenyl)-1H-pyrazol-5-yl)- 1'-(4-methoxybenzyl)-2'-oxospiro[cyclobutane-1,3'-indolin]-7 '-yl)oxy)piperidine-1- carboxylate (0.6 g, 0.92 mmol) in DCM (5.0 mL) was added TFA (1.0 mL) followed by stirring at RT for 3 h. TLC was monitored, and the reaction mixture was slowly poured into aqueous NaHCO ₃ and extracted with DCM. The organic layer was dried over sodium sulphate, concentrated and purified by CombiFlash® to afford the title compound as yellow solid (0.15 g).1H NMR (400 MHz, DMSO–d6): δ 7.79 (d, J = 2.0 Hz, 1H), 7.64– 7.61 (m, 1H), 7.60– 7.50 (m, 1H), 7.38– 7.34 (m, 2H), 7.17 (d, J =1.5 Hz, 1H), 7.06 (d, J =8.4 Hz, 2H), 6.83 (d, J =8.8 Hz, 2H), 6.77 (d, J =1.9 Hz, 1H), 6.61 (d, J =1.0 Hz, 1H), 4.97 (s, 2H), 4.02– 4.00 (m, 1H), 3.69 (s, 3H), 2.81– 2.78 (m, 2H), 2.44– 2.33 (m, 5H), 2.24– 2.04 (m, 4H), 1.52– 1.50 (m, 2H), 1.19– 1.13 (m, 2H); LCMS: m/z 553.3 (M+H).

Step-iii: 5'-(1-(2-Fluorophenyl)-1H-pyrazol-5-yl)-7'-(piperidin-4-ylox y)spiro- [cyclobutane-1,3'-indolin]-2'-one The compound was prepared using the process described in step-ii of Example-X. 1H NMR (400 MHz, DMSO–d6): δ 10.32 (s, 1H), 7.78 (d, J = 2.0 Hz, 1H), 7.62– 7.50 (m, 2H), 7.38– 7.33 (m, 2H), 7.11 (s, 1H), 6.74 (d, J =1.9 Hz, 1H), 6.58 (s, 1H), 4.00– 3.95 (m, 1H), 2.89– 2.86 (m, 2H), 2.40– 2.35 (m, 5H), 2.16– 1.98 (m, 4H), 1.60– 1.57 (m, 2H), 1.33– 1.24 (m, 2H); LCMS: m/z 433.3 (M+H). The below compounds were prepared by procedure similar to the one described in three steps of Example-XXVII with appropriate variations in reactants, quantities of reagents and reaction conditions. The physiochemical characteristics of the compounds are also summarized in the table below.

Example-XXVIII: 7'-((3-Fluoro-1-methylpiperidin-4-yl)oxy)-5'-(1-phenyl-1H-py razol- 5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one (Compound-61)

Step-i: 7'-((3-Fluoro-1-methylpiperidin-4-yl)oxy)-1'-(4-methoxybenzy l)-5'-(1- phenyl-1H-pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-on e

To a solution of 7'-((3-fluoropiperidin-4-yl)oxy)-1'-(4-methoxybenzyl)-5'-(1- phenyl-1H-pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-on e (0.3 g, 0.54 mmol) in mixture of THF (6 mL) and MeOH (6 mL) was added aqueous formaldehyde 30 % (0.5 mL) followed by stirring at RT for 16 h. The reaction mixture was cooled to 0 ºC, and sodium borohydride (0.06 g, 1.62 mmol) was added followed by stirring at RT for 2 h. TLC was monitored, and the reaction mixture was quenched with aqueous NH ₄ Cl and extracted with DCM. The organic layer was dried over sodium sulphate and

concentrated under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as off white solid (0.16 g, 52 %).1H NMR (400 MHz, DMSO-d ₆ ): δ 7.74 (d, J = 1.5 Hz, 1H), 7.47– 7.40 (m, 3H), 7.31 (d, J = 7.3 Hz, 2H), 7.17 (s, 1H), 7.08 (d, J = 8.3 Hz, 2H), 6.84 (d, J = 8.3 Hz, 2H), 6.74 (d, J = 1.5 Hz, 1H), 6.71 (s, 1H), 5.04– 4.92 (m, 2H), 4.49– 4.35 (m, 1H), 4.06– 4.00 (m, 1H), 3.69 (s, 3H), 2.92– 2.88 (m, 1H), 2.50– 2.40 (m, 3H), 2.24– 2.18 (m, 3H), 2.16 (s, 3H), 2.08– 1.97 (m, 2H), 1.89– 1.80 (m, 1H), 1.59– 1.51 (m, 1H), 1.18– 1.07 (m, 1H); LCMS: m/z567.3 (M+H).

Step-ii: 7'-((3-Fluoro-1-methylpiperidin-4-yl)oxy)-5'-(1-phenyl-1H-py razol-5- yl)spiro[cyclobutane-1,3'-indolin]-2'-one The compound was prepared using the process described in step-ii of Example-X. 1H NMR (400 MHz, DMSO-d6): δ 10.39 (s, 1H), 7.74 (d, J = 1.9 Hz, 1H), 7.46– 7.38 (m, 3H), 7.30 (d, J = 7.3 Hz, 2H), 7.09 (s, 1H), 6.71 (d, J = 1.9 Hz, 2H), 4.64– 4.46 (m, 1H), 4.05– 3.97 (m, 1H), 3.01– 2.96 (m, 1H), 2.41– 2.33 (m, 2H), 2.21– 1.91 (m, 10H), 1.69– 1.60 (m, 1H), 1.52– 1.49 (m, 1H); LCMS: m/z 447.2 (M+H). The below compound was prepared by procedure similar to the one described in three steps of Example-XXVIII with appropriate variations in reactants, quantities of reagents and reaction conditions. The physiochemical characteristics of the compound are also summarized in the table below.

Example-XXIX: 7'-Cyclopropyl-5'-(1-phenyl-1H-pyrazol-5-yl)spiro[cyclobutan e-1,3'- indolin -2'-one Com ound-63

Step-i: 7'-Bromo-5'-(1-phenyl-1H-pyrazol-5-yl)spiro[cyclobutane-1,3' -indolin]-2'- one

The compound was prepared using the process described in step-ii of Example-X. 1H NMR (400 MHz, DMSO-d6): δ 10.67 (s, 1H), 7.75 (s, 1H), 7.45-7.43 (m, 3H), 7.41- 7.29 (m, 3H), 7.22 (s, 1H), 6.74 (s, 1H), 2.37-2.33 (m, 2H), 2.07-1.90 (m, 4H); LC-MS: m/z 396.1 (M+H).

Step-ii: 7'-cyclopropyl-5'-(1-phenyl-1H-pyrazol-5-yl)spiro[cyclobutan e-1,3'- indolin]-2'-one

The compound was prepared using the process described in step-ii of Example- III.1H NMR (400 MHz, DMSO-d ₆ ): δ 10.53 (s, 1H), 7.71 (d, J=1.4 Hz, 1H), 7.45-7.39 (m, 3H), 7.26 (d, J=7.3 Hz, 2H), 7.17 (s, 1H), 6.66 (d, J=1.4 Hz, 1H), 6.43 (s, 1H), 2.38-2.35 (m, 2H), 2.12-2.09 (m, 3H), 1.99-1.96 (m, 1H), 1.88-1.84 (m, 1H), 0.82-0.77 (m, 2H), 0.36-0.32 (m, 2H); LC-MS: m/z 356.2 (M+H). Example-XXX: 7'-Cyclopropoxy-5'-(1-phenyl-1H-pyrazol-5-yl)spiro[cyclobuta ne-1,3'- indolin -2'-one Com ound-64

Step-i: 7'-Cyclopropoxy-1'-(4-methoxybenzyl)-5'-(1-phenyl-1H-pyrazol -5-yl)- spiro[cyclobutane-1,3'-indolin]-2'-one

In a sealed tube, to a stirred solution of 7'-hydroxy-1'-(4-methoxybenzyl)-5'-(1- phenyl-1H-pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-on e (0.2 g, 0.44 mmol) in DMF (3.0 mL) were added cesium carbonate (0.43 g, 1.32 mmol), potassium iodide (0.007g, 0.044 mmol) and bromo cyclopropane (0.35 mL, 4.4 mmol) followed by heating to 170 ºC for 16 h. TLC was monitored, and the reaction mixture was cooled to RT, diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulphate and concentrate under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as pale brown gummy mass (0.08 g, 36 %). LC-MS: m/z 492.2 (M+H).

Step-ii: 7'-Cyclopropoxy-5'-(1-phenyl-1H-pyrazol-5-yl)spiro[cyclobuta ne-1,3'- indolin]-2'-one

The compound was prepared using the process described in step-ii of Example-X. 1H NMR (400 MHz, DMSO-d ₆ ): δ 10.30 (s, 1H), 7.75 (d, J = 1.5 Hz, 1H), 7.47– 7.39 (m, 3H), 7.31 (d, J = 7.4 Hz, 2H), 7.11 (s, 1H), 6.90 (s, 1H), 6.80 (s, 1H), 3.64– 3.60 (m, 1H), 2.40– 2.33 (m, 2H), 2.20– 2.10 (m, 4H), 0.86 (t, J = 6.4 Hz, 2H), 0.53– 0.48 (m, 2H);LC-MS: m/z 372.3 (M+H). Example-XXXI: 7'-(2-(dimethylamino)ethoxy)-5'-(1-phenyl-1H-pyrazol-5-yl)sp iro- c clobutane-13'-indolin -2'-one Com ound-65

Step-i: 7'-(2-(Dimethylamino)ethoxy)-1'-(4-methoxybenzyl)-5'-(1-phen yl-1H- pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one

To an ice cold solution of 7'-hydroxy-1'-(4-methoxybenzyl)-5'-(1-phenyl-1H- pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one (0.3 g, 0.66 mmol) in THF (10 mL) was added NaH (60 %) (0.08 g, 1.98 mmol) followed by 2-bromo-N,N-dimethylethan-1- amine hydrochloride (0.19g, 1.0 mmol). The mixture was then stirred at RT for 16 h. TLC was monitored, and the reaction mixture was quenched with ice water and extracted with EtOAc. The organic layer dried over sodium sulphate and concentrate under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as pale brown solid (0.2 g, 58 %).1H NMR (400 MHz, DMSO–d ₆ ): δ 7.74 (d, J = 1.0 Hz, 1H), 7.46– 7.39 (m, 3H), 7.33– 7.31 (m, 2H), 7.16 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 1.2 Hz, 1H), 6.84 (d, J = 8.9 Hz, 2H), 6.79 (d, J = 1.3 Hz, 1H), 6.72 (d, J = 1.8 Hz, 1H), 4.99 ( s, 2H), 3.79 (t, J = 5.8 Hz, 2H), 3.69 (s, 3H), 2.41– 2.36 (m, 4H), 2.18– 2.14 (m, 3H), 2.12 (s, 6H), 1.96– 1.94 (m, 1H); LCMS: m/z 523.3 (M+H).

Step-ii: 7'-(2-(Dimethylamino)ethoxy)-5'-(1-phenyl-1H-pyrazol-5-yl)sp iro[cyclo- butane-1,3'-indolin]-2'-one:

The compound was prepared using the process described in step-ii of Example-X. 1H NMR (400 MHz, CD ₃ OD): δ 7.72 (d, J = 1.9 Hz, 1H), 7.47– 7.40 (m, 3H), 7.33– 7.31 (m, 2H), 6.97 (s, 1H), 6.75 (s, 1H), 6.64 ( d, J = 2 Hz, 1H), 3.92 (t, J = 5.3 Hz, 2H), 2.68 (t, J = 5.3Hz, 2H), 2.53– 2.46 (m, 2H), 2.31 (s, 6H), 2.22– 2.02 (m, 4H); LCMS: m/z 403.2 (M+H). Example-XXXII: 7'-((2-Oxo-1,2-dihydropyridin-4-yl)oxy)-5'-(1-phenyl-1H-pyra zol-5- yl)spiro[cyclobutane-1,3'-indolin]-2'-one (Compound-66)

Step-i: 7'-((2-Chloropyridin-4-yl)oxy)-1'-(4-methoxybenzyl)-5'-(1-ph enyl-1H- pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one

To a stirred solution of 7'-hydroxy-1'-(4-methoxybenzyl)-5'-(1-phenyl-1H- pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one (1.10 g, 2.43 mmol) and 2-chloro-4- fluoropyridine (0.96 g, 7.30 mmol) in DMF (10 mL) was added potassium carbonate (1.10 g, 7.30 mmol) followed by heating to 100 ºC for 16 h. TLC was monitored, and the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as brown solid (1.15 g, 84 %).1H NMR (400 MHz, DMSO-d ₆ ): 8.05 (d, J = 6.3 Hz, 1H), 7.74 (d, J = 1.4 Hz, 1H), 7.54 (s, 1H), 7.43-7.39 (m, 2H), 7.35-7.28 (m, 3H), 6.83 (d, J = 8.3 Hz, 2H), 6.75 (d, J = 1.4 Hz, 1H), 6.65-6.62 (m, 3H), 6.52-6.51 (m, 2H), 4.80 (s, 2H), 3.64 (s, 3H), 2.56- 2.53 (m, 1H), 2.42– 2.25 (m, 4H), 2.10– 2.07 (m, 1H). LCMS m/z564.2 (M+H)+.

Step-ii: 7'-((2-Chloropyridin-4-yl)oxy)-5'-(1-phenyl-1H-pyrazol-5-yl) spiro[cyclo- butane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-ii of Example-X. 1H NMR (400 MHz, DMSO-d ₆ ): 10.71 (s, 1H), 8.23 (d, J = 5.9 Hz, 1H), 7.75 (d, J = 1.5 Hz, 1H), 7.46– 7.31 (m, 5H), 6.93 (d, = 2.4 Hz, 1H), 6.81 (d, J = 0.9 Hz, 1H), 6.75 (d, J = 1.5 Hz, 1H), 6.73– 6.71 (m, 2H), 2.45– 2.39 (m, 2H), 2.27– 2.01 (m, 4H). LCMS m/z 443.1 (M+H)+.

Step-iii: 7'-((2-Oxo-1,2-dihydropyridin-4-yl)oxy)-5'-(1-phenyl-1H-pyra zol-5-yl)- spiro[cyclobutane-1,3'-indolin]-2'-one In a seated tube, a solution of 7'-((2-chloropyridin-4-yl)oxy)-5'-(1-phenyl-1H- pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one (0.36 g, 0.64 mmol) in TFA (6 mL) was heated to 120 ºC for 16 h. TLC was monitored, and the reaction mixture was concentrated under reduced pressure and purified by CombiFlash® to afford the title compound as white solid (0.07 g, 26 %).1H NMR (400 MHz, DMSO-d ₆ ): 10.96 (bs, 2H), 7.75 (s, 1H), 7.46– 7.42 (m, 2H), 7.37– 7.31 (m, 5H), 6.75 (d, J = 11.3 Hz, 2H), 5.88 (d, J = 7.3 Hz, 1H), 5.24 (s, 1H), 2.43– 2.40 (m, 2H), 2.19– 2.15 (m, 3H), 2.11– 1.97 (m, 1H) LCMS m/z 425.2 (M+H)+. Example-XXXIII: 5'-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)-7'-((1-methylpiperidi n-4-yl)- oxy)spiro[cyclobutane-1,3'-indolin]-2'-one (Compound-67)

Step-i: (E)-7'-bromo-5'-(3-(dimethylamino)but-2-enoyl)-1'-(4-methoxy benzyl)- spiro[cyclobutane-1,3'-indolin]-2'-one

A solution of 5'-acetyl-7'-bromo-1'-(4-methoxybenzyl)spiro[cyclobutane-1,3 '- indolin]-2'-one (0.2 g, 0.48 mmol) in 1,1-dimethoxy-N,N-dimethylethan-1-amine (2.0 mL) was heated to 120 ºC for 16 h. TLC was monitored, and the reaction mixture was concentrated under reduced pressure and purified by CombiFlash® to afford the title compound as yellow solid (0.16 g, 69 %).1H NMR (400 MHz, DMSO–d ₆ ): δ 8.05 (d, J = 1.5 Hz, 1H), 7.78 (d, J = 1.5 Hz, 1H), 7.04 (d, J = 8.3 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 5.63 (s, 1H), 5.22 (s, 2H), 3.70 ( s, 3H), 3.08 ( s, 6H), 2.58 (s, 3H), 2.40– 2.18 (m, 6H); LCMS: m/z 483.1 (M+H).

Step-ii: 7'-Bromo-1'-(4-methoxybenzyl)-5'-(3-methyl-1-phenyl-1H-pyraz ol-5-yl)- spiro[cyclobutane-1,3'-indolin]-2'-one The compound was prepared using the process described in step-i of Example- XV.1H NMR (400 MHz, DMSO–d6): δ 7.46– 7.36 (m, 3H), 7.33– 7.28 (m, 3H), 7.24 (s, 1H), 7.04 (d, J = 8.3 Hz, 2H), 6.87 (d, J = 7.9 Hz, 2H), 6.57 (s, 1H), 5.16 (s, 2H), 3.70 ( s, 3H), 2.44– 2.41 (m, 2H), 2.27 ( s, 3H), 2.18– 2.13 (m, 3H), 1.99– 1.91 (m, 1H); LCMS: m/z 528.2 (M+H).

Step-iii: 7'-Hydroxy-1'-(4-methoxybenzyl)-5'-(3-methyl-1-phenyl-1H-pyr azol-5- yl)spiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-ii of Example- XX.1H NMR (400 MHz, DMSO–d ₆ ): δ 9.88 (s, 1H), 7.42– 7.33 (m, 3H), 7.27– 7.25 (m, 2H), 7.18 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 8.3Hz, 2H), 6.78 (d, J = 1.5 Hz, 1H), 6.65 (d, J = 1.5 Hz, 1H), 6.37 (s, 1H), 4.96 (s, 2H), 3.69 ( s, 3H), 2.38– 2.36 (m, 2H), 2.26 ( s, 3H), 2.09– 1.99 (m, 4H); LCMS: m/z 466.2 (M+H).

Step-iv: 1'-(4-Methoxybenzyl)-5'-(3-methyl-1-phenyl-1H-pyrazol-5-yl)- 7'-((1- methylpiperidin-4-yl)oxy)spiro[cyclobutane-1,3'-indolin]-2'- one

The compound was prepared using the process described in step-iii of Example- XX.1H NMR (400 MHz, DMSO–d6): δ 7.44– 7.35 (m, 3H), 7.33– 7.26 (m, 2H), 7.15 (d, J = 1.0 Hz, 1H), 7.05 (d, J = 7.8 Hz, 2H), 6.84 (d, J = 7.8 Hz, 2H), 6.56– 6.53 (m, 2H), 4.99 (s, 2H), 3.98-3.96 (m, 1H), 3.69 ( s, 3H), 2.45– 2.38 (m, 3H), 2.27 ( s, 3H), 2.23– 2.03 (m, 8H), 1.89– 1.87 (m, 2H), 1.51– 1.49 (m, 2H), 1.33– 1.32 (m, 2H); LCMS: m/z 563.3 (M+H).

Step-v: 5'-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)-7'-((1-methylpiperidi n-4-yl)oxy)- spiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-ii of Example-X. 1H NMR (400 MHz, DMSO–d ₆ ): δ 10.38 (s, 1H), 7.43– 7.35 (m, 3H), 7.25 (d, J = 7.9 Hz, 2H), 7.08 (s, 1H), 6.58 (s, 1H), 6.50 ( s, 1H), 4.08– 4.03 (m, 1H), 2.68-2.67 (m, 2H), 2.41– 2.33 (m, 4H), 2.27 ( s, 3H), 2.19– 2.01 (m, 7H), 1.63– 1.61 (m, 2H), 1.52 – 1.50 (m, 2H); LCMS: m/z 443.3 (M+H). Example-XXXIV: 7'-((1-Methylpiperidin-4-yl)oxy)-5'-(1-phenyl-1H-1,2,4-triaz ol-5-yl)- spiro[cyclobutane-1,3'-indolin]-2'-one (Compound-68)

Step-i: 7'-Nitro-5'-(1-phenyl-1H-1,2,4-triazol-5-yl)spiro[cyclobutan e-1,3'- indolin]-2'-one

The compound was prepared using the process described in step-ii of Example- III.1H NMR (400 MHz, DMSO-d ₆ ): δ 11.26 (s, 1H), 8.31 (s, 1H), 8.08 (d, J=1.0 Hz, 1H), 7.82 (d, J=1.0 Hz, 1H), 7.57-7.51 (m, 5H), 2.46-2.40 (m, 2H), 2.17-2.15 (m, 3H), 1.95-1.91 (m, 1H); LC-MS: m/z 362.1 (M+H).

Step-ii: 7-Amino-5'-(1-phenyl-1H-1,2,4-triazol-5-yl)spiro[cyclobutane -1,3'- indolin]-2'-one

The compound was prepared using the process described in step-i of Example-I. 1H NMR (400 MHz, DMSO-d ₆ ): δ 9.94 (s, 1H), 8.16 (s, 1H), 7.52-7.51 (m, 3H), 7.42- 7.40 (m, 2H), 6.86 (s, 1H), 6.60 (s, 1H), 5.09 (s, 2H), 2.38-2.31 (m, 2H), 2.06-2.02 (m, 1H), 1.97-1.90 (m, 2H), 1.84-1.79 (m, 1H); LC-MS: m/z 332.2 (M+H).

Step-iii: 7'-Bromo-5'-(1-phenyl-1H-1,2,4-triazol-5-yl)spiro[cyclobutan e-1,3'- indolin]-2'-one

The compound was prepared using the process described in step-i of Example- III.1H NMR (400 MHz, DMSO-d ₆ ): δ 10.84 (s, 1H), 8.26 (s, 1H), 7.56-7.55 (m, 3H), 7.48-7.44 (m, 4H), 2.43-2.33 (m, 2H), 2.14-2.04 (m, 3H), 1.94-1.86 (m, 1H); LC-MS: m/z 397.1 (M+2H). Step-iv: 7'-Bromo-1'-(4-methoxybenzyl)-5'-(1-phenyl-1H-1,2,4-triazol- 5-yl)spiro- [cyclobutane-1,3'-indolin]-2'-one

To an ice cold solution of 7'-bromo-5'-(1-phenyl-1H-1,2,4-triazol-5-yl)spiro- [cyclobutane-1,3'-indolin]-2'-one (0.31 g, 0.78 mmol) in DMF (10 mL) was added cesium carbonate (0.51 g, 1.56 mmol) followed by 1-(chloromethyl)-4-methoxybenzene (0.13 mL, 0.94 mmol). The mixture was stirred at RT for 3 h. TLC was monitored, and the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulphate and concentrated under reduced pressure and column purified to afford the title compound as pale yellow solid (0.35 g, 87 %).1H NMR (400 MHz, DMSO-d ₆ ): δ 8.27 (s, 1H), 7.54-7.49 (m, 7H), 7.04 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.3 Hz, 2H), 5.17 (s, 2H), 3.70 (s, 3H), 2.47-2.43 (m, 2H), 2.18-2.13 (m, 3H), 1.91- 1.87 (m, 1H); LC-MS: m/z 517.1 (M+2H).

Step-v: 7'-Hydroxy-1'-(4-methoxybenzyl)-5'-(1-phenyl-1H-1,2,4-triazo l-5-yl)- spiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-ii of Example- XX.1H NMR (400 MHz, DMSO-d6): δ 10.09 (s, 1H), 8.20 (s, 1H), 7.56-7.53 (m, 3H), 7.45-7.43 (m, 2H), 7.19 (d, J=8.4 Hz, 2H), 7.08 (s, 1H), 6.88-6.84 (m, 3H), 4.98 (s, 2H), 3.69 (s, 3H), 2.41-2.35 (m, 2H), 2.11-1.96 (m, 3H), 1.85-1.81 (m, 1H); LC-MS: m/z 453.2 (M+H).

Step-vi: 1-(4-Methoxybenzyl)-7'-((1-methylpiperidin-4-yl)oxy)-5'-(1-p henyl-1H- 1,2,4-triazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-iii of Example- XX.1H NMR (400 MHz, DMSO-d ₆ ): δ 8.22 (s, 1H), 7.57-7.53 (m, 3H), 7.46-7.44 (m, 2H), 7.40 (s, 1H), 7.04 (d, J=8.8 Hz, 2H), 6.85 (d, J=8.8 Hz, 2H), 6.80 (s, 1H), 5.01 (s, 2H), 3.96-3.86 (m, 1H), 3.68 (s, 3H), 2.76-2.74 (m, 2H), 2.66-2.60 (m, 1H), 2.45-2.37 (m, 4H), 2.32-2.23 (m, 4H), 1.97-1.84 (m, 2H), 1.60-1.49 (m, 4H); LC-MS: m/z 550.3 (M+H).

Step-vii: 7'-((1-Methylpiperidin-4-yl)oxy)-5'-(1-phenyl-1H-1,2,4-triaz ol-5-yl)- spiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-ii of Example-X. 1H NMR (400 MHz, DMSO-d ₆ ): δ 10.52 (s, 1H), 8.21 (s, 1H), 7.57-7.53 (m, 3H), 7.44- 7.42 (m, 2H), 7.28 (s, 1H), 6.86 (s, 1H), 4.15-4.13 (m, 1H), 2.90-2.84 (m, 2H), 2.42- 2.32 (m, 6H), 2.17-2.14 (m, 4H), 2.12-1.95 (m, 1H), 1.75-1.71 (m, 2H), 1.64-1.57 (m, 2H); LC-MS: m/z 430.3 (M+H). Example-XXXV: 5'-(4-Methoxy-1-phenyl-1H-pyrazol-5-yl)-7'-((1-methylpiperid in-4- l ox s iro c clobutane-13'-indolin -2'-one Com ound-69

Step-i: 7'-Bromo-5'-(2-bromoacetyl)-1'-(4-methoxybenzyl)spiro[cyclob utane-1,3'- indolin]-2'-one

To an ice cold solution of 5'-acetyl-7'-bromo-1'-(4-methoxybenzyl)spiro[cyclo- butane-1,3'-indolin]-2'-one (2.6 g, 6.28 mmol) in THF (30 mL) was added trimethyl- phenyl ammonium tribromide (2.4 g, 6.28 mmol) followed by stirring at RT for 16 h. TLC was monitored, and the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as pale yellow thick liquid (2.2 g).1H NMR (400 MHz, DMSO- d ₆ ): 8.29 (d, J = 1.4 Hz, 1H), 8.03 (d, J = 1.4 Hz, 1H), 7.06– 7.04 (m, 2H), 6.88 (d, J = 8.9 Hz, 2H), 5.25 (s, 2H), 4.97 (s, 2H), 3.71 (s, 3H), 2.54– 2.50 (m, 4H), 2.38– 2.22 (m, 2H).

Step-ii: 7'-Bromo-5'-(2-methoxyacetyl)-1'-(4-methoxybenzyl)spiro[cycl obutane- 1,3'-indolin]-2'-one

To a stirred solution of 7'-bromo-5'-(2-bromoacetyl)-1'-(4-methoxybenzyl)spiro- [cyclobutane-1,3'-indolin]-2'-one (2.2 g, 4.46 mmol) in MeOH (30 mL) were added silver (I) carbonate (1.84 g, 6.69 mmol) and boron trifluoride diethyl ether complex (1.3 mL) followed by heating to 50 ºC for 16 h. TLC was monitored, and the reaction mixture was concentrated, diluted with EtOAc and washed with water and brine. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as pale yellow oil (1.2 g).1H NMR (400 MHz, DMSO- d ₆ ): 8.18 (d, J = 1.4 Hz, 1H), 7.92 (d, J = 1.5 Hz, 1H), 7.03 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.3 Hz, 2H), 5.24 (s, 2H), 4.81 (s, 2H), 3.70 (s, 3H), 3.36 (s, 3H), 2.57– 2.50 (m, 2H), 2.49– 2.46 (m, 2H), 2.38– 2.19 (m, 2H). LCMS m/z 443.9 (M+H)+.

Step-iii: (Z)-7'-bromo-5'-(3-(dimethylamino)-2-methoxyacryloyl)-1'-(4- methoxy- benzyl)spiro[cyclobutane-1,3'-indolin]-2'-one

A solution of 7'-bromo-5'-(2-methoxyacetyl)-1'-(4-methoxybenzyl)spiro[cycl o- butane-1,3'-indolin]-2'-one (1.2 g, 2.70 mmol) in DMF-DMA (12 mL) was heated to 90 ºC for 16 h. TLC was monitored, and the reaction mixture was concentrated under reduced pressure and purified by CombiFlash® to afford the title compound as pale yellow solid (1.4 g).1H NMR (400 MHz, DMSO- d ₆ ): 7.84 (s, 1H), 7.52 (s, 1H), 7.09– 7.06 (m, 2H), 6.88– 6.86 (m, 2H), 6.78 (s, 1H), 5.21 (s, 2H), 3.71 (s, 3H), 3.46 (s, 3H), 3.08 (s, 6H), 2.50– 2.47 (m, 3H), 2.35– 2.12 (m, 3H). LCMS m/z501.0 (M+2H)+.

Step-iv: 7'-Bromo-5'-(4-methoxy-1-phenyl-1H-pyrazol-5-yl)-1'-(4-metho xy- benzyl)spiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-i of Example- XV.1H NMR (400 MHz, DMSO- d ₆ ): 8.46 (s, 1H), 8.20 (s, 1H), 7.94 (s, 1H), 7.90 (d, J = 8.3 Hz, 2H), 7.51 (d, J = 7.3 Hz, 2H), 7.29 (t, J = 7.4 Hz, 1H), 7.08 (d, J = 8.3 Hz, 2H), 6.89 (d, J = 8.3 Hz, 2H), 5.23 (s, 2H), 3.92 (s, 3H), 3.71 (s, 3H), 2.54– 2.50 (m, 4H), 2.41– 2.20 (m, 2H). LCMS m/z545.9 (M+H)+.

Step-v: 7'-Hydroxy-5'-(4-methoxy-1-phenyl-1H-pyrazol-5-yl)-1'-(4-met hoxy- benzyl)spiro[cyclobutane-1,3'-indolin]-2'-one’

The compound was prepared using the process described in step-ii of Example- XX.1H NMR (400 MHz, DMSO- d ₆ ): 9.85 (s, 1H), 7.75 (s, 1H), 7.42– 7.39 (m, 2H), 7.35– 7.32 (m, 1H), 7.26 (d, J = 8.8 Hz, 2H), 7.19 (d, J = 8.3 Hz, 2H), 6.86 (d, = 8.3 Hz, 2H), 6.81 (d, J = 1.5 Hz, 1H), 6.61 (d, J = 1.5 Hz, 1H), 4.97 (s, 2H), 3.80 (s, 3H), 3.70 (s, 3H), 2.39– 2.32 (m, 2H), 2.11– 2.00 (m, 1H), 1.97– 1.90 (m, 2H), 1.89– 1.80 (m, 1H). LCMS m/z 482.0 (M+H)+. Step-vi: 5'-(4-Methoxy-1-phenyl-1H-pyrazol-5-yl)-1'-(4-methoxybenzyl) -7'-((1- methylpiperidin-4-yl)oxy)spiro[cyclobutane-1,3'-indolin]-2'- one

The compound was prepared using the process described in step-iii of Example- XX. LCMS: m/z 579.1 (M+H).

Step-vii: 5'-(4-Methoxy-1-phenyl-1H-pyrazol-5-yl)-7'-((1-methylpiperid in-4-yl)- oxy)spiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-ii of Example-X. 1H NMR (400 MHz, DMSO- d ₆ ): 10.32 (s, 1H), 7.75 (s, 1H), 7.43– 7.39 (m, 2H), 7.36 – 7.32 (m, 1H), 7.25 (d, J = 7.3 Hz, 2H), 7.00 (s, 1H), 6.57 (d, J = 2.2 Hz, 1H), 3.97– 3.95 (m, 1H), 3.82 (s, 3H), 2.58– 2.52 (m, 2H), 2.39– 2.32 (m, 2H), 2.18– 2.04 (m, 7H), 1.99– 1.96 (m, 2H), 1.66– 1.63 (m, 2H), 1.52– 1.44 (m, 2H). LCMS m/z 459.3 (M+H)+. Example-XXXVI: 7'-((2,6-Dimethylpiperidin-4-yl)oxy)-5'-(3-methyl-1-phenyl-1 H- razol-5- l s iro c clobutane-13'-indolin -2'-one Com ound-70

Step-i: tert-Butyl 4-((1'-(4-methoxybenzyl)-5'-(3-methyl-1-phenyl-1H-pyrazol-5- yl)-2'-oxospiro[cyclobutane-1,3'-indolin]-7'-yl)oxy)-2,6-dim ethylpiperidine-1-carboxylate The compound was prepared using the process described in step-iii of Example- XX.1H NMR (400 MHz, DMSO-d ₆ ): δ 7.45-7.41 (m, 2H), 7.36-7.34 (m, 1H), 7.28 (d, J=7.4 Hz, 2H), 7.19 (d, J=1.0 Hz, 1H), 7.02 (d, J=8.3 Hz, 2H), 6.83 (d, J=8.3 Hz, 2H), 6.55 (s, 2H), 4.98 (s, 2H), 3.93-3.89 (m, 1H), 3.68 (s, 3H), 2.42-2.41 (m, 3H), 2.28- 2.20 (m, 6H), 2.08-1.85 (m, 4H), 1.72-1.69 (m, 2H), 1.38 (s, 9H), 1.01 (d, J=6.3 Hz, 6H); LC-MS: m/z 677.1 (M+H). Step-ii: 7'-((2,6-Dimethylpiperidin-4-yl)oxy)-1'-(4-methoxybenzyl)-5' -(3-methyl- 1-phenyl-1H-pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'- one

The compound was prepared using the process described in step-ii of Example- XXVII.1H NMR (400 MHz, DMSO-d ₆ ): δ 7.52-7.32 (m, 3H), 7.27 (d, J=7.8 Hz, 2H), 7.15 (s, 1H), 7.06 (d, J=8.4 Hz, 2H), 7.00-6.93 (m, 1H), 6.85 (d, J=8.3 Hz, 2H), 6.62 (s, 1H), 6.52 (s, 1H), 4.96 (s, 2H), 4.24-4.21 (m, 1H), 3.69 (s, 3H), 3.24-3.23 (m, 1H), 2.80-2.78 (m, 1H), 2.42-2.39 (m, 2H), 2.32-2.23 (m, 6H), 2.04-2.00 (m, 1H), 1.57-1.49 (m, 2H), 1.33-1.23 (m, 2H), 1.00 (d, J=6.9 Hz, 3H), 0.91 (d, J=5.9 Hz, 3H); LC-MS: m/z 577.1 (M+H).

Step-iii: 7'-((2,6-Dimethylpiperidin-4-yl)oxy)-5'-(3-methyl-1-phenyl-1 H-pyrazol- 5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-ii of Example-X. 1H NMR (400 MHz, DMSO-d6): δ 10.30 (s, 1H), 7.43-7.39 (m, 2H), 7.35-7.31 (m, 1H), 7.27-7.25 (m, 2H), 7.11 (s, 1H), 6.54 (s, 1H), 6.49 (s, 1H), 4.18-4.16 (m, 1H), 3.26- 3.24 (m, 2H), 2.80-2.76 (m, 1H), 2.41-2.35 (m, 2H), 2.27 (s, 3H), 2.21-2.19 (m, 4H), 2.17-2.13 (m, 1H), 1.68-1.65 (m, 1H), 1.56-1.53 (m, 1H), 1.45-1.41 (m, 1H), 0.99 (d, J=6.9 Hz, 3H), 0.94 (d, J=6.4 Hz, 3H); LC-MS: m/z 457.1 (M+H). Example-XXXVII: 5'-(1-Phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-7'-((1,2,6 -tri- meth l i eridin-4- l ox s iro c clobutane-13'-indolin -2'-one Com ound-71

Step-i: 1-(7'-Bromo-1'-(4-methoxybenzyl)-2'-oxospiro[cyclobutane-1,3 '-indolin]- 5'-yl)-4,4,4-trifluorobutane-1,3-dione

To an ice cold solution of ethyl 2,2,2-trifluoroacetate (0.43 mL, 3.62 mmol) in THF (10 mL) was added NaH (60 %) (0.29 g, 7.24 mmol) followed by stirring at 0 ºC. Then 5'-acetyl-7'-bromo-1'-(4-methoxybenzyl)spiro[cyclobutane-1,3 '-indolin]-2'-one (1.0 g, 2.41 mmol) was added followed by stirring at RT for 16 h. TLC was monitored, and the reaction mixture was quenched with ice water and extracted with EtOAc. The organic layer was dried over sodium sulphate, concentrated under reduced pressure and column purified to afford the title compound (0.5 g, 41 %).1H NMR (400 MHz, DMSO-d ₆ ): δ 8.17 (d, J=0.9 Hz, 1H), 7.91 (d, J=1.5 Hz, 1H), 7.03 (d, J=8.9 Hz, 2H), 6.88-6.85 (m, 2H), 5.23 (s, 4H), 3.70 (s, 3H), 2.44-2.37 (m, 2H), 2.28-2.18 (m, 4H).

Step-ii: 7'-Bromo-1'-(4-methoxybenzyl)-5'-(1-phenyl-3-(trifluoromethy l)-1H- pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-i of Example- XV.1H NMR (400 MHz, DMSO-d ₆ ): δ 7.52-7.50 (m, 3H), 7.45-7.42 (m, 3H), 7.34 (d, J=2.0 Hz, 2H), 7.03 (d, J=8.4 Hz, 2H), 6.87-6.85 (m, 2H), 5.15 (s, 2H), 3.70 (s, 3H), 2.44-2.43 (m, 2H), 2.18-2.15 (m, 3H), 1.98-1.93 (m, 1H); LC-MS: m/z 583.7 (M+H).

Step-iii: 7'-Hydroxy-1'-(4-methoxybenzyl)-5'-(1-phenyl-3-(trifluoromet hyl)-1H- pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-ii of Example- XX.1H NMR (400 MHz, DMSO-d ₆ ): δ 9.96 (s, 1H), 7.50-7.47 (m, 3H), 7.39-7.38 (m, 2H), 7.18 (d, J=8.3 Hz, 2H), 7.11 (s, 1H), 6.93 (s, 1H), 6.84 (d, J=8.3 Hz, 2H), 6.67 (s, 1H), 4.97 (s, 2H), 3.69 (s, 3H), 2.45-2.35 (m, 2H), 2.16-2.05 (m, 3H), 1.98-1.93 (m, 1H); LC-MS: m/z 520.0 (M+H).

Step-iv: tert-Butyl 4-((1'-(4-methoxybenzyl)-2'-oxo-5'-(1-phenyl-3-(trifluoro- methyl)-1H-pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-7'-y l)oxy)-2,6-dimethylpipe- ridine-1-carboxylate

The compound was prepared using the process described in step-iii of Example- XX.1H NMR (400 MHz, DMSO-d ₆ ): δ 7.60-7.47 (m, 3H), 7.42-7.40 (m, 2H), 7.29 (d, J=8.8 Hz, 2H), 7.01 (d, J=8.3 Hz, 2H), 6.83 (d, J=8.8 Hz, 2H), 6.65 (s, 1H), 4.99 (s, 2H), 3.94-3.93 (m, 1H), 3.68 (s, 3H), 2.43-2.42 (m, 2H), 2.28-1.98 (m, 4H), 1.90-1.87 (m, 2H), 1.73-1.70 (m, 4H), 1.39 (s, 9H), 1.04-1.00 (m, 6H). Step-v: 7'-((2,6-Dimethylpiperidin-4-yl)oxy)-1'-(4-methoxybenzyl)-5' -(1-phenyl- 3-(trifluoromethyl)-1H-pyrazol-5-yl)spiro[cyclobutane-1,3'-i ndolin]-2'-one

The compound was prepared using the process described in step-ii of Example- XXVII.1H NMR (400 MHz, DMSO-d ₆ ): δ 7.50-7.47 (m, 3H), 7.42-7.40 (m, 2H), 7.26 (s, 2H), 7.04 (d, J=8.3 Hz, 2H), 6.84 (d, J=8.8 Hz, 2H), 6.73 (d, J=1.0 Hz, 1H), 4.97- 4.96 (m, 2H), 4.30-4.21 (m, 1H), 3.69 (s, 3H), 3.28-3.26 (m, 1H), 2.87-2.81 (m, 1H), 2.44-2.41 (m, 4H), 2.26-2.21 (m, 3H), 2.09-2.01 (m, 1H), 1.59-1.52 (m, 2H), 1.41-1.32 (m, 1H), 1.04 (d, J=6.8 Hz, 3H), 0.93 (d, J=6.4 Hz, 3H); LC-MS: m/z 631.1 (M+H).

Step-vi: 1'-(4-Methoxybenzyl)-5'-(1-phenyl-3-(trifluoromethyl)-1H-pyr azol-5-yl)- 7'-((1,2,6-trimethylpiperidin-4-yl)oxy)spiro[cyclobutane-1,3 '-indolin]-2'-one

The compound was prepared using the process described in step-i of Example- XXVIII.1H NMR (400 MHz, DMSO-d ₆ ): δ 7.50-7.48 (m, 3H), 7.42-7.40 (m, 2H), 7.28 (s, 2H), 7.03 (d, J=8.4 Hz, 2H), 6.84 (d, J=8.3 Hz, 2H), 6.71 (s, 1H), 5.01-4.92 (m, 2H), 4.23-4.21 (m, 1H), 3.68 (s, 3H), 2.97-2.93 (m, 1H), 2.47-2.42 (m, 4H), 2.27-2.05 (m, 7H), 1.60-1.47 (m, 3H), 0.98-0.87 (m, 6H); LC-MS: m/z 645.1 (M+H).

Step-vii: 5'-(1-Phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-7'-((1,2,6 -trimethyl- piperidin-4-yl)oxy)spiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-ii of Example-X. 1H NMR (400 MHz, DMSO-d ₆ ): δ 10.39 (s, 1H), 7.52-7.50 (m, 3H), 7.48-7.39 (m, 2H), 7.25 (s, 1H), 7.21 (s, 1H), 6.67 (s, 1H), 4.23-4.21 (m, 1H), 3.07-3.03 (m, 1H), 2.42- 2.35 (m, 3H), 2.19-2.01 (m, 7H), 1.69-1.61 (m, 3H), 1.25-1.23 (m, 1H), 0.96-.083 (m, 6H); LC-MS: m/z 525.0 (M+H). Example-XXXVIII: 7'-((1-Methylpiperidin-4-yl)oxy)-5'-(1-phenyl-3-(trifluorome thyl)- 1H-pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one (Compound-72)

Step-i: 1'-(4-Methoxybenzyl)-7'-((1-methylpiperidin-4-yl)oxy)-5'-(1- phenyl-3- (trifluoromethyl)-1H-pyrazol-5-yl)spiro[cyclobutane-1,3'-ind olin]-2'-one The compound was prepared using the process described in step-iii of Example- XX.1H NMR (400 MHz, DMSO–d6): δ 7.51 (d, J = 5.4 Hz, 2H), 7.49– 7.41 (m, 2H), 7.30– 7.26 (m, 2H), 7.05– 6.95 (m, 3H), 6.84 (d, J = 8.8 Hz, 2H), 6.68 (s, 1H), 5.03 (s, 2H), 4.02– 4.01 (m, 1H), 3.69 (s, 3H), 2.43-2.33 (m, 4H), 2.23– 2.18 (m, 3H), 2.08– 2.01 (m, 4H), 1.99– 1.93 (m, 2H), 1.50– 1.42 (m, 2H), 1.23– 1.18 (m, 2H): LCMS: m/z 617.0 (M+H).

Step-ii: 7'-((1-Methylpiperidin-4-yl)oxy)-5'-(1-phenyl-3-(trifluorome thyl)-1H- pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-ii of Example-X. 1H NMR (400 MHz, DMSO–d ₆ ): δ 10.47 (s, 1H), 7.48– 7.47 (m, 3H), 7.39– 7.37 (m, 2H), 7.24– 7.23 (m, 1H), 7.14 (s, 1H), 6.72 (s, 1H), 4.21– 4.18 (m, 1H), 2.84-2.80 (m, 2H), 2.37– 2.25 (m, 6H), 2.20– 1.99 (m, 5H), 1.78– 1.45 (m, 4H); LCMS: m/z 497.0 (M+H). Example-XXXIX: 7'-((6-Aminopyridin-3-yl)oxy)-5'-(1-phenyl-1H-pyrazol-5- l s iro c clobutane-13'-indolin -2'-one Com ound-73

Step-i: 1'-(4-Methoxybenzyl)-7'-((6-nitropyridin-3-yl)oxy)-5'-(1-phe nyl-1H- pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one

To a stirred solution of 7'-hydroxy-1'-(4-methoxybenzyl)-5'-(1-phenyl-1H- pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one (0.5 g, 1.10 mmol) and 5-chloro-2- nitropyridine (0.7 g, 4.40 mmol) in DMF (6 mL) was added potassium carbonate (0.45 g, 3.30 mmol) followed by stirring at RT for 16 h. TLC was monitored, and the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as pale brown gummy mass (0.6 g).

LCMS: m/z 574.0 (M+H).

Step-ii: 7'-((6-Aminopyridin-3-yl)oxy)-1'-(4-methoxybenzyl)-5'-(1-phe nyl-1H- pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-iv of Example-I. 1H NMR (400 MHz, DMSO-d ₆ ): δ 7.68 (d, J = 0.9 Hz, 1H), 7.37– 7.30 (m, 6H), 7.20– 7.17 (m, 2H), 7.06 (d, J = 8.3 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 6.63 (s, 1H), 6.29– 6.25 (m, 2H), 5.85 (m, 2H), 4.95 (s, 2H), 3.69 (s, 3H), 2.32– 2.23 (m, 4H), 2.09– 2.04 (m, 2H); LCMS: m/z544.0 (M+H).

Step-iii: 7'-((6-Aminopyridin-3-yl)oxy)-5'-(1-phenyl-1H-pyrazol-5-yl)s piro[cyclo- butane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-ii of Example-X. 1H NMR (400 MHz, DMSO-d6): δ 10.64 (s, 1H),δ 7.69 (d, J = 1.5 Hz, 1H), δ 7.60 (d, J = 3.0 Hz, 1H), 7.41– 7.38 (m, 3H), 7.22– 7.19 (m, 3H), 6.94– 6.91 (m, 1H), 6.62 (d, J = 1.9 Hz, 1H), 6.37– 6.31 (m, 2H) 5.84 (s, 2H), 2.44– 2.32 (m, 2H), 2.12– 2.05 (m, 3H), 2.03– 1.97 (m, 1H); LCMS: m/z 424.0 (M+H). Example-XL: 5'-(4-Methyl-1-phenyl-1H-pyrazol-5-yl)-7'-((1-methylpiperidi n-4-yl)oxy)- spiro[cyclobutane-1,3'-indolin]-2'-one (Compound-74)

Step-i: 5'-Propionylspiro[cyclobutane-1,3'-indolin]-2'-one To a cold suspension of AlCl ₃ (6.1 g, 46.25 mmol) in DCE (60 mL) was added propionyl chloride (1.9 mL, 22.2 mmol) followed by stirring for 15 min. Spiro[cyclo- butane-1,3'-indolin]-2'-one (3.2 g, 18.50 mmol) was then added and the reaction mixture was stirred at RT for 16 h. TLC was monitored, and the reaction mixture was quenched with ice and extracted with EtOAc. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as brown solid (2.5 g).1H NMR (400 MHz, DMSO-d ₆ ): δ 10.60 (s, 1H), 8.14 (d, J = 1.5 Hz, 1H), 7.89– 7.85 (m, 1H), 6.88 (d, J = 7.8 Hz, 1H), 3.03 (q, J = 6.9 Hz, 2H), 2.46– 2.32 (m, 4H), 2.29– 2.16 (m, 2H), 1.09 (t, J = 7.3 Hz, 3H); LCMS: m/z 230.0 (M+H).

Step-ii: 7'-Bromo-5'-propionylspiro[cyclobutane-1,3'-indolin]-2'-one

To a suspension of AlCl ₃ (2.61 g, 19.65 mmol) in CHCl ₃ (30 mL) was added 5'- propionylspiro[cyclobutane-1,3'-indolin]-2'-one (1.5 g, 6.55 mmol) followed by heating to 60 ºC for 1 h. The reaction mixture cooled to RT, then bromine (0.7 mL, 13.1 mmol) was added followed by stirring at RT for 16 h. TLC was monitored, and the reaction mixture was quenched with aqueous NaHCO3 solution and extracted with DCM. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as off white solid (1.5 g, 75 %).1H NMR (400 MHz, DMSO-d ₆ ): δ 10.92 (s, 1H), 8.13 (s, 1H), 7.97 (d, J = 1.4 Hz, 1H), 3.05 (q, J = 6.9 Hz, 2H), 2.46– 2.40 (m, 4H), 2.26– 2.09 (m, 2H), 1.08 (t, J = 7.3 Hz, 3H).

Step-iii: 7'-Bromo-1'-(4-methoxybenzyl)-5'-propionylspiro[cyclobutane- 1,3'- indolin]-2'-one

To an ice cold solution of 7'-bromo-5'-propionylspiro[cyclobutane-1,3'-indolin]- 2'-one (1.6 g, 5.19 mmol) in DMF (40 mL) was added cesium carbonate (4.2 g, 12.98 mmol) followed by 1-(chloromethyl)-4-methoxybenzene (0.85 mL, 6.23 mmol). The mixture was stirred at RT for 6 h. TLC was monitored, and the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulphate and concentrated under reduced pressure and column purified to afford the title compound as brown solid (1.2 g, 54 %).1H NMR (400 MHz, DMSO-d ₆ ): δ 8.23 (s, 1H), 7.94 (s, 1H), 7.04 (d, J = 8.3 Hz, 2H), 6.87 (d, J = 8.3 Hz, 2H), 5.24 (s, 2H), 3.70 (s, 3H), 3.07 (q, J = 6.9 Hz, 2H), 2.56– 2.51 (m, 3H), 2.39– 2.22 (m, 3H), 1.08 (t, J = 6.9 Hz, 3H); LCMS: m/z 430.0 (M+2H). Step-iv: (E)-7'-Bromo-5'-(3-(dimethylamino)-2-methylacryloyl)-1'-(4-m ethoxy- benzyl)spiro[cyclobutane-1,3'-indolin]-2'-one

A solution of 7'-bromo-1'-(4-methoxybenzyl)-5'-propionylspiro[cyclobutane- 1,3'- indolin]-2'-one(1.1 g, 2.57 mmol) in DMF-DMA (10 mL) was heated to 100 ºC for 16 h. TLC was monitored, and the reaction mixture was concentrated under reduced pressure and purified by CombiFlash® to afford the title compound as pale yellow solid (1.0 g). LCMS: m/z 483.0 (M+1H).

Step-v: 7'-Bromo-1'-(4-methoxybenzyl)-5'-(4-methyl-1-phenyl-1H-pyraz ol-5-yl)- spiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-i of Example- XV.1H NMR (400 MHz, DMSO-d ₆ ): δ 7.65 (s, 1H), 7.40– 7.32 (m, 4H), 7.26– 7.24 (m, 3H), 7.07 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.3 Hz, 2H), 5.17 (s, 2H), 3.71 (s, 3H), 2.44– 2.40 (m, 2H), 2.20– 2.16 (m, 3H), 2.16 (s, 3H), 1.99– 1.97 (s, 1H); LCMS: m/z530.0 (M+2H).

Step-vi: 7'-Hydroxy-1'-(4-methoxybenzyl)-5'-(4-methyl-1-phenyl-1H-pyr azol-5- yl)spiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-ii of Example- XX.1H NMR (400 MHz, DMSO-d ₆ ): δ 9.86 (s, 1H), 7.61 (s, 1H), 7.39– 7.35 (m, 2H), 7.31– 7.27 (m, 1H), 7.23– 7.21 (m, 4H), 6.86 (d, J = 8.8 Hz, 2H), 6.76 (s, 1H), 6.63 (s, 1H), 4.98 (s, 2H), 3.70 (s, 3H), 2.44– 2.34 (m, 2H), 2.20– 1.90 (m, 7H); LCMS: m/z466.1 (M+H).

Step-vii: 1'-(4-Methoxybenzyl)-5'-(4-methyl-1-phenyl-1H-pyrazol-5-yl)- 7'-((1- methylpiperidin-4-yl)oxy)spiro[cyclobutane-1,3'-indolin]-2'- one

The compound was prepared using the process described in step-iii of Example- XX. The product was as such taken forward to next step without further

characterization.

Step-viii: 5'-(4-Methyl-1-phenyl-1H-pyrazol-5-yl)-7'-((1-methylpiperidi n-4-yl)- oxy)spiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-ii of Example-X. 1H NMR (400 MHz, DMSO-d ₆ ): δ 10.34 (s, 1H), 7.62 (s, 1H), 7.39– 7.35 (m, 2H), 7.31– 7.29 (m, 1H), 7.21 (d, J = 7.3 Hz, 2H), 7.00 (s, 1H), 6.57 (s, 1H), 4.06– 4.04 (m, 1H), 2.58– 2.51 (m, 2H), 2.41– 2.36 (m, 2H), 2.17– 2.12 (m, 9H), 2.06– 2.01 ( m, 3H), 2.63– 2.61 (m, 2H), 2.53– 2.51 (m, 2H); LCMS: m/z443.1 (M+H). Example- XLI: 7'-((1-Methyl-2-oxo-1,2-dihydropyridin-4-yl)oxy)-5'-(1-pheny l-1H- pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one (Compound-75)

Step-i: 1'-(4-Methoxybenzyl)-7'-((2-oxo-1,2-dihydropyridin-4-yl)oxy) -5'-(1- phenyl-1H-pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-on e

The compound was prepared using the process described in step-iii of Example- XXXII.1H NMR (400 MHz, DMSO-d ₆ ): δ 11.36 (s, 1H), 7.74 (d, J = 1.5 Hz, 1H), 7.45 – 7.41 (m, 3H), 7.37– 7.23 (m, 4H), 6.96 (d, J = 8.8 Hz, 2H), 6.76 (d, J = 8.8 Hz, 2H), 6.75 (s, 1H), 6.69 (d, J = 1.5 Hz, 1H), 5.69 (dd, J = 7.3 & 2.4 Hz, 1H), 5.14 (d, J = 2.4 Hz, 1H), 4.73 (s, 2H), 3.68 (s, 3H), 2.37– 2.20 (m, 4H), 2.06– 1.91 (m, 2H); LCMS: m/z545.1 (M+H).

Step-ii: 1'-(4-Methoxybenzyl)-7'-((1-methyl-2-oxo-1,2-dihydropyridin- 4-yl)oxy)- 5'-(1-phenyl-1H-pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin] -2'-one

To an ice cold solution of 1'-(4-methoxybenzyl)-7'-((2-oxo-1,2-dihydropyridin-4- yl)oxy)-5'-(1-phenyl-1H-pyrazol-5-yl)spiro[cyclobutane-1,3'- indolin]-2'-one (0.2 g, 0.37 mmol) in THF was added LiHMDS 1.0 M in THF (1.1 mL, 1.11 mmol) followed by methyl iodide (0.13 mL, 2.22 mmol). The mixture was stirred at RT for 4 h. TLC was monitored, and the reaction mixture was quenched with aqueous NH ₄ Cl solution and extracted with EtOAc. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as pale yellow gummy mass (0.2 g, 97 %).1H NMR (400 MHz, DMSO-d ₆ ): δ 7.70 (s, 1H), 7.42– 7.38 (m, 2H), 7.33-7.31 (m, 3H), 7.14– 7.09 (m, 2H), 7.02– 6.99 (m, 2H), 6.72– 6.70 (m, 3H), 6.47 (s, 1H), 5.79 (dd, J = 7.3 & 2.4 Hz, 1H), 5.47 (d, J = 2.5 Hz, 1H), 4.83 (s, 2H), 3.74 (s, 3H), 3.45 (s, 3H), 2.70– 2.63 (m, 2H), 2.41– 2.16 (m, 3H), 2.07– 1.98 (m, 1H); LCMS: m/z 559.1 (M+H).

Step-iii: 7'-((1-Methyl-2-oxo-1,2-dihydropyridin-4-yl)oxy)-5'-(1-pheny l-1H- pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-ii of Example-X. 1H NMR (400 MHz, DMSO-d ₆ ): δ 10.68 (s, 1H), δ 7.74 (s, 1H), δ 7.64 (d, J = 7.3 Hz, 1H), 7.44– 7.37 (m, 3H), 7.34– 7.30 (m, 3H), 6.75 (d, J = 8.3 Hz, 2H), 5.94 (d, J = 5.4 Hz, 1H), 5.35 (s, 1H), 3.36 (s, 3H), 2.42– 2.31 (m, 2H), 2.21– 1.99 (m, 4H); LCMS: m/z 439.0 (M+H). Example-XLII: 5'-(5-Amino-2-(2,4-difluorophenoxy)phenyl)-7'-((1-methylpipe ridin-4- l ox s iro c clobutane-13'-indolin -2'-one Com ound-76

Step-i: 5'-(2-(2,4-Difluorophenoxy)-5-nitrophenyl)-1'-(4-methoxybenz yl)-7'-((1- methylpiperidin-4-yl)oxy)spiro[cyclobutane-1,3'-indolin]-2'- one

The compound was prepared using the process described in step-ii of Example- III. LCMS: m/z 656.1 (M+H).

Step-ii: 5'-(5-Amino-2-(2,4-difluorophenoxy)phenyl)-1'-(4-methoxybenz yl)-7'- ((1-methylpiperidin-4-yl)oxy)spiro[cyclobutane-1,3'-indolin] -2'-one

The compound was prepared using the process described in step-iv of Example-I. 1H NMR (400 MHz, DMSO-d ₆ ): δ 7.33-7.25 (m, 2H), 7.04-7.02 (m, 2H), 6.87-6.84 (m, 5H), 6.72 (s, 1H), 6.62-6.60 (m, 2H), 5.18-5.16 (bs, 2H), 5.02-5.01 (bs, 2H), 4.08– 4.06 (m, 1H), 3.70 (s, 3H), 3.17-3.16 (m, 2H), 2.67-2.24 (m, 11H), 1.80-1.75 (m, 2H), 1.57– 1.54 (m, 2H).

Step-iii: 5'-(5-Amino-2-(2,4-difluorophenoxy)phenyl)-7'-((1-methylpipe ridin-4- yl)oxy)spiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-ii of Example-X. 1H NMR (400 MHz, DMSO-d ₆ ): δ 10.24 (s, 1H), 7.30-7.27 (m, 1H), 7.17 (s, 1H), 6.86-6.81 (m, 3H), 6.72 (s, 1H), 6.61-6.59 (m, 2H), 5.16 (s, 2H), 4.05– 4.01 (m, 1H), 2.80-2.33 (m, 8H), 2.19-2.17 (m, 5H), 1.74– 1.59 (m, 4H); LCMS: m/z 506.1 (M+H). Example-XLIII: N-(4-(2,4-difluorophenoxy)-3-(7'-((1-methylpiperidin-4-yl)ox y)-2'- oxospiro[cyclobutane-1,3'-indolin]-5'-yl)phenyl)ethanesulfon amide (Compound-77)

Step-i: Synthesis of N-(4-(2,4-difluorophenoxy)-3-(1'-(4-methoxybenzyl)-7'-((1- methylpiperidin-4-yl)oxy)-2'-oxospiro[cyclobutane-1,3'-indol in]-5'-yl)phenyl)ethane- sulfonamide

To a cold solution of 5'-(5-amino-2-(2,4-difluorophenoxy)phenyl)-1'-(4-methoxy- benzyl)-7'-((1-methylpiperidin-4-yl)oxy)spiro[cyclobutane-1, 3'-indolin]-2'-one (0.2 g, 0.32 mmol) in DCM (5 mL) was added pyridine (0.13 mL, 1.6 mmol) followed by ethanesulfonyl chloride (0.03 mL, 0.35 mmol). The mixture was stirred at RT for 3 h. TLC was monitored, and the reaction mixture was diluted with DCM and washed with water and aqueous NaHCO3 solution. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as off white solid (0.15 g, 65 %). LCMS: m/z 718.1 (M+H).

Step-ii: N-(4-(2,4-difluorophenoxy)-3-(7'-((1-methylpiperidin-4-yl)ox y)-2'-oxo- spiro[cyclobutane-1,3'-indolin]-5'-yl)phenyl)ethanesulfonami de The compound was prepared using the process described in step-ii of Example-X. 1H NMR (400 MHz, DMSO-d6): δ 10.29 (s, 1H), 9.84 (bs, 1H), 7.38-7.22 (m, 4H), 7.12 (d, J = 8.8 Hz, 1H), 7.04-7.01 (m, 1H), 6.87 (s, 1H), 6.70-6.68 (m, 1H), 4.08– 4.05 (m, 1H), 3.16 (q, J=7.3 Hz, 2H), 2.67-2.40 (m, 5H), 2.23– 2.09 (m, 8H), 1.74– 1.70 (m, 2H), 1.58– 1.50 (m, 2H),1.34– 1.23 ( m, 3H); LCMS: m/z598.1 (M+H). Example-XLIV: 7'-((1-Methylpiperidin-4-yl)oxy)-5'-(3-morpholino-1-phenyl-1 H- razol-5- l s iro c clobutane-13'-indolin -2'-one Com ound-78

Step-i: 5'-(3,3-Bis(methylthio)acryloyl)-7'-bromo-1'-(4-methoxybenzy l)spiro- [cyclobutane-1,3'-indolin]-2'-one

To an ice cold suspension of sodium hydride (60 %) (1.2 g, 30.17 mmol) in THF (100 mL) was added 5'-acetyl-7'-bromo-1'-(4-methoxybenzyl)spiro[cyclobutane-1,3 '- indolin]-2'-one (5.0 g, 12.07 mmol) followed by stirring for 10 min. Carbon disulphide (0.87 mL, 14.48 mmol) was added at 0 ºC followed by stirring for 30 min. Methyl iodide (2.25 mL, 36.21 mmol) was then added followed by stirring at RT for 16 h. TLC was monitored and the reaction mixture was quenched with ice water and extracted with EtOAc. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as yellow solid (3.7 g, 59 %).1H NMR (400 MHz, DMSO-d6): δ 8.19 (d, J=1.5 Hz, 1H), 7.96 (d, J=1.9 Hz, 1H), 7.05 (d, J=8.8Hz, 2H), 6.88 (s, 1H), 6.86 (d, J=1.9 Hz, 2H), 5.24 (s, 2H), 3.70 (s, 3H), 2.56-2.53 (m, 2H), 2.50 (s, 6H), 2.47-2.33 (m, 4H); LC-MS: m/z 518.1 (M+H).

Step-ii: 7'-Bromo-1'-(4-methoxybenzyl)-5'-(3-(methylthio)-3-morpholin o- acryloyl)spiro[cyclobutane-1,3'-indolin]-2'-one To a suspension of 5'-(3,3-bis(methylthio)acryloyl)-7'-bromo-1'-(4-methoxy- benzyl)spiro[cyclobutane-1,3'-indolin]-2'-one (2.1 g, 4.05 mmol) in toluene (25 mL) was added morpholine (0.17 mL, 2.02 mmol) followed by heating at 100 ºC for 6 h. TLC was monitored and the reaction mixture was concentrated under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as yellow solid (0.6 g, 26 %).1H NMR (400 MHz, DMSO-d ₆ ): δ 8.12 (d, J=1.5 Hz, 1H), 7.84 (d, J=1.5 Hz, 1H), 7.04 (d, J=8.8Hz, 2H), 6.88-6.86 (m, 2H), 6.01-5.98 (m, 1H), 5.23 (s, 2H), 3.70 (s, 3H), 3.69-3.68 (m, 4H), 3.47-3.42 (m, 4H), 2.47-2.43 (m, 3H), 2.39-2.19 (m, 6H).

Step-iii: 7'-Bromo-1'-(4-methoxybenzyl)-5'-(3-morpholino-1-phenyl-1H-p yrazol- 5-yl)spiro [cyclobutane-1,3'-indolin]-2'-one

To a suspension of 7'-bromo-1'-(4-methoxybenzyl)-5'-(3-(methylthio)-3-morpho- linoacryloyl)spiro[cyclobutane-1,3'-indolin]-2'-one (0.6 g, 1.08 mmol) in tBuOH (20 mL) was added phenyl hydrazine hydrochloride (0.31 g, 2.16 mmol) and DABCO (0.24 mL, 2.16 mmol) followed by heating at 90 ºC for 16 h. TLC was monitored and the reaction mixture was concentrated under reduced pressure. The residue was purified by

CombiFlash® to afford the title compound as white solid (0.5 g, 77 %).1H NMR (400 MHz, DMSO-d ₆ ): δ 7.42-7.39 (m, 2H), 7.36-7.31 (m, 2H), 7.27-7.25 (m, 3H), 7.04 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 6.38 (s, 1H), 5.16 (s, 2H), 3.74-3.72 (m, 4H), 3.70 (s, 3H), 3.18 (d, J=4.4 Hz, 4H), 2.45-2.42 (m, 2H), 2.21-2.14 (m, 4H); LC-MS: m/z 599.0 (M+H).

Step-iv: 7'-Hydroxy-1'-(4-methoxybenzyl)-5'-(3-morpholino-1-phenyl-1H - pyrazol-5-yl)spiro [cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-ii of Example- XX.1H NMR (400 MHz, DMSO-d ₆ ): δ 9.84 (s, 1H), 7.37 (d, J=7.3 Hz, 2H), 7.34-7.17 (m, 5H), 6.86-6.84 (m, 3H), 6.64 (d, J=1.5 Hz, 1H), 6.16 (s, 1H), 4.97 (s, 2H), 3.73- 3.71 (m, 4H), 3.70 (s, 3H), 3.17 (d, J=4.4 Hz, 4H), 2.41-2.32 (m, 2H), 2.10-2.06 (m, 4H); LC-MS: m/z 537.1 (M+H).

Step-v:1'-(4-Methoxybenzyl)-7'-((1-methylpiperidin-4-yl)oxy) -5'-(3-morpholino- 1-phenyl-1H-pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'- one

The compound was prepared using the process described in step-iii of Example- XX.1H NMR (400 MHz, DMSO-d ₆ ): δ 7.40-7.36 (m, 2H), 7.31-7.28 (m, 1H), 7.24-7.23 (m, 2H), 7.18 (d, J=1.5 Hz, 1H), 7.05 (d, J=8.8 Hz, 2H), 6.84 (d, J=8.8 Hz, 2H), 6.56 (s, 1H), 6.32 (s, 1H), 5.00 (s, 2H), 3.98-3.96 (m, 1H), 3.71 (t, J=4.6 Hz, 4H), 3.69 (s, 3H), 3.18 (d, J=4.6 Hz, 4H), 2.46-2.32 (m, 3H), 2.29-2.18 (m, 3H), 2.08 (s, 3H), 2.06- 2.02 (m, 2H), 1.99-1.89 (m, 2H), 1.51-1.49 (m, 2H), 1.33-1.26 (m, 2H); LC-MS: m/z 634.2 (M+H).

Step-vi: 7'-((1-Methylpiperidin-4-yl)oxy)-5'-(3-morpholino-1-phenyl-1 H-pyrazol- 5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-ii of Example-X. 1H NMR (400 MHz, DMSO-d ₆ ): δ 10.40 (s, 1H), 7.40-7.36 (m, 2H), 7.31-7.27 (m, 1H), 7.22 (d, J=7.8 Hz, 2H), 7.11 (s, 1H), 6.59 (s, 1H), 6.30 (s, 1H), 4.07-4.05 (m, 1H), 3.74-3.72 (m, 4H), 3.19-3.17 (m, 4H), 2.71-2.67 (m, 2H), 2.42-1.99 (m, 11H), 1.65- 1.63 (m, 2H), 1.54-1.52 (m, 2H); LC-MS: m/z 514.2 (M+H). Example-XLV: 7'-Methoxy-5'-(1-(3-morpholinophenyl)-1H-pyrazol-5-yl)spiro- c clobutane-13'-indolin -2'-one Com ound-79

Step-i: 7'-Bromo-1'-(4-methoxybenzyl)-5'-(1-(3-nitrophenyl)-1H-pyraz ol-5-yl)- spiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-i of Example- XV.1H NMR (400 MHz, DMSO-d ₆ ): δ 8.24-8.15 (m, 2H), 7.88-7.84 (m, 1H), 7.73- 7.66 (m, 2H), 7.51-7.40 (m, 2H), 7.04 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 6.82 (d, J=1.9 Hz, 1H), 5.20 (s, 2H), 3.70 (s, 3H), 2.46-2.42 (m, 2H), 2.24-2.17 (m, 4H).

Step-ii: 5'-(1-(3-Aminophenyl)-1H-pyrazol-5-yl)-7'-bromo-1'-(4-methox ybenzyl)- spiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-iv of Example-I. LC-MS: m/z 529.1 (M+H). Step-iii: 7'-Bromo-1'-(4-methoxybenzyl)-5'-(1-(3-morpholinophenyl)-1H- pyrazol- 5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one

To a solution of 5'-(1-(3-aminophenyl)-1H-pyrazol-5-yl)-7'-bromo-1'-(4- methoxybenzyl)spiro[cyclobutane-1,3'-indolin]-2'-one (0.3 g, 0.57 mmol) in DMF (15 mL) were added 1-chloro-2-(2-chloroethoxy)ethane (0.33 mL, 2.85 mmol), sodium iodide (0.25 g, 1.71 mmol) and potassium carbonate (0.16 g, 1.14 mmol) then heated to 150ºC for 16h. TLC was monitored, reaction mixture poured into ice water, solids were filtered off, washed with water and dried under reduced pressure. The solid was purified by CombiFlash® to afford title compound as off white solid (0.28 g, 82%). LC-MS: m/z 601.2 (M+2H).

Step-iv: 7'-Hydroxy-1'-(4-methoxybenzyl)-5'-(1-(3-morpholinophenyl)-1 H- pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-ii of Example- XX.1H NMR (400 MHz, DMSO-d ₆ ): δ 10.01-9.98 (bs, 1H), 7.69 (d, J=2.0 Hz, 1H), 7.27-7.16 (m, 3H), 6.94-6.92 (m, 1H), 6.86-6.67 (m, 6H), 6.54 (d, J=2.0 Hz, 1H), 4.98 (s, 2H), 3.70 (s, 3H), 3.62 (t, J=8.6 Hz, 4H), 2.96 (t, J=4.9 Hz, 4H), 2.40-2.33 (m, 3H), 2.19-2.06 (m, 3H); LC-MS: m/z 537.3 (M+H).

Step-v: 7'-Methoxy-1'-(4-methoxybenzyl)-5'-(1-(3-morpholinophenyl)-1 H- pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-b of Inter- mediate-19.1H NMR (400 MHz, DMSO-d ₆ ): δ 7.70 (d, J=1.5 Hz, 1H), 7.28-7.24 (m, 1H), 7.12 (d, J=8.8 Hz, 2H), 7.01 (d, J=1.5 Hz, 1H), 6.99-6.87 (m, 1H), 6.86-6.81 (m, 4H), 6.78-6.69 (m, 2H), 4.93 (s, 2H), 3.70 (s, 3H), 3.68-3.64 (m, 4H), 3.63 (s, 3H), 2.97 (t, J=4.7 Hz, 4H), 2.44-2.37 (m, 2H), 2.18-1.96 (m, 4H); LC-MS: m/z 551.3 (M+H).

Step-vi: 7'-Methoxy-5'-(1-(3-morpholinophenyl)-1H-pyrazol-5-yl)spiro[ cyclo- butane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-ii of Example-X. 1H NMR (400 MHz, DMSO-d ₆ ): δ 10.37 (s, 1H), 7.70 (d, J=1.9 Hz, 1H), 7.25 (t, J=7.8 Hz, 1H), 6.97-6.95 (m, 2H), 6.86 (s, 1H), 6.79 (s, 1H), 6.68-6.66 (m, 2H), 3.68-3.65 (m, 7H), 3.03-3.00 (m, 4H), 2.37-2.33 (m, 2H), 2.15-1.95 (m, 4H); LC-MS: m/z 431.2 (M+H). The below compound was prepared by procedure similar to the one described in Example-XLV with appropriate variations in reactants, quantities of reagents and reaction conditions. The physiochemical characteristics of the compounds are also summarized in the table below.

Example-XLVI: 7'-Methoxy-5'-(1-(4-((1-methylpiperidin-4-yl)oxy)phenyl)-1H- pyrazol- 5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one (Compound-81)

Step-i: 5'-(1-(4-Bromophenyl)-1H-pyrazol-5-yl)-7'-methoxy-1'-(4-meth oxy- benzyl)spiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-i of Example- XV using 4-bromophenylhydrazine as starting material. 1H NMR (400 MHz, DMSO-d ₆ ): δ 7.77 (d, J=2.0 Hz, 1H), 7.64 (d, J=8.8 Hz, 2H), 7.26 (d, J=8.9 Hz, 2H), 7.15 (d, J=8.3 Hz, 2H), 6.99 (d, J=1.5 Hz, 1H), 6.86-6.82 (m, 3H), 6.72 (d, J=1.5 Hz, 1H), 4.94 (s, 2H), 3.70 (s, 3H), 3.60 (s, 3H), 2.44-2.40 (m, 2H), 2.20-2.11 (m, 3H), 2.08-1.91 (m, 1H); LC-MS: m/z 544.2 (M+H). Step-ii: 5'-(1-(4-Hydroxyphenyl)-1H-pyrazol-5-yl)-7'-methoxy-1'-(4-me thoxy- benzyl)spiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-ii of Example- XX.1H NMR (400 MHz, DMSO-d ₆ ): δ 9.73 (s, 1H), 7.66 (d, J=1.4 Hz, 1H), 7.15-7.09 (m, 4H), 6.99 (d, J=0.9 Hz, 1H), 6.86-6.81 (m, 4H), 6.79 (s, 1H), 6.88 (d, J=1.9 Hz, 1H), 4.92 (s, 2H), 3.70 (s, 3H), 3.57 (s, 3H), 2.46-2.40 (m, 2H), 2.15-1.97 (m, 4H); LC- MS: m/z 482.2 (M+H).

Step-iii: 7'-Methoxy-1'-(4-methoxybenzyl)-5'-(1-(4-((1-methylpiperidin -4-yl)- oxy)phenyl)-1H-pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]- 2'-one

The compound was prepared using the process in step-iii of Example-XX. LC- MS: m/z 579.3 (M+H).

Step-iv: 7'-Methoxy-5'-(1-(4-((1-methylpiperidin-4-yl)oxy)phenyl)-1H- pyrazol-5- yl)spiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-ii of Example-X. 1H NMR (400 MHz, DMSO-d ₆ ): δ 10.37 (s, 1H), 7.69 (d, J=2.0 Hz, 1H), 7.20 (d, J=8.8 Hz, 2H), 7.01 (d, J=8.8 Hz, 2H), 6.84 (d, J=1.0 Hz, 1H), 6.78 (d, J=1.4 Hz, 1H), 6.67 (d, J=1.9 Hz, 1H), 4.42-4.39 (m, 1H), 3.65 (s, 3H), 2.62-2.60 (m, 2H), 2.47-2.32 (m, 2H), 2.21-2.19 (m, 5H), 2.06-2.01 (m, 3H), 1.93-1.90 (m, 3H), 1.64-1.62 (m, 2H); LC- MS: m/z 459.3 (M+H). The below compound was prepared by procedure similar to the one described in Example-XLVI with appropriate variations in reactants, quantities of reagents and reaction conditions. The physiochemical characteristics of the compounds are also summarized in the table below.

Example-XLVII: 7'-((1-Methylpiperidin-4-yl)oxy)-5'-(2-phenyl-1H-imidazol-1- yl)spiro c clobutane-13'-indolin -2'-one Com ound-83

Step-i: 7’-Bromo-1'-(4-methoxybenzyl)-5'-nitrospiro[cyclobutane-1, 3'-indolin]-2'-one To an ice cold solution of 7'-bromo-5'-nitrospiro[cyclobutane-1,3'-indolin]-2'-one (13.0 g, 43.77 mmol) in DMF (130 mL) was added Cs ₂ CO ₃ (28.5 g, 87.51 mmol) and 4- methoxybenzyl chloride (7.2 mL, 52.5 mmol) followed by stirring at RT for 3 h. TLC was monitored, the reaction mixture diluted with ice water and extracted with EtOAc. The organic layer was dried over sodium sulphate and concentrated. The residue was purified by combi-flash to afford the title compound as pale brown solid (12.0 g, 66 %). 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.56 (d, J=1.9 Hz, 1H), 8.26 (d, J=2.4 Hz, 1H), 7.06 (d, J=8.3 Hz, 2H), 6.87 (d, J=8.4 Hz, 2H), 5.26 (s, 2H), 3.71 (s, 3H), 2.63-2.53 (m, 2H), 2.51-2.24 (m, 4H).

Step-ii: 7'-Hydroxy-1'-(4-methoxybenzyl)-5'-nitrospiro[cyclobutane-1, 3'-indolin]- 2'-one

To a solution of 7’-bromo-1'-(4-methoxybenzyl)-5'-nitrospiro[cyclobutane-1, 3'- indolin]-2'-one (10.0 g, 23.96 mmol) in 1,4-dioxane (60 mL) and H ₂ O (40 mL) was added KOH (4.1 g, 71.89 mmol) followed by degassing with nitrogen purging for 20 min. Then tBuXPhos (1.0 g, 2.39 mmol) and Pd ₂ (dba) ₃ (2.20 g, 2.39 mmol) were added followed by again degassing with nitrogen purging for 20 min. The mixture was heated at 100 °C for 16 h. TLC was monitored and the mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (250 ml), washed with water (250 mL) and brine (250 mL), dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by combi-flash to afford title compound as pale brown solid (3.5 g, 42 %).1H NMR (400 MHz, DMSO-d ₆ ) δ 10.76 (s, 1H), 8.06 (d, J=2.5 Hz, 1H), 7.63 (d, J=2.0 Hz, 1H), 7.18 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 5.06 (s, 2H), 3.70 (s, 3H), 2.51-2.19 (m, 6H); LC-MS: m/z 355.1 (M+H).

Step-iii: 1'-(4-Methoxybenzyl)-7'-((1-methylpiperidin-4-yl)oxy)-5'-nit rospiro- [cyclobutane-1,3'-indolin]-2'-one

To a cold solution of 1-methylpiperidin-4-ol (6.5 g, 56.48 mmol) in THF (140 mL) was added triphenyl phosphine (14.8 g, 56.48 mmol) and DIAD (11.1 mL, 56.48 mmol) followed by stirring at 0 ºC for 15 min. Then 7'-hydroxy-1'-(4-methoxybenzyl)-5'- nitrospiro[cyclobutane-1,3'-indolin]-2'-one (5.0 g, 14.12 mmol) was added followed by stirring at RT for 16 h. TLC was monitored, and the mixture was diluted with EtOAc and washed with water. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by combi-flash to afford the title compound as yellow solid (7.5 g).1H NMR (400 MHz, DMSO-d6) δ 8.20 (d, J=1.4 Hz, 1H), 7.77 (d, J=1.5 Hz, 1H), 7.05 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 5.12 (s, 2H), 4.60-4.59 (m, 1H), 3.69 (s, 3H), 2.67-2.45 (m, 5H), 2.32-2.11 (m, 8H), 1.89-1.84 (m, 2H), 1.53-1.51 (m, 2H); LC-MS: m/z 452.1 (M+H).

Step-iv: 5'-Amino-1'-(4-methoxybenzyl)-7'-((1-methylpiperidin-4-yl)ox y)spiro [cyclobutane-1,3'-indolin]-2'-one

To a solution of 1'-(4-methoxybenzyl)-7'-((1-methylpiperidin-4-yl)oxy)-5'-nit ro- spiro[cyclobutane-1,3'-indolin]-2'-one (15.0 g, 33.25 mmol) in EtOH (150 mL) and H ₂ O (30 mL) were added iron powder (9.3 g, 166.25 mmol) and NH ₄ Cl (8.81 g, 166.25 mmol) followed by heating at 100 oC for 2 h. TLC was monitored, and the mixture was cooled to RT, filtered through Celite® and washed with EtOAc. The combined filtrate was concentrated. The residue was diluted with water, extracted with EtOAc (500 mL), washed with brine (500 mL), dried over sodium sulphate, concentrated under reduced pressure and purified by combi-flash to afford the title compound as pale yellow solid (8.3 g).1H NMR (400 MHz, DMSO-d6) δ 7.05 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 6.51 (d, J=1.4 Hz, 1H), 6.19 (d, J=2.0 Hz, 1H), 4.95 (bs, 4H), 4.30-4.28 (m, 1H), 3.69 (s, 3H), 3.16-2.62 (m, 4H), 2.46-2.36 (m, 5H), 2.26-2.08 (m, 4H), 1.92-1.91 (m, 2H), 1.66-1.65 (m, 2H); LC-MS: m/z 422.1 (M+H).

Step-v: 1'-(4-Methoxybenzyl)-7'-((1-methylpiperidin-4-yl)oxy)-5'-(2- phenyl-1H- imidazol-1-yl)spiro[cyclobutane-1,3'-indolin]-2'-one To a solution of 5'-amino-1'-(4-methoxybenzyl)-7'-((1-methylpiperidin-4-yl)ox y)- spiro[cyclobutane-1,3'-indolin]-2'-one (0.1 g, 0.24 mmol) and benzaldehyde (0.05 mL, 0.48 mmol) in MeOH (5 mL) was added glyoxal (0.02 mL, 0.48 mmol) and ammonium carbonate (0.05 g, 0.48 mmol) followed by heating at 60 ºC for 16 h. TLC was monitored, and the mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as pale brown oil (0.07 g, 54 %).1H NMR (400 MHz, DMSO-d ₆ ): δ 7.58 (s, 1H), 7.34-7.30 (m, 5H), 7.25 (d, J=1.2 Hz, 1H), 7.16 (s, 1H), 7.06 (d, J=8.2 Hz, 2H), 6.86 (d, J=8.3 Hz, 2H), 6.73 (d, J=1.4 Hz, 1H), 5.03 (s, 2H), 4.16-4.14 (m, 1H), 3.70 (s, 3H), 2.44-2.18 (m, 7H), 2.15-2.05 (m, 4H), 1.94-1.91 (m, 2H), 1.55-1.52 (m, 2 H), 1.34-1.29 (m, 2H); LC-MS: m/z 549.3 (M+H).

Step-vi: 7'-((1-Methylpiperidin-4-yl)oxy)-5'-(2-phenyl-1H-imidazol-1- yl)spiro- [cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-ii of Example-X. 1H NMR (400 MHz, DMSO-d6): δ 10.43 (s, 1H), 7.51 (d, J=1.0 Hz, 1H), 7.37-7.30 (m, 5H), 7.18-7.16 (m, 2H), 6.76 (s, 1H), 4.23-4.21 (m, 1H), 2.68-2.33 (m, 5H), 2.26-2.03 (m, 8H), 1.69-1.67 (m, 2H), 1.56-1.54 (m, 2 H); LC-MS: m/z 427.2 (M-H). Example-XLVIII: 7'-Methoxy-5'-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl) spiro- c clobutane-13'-indolin -2'-one Com ound-84

Step-i: 7'-Methoxy-1'-(4-methoxybenzyl)-5'-(1-(tetrahydro-2H-pyran-4 -yl)-1H- pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process in step-i of Example-XV.1H NMR (400 MHz, DMSO-d ₆ ): δ 7.52 (d, J=2.0 Hz, 1H), 7.30 (d, J=1.0 Hz, 1H), 7.19 (d, J=8.8 Hz, 2H), 6.93 (s, 1H), 6.88 (d, J=8.3 Hz, 2H), 6.33 (d, J=1.5 Hz, 1H), 4.99 (s, 2H), 4.43-4.44 (m, 1H), 3.96-3.90 (m, 2H), 3.78 (s, 3H), 3.70 (s, 3H), 3.39-3.32 (m, 2H), 2.50-2.48 (m, 4H), 2.37-1.98 (m, 4H), 1.85-1.82 (m, 2H); LC-MS: m/z 474.3 (M+H).

Step-ii: 7'-Methoxy-5'-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl) spiro- [cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-ii of Example-X. 1H NMR (400 MHz, DMSO-d ₆ ): δ 10.44 (s, 1H), 7.53 (d, J=1.5 Hz, 1H), 7.23 (d, J=0.9 Hz, 1H), 6.91 (d, J=1.5 Hz, 1H), 6.33 (d, J=1.9 Hz, 1H), 4.44-4.42 (m, 1H), 3.95-3.90 (m, 2H), 3.85 (s, 3H), 3.63 (t, J=11.7 Hz, 2H), 2.47-2.30 (m, 4H), 2.20-2.08 (m, 4H), 1.85-1.82 (m, 2H); LC-MS: m/z 354.2 (M+H). The below compound was prepared by procedure similar to the one described in Example-XLVIII with appropriate variations in reactants, quantities of reagents and reaction conditions. The physiochemical characteristics of the compounds are also summarized in the table below.

Example-XLIX: 7'-((2-Methyl-2-azaspiro[3.3]heptan-6-yl)oxy)-5'-(1-phenyl-1 H- pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one (Compound-86)

Step-i: tert-Butyl-6-((1'-(4-methoxybenzyl)-2'-oxo-5'-(1-phenyl-1H-p yrazol-5- yl)spiro [cyclobutane-1,3'-indolin]-7'-yl)oxy)-2-azaspiro[3.3]heptane -2-carboxylate

To a solution of 7'-hydroxy-1'-(4-methoxybenzyl)-5'-(1-phenyl-1H-pyrazol-5-yl )- spiro[cyclobutane-1,3'-indolin]-2'-one (0.1 g, 0.22 mmol) in DMF (3 mL) was added potassium carbonate (0.09 g, 0.66 mmol) and tert-butyl 6-((methylsulfonyl)oxy)-2-aza- spiro[3.3]heptane-2-carboxylate (0.08 g, 0.26 mmol) followed by heating in 100 ºC for 16 h. TLC was monitored, and the mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as off-white solid (0.12 g, 84 %).1H NMR (400 MHz, DMSO-d ₆ ): δ 7.74 (d, J=2.0 Hz, 1H), 7.46-7.41 (m, 2H), 7.37-7.31 (m, 1H), 7.30-7.29 (m, 1H), 7.10 (s, 1H), 7.03 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.3 Hz, 2H), 6.70 (d, J=1.9 Hz, 1H), 6.47 (d, J=0.9 Hz, 1H), 4.95 (s, 2H), 4.89-4.86 (m, 1H), 3.85-3.70 (m, 7H), 2.67-2.65 (m, 2H), 2.49- 2.42 (m, 2H), 2.26-2.24 (m, 4H), 2.19-2.17 (m, 2H), 1.37 (s, 9H).

Step-ii: 7'-((2-Azaspiro[3.3]heptan-6-yl)oxy)-1'-(4-methoxybenzyl)-5' -(1-phenyl- 1H-pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one trifluoro acetate

The compound was prepared using the process described in step-a of Inter- mediate-23 and proceeded further without purification for the next step.

Step-iii: 1'-(4-Methoxybenzyl)-7'-((2-methyl-2-azaspiro[3.3]heptan-6-y l)oxy)-5'- (1-phenyl-1H-pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2' -one

To a solution of 7'-((2-Azaspiro[3.3]heptan-6-yl)oxy)-1'-(4-methoxybenzyl)-5' - (1-phenyl-1H-pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2' -one trifluoro acetate (0.04 g) in mixture of MeOH (1 mL) was added aqueous formaldehyde 30 % (1 mL) and acetic acid (0.1 mL) followed by stirring at RT for 16 h. The mixture was cooled to 0 ºC, and sodium borohydride (0.12 g) was added followed by stirring at RT for 1 h. TLC was monitored, and the reaction mixture was quenched with aqueous NH ₄ Cl and extracted with DCM. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as off white solid (0.03 g).1H NMR (400 MHz, DMSO-d ₆ ): δ 7.74 (d, J=1.5 Hz, 1H), 7.48-7.44 (m, 3H), 7.30 (d, J=7.3 Hz, 2H), 7.13 (d, J=1.4 Hz, 1H), 7.03 (d, J=8.8 Hz, 2H), 6.87-6.83 (m, 2H), 6.70 (d, J=2.0 Hz, 1H), 6.44 (d, J=1.0 Hz, 1H), 4.95 (s, 2H), 4.26-4.23 (m, 1H), 3.75-3.70 (m, 5H), 3.46-3.44 (m, 2H), 2.67-2.63 (m, 2H), 2.43-2.41 (m, 2H), 2.24-2.20 (m, 5H), 2.04-2.02 (m, 2H), 1.88-1.84 (m, 2H); LC-MS: m/z 561.3 (M+H).

Step-iv: 7'-((2-Methyl-2-azaspiro[3.3]heptan-6-yl)oxy)-5'-(1-phenyl-1 H-pyrazol- 5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-ii of Example-X. 1H NMR (400 MHz, DMSO-d ₆ ): δ 10.34 (s, 1H), 7.74 (d, J=2.0 Hz, 1H), 7.48-7.39 (m, 3H), 7.31-7.29 (m, 2H), 7.05 (s, 1H), 6.67 (d, J=1.5 Hz, 1H), 6.46 (d, J=1.5 Hz, 1H), 4.36-4.33 (m, 1H), 3.77-3.75 (m, 4H), 2.60 (s, 3H), 2.46-2.32 (m, 4H), 2.14-1.98 (m, 6H); LC-MS: m/z 441.3 (M+H). Example-L: 7'-((2-Azaspiro[3.3]heptan-6-yl)oxy)-5'-(1-phenyl-1H-pyrazol -5-yl)- s iro c clobutane-13'-indolin -2'-one Com ound-87

The compound was prepared using the process described in step-ii of Example- XXVII.1H NMR (400 MHz, DMSO-d6): δ 10.35-10.25 (bs, 1H), 7.73 (d, J=1.5 Hz, 1H), 7.48-7.40 (m, 3H), 7.31 (d, J=7.3 Hz, 2H), 7.09 (d, J=0.9 Hz, 1H), 6.69 (d, J=1.5 Hz, 1H), 6.41 (s, 1H), 4.24-4.21 (m, 1H), 3.42 (s, 2H), 3.37 (s, 2H), 2.40-2.29 (m, 5H), 2.17-2.12 (m, 3H), 2.01-1.93 (m, 3H); LC-MS: m/z 427.2 (M+H). Example-LI: 7'-((1-Methylpiperidin-4-yl)oxy)-5'-(1-phenyl-1H-1,2,3-triaz ol-5- l s iro c clobutane-13'-indolin -2'-one Com ound-88

Step-i: 1'-(4-Methoxybenzyl)-7'-((1-methylpiperidin-4-yl)oxy)-5'-(1- phenyl-1H- 1,2,3-triazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one To a solution of 1-phenyl-1H-1,2,3-triazole (0.25 g, 1.72 mmol) and 5'-bromo-1'- (4-methoxybenzyl)-7'-((1-methylpiperidin-4-yl)oxy)spiro[cycl obutane-1,3'-indolin]-2'- one (0.83 g, 1.72 mmol) in DMF (10 mL) was added Cs ₂ CO ₃ (1.12 g, 3.44 mmol) followed by degassing with nitrogen purging for 15 min. Tri(o-tolyl)phosphine (0.1 g, 0.34 mmol) and Pd(OAc) ₂ (0.04 g, 0.17 mmol) were then added followed by degassing with nitrogen purging for 15 min. The mixture was then heated in 130 ºC for 16 h. TLC was monitored, the mixture diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as pale green oil (0.28 g).1H NMR (400 MHz, DMSO-d ₆ ): δ 8.18 (s, 1H), 7.57-7.55 (m, 1H), 7.49-7.46 (m, 2H), 7.25-7.25 (m, 2H), 7.07-7.03 (m, 3H), 6.99-6.94 (m, 1H), 6.87-6.85 (m, 2H), 5.09 (s, 2H), 4.46-4.45 (m, 1H), 3.69 (s, 3H), 2.44-2.06 (m, 11H), 1.91-1.82 (m, 2H), 1.59- 1.57 (m, 2H), 1.43-1.41 (m, 2H).

Step-ii: 7'-((1-Methylpiperidin-4-yl)oxy)-5'-(1-phenyl-1H-1,2,3-triaz ol-5-yl)spiro- [cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-ii of Example-X. 1H NMR (400 MHz, DMSO-d ₆ ): δ 10.41 (s, 1H), 8.15 (s, 1H), 7.57-7.55 (m, 3H), 7.46- 7.43 (m, 2H), 7.19 (s, 1H), 6.65 (s, 1H), 4.01-3.99 (m, 1H), 2.67-2.62 (m, 2H), 2.44- 2.42 (m, 2H), 2.39-1.99 (m, 9H), 1.63-1.61 (m, 2H), 1.49-1.47 (m, 2H); LC-MS: m/z 430.2 (M+H). Example-LII: 7'-Methoxy-5'-(1-(piperidin-4-yl)-1H-pyrazol-5-yl)spiro[cycl obutane-1,3'- indolin]-2'-one (Compound-89)

Step-i: 5'-(1-(1-Benzylpiperidin-4-yl)-1H-pyrazol-5-yl)-7'-methoxy-1 '-(4- methoxybenzyl) spiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-i of Example- XV. LC-MS: m/z 563.4 (M+H).

Step-ii:5'-(1-(1-benzylpiperidin-4-yl)-1H-pyrazol-5-yl)-7'-m ethoxyspiro[cyclo- butane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-ii of Example-X. 1H NMR (400 MHz, DMSO-d ₆ ): δ 10.62 (s, 1H), 8.22 (s, 1H), 7.59 (s, 1H), 7.34-7.27 (m, 5H), 6.80 (s, 1H), 6.32 (d, J=1.9 Hz, 1H), 4.19-4.17 (m, 1H), 3.86 (s, 3H), 3.51 (s, 2H), 2.90-2.87 (m, 2H), 2.43-2.31 (m, 4H), 2.21-1.99 (m, 6H), 1.87-1.85 (m, 2H); LC- MS: m/z 443.2 (M+H).

Step-iii: 7'-Methoxy-5'-(1-(piperidin-4-yl)-1H-pyrazol-5-yl)spiro[cycl obutane- 1,3'-indolin]-2'-one

To a stirring solution of 5'-(1-(1-benzylpiperidin-4-yl)-1H-pyrazol-5-yl)-7'- methoxy spiro[cyclobutane-1,3'-indolin]-2'-one (0.18 g, 0.41 mmol) in MeOH (10 mL) was added 10 % Pd-C (0.15 g) followed by stirring under hydrogen bladder pressure at RT for 16 h. TLC was monitored, and the mixture was filtered through Celite® and washed with EtOAc. The combined filtrates were concentrated under reduced pressure and purified by CombiFlash® followed by preparative HPLC to afford the title compound as off-white solid (0.01g).1H NMR (400 MHz, DMSO-d ₆ ): δ 10.44 (s, 1H), 7.50 (s, 1H), 7.21 (s, 1H), 6.89 (s, 1H), 6.31 (s, 1H), 4.27-4.21 (m, 1H), 3.84 (s, 3H), 3.04-3.01 (m, 2H), 2.45-2.41 (m, 4H), 2.38-2.29 (m, 3H), 2.26-2.18 (m, 2H), 2.05-1.96 (m, 2H), 1.82-1.79 (m, 2H); LC-MS: m/z 353.2 (M+H). Example-LIII: 5'-(1-Phenyl-1H-pyrazol-5-yl)-7'-((1-(2,2,2-trifluoroethyl)p iperidin-4- yl)oxy)spiro[cyclobutane-1,3'-indolin]-2'-one (Compound-90)

Step-i: tert-Butyl4-((1'-(4-methoxybenzyl)-2'-oxo-5'-(1-phenyl-1H-py razol-5- yl)spiro[cyclobutane-1,3'-indolin]-7'-yl)oxy)piperidine-1-ca rboxylate

The compound was prepared using the process described in step-iii of Example- XLVII.1H NMR (400 MHz, DMSO-d ₆ ): δ 9.58-9.56 (bs, 1H), 7.74 (d, J=2.0 Hz, 1H), 7.47-7.38 (m, 3H), 7.31 (d, J=7.3 Hz, 2H), 7.18 (s, 1H), 7.01 (d, J=8.8 Hz, 2H), 6.82 (d, J=8.3 Hz, 2H), 6.73 (d, J=1.5 Hz, 1H), 6.64 (s, 1H), 4.98 (s, 2H), 4.20-4.18 (m, 1H), 3.68 (s, 3H), 3.50-3.48 (m, 2H), 2.82-2.80 (m, 2H), 2.47-2.42 (m, 3H), 2.27-2.23 (m, 3H), 2.05-2.03 (m, 1H), 1.50-1.48 (m, 2H), 1.39 (s, 9H); LC-MS: m/z 635.4 (M+H).

Step-ii: 1'-(4-Methoxybenzyl)-5'-(1-phenyl-1H-pyrazol-5-yl)-7'-(piper idin-4- yloxy)spiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-a of

Intermediate-23. LC-MS: m/z 535.3 (M+H).

Step-iii: 1'-(4-Methoxybenzyl)-5'-(1-phenyl-1H-pyrazol-5-yl)-7'-((1-(2 ,2,2- trifluoroethyl) piperidin-4-yl)oxy)spiro[cyclobutane-1,3'-indolin]-2'-one

In a sealed tube, a solution of 1'-(4-methoxybenzyl)-5'-(1-phenyl-1H-pyrazol-5- yl)-7'-(piperidin-4-yloxy)spiro[cyclobutane-1,3'-indolin]-2' -one (0.12 g, 0.22 mmol) in DMSO (5 mL) was added triethyl amine (0.05 mL, 0.33 mmol) and 1,1,1-trifluoro-2- iodoethane (0.03 mL, 0.33 mmol) followed by heating at 110 ºC for 8 h. TLC was monitored, and the mixture was diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as off white solid (0.08 g, 57 %).1H NMR (400 MHz, DMSO-d ₆ ): δ 7.75 (d, J=1.9 Hz, 1H), 7.47-7.32 (m, 3H), 7.31 (d, J=6.8 Hz, 2H), 7.19 (d, J=1.4 Hz, 1H), 7.05 (d, J=8.8 Hz, 2H), 6.85 (d, J=8.3 Hz, 2H), 6.74 (d, J=1.5 Hz, 1H), 6.59 (d, J=1.0 Hz, 1H), 5.00 (s, 2H), 4.02- 4.01 (m, 1H), 3.68 (s, 3H), 3.10-3.02 (m, 2H), 2.61-2.58 (m, 2H), 2.46-2.40 (m, 2H), 2.32-2.21 (m, 5H), 2.07-2.03 (m, 1H), 1.49-1.47 (m, 2H), 1.29-1.24 (m, 2H); LC-MS: m/z 617.3 (M+H).

Step-iv: 5'-(1-Phenyl-1H-pyrazol-5-yl)-7'-((1-(2,2,2-trifluoroethyl)p iperidin-4- yl)oxy)spiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-iii of Example- X.1H NMR (400 MHz, DMSO-d ₆ ): δ 10.35 (s, 1H), 7.73 (d, J=1.5 Hz, 1H), 7.46-7.36 (m, 3H), 7.31-7.28 (m, 2H), 7.11 (d, J=1.0 Hz, 1H), 6.99 (d, J=2.0 Hz, 1H), 6.59 (d, J=1.0 Hz, 1H), 4.05-4.00 (m, 1H), 3.14 (q, J=10.2 Hz, 2H), 2.82-2.79 (m, 2H), 2.42- 2.33 (m, 4H), 2.21-1.99 (m, 4H), 1.64-1.61 (m, 2H), 1.51-1.42 (m, 2H); LC-MS: m/z 497.2 (M+H). Example-LIV: 7'-(6-Methyl-2,6-diazaspiro[3.3]heptan-2-yl)-5'-(1-phenyl-1H - razol-5- l s iro c clobutane-13'-indolin -2'-one Com ound-91

Step-i: 1'-(4-Methoxybenzyl)-7'-(6-methyl-2,6-diazaspiro[3.3]heptan- 2-yl)-5'-(1- phenyl-1H-pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-on e

The compound was prepared using the process described in step-i of Example-X. LC-MS: m/z 546.3 (M+H).

Step-ii: 7'-(6-Methyl-2,6-diazaspiro[3.3]heptan-2-yl)-5'-(1-phenyl-1H -pyrazol-5- yl)spiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-iii of Example- X.1H NMR (400 MHz, DMSO-d ₆ ): δ 9.69 (s, 1H), 7.71 (d, J=1.4 Hz, 1H), 7.46-7.39 (m, 3H), 7.29 (d, J=7.4 Hz, 2H), 6.80 (d, J=1.0 Hz, 1H), 6.65 (d, J=1.9 Hz, 1H), 6.18 (d, J=1.5 Hz, 1H), 3.77 (s, 4H), 3.24 (s, 4H), 2.44-2.33 (m, 2H), 2.21 (s, 3H), 2.10-1.91 (m, 4H); LC-MS: m/z 426.2 (M+H). The below compound was prepared by procedure similar to the one described in Example-LIV with appropriate variations in reactants, quantities of reagents and reaction conditions. The physiochemical characteristics of the compounds are also summarized in the table below.

Example-LV: 7'-((2-Oxaspiro[3.3]heptan-6-yl)oxy)-5'-(1-phenyl-1H-pyrazol -5- l s iro c clobutane-13'-indolin -2'-one Com ound-94

Step-i: 7'-Hydroxy-5'-(1-phenyl-1H-pyrazol-5-yl)spiro[cyclobutane-1, 3'-indolin]- 2'-one

The compound was prepared using the process described in step-iii of Example- X.1H NMR (400 MHz, DMSO-d ₆ ): δ 10.08 (s, 1H), 9.60 (s, 1H), 7.72 (d, J=1.5 Hz, 1H), 7.45-7.35 (m, 3H), 7.29 (d, J=7.3 Hz, 2H), 6.77 (d, J=1.5 Hz, 1H), 6.62 (d, J=1.5 Hz, 1H), 6.57 (d, J=1.9 Hz, 1H), 2.37-2.34 (m, 2H), 2.10-2.00 (m, 3H), 1.94-1.88 (m, 1H); LC-MS: m/z 332.2 (M+H). Step-ii: 7'-((2-Oxaspiro[3.3]heptan-6-yl)oxy)-5'-(1-phenyl-1H-pyrazol -5-yl)spiro- [cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step iii of Example- XLVII 1H NMR (400 MHz, DMSO-d ₆ ): δ 10.32 (s, 1H), 7.74 (s, 1H), 7.47-7.41 (m, 3H), 7.30 (d, J=7.3 Hz, 2H), 7.08 (s, 1H), 6.69 (s, 1H), 6.43 (s, 1H), 4.53 (s, 2H), 4.48 (s, 2H), 4.27-4.24 (m, 1H), 2.45-2.33 (m, 4H), 2.15-2.01 (m, 6H); LC-MS: m/z 428.2 (M+H). Example-LVI: 5'-(1-Methyl-2-oxo-3-phenyl-2,3-dihydro-1H-imidazol-4-yl)-7' - ((1-methylpiperidin-4-yl)oxy)spiro[cyclobutane-1,3'-indolin] -2'-one (Compound-95)

Step-i: 7'-Bromo-5'-(2-bromoacetyl)-1'-(4-methoxybenzyl)spiro[cyclob utane-1,3'- indolin]-2'-one

To a solution of 5'-acetyl-7'-bromo-1'-(4-methoxybenzyl)spiro[cyclobutane-1,3 '- indolin]-2'-one (3.0 g, 7.24 mmol) in AcOH (45 mL) was added HBr in acetic acid (1.8 mL) and bromine (0.37 mL, 7.24 mmol) followed by heating at 70 ºC for 1 h. TLC was monitored, and the mixture was poured into aqueous NaHCO ₃ and extracted with EtOAc. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as off white solid (1.1 g, 31 %).1H NMR (400 MHz, DMSO-d ₆ ): δ 8.28 (d, J=1.5 Hz, 1H), 8.02 (d, J=1.5 Hz, 1H), 7.05 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.3 Hz, 2H), 5.25 (s, 2H), 4.95 (s, 2H), 3.70 (s, 3H), 2.59-2.50 (m, 4H), 2.47-2.23 (m, 2H); LC-MS: m/z 494.0 (M+H).

Step-ii: tert-Butyl(2-(7'-bromo-1'-(4-methoxybenzyl)-2'-oxospiro[cycl obutane- 1,3'-indolin]-5'-yl)-2-oxoethyl)(methyl)carbamate To an ice cold solution of 7'-bromo-5'-(2-bromoacetyl)-1'-(4-methoxybenzyl)- spiro[cyclobutane-1,3'-indolin]-2'-one (1.0 g, 2.02 mmol) in THF (10 mL) was added methylamine in THF(2M) (1.2 mL, 2.42 mmol) followed by stirring for 2 h at 0 ºC. Triethyl amine (0.84 mmol, 6.06 mmol) and (Boc) ₂ O (1.4 mL, 6.06 mmol) were added followed by stirring at RT for 16 h. TLC was monitored, and the mixture was diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as pale yellow oil (0.72 g, 65 %).1H NMR (400 MHz, DMSO-d ₆ ): δ 8.25 (d, J=3.9 Hz, 1H), 7.96 (d, J=5.9 Hz, 1H), 7.04 (d, J=7.8 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 5.25 (s, 2H), 4.74 (s, 2H), 3.70 (s, 3H), 2.85-2.82 (m, 3H), 2.44-2.50 (m, 4H), 2.34-2.24 (m, 2H), 1.42-1.29 (m, 9H).

Step-iii: 7'-Bromo-1'-(4-methoxybenzyl)-5'-(1-methyl-2-oxo-3-phenyl-2, 3- dihydro-1H-imidazol-4-yl)spiro[cyclobutane-1,3'-indolin]-2'- one

HCl in 1,4-dioxane was added to tert-butyl (2-(7'-bromo-1'-(4-methoxybenzyl)- 2'-oxospiro[cyclobutane-1,3'-indolin]-5'-yl)-2-oxoethyl)(met hyl)carbamate (0.7 g, 1.29 mmol) at 0 ºC followed by stirring at RT for 2 h. TLC was monitored, and the mixture was concentrated under reduced pressure. The residue was dissolved in toluene (10 mL) and cooled to 0 ºC. Triethyl amine (0.36 mL, 2.58 mmol) and phenyl isocyanate (0.17 mL, 1.55 mmol) were added followed by stirring at RT for 16 h. TLC was monitored, and the mixture was diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as off white solid (0.32 g, 45 %). 1H NMR (400 MHz, DMSO-d ₆ ): δ 7.46-7.42 (m, 2H), 7.39-7.37 (m, 1H), 7.22 (d, J=7.3 Hz, 2H), 7.12 (s, 2H), 7.05 (d, J=1.5 Hz, 1H), 7.00 (d, J=8.8 Hz, 2H), 6.85 (d, J=8.8 Hz, 2H), 5.11 (s, 2H), 3.69 (s, 3H), 3.26 (s, 3H), 2.44-2.41 (m, 2H), 2.10-2.07 (m, 4H); LC-MS: m/z 546.1 (M+2H).

Step-iv: 7'-Hydroxy-1'-(4-methoxybenzyl)-5'-(1-methyl-2-oxo-3-phenyl- 2,3- dihydro-1H-imidazol-4-yl)spiro[cyclobutane-1,3'-indolin]-2'- one

The compound was prepared using the process described in step-ii of Example- XLVII.1H NMR (400 MHz, DMSO-d ₆ ): δ 9.75 (s, 1H), 7.42-7.38 (m, 2H), 7.36-7.29 (m, 1H), 7.18-7.15 (m, 4H), 6.84 (s, 2H), 6.82 (s, 1H), 6.56 (d, J=1.5 Hz, 1H), 6.51 (d, J=1.5 Hz, 1H), 4.92 (s, 2H), 3.69 (s, 3H), 3.25 (s, 3H), 2.38-2.31 (m, 2H), 2.11-2.08 (m, 1H), 1.97-1.86 (m, 3H); LC-MS: m/z 482.2 (M+H). Step-v: 1'-(4-Methoxybenzyl)-5'-(1-methyl-2-oxo-3-phenyl-2,3-dihydro -1H- imidazol-4-yl)-7'-((1-methylpiperidin-4-yl)oxy)spiro[cyclobu tane-1,3'-indolin]-2'-one The compound was prepared using the process described in step-iii of Example- XLVII.1H NMR (400 MHz, DMSO-d ₆ ): δ 7.44-7.40 (m, 2H), 7.35-7.33 (m, 1H), 7.19 (d, J=7.4 Hz, 2H), 7.04 (s, 2H), 7.01-7.00 (m, 2H), 6.83 (d, J=8.8 Hz, 2H), 6.36 (s, 1H), 4.95 (s, 2H), 3.84-3.82 (m, 1H), 3.68 (s, 3H), 3.26 (s, 3H), 2.78-2.76 (m, 1H), 2.41- 2.38 (m, 4H), 2.17-2.13 (m, 4H), 2.08-1.88 (m, 4H), 1.61-1.59 (m, 1H), 1.48-1.45 (m, 3H); LC-MS: m/z 579.3 (M+H).

Step-vi: 5'-(1-Methyl-2-oxo-3-phenyl-2,3-dihydro-1H-imidazol-4-yl)-7' -((1- methylpiperidin-4-yl)oxy)spiro[cyclobutane-1,3'-indolin]-2'- one

The compound was prepared using the process described in step-iii of Example- X.1H NMR (400 MHz, DMSO-d ₆ ): δ 10.23 (s, 1H), 7.43-7.39 (m, 2H), 7.35-7.31 (m, 1H), 7.18 (d, J=7.9 Hz, 2H), 6.98 (s, 1H), 6.94 (s, 1H), 6.36 (s, 1H), 3.88-3.86 (m, 1H), 3.26 (s, 3H), 2.67-2.61 (m, 2H), 2.38-2.34 (m, 2H), 2.20-2.00 (m, 9H), 1.58-1.56 (m, 2H), 1.45-1.43 (m, 2H); LC-MS: m/z 459.2 (M+H). The below compound was prepared by procedure similar to the one described in Example-LVI with appropriate variations in reactants, quantities of reagents and reaction conditions. The physiochemical characteristics of the compounds are also summarized in the table below.

Example-LVII: 5'-(3-((2-Hydroxyethyl)(methyl)amino)-1-phenyl-1H-pyrazol-5- yl)-7'- ((1-methylpiperidin-4-yl)oxy)spiro[cyclobutane-1,3'-indolin] -2'-one (Compound-99) Step-i: 5'-(3,3-Bis(methylthio)acryloyl)-7'-bromo-1'-(4-methoxybenzy l)spiro- [cyclobutane-1,3'-indolin]-2'-one

To an ice cold suspension of NaH (60%) (1.9 g, 48.30 mmol) in THF (100 mL) was added 5'-acetyl-7'-bromo-1'-(4-methoxybenzyl)spiro[cyclobutane-1,3 '-indolin]-2'- one (10.0 g, 24.15 mmol) followed by stirring at RT for 30 min. The mixture was cooled to 0 ºC, carbon disulphide (1.6 mL, 26.56 mmol) was added followed by stirring at RT for 4 h. The mixture was cooled to 0 ºC and methyl iodide (4.5 mL, 72.45 mmol) was added followed by stirring at RT for 16 h. TLC was monitored, and the reaction mixture was quenched with ice water and extracted with EtOAc. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as yellow solid (4.2 g, 33 %).1H NMR (400 MHz, DMSO-d ₆ ): δ 8.19 (d, J=1.5 Hz, 1H), 7.96 (d, J=1.9 Hz, 1H), 7.05 (d, J=8.8Hz, 2H), 6.88 (s, 1H), 6.86 (d, J=1.9 Hz, 2H), 5.24 (s, 2H), 3.70 (s, 3H), 2.56-2.53 (m, 2H), 2.50 (s, 6H), 2.47-2.33 (m, 4H); LC-MS: m/z 518.1 (M+H).

Step-ii: 7'-Bromo-5'-(3-((2-((tert-butyldimethylsilyl)oxy)ethyl)(meth yl)amino)-3- (methylthio)acryloyl)-1'-(4-methoxybenzyl)spiro[cyclobutane- 1,3'-indolin]-2'-one

The compound was prepared using the process described in step-ii of Example- XLIV using 2-((tert-butyldimethylsilyl)oxy)-N-methylethan-1-amine as a starting material.1H NMR (400 MHz, DMSO-d ₆ ): δ 8.08 (d, J=1.4 Hz, 1H), 7.80 (d, J=1.5 Hz, 1H), 7.04 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 5.86 (s, 1H), 5.22 (s, 2H), 3.79 (t, J=6.4 Hz, 2H), 3.71-3.69 (m, 5H), 3.13 (s, 3H), 2.52-2.50 (m, 2H), 2.43 (s, 3H), 2.39- 2.21 (m, 4H), 0.86 (s, 9H), 0.06 (s, 6H).

Step-iii: 7'-Bromo-5'-(3-((2-((tert-butyldimethylsilyl)oxy)ethyl)(meth yl)amino)-1- phenyl-1H-pyrazol-5-yl)-1'-(4-methoxybenzyl)spiro[cyclobutan e-1,3'-indolin]-2'-one The compound was prepared using the process described in step-iii of Example- XLIV.1H NMR (400 MHz, DMSO-d ₆ ): δ 7.40-7.29 (m, 4H), 7.52-7.22 (m, 3H), 7.04 (d, J=8.3 Hz, 2H), 6.87 (d, J=8.8Hz, 2H), 6.20 (s, 1H), 5.16 (s, 2H), 3.79 (t, J=5.9 Hz, 2H), 3.70 (s, 3H), 3.37 (t, J=5.9 Hz, 2H), 2.94 (s, 3H), 2.45-2.42 (m, 2H), 2.21-2.16 (m, 3H), 1.99-1.97 (m, 1H), 0.85 (s, 9H), 0.03 (s, 6H); LC-MS: m/z 701.2 (M+H).

Step-iv: 7'-Hydroxy-5'-(3-((2-hydroxyethyl)(methyl)amino)-1-phenyl-1H -pyrazol- 5-yl)-1'-(4-methoxybenzyl)spiro[cyclobutane-1,3'-indolin]-2' -one

The compound was prepared using the process described in step-iv of Example- XLIV.1H NMR (400 MHz, DMSO-d ₆ ): δ 9.81 (s, 1H), 7.36-7.32 (m, 2H), 7.25-7.18 (m, 5H), 6.86 (d, J=1.5 Hz, 2H), 6.84 (s, 1H), 6.64 (d, J=1.5Hz, 1H), 5.99 (s, 1H), 4.97 (s, 2H), 4.61-4.59 (m, 1H), 3.70 (s, 3H), 3.60 (t, J=6.4 Hz, 2H), 3.32-3.30 (m, 2H), 2.92 (s, 3H), 2.39-2.33 (m, 2H), 2.15-2.10 (m, 3H), 1.99-1.97 (m, 1H); LC-MS: m/z 525.2 (M+H).

Step-v: 5'-(3-((2-Hydroxyethyl)(methyl)amino)-1-phenyl-1H-pyrazol-5- yl)-1'-(4- methoxybenzyl)-7'-((1-methylpiperidin-4-yl)oxy)spiro[cyclobu tane-1,3'-indolin]-2'-one In a sealed tube, to a stirring solution of 7'-hydroxy-5'-(3-((2-hydroxyethyl)- (methyl)amino)-1-phenyl-1H-pyrazol-5-yl)-1'-(4-methoxybenzyl )spiro[cyclobutane-1,3'- indolin]-2'-one (1.0 g, 1.91 mmol) and 4-chloro-1-methylpiperidine (1.04 g, 7.63 mmol) in DMSO (10 mL) was added potassium carbonate (0.79 g, 5.73 mmol) followed by heating at 130 ºC for 16 h. TLC was monitored, and the mixture was poured into water and extracted with EtOAc. The organic layer dried over sodium sulphate and

concentrated under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as white solid (0.3 g, 25 %).1H NMR (400 MHz, DMSO-d ₆ ): δ 7.38-7.34 (m, 2H), 7.22-7.20 (m, 4H), 7.05 (d, J=8.3 Hz, 2H), 6.84 (d, J=8.8Hz, 2H), 6.54 (s, 1H), 6.16 (s, 1H), 5.00 (s, 2H), 4.60-4.59 (m, 1H), 3.98-3.96 (m, 1H), 3.69 (s, 3H), 3.61-3.59 (m, 2H), 2.93 (s, 3H), 2.54-2.39 (m, 6H), 2.30-2.25 (m, 3H), 2.09-2.06 (m, 4H), 1.98-1.96 (m, 2H), 1.49-1.47 (m, 2H), 1.30-1.28 (m, 2H); LC-MS: m/z 622.3 (M+H).

Step-vi: 5'-(3-((2-Hydroxyethyl)(methyl)amino)-1-phenyl-1H-pyrazol-5- yl)-7'- ((1-methylpiperidin-4-yl)oxy)spiro[cyclobutane-1,3'-indolin] -2'-one

The compound was prepared using the process described in step-iii of Example- X.1H NMR (400 MHz, DMSO-d ₆ ): δ 10.32 (s, 1H), 7.38-7.36 (m, 2H), 7.34-7.19 (m, 3H), 7.13 (d, J=1.0 Hz, 1H), 6.54 (d, J=1.0Hz, 1H), 6.12 (s, 1H), 4.59 (t, J=5.3 Hz, 1H), 3.98-3.96 (m, 1H), 3.64-3.59 (m, 2H), 3.34-3.32 (m, 2H), 2.93 (s, 3H), 2.55-2.52 (m, 2H), 2.40-2.38 (m, 2H), 2.22-2.15 (m, 6H), 1.95-1.93 (m, 3H), 1.61-1.59 (m, 2H), 1.47-1.44 (m, 2H); LC-MS: m/z 502.3 (M+H). Example-LVIII: 5'-(5-Ethoxy-1-phenyl-1H-pyrazol-3-yl)-7'-((1-methylpiperidi n-4-yl)- oxy)spiro[cyclobutane-1,3'-indolin]-2'-one (Compound-100)

Step-i: 5'-(5-Ethoxy-1-phenyl-1H-pyrazol-3-yl)-1'-(4-methoxybenzyl)- 7'-((1- methylpiperidin-4-yl)oxy)spiro[cyclobutane-1,3'-indolin]-2'- one

To a stirring solution of 5-ethoxy-3-iodo-1-phenyl-1H-pyrazole (117 mg, 0.375 mmol) and 1'-(4-methoxybenzyl)-7'-((1-methylpiperidin-4-yl)oxy)-5'-(4, 4,5,5-tetra- methyl-1,3,2-dioxaborolan-2-yl)spiro[cyclobutane-1,3'-indoli n]-2'-one (200 mg, 0.375 mmol) in 1,4-dioxane (8.0 ml) and water (2.0 ml) was added 238 mg (1.125 mmol) of K ₃ PO ₄ followed by purging with nitrogen gas for 20 min. Pd(amphos)Cl ₂ (26 mg, 0.037 mmol) was then added followed by purging with nitrogen gas for 20 min and heating to 100 ºC. The mixture was diluted with EtOH and washed with water. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as pale brown sticky solid (200 mg). LC-MS: m/z 592.7 (M+).

Step-ii: 5'-(5-Ethoxy-1-phenyl-1H-pyrazol-3-yl)-7'-((1-methylpiperidi n-4-yl)- oxy)spiro [cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-iii of Example- X.1H NMR (400 MHz, DMSO-d ₆ ): δ 10.33 (s, 1H), 7.72 (d, J=7.3 Hz, 2H), 7.68 (d, J=0.9 Hz, 1H), 7.50 (t, J=7.3 Hz, 2H), 7.38 (s, 1H), 7.33-7.31 (m, 1H), 6.49 (s, 1H), 4.43-4.41 (m, 1H), 4.30 (q, J=6.8Hz, 2H), 3.55-3.51 (m, 2H), 2.70-2.67 (m, 2H), 2.46- 2.33 (m, 2H), 2.25-2.21 (m, 7H), 1.89-1.87 (m, 2H), 1.73-1.71 (m, 2H), 1.42 (t, J=7.4 Hz, 3H); LC-MS: m/z 472.7 (M+). Example-LIX: 7'-((1-Imino-1-oxidohexahydro-1λ6-thiopyran-4-yl)oxy)-5'-(1 -phenyl- 1H-pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one (Compound-101)

Compound-101 Step-i: 1'-(4-Methoxybenzyl)-5'-(1-phenyl-1H-pyrazol-5-yl)-7'-((tetr ahydro-2H- thiopyran-4-yl)oxy)spiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-iii of Example- XLVII. LC-MS: m/z 552.2 (M+H).

Step-ii: N-(4-((1'-(4-Methoxybenzyl)-2'-oxo-5'-(1-phenyl-1H-pyrazol-5 -yl)spiro- [cyclobutane-1,3'-indolin]-7'-yl)oxy)tetrahydro-2H-1λ4-thio pyran-1-ylidene)cyanamide To a solution of 1'-(4-methoxybenzyl)-5'-(1-phenyl-1H-pyrazol-5-yl)-7'-((tetr a- hydro-2H-thiopyran-4-yl)oxy)spiro[cyclobutane-1,3'-indolin]- 2'-one (0.4 g, 0.72 mmol) in degassed MeOH (15 mL) was added cyanamide (0.04 g, 0.94 mmol), tBuOK (0.1 g, 0.87 mmol) and NBS (0.19 g, 1.09 mmol) followed by stirring at RT for 4 h. The mixture was concentrated, diluted with EtOAc and washed with aqueous sodium thiosulfate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as pale brown oil (0.3 g). LC-MS: m/z 592.2 (M+H).

Step-iii: N-(4-((1'-(4-Methoxybenzyl)-2'-oxo-5'-(1-phenyl-1H-pyrazol-5 -yl)spiro [cyclobutane-1,3'-indolin]-7'-yl)oxy)-1-oxidotetrahydro-2H-1 λ6-thiopyran-1-ylidene)- cyanamide

To a solution of N-(4-((1'-(4-methoxybenzyl)-2'-oxo-5'-(1-phenyl-1H-pyrazol-5 - yl)spiro[cyclobutane-1,3'-indolin]-7'-yl)oxy)tetrahydro-2H-1 λ4-thiopyran-1-ylidene)- cyanamide (0.3 g, 0.51 mmol) in EtOH (10 mL) was added potassium carbonate (0.21 g, 1.52 mmol) and mCPBA (0.13 g, 0.76 mmol) followed by stirring at RT for 4 h. The reaction mixture was quenched with aqueous sodium thiosulfate and extracted with EtOAc. The organic layer was washed with aqueous NaHCO _3, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by combi- flash to afford the title compound as pale yellow oil (0.2 g). LC-MS: m/z 607.2 (M+H).

Step-iv: 2,2,2-Trifluoro-N-(4-((1'-(4-methoxybenzyl)-2'-oxo-5'-(1-phe nyl-1H- pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-7'-yl)oxy)-1-ox idotetrahydro-2H-1λ6-thio- pyran-1-ylidene)acetamide

To an ice cold solution of N-(4-((1'-(4-methoxybenzyl)-2'-oxo-5'-(1-phenyl-1H- pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-7'-yl)oxy)-1-ox idotetrahydro-2H-1λ6-thio- pyran-1-ylidene)cyanamide (0.2 g, 0.33 mmol) in DCM (5 mL) was added TFAA (0.14 mL, 0.99 mmol) followed by stirring at RT for 2 h. The mixture was diluted with DCM and washed with water. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as pale yellow sticky mass (0.2 g). LC-MS: m/z 679.2 (M+H).

Step-v: 7'-((1-Imino-1-oxidohexahydro-1λ6-thiopyran-4-yl)oxy)-1'-(4 -methoxy- benzyl)-5'-(1-phenyl-1H-pyrazol-5-yl)spiro[cyclobutane-1,3'- indolin]-2'-one

To a solution of 2,2,2-trifluoro-N-(4-((1'-(4-methoxybenzyl)-2'-oxo-5'-(1-phe nyl- 1H-pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-7'-yl)oxy)-1 -oxidotetrahydro-2H-1λ6- thiopyran-1-ylidene)acetamide (0.2 g, 0.29 mmol) in MeOH (5 mL) was added potassium carbonate (0.24 g, 1.76 mmol) followed by stirring at RT for 2 h. The mixture was filtered and concentrated under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as pale yellow sticky solid (0.1 g). LC-MS: m/z 583.2 (M+H).

Step-vi: 7'-((1-Imino-1-oxidohexahydro-1λ6-thiopyran-4-yl)oxy)-5'-(1 -phenyl- 1H-pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-iii of Example- X.1H NMR (400 MHz, DMSO-d ₆ ): δ 10.73 (s, 1H), 7.73 (d, J=1.4 Hz, 1H), 7.46-7.38 (m, 3H), 7.29 (d, J=7.3 Hz, 2H), 7.04 (s, 1H), 6.72 (s, 1H), 6.69 (d, J=2.0, 1H), 4.48- 4.46 (m, 1H), 3.46-3.44 (m, 2H), 2.79-2.76 (m, 3H), 2.40-2.33 (m, 2H), 2.18-2.14 (m, 3H), 1.99-1.95 (m, 5H); LC-MS: m/z 463.2 (M+H). Example-LX: 5'-(4-(Ethylsulfonyl)-1-phenyl-1H-1,2,3-triazol-5-yl)-7'-((1 -methyl- piperidin-4-yl)oxy)spiro[cyclobutane-1,3'-indolin]-2'-one (Compound-102)

Step-i: 7'-Bromo-5'-(2-(ethylthio)acetyl)-1'-(4-methoxybenzyl)spiro[ cyclobutane- 1,3'-indolin]-2'-one

To a solution of 7'-bromo-5'-(2-bromoacetyl)-1'-(4-methoxybenzyl)spiro[cyclo- butane-1,3'-indolin]-2'-one (1.0 g, 2.03 mmol) in THF (10 mL) were added sodium acetate (0.18 g, 2.23 mmol) and ethanethiol (0.15 mL, 2.03 mmol) followed by stirring at RT for 16 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as pale brown oil (1.0 g).1H NMR (400 MHz, DMSO-d ₆ ): δ 8.26 (d, J=1.4 Hz, 1H), 8.00 (d, J=1.5 Hz, 1H), 7.05 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.8Hz, 2H), 5.24 (s, 2H), 4.02 (s, 2H), 3.71 (s, 3H), 2.49-2.47 (m, 6H), 2.32-2.18 (m, 2H), 1.99-1.96 (m, 3H); LC-MS: m/z 474.0 (M+H).

Step-ii: 7'-Bromo-5'-(4-(ethylthio)-1-phenyl-1H-1,2,3-triazol-5-yl)-1 '-(4- methoxybenzyl)spiro[cyclobutane-1,3'-indolin]-2'-one

To a solution of 7'-bromo-5'-(2-(ethylthio)acetyl)-1'-(4-methoxybenzyl)spiro- [cyclobutane-1,3'-indolin]-2'-one (1.0 g, 2.11 mmol) in DMSO (10 mL) were added DBU (0.16 mL, 1.05 mmol) and azidobenzene (1.5 g, 12.66 mmol) followed by stirring at RT for 16 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as pale brown solid (0.55 g, 45 %).1H NMR (400 MHz, DMSO-d ₆ ): δ 7.55-7.52 (m, 3H), 7.50-7.46 (m, 2H), 7.46 (d, J=1.9 Hz, 1H), 7.37 (d, J=1.4 Hz, 1H), 7.05 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.8Hz, 2H), 5.16 (s, 2H), 3.71 (s, 3H), 3.00 (q, J=7.3 Hz, 2H), 2.47-2.42 (m, 2H), 2.20-1.95 (m, 4H), 1.26 (t, J=7.3 Hz, 3H); LC-MS: m/z 575.1 (M+H). Step-iii: 7'-Bromo-5'-(4-(ethylsulfonyl)-1-phenyl-1H-1,2,3-triazol-5-y l)-1'-(4- methoxybenzyl)spiro[cyclobutane-1,3'-indolin]-2'-one

To an ice cold solution of 7'-bromo-5'-(4-(ethylthio)-1-phenyl-1H-1,2,3-triazol-5- yl)-1'-(4-methoxybenzyl)spiro[cyclobutane-1,3'-indolin]-2'-o ne (0.7 g, 1.22 mmol) in chloroform (15 mL) was added mCPBA (1.05 g, 6.10 mmol) followed by stirring at RT for 16 h. The mixture was diluted with DCM and washed with aqueous NaHCO ₃ and brine. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as off- white solid (0.5 g, 67 %).1H NMR (400 MHz, DMSO-d ₆ ): δ 7.63 (d, J=1.4 Hz, 1H), 7.54-7.51 (m, 6H), 7.04 (d, J=8.3 Hz, 2H), 6.87 (d, J=8.3Hz, 2H), 5.15 (s, 2H), 3.71 (s, 3H), 3.47-3.42 (m, 2H), 2.42-2.40 (m, 2H), 2.21-2.14 (m, 4H), 1.26 (t, J=7.4 Hz, 3H); LC-MS: m/z 607.1 (M+H).

Step-iv: 5'-(4-(Ethylsulfonyl)-1-phenyl-1H-1,2,3-triazol-5-yl)-7'-hyd roxy-1'-(4- methoxybenzyl)spiro[cyclobutane-1,3'-indolin]-2'-one

The compound was prepared using the process described in step-iv of Example- XLIV.1H NMR (400 MHz, DMSO-d6): δ 10.07 (s, 1H), 7.57-7.46 (m, 5H), 7.19 (d, J=8.3 Hz, 2H), 7.02 (d, J=1.4 Hz, 1H), 6.88-6.83 (m, 3H), 4.97 (s, 2H), 3.75 (s, 3H), 3.47-3.43 (m, 2H), 2.41-2.33 (m, 2H), 2.19-1.97 (m, 4H), 1.25 (t, J=7.4 Hz, 3H); LC- MS: m/z 545.2 (M+H).

Step-v: 5'-(4-(Ethylsulfonyl)-1-phenyl-1H-1,2,3-triazol-5-yl)-1'-(4- methoxy- benzyl)-7'-((1-methylpiperidin-4-yl)oxy)spiro[cyclobutane-1, 3'-indolin]-2'-one

The compound was prepared using the process described in Step-iii of Example- XLVII. LC-MS: m/z 642.2 (M+H).

Step-vi: 5'-(4-(Ethylsulfonyl)-1-phenyl-1H-1,2,3-triazol-5-yl)-7'-((1 -methyl- piperidin-4-yl)oxy)spiro[cyclobutane-1,3'-indolin]-2'-one

The process of this step was adopted from step-iii of Example-X.1H NMR (400 MHz, DMSO-d6): δ 10.52 (s, 1H), 7.53-7.48 (m, 5H), 7.19 (s, 1H), 6.99 (s, 1H), 4.23- 4.21 (m, 1H), 3.43 (q, J=7.3 Hz, 2H), 2.41-2.33 (m, 6H), 2.24-1.91 (m, 7H), 1.76-1.74 (m, 2H), 1.62-1.58 (m, 2H), 1.24 (t, J=7.3 Hz, 3H); LC-MS: m/z 522.2 (M+H). Example-LXI: 7'-((1-Methylpiperidin-4-yl)oxy)-5'-(1-phenyl-1H-pyrazol-5yl )spiro- [cyclopentane-1,3'-indolin]-2'-one (Compound-103)

Step-i: N'-Phenylcyclopentanecarbohydrazide

To a solution of phenyl hydrazine hydrochloride (20 g, 138.3 mmol) in DMF (100 mL) at -30 oC were added pyridine (60 mL) and cyclopentanecarbonyl chloride (16.8 mL, 138.3 mmol) dropwise followed by stirring at -30 oC for 1 h. The mixture was poured into crushed ice and the solid formed was filtered off, washed with water and dried under reduced pressure to afford the title product as off white solid (25.0 g, 88 %). 1H NMR (400 MHz, DMSO-d6): δ 9.58 (s, 1H), 7.80-7.60 (m, 1H), 7.12 (t, J=8.8 Hz, 2H), 6.66 (d, J=7.8 Hz, 1H), 2.51-2.50 (m, 1H), 1.82-1.80 (m, 2H ), 1.67-1.53 (m, 8H); LC-MS: m/z 205.2 (M+H).

Step-ii: Spiro[cyclopentane-1,3'-indolin]-2'-one

To a solution of N'-phenylcyclopentanecarbohydrazide (25 g, 122.5 mmol) in quinoline (25 mL) was added calcium oxide (68.3 g, 1220.0 mmol) followed by heating the mixture to 260 oC on preheated sand bath. Stirring was continued for 3 h. The mixture was cooled to RT and quenched with 6 N HCl dropwise. The mixture was extracted with EtOAc (500 ml x 2). The combined organic layer was washed with water (500 mL) and brine (500 mL), dried over sodium sulphate and concentrated under reduced pressure. The residue was purified on silica gel (60-120 mesh) to afford the title product as brown solid (14.0 g, 61 %).1H NMR (400 MHz, DMSO-d6): δ 10.25 (s, 1H), 7.21 (d, J=7.3 Hz, 1H), 7.16-7.12 (m, 1H), 6.96-6.92 (m, 1H), 6.81 (d, J=7.9 Hz, 1H), 1.97-1.90 (m, 6H ), 1.76-1.72 (m, 2H); LC-MS: m/z 188.1 (M+H).

Step-iii: 5'-Acetylspiro[cyclopentane-1,3'-indolin]-2'-one

To a cold suspension of AlCl ₃ (5.3 g, 40.1 mmol) in DCE (50 mL) was added acetyl chloride (2.3 mL, 32.08 mmol) followed by stirring for 15 min. Spiro[cyclo- pentane-1,3'-indolin]-2'-one (3.0 g, 16.04 mmol) was then added and the mixture was stirred at RT for 16 h. The mixture was quenched with ice and extracted with EtOAc. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by combi flash to afford the title compound as pale brown solid (2.5 g, 69 %).1H NMR (400 MHz, DMSO-d6): δ 10.70 (s, 1H), 7.86 (d, J=8.3 Hz, 1H), 7.78 (s, 1H), 6.92 (d, J=7.9 Hz, 1H), 2.53 (s, 3H), 2.01-1.91 (m, 6H), 1.85-1.80 (m, 2H); LC-MS: m/z 230.2 (M+H).

Step-iv: 5'-Acetyl-7'-bromospiro[cyclopentane-1,3'-indolin]-2'-one

To an ice cold solution of 5'-acetylspiro[cyclopentane-1,3'-indolin]-2'-one (2.5 g, 10.91 mmol) in H ₂ SO ₄ (25 mL) was added NBS (3.9 g, 21.82 mmol) followed by stirring at RT for 2 h. The mixture was poured into crushed ice and the solid formed was filtered off, washed with water and dried under reduced pressure to afford the title product as brown solid (3.0 g). 1H NMR (400 MHz, DMSO-d6): δ 11.15 (s, 1H), 7.97 (d, J=1.0 Hz, 1H), 7.76 (s, 1H), 2.55 (s, 3H), 2.02-1.77 (m, 8H); LC-MS: m/z 306.0 (M-H).

Step-v: 5'-Acetyl-7'-bromo-1'-(4-methoxybenzyl)spiro[cyclopentane-1, 3'-indolin]- 2'-one

To an ice cold solution of 5'-acetyl-7'-bromospiro[cyclopentane-1,3'-indolin]-2'- one (3.0 g, 9.74 mmol) in acetonitrile (30 mL) were added cesium carbonate (7.9 g, 24.35 mmol) and 1-(chloromethyl)-4-methoxybenzene (1.99 mL, 14.61 mmol) followed by stirring at RT for 4 h. The mixture was filtered and concentrated under reduced pressure to afford the title compound as brown oil (2.5 g).1H NMR (400 MHz, DMSO– d6): δ 7.94 (s, 1H), 7.86 (s, 1H), 7.06 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 5.26 (s, 2H), 3.71 (s, 3H), 2.55 (s, 3H), 2.08–1.94 (m, 8H); LCMS: m/z 428.1(M+H).

Step-vi: 7'-Bromo-5'-(3-(dimethylamino)acryloyl)-1'-(4-methoxybenzyl) spiro [cyclopentane-1,3'-indolin]-2'-one

A solution of 5'-acetyl-7'-bromo-1'-(4-methoxybenzyl)spiro[cyclopentane-1, 3'- indolin]-2'-one (2.5 g, 5.84 mmol) in DMF.DMA (25 mL) was heated at 100 ºC for 16 h. The mixture was concentrated under reduced pressure and column-purified to afford the title compound as brown solid (2.2 g).1H NMR (400 MHz, DMSO–d6): δ 7.91 (s, 1H), 7.82 (s, 1H), 7.71 (d, J = 12.2 Hz, 1H), 7.07 (d, J = 8.3 Hz, 2H), 6.89 (d, J = 8.3 Hz, 2H), 5.84 (d, J = 11.7 Hz, 1H),5.24 (s, 2H), 3.70 (s, 3H), 3.14 (s, 3H), 2.94 (s, 3H), 2.08–1.87 (m, 8H); LCMS: m/z 483.2 (M+H).

Step-vii: 7'-Bromo-1'-(4-methoxybenzyl)-5'-(1-phenyl-1H-pyrazol-5-yl)s piro- [cyclopentane-1,3'-indolin]-2'-one

To a solution of 7'-bromo-5'-(3-(dimethylamino)acryloyl)-1'-(4-methoxy- benzyl)spiro [cyclopentane-1,3'-indolin]-2'-one (2.2 g, 4.55 mmol) in EtOH (20 mL) were added phenyl hydrazine hydrochloride (0.99 g, 6.82 mmol) and AcOH (0.2 mL) followed by heating the mixture at 100 ºC for 16 h. The mixture was then concentrated under reduced pressure and purified by combi-flash to afford the title compound as pale brown solid (1.5 g, 62 %).1H NMR (400 MHz, DMSO–d6): δ 7.74 (d, J = 2.0 Hz, 1H), 7.47– 7.40 (m, 4H), 7.39 (d, J =1.4 Hz, 2H), 7.06 (d, J =8.8 Hz, 2H), 6.91-6.87 (m, 3H), 6.74 (d, J =1.3 Hz, 1H), 5.19 (s, 2H), 3.71 (s, 3H), 2.08– 1.83 (m, 4H), 1.64– 1.60 (m, 4H); LCMS: m/z 528.2 (M+H).

Step-viii: 7'-Hydroxy-1'-(4-methoxybenzyl)-5'-(1-phenyl-1H-pyrazol-5-yl )spiro- [cyclopentane-1,3'-indolin]-2'-one

To a solution of 7'-bromo-1'-(4-methoxybenzyl)-5'-(1-phenyl-1H-pyrazol-5-yl)- spiro [cyclopentane-1,3'-indolin]-2'-one (1.5 g, 2.84 mmol) in 1,4-dioxane (10 mL) and H ₂ O (3 mL) was added KOH (0.48 g, 8.52 mmol) followed by degassing with nitrogen purging for 20 min. Then tBuXPhos (0.12 g, 0.28 mmol) and Pd ₂ (dba) ₃ (0.25 g, 0.28 mmol) were added followed by degassing with nitrogen purging for 20 min. Then the mixture was heated at 100 °C for 16 h. The mixture was then diluted with EtOAc and washed with water and brine. The organic layer was dried over sodium sulphate and concentrated under reduced pressure and purified by combi-flash to afford the title compound as pale yellow solid (0.7 g, 53 %).1H NMR (400 MHz, DMSO–d6): δ 9.89 (s, 1H), 7.70 (d, J=1.9 Hz, 1H), 7.44– 7.29 (m, 3H), 7.26 (d, J =7.3 Hz, 2H), 7.18 (d, J=8.8 Hz, 2H), 6.86 (d, J =8.3 Hz, 2H), 6.74 (d, J=1.0 Hz, 1H), 6.53 (d, J=2.0 Hz, 1H), 6.34 (d, J=1.0 Hz, 1H), 4.99 (s, 2H), 3.70 (s, 3H), 1.89– 1.81 (m, 4H), 1.58– 1.52 (m, 4H); LCMS: m/z 466.2 (M+H).

Step-ix: 1'-(4-Methoxybenzyl)-7'-((1-methylpiperidin-4-yl)oxy)-5'-(1- phenyl-1H- pyrazol-5-yl)spiro[cyclopentane-1,3'-indolin]-2'-one To an ice cold solution of 1-methylpiperidin-4-ol (0.37 g, 3.20 mmol) in THF (10 mL) was added triphenyl phosphine (0.84 g, 3.20 mmol) followed by DIAD (0.5 mL, 2.56 mmol). The mixture was stirred at 0 ºC for 15 minutes. Then 7'-hydroxy-1'-(4- methoxybenzyl)-5'-(1-phenyl-1H-pyrazol-5-yl)spiro[cyclopenta ne-1,3'-indolin]-2'-one (0.3 g, 0.64 mmol) was added followed by stirring at RT for 16 h. The mixture was diluted with EtOAc and washed with water. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by combi- flash to afford the title compound as pale yellow oil (0.25 g, 69 %).1H NMR (400 MHz, DMSO–d6): δ 7.72 (s, 1H), 7.46–7.33 (m, 3H), 7.29 (d, J =7.8 Hz, 2H), 7.06 (d, J =8.4 Hz, 2H), 6.86 (d, J =8.3 Hz, 2H), 6.72-6.66 (m, 3H), 5.03 (s, 2H), 4.07–4.02 (m, 1H), 3.69 (s, 3H), 2.47–2.41 (m, 2H), 2.09 (s, 3H), 1.95–1.93 (m, 7H), 1.89–1.55 (m,7H); LCMS: m/z 563.3 (M+H).

Step-x: 7'-((1-Methylpiperidin-4-yl)oxy)-5'-(1-phenyl-1H-pyrazol-5-y l)spiro- [cyclopentane-1,3'-indolin]-2'-one

To an ice cold solution of 1'-(4-methoxybenzyl)-7'-((1-methylpiperidin-4-yl)oxy)- 5'-(1-phenyl-1H-pyrazol-5-yl)spiro[cyclopentane-1,3'-indolin ]-2'-one (0.2 g, 0.35 mmol) in DCM (5 mL) was added TFA (1.5 mL) and trifluoromethanesulfonic acid (0.5 mL) followed by stirring at RT for 2 h. The mixture was slowly poured in aqueous NaHCO ₃ and extracted with DCM. The organic layer was dried over Na ₂ SO ₄ , concentrated under reduced pressure and purified by combi-flash to afford the title compound as off white solid (0.04 g, 25 %).1H NMR (400 MHz, DMSO–d6): δ 10.38 (s, 1H), 7.71 (d, J = 1.5 Hz, 1H), 7.45– 7.36 (m, 3H), 7.27 (d, J=7.40 Hz, 2H), 6.67-6.65 (m, 3H), 4.06–4.01 (m, 1H), 2.67–2.57 (m, 2H), 2.16 (s, 3H), 2.08–1.81 (m, 6H), 1.70–1.61 (m, 6H), 1.55– 1.47 (m, 2H); LCMS: m/z 443.3 (M+H). Example-LXII: 7'-Methoxy-5'-(1-phenyl-1H-pyrazol-5-yl)spiro[cyclopentane-1 ,3'- indolin -2'-one Com ound-104

Step-i: 7'-Methoxy-1'-(4-methoxybenzyl)-5'-(1-phenyl-1H-pyrazol-5-yl )spiro- [cyclopentane-1,3'-indolin]-2'-one

To a stirring solution of 7'-hydroxy-1'-(4-methoxybenzyl)-5'-(1-phenyl-1H- pyrazol-5-yl)spiro[cyclopentane-1,3'-indolin]-2'-one (0.07 g, 0.15 mmol) in acetonitrile (5 mL) was added potassium carbonate (0.05 g, 0.37 mmol) and methyl iodide (0.047 mL, 0.75 mmol) followed by stirred at RT for 1 h. TLC was monitored, and the mixture diluted with water and extracted with EtOAc. The organic layer dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as pale yellow oil (0.075 g) which was used further step without purification. LCMS: m/z 480.1 (M+H).

Step-ii: 7'-Methoxy-5'-(1-phenyl-1H-pyrazol-5-yl)spiro[cyclopentane-1 ,3'- indolin]-2'-one

The compound was prepared using the process described in step-x of Example- LXI.1H NMR (400 MHz, DMSO–d6): δ 10.44 (s, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.45– 7.38 (m, 3H), 7.27 (d, J=7.3 Hz, 2H), 6.84 (d, J=1.0 Hz, 1H), 6.67 (d, J=1.9 Hz, 1H), 6.48 (s, 1H), 3.71 (s, 3H), 1.87–1.76 (m, 4H), 1.57–1.51 (m, 4H); LCMS: m/z 360.0 (M+H). Example-LXIII: 5'-(1-Phenyl-1H-pyrazol-5-yl)-7'-(pyridin-2-yloxy)spiro[cycl opentane- 1,3'-indolin]-2'-one (Compound-105)

Step-i: 1'-(4-Methoxybenzyl)-5'-(1-phenyl-1H-pyrazol-5-yl)-7'-(pyrid in-2-yloxy)- spiro[cyclopentane-1,3'-indolin]-2'-one

To a stirring solution of 7'-hydroxy-1'-(4-methoxybenzyl)-5'-(1-phenyl-1H- pyrazol-5-yl)spiro[cyclopentane-1,3'-indolin]-2'-one (0.12 g, 0.26 mmol) in DMF (5 mL) was added potassium carbonate (0.11 g, 0.78 mmol) and 2-fluoropyridine (0.045 mL, 0.52 mmol) followed by heating at 130 ºC for 16 h. TLC was monitored, and the mixture was diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as pale yellow oil (0.15 g) which was used further step without purification. 1H NMR (400 MHz, DMSO–d6): δ 8.05-8.04 (m, 1H), 7.78-7.74 (m, 1H), 7.70 (d, J = 2.0 Hz, 1H), 7.44– 7.32 (m, 3H), 7.27 (d, J=7.3 Hz, 2H), 7.09-7.06 (m, 1H), 6.96 (d, J=8.9 Hz, 2H), 6.89 (d, J=1.4 Hz, 1H), 6.81 (d, J=1.5 Hz, 2H), 6.72 (d, J=8.9 Hz, 2H), 6.65 (d, J=2.0 Hz, 1H), 4.76 (s, 2H), 3.66 (s, 3H), 1.93–1.80 (m, 4H), 1.74–1.68 (m, 4H); LCMS: m/z 543.1 (M+H).

Step-ii: 5'-(1-Phenyl-1H-pyrazol-5-yl)-7'-(pyridin-2-yloxy)spiro [cyclopentane- 1,3'-indolin]-2'-one

The compound was prepared using the process described in step-x of Example- LXI.1H NMR (400 MHz, DMSO–d6): δ 10.61 (s, 1H), 8.11-8.09 (m, 1H), 7.84-7.79 (m, 1H), 7.70 (d, J = 1.9 Hz, 1H), 7.45– 7.37 (m, 3H), 7.28 (d, J=7.3 Hz, 2H), 7.12- 7.09 (m, 1H), 6.98 (d, J=8.3 Hz, 1H), 6.90 (d, J=1.5 Hz, 1H), 6.78 (d, J=1.5 Hz, 1H), 6.65 (d, J=2.0 Hz, 1H), 1.91–1.81 (m, 4H), 1.65–1.61 (m, 4H); LCMS: m/z 423.1 (M+H). The following compounds can be prepared by procedure similar as described above with appropriate variations in reactants, quantities of reagents and reaction conditions such modifications being known to the one ordinary skilled in the art.

Biological Data: Bet BRD4 BD1 inhibition The Bet bromodomain TR-FRET assay has been used to identify compounds that bind to Bet BRD4 BD1 bromodomain and prevent its interaction with acetylated histone peptides (Chung, C. et al., J. Med. Chem., 54, 3827-3838, 2011). In the assay, optimized concentration of in-house Bet BRD4 BD1bromodomain protein and 300 nM of acetyl histone peptide substrate were diluted in assay buffer (50 mM HEPES, pH: 7.5, 50 mM NaCl, 500 µM CHAPS) and were added to the positive control and test control wells in a 384 well plate. Substrate control wells have 300 nM of acetyl histone peptide substrate diluted in assay buffer. Buffer blank wells were added with assay buffer. The reaction mixture was allowed for incubation at RT for 30 min. Stock solutions of test compounds at 20 mM DMSO were prepared. Compounds were serially diluted and added to the test wells in 384-well polypropylene plates. The reaction mixture was further incubated for 30 min at RT on a plate shaker.2 nM of Europium labeled streptavidin and 10 nM of XL-665 labeled antibody diluted in detection buffer (50 mM HEPES, pH: 7.5, 50 mM NaCl, 500 µM CHAPS and 800 mM KF) were added to all the wells excluding the buffer blank wells. The reaction plate was incubated for additional 30 min at RT on plate shaker. The plate was read in Perkin Elmer WALLAC 1420 Multilabel Counter Victor 3 (Ex: 340 nm Em: 615 and 665 nm). The amount of displacement of the peptide was measured as ratio of specific 665 nm energy transfer signal to 615 nm signals. The IC ₅₀ of the compounds was determined by fitting the dose response data to sigmoid curve fitting equation using Graph Pad Prism software V5. The compounds were screened in the above mentioned assay and the results (IC ₅₀ ) are summarized in the table below. The IC ₅₀ values of the compounds are set forth in below Table 1 wherein“A” refers to an IC ₅₀ value of less than 600 nM,“B” refers to IC50 value in range of 600.01 to 1000 nM and“C” refers to IC50 value of greater than 1000 nM. Table 1. Selectivity for BD1 inhibition over BD2 inhibition The selectivity ratio of the compounds for BD1 inhibition over BD2 inhibition can be determined using the fluorescence resonance energy transfer (TR-FRET) assay protocol described above using both BRD4 BD1 and BRD4 BD2 proteins. The compounds were screened in the above mentioned assay for determining the selectivity for BRD4 BD1 inhibition over BRD4 BD2 inhibition. The results are summarized in the Table 2 below wherein“A” refers to selectivity higher than 10 fold, “B” refers to selectivity lower than 10 fold. The selectivity ratios were calculated based on IC ₅₀ values for BD1 and BD2 inhibition. The compounds appeared to exhibit substantial selectivity for inhibiting BD1 protein over BD2 protein.

Table 2.