# Patent

## Title
Heterocyclic compounds

## Abstract

The present invention relates to heterocyclic compounds of the general formula (I) their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, and polymorphs. The invention also relates to processes for the preparation of the compounds of invention, pharmaceutical compositions containing the compounds and their use as selective Bruton's Tyrosine Kinase (BTK) inhibitors.

## Background
This application is the U.S. national phase of International Application No. PCT/IN2015/000063 filed 2 Feb. 2015, which designated the U.S. and claims priority to IN Patent Application Nos. 362/MUM/2014 filed 3 Feb. 2014, and 2271/MUM/2014 filed 11 Jul. 2014, the entire contents of each of which are hereby incorporated by reference.
FIELD OF INVENTION
The present invention relates to novel heterocyclic compounds of the general formula (I) their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, and polymorphs. The invention also relates to processes for the preparation of the compounds of invention, pharmaceutical compositions containing the compounds and their use as selective Bruton's Tyrosine Kinase (BTK) inhibitors.
BACKGROUND OF THE INVENTION
Bruton's Tyrosine Kinase (BTK) is a member of the Tec family kinases with a well-characterized role in B-cell receptor (BCR)-signaling and B-cell activation (Schwartzberg, P. L., Finkelstein, L. D and Readinger, J. A., Nat. Rev. Immunol., 2005, 5, 284-295). BTK is a key signaling enzyme expressed in all hematopoietic cells types, except T lymphocytes and natural killer cells. BTK is activated by the upstream Src-family kinases Blk, Lyn and Fyn and it lead to downstream activation of essential cell survival pathways such as NF-KB and MAPK (Afar, D. E., Park, H., Howell, B. W., Rawlings, D. J., Cooper, J and Witte, O. N., Mol. Cell Biol., 1996, 16(7), 3465-3471). In turn, BTK phosphorylates and activates phospholipase-C (PLC), leading to Ca2+ mobilization and activation of NF-KB and MAP kinase pathways (Bajpai, U. D., Zhang, K., Teutsch, M., Sen, R and Wortis, H. H., J. Exp. Med., 2000, 191, 1735-1744).
BTK is intimately involved in multiple signal-transduction pathways regulating survival, activation, proliferation and differentiation of B-lineage lymphoid cells. BTK is an upstream activator of multiple antiapoptotic signaling molecules and networks, including the signal transducer and activator of transcription 5 (STATS) protein, phosphatidylinositol (PI) 3-kinase/AKT/mammalian target of rapamycin (mTOR) pathway, and nuclear factor kappa B (NF-κB) (Mahajan, S., Vassilev, A., Sun, N., Ozer. Z., Mao, C and Uckun, F. M., J. Biol. Chem., 2001, 276, 31216-31228; Ortolano, S., Hwang, I. Y., Han, S. B and Kehrl, J. H., Eur. J. Immunol., 2006, 36, 1285-1295). This downstream signal transduction protein is a critical effector molecule that governs normal B-cell development, differentiation and functioning and has also been implicated in initiation, survival and progression of mature B-cell lymphoproliferative disorders (Kuppers, R., Nat. Rev. Cancer, 2005, 5(4), 251-262).
In B-cells, BTK is important for B-cell antigen receptor-, CD40- and Toll-like receptor 4-mediated activation and proliferation. Furthermore, BTK plays a role in B-cell antigen processing and presentation (Satterthwaite, A. B., Witte, O. N., Immunol. Rev., 2000, 175, 120-127). It is noteworthy that BTK is also essential in Fc receptor-mediated inflammatory cytokine production [tumor necrosis factor , interleukin (IL)-1 and IL-6] in monocytes/macrophages and therefore can contribute to immune complex-induced disease. BTK is abundantly expressed in malignant cells from patients with B-cell precursor (BCP)-acute lymphoblastic leukemia (ALL; the most common form of cancer in children and adolescents), chronic lymphocytic leukemia (CLL), and non-Hodgkin's lymphoma (NHL) (Khan, W. N., Immunol. Res., 2001, 23, 147-156). Consequently, BTK has emerged as a new molecular target for treatment of B-lineage leukemia's and lymphomas.
BTK mutations in human cause an inherited disease X-linked agammaglobulinemia, characterized by a lack of peripheral B-cells and low levels of serum Ig. Thus, BTK is a uniquely attractive kinase target for selective B-cell inhibition and small molecule based BTK inhibitors offers therapeutic benefit in the treatment of lymphoma and autoimmune diseases (Valiaho, J., Smith, C. I., Vihinen, M., Hum. Mutat., 2006, 27(12), 1209-1217).
BTK was recently identified in a siRNA screen as an essential kinase for survival in a subset of diffuse large-cell lymphomas driven by activated BCR, where an irreversible BTK inhibitor, PCI-32765 (Ibrutinib), was shown to promote apoptosis. A second study of Ibrutinib recently demonstrated in vivo clinical responses in dogs with aggressive B-cell lymphomas (Honigberg, L. A., Smith, A. M., Sirisawad, M., Verner, E., Loury, D., Chang, B., Li, S., Pan, Z., Thamm, D. H., Miller, R. A., Buggy, J. J., Proc. Natl. Acad. Sci., USA., 2010, 107(29), 13075-13080).
Thus BTKs are important in the regulation of many cellular processes including cell cycle regulation, proliferation, survival, apoptosis and motility and are significant components of the molecular mechanisms of diseases such as cancer, diabetes and immune inflammation (Buggy, J. J., Elias, L., Int. Rev. Immunol., 2012, 31(2), 119-132).
PRIOR ART
Published patent applications US2008/0076921, US2008/0108636, US2011/224235, US2012/100138/US2012/087915, US2012/183535, US2012/129873, US2012/129821, US2012/053189, WO2008/039218, WO2008/054827, WO2008/121742, WO2010/009342, WO2011/046964, WO2014/078578 and WO2011/153514, by Pharmacyclics Inc., discloses pyrazolo-pyrimidin-amine derivatives as BTK inhibitors for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, such as cancer, including lymphoma and inflammatory diseases or conditions. Hoffmann La Roche (WO2010/100070, US2010/222325, WO2010/122038, US2010/273768, WO2012/020008, US2012/040949, WO2010/000633, US2010/004231, WO2010/006947, US2010/016301, WO2014/064131, WO2014/076104, WO2014/083026, WO2014/090715), Biogen Idec Inc (WO2011/029046, US2012/157443, WO2011/029043, US2012/157442), CGI Pharmaceuticals Inc (WO2006/099075, US2006/229337, WO2009/137596, US2011/118233, WO2010/056875, US2011/301145, WO2010/068788), Avila Therapeutics Inc (US2012/0277832, WO2012/021444), BMS (WO2002/38797, US2003/040461), Boehringer (WO2014/025976), Principia (US2014/8673925), Ono Pharmaceuticals (US2013/0217880), Merck Sharp & Dohme (WO2013/010380, WO2014/093230) and Cellular Genomics Inc (WO2005/005429, US2005/101604) discloses diverse class of heterocyclic compounds as BTK inhibitors. BASF (WO2001/019829 and WO2002/080926) disclosed certain class of heterocyclic compounds as protein kinase inhibitors. Some of the recent patent application such as WO2014/187262, WO2014/188173, WO2014/161799, CN104086551, WO2014/135473, WO2014/116504, WO2014/113942, US2014/0206681, and WO2014/064131 discloses diverse class of heterocyclic compound as BTK inhibitors.
Since the ATP binding site of BTK shows a close homology to that of other Src-family kinases, such as lymphocyte-specific protein tyrosine kinase (LCK) and LYN, it is often difficult to find an ATP competitive inhibitor having sufficient selectivity. A lack of selectivity of an inhibitor for BTK over these kinases could potentially have negative consequences. BTK is a member of a group of eleven tyrosine kinases (the Tec family kinases, EGFR, Jak3, ErbB2, ErbB4, and BLK) that contain a conserved cysteine residue adjacent to the ATP-binding site. This cysteine (Cys481 in BTK) is a potential nucleophilic site which could form a covalent adduct with an electrophilic inhibitor. As the inhibitory activity of such an inhibitor is dependent on the covalent interaction, this cysteine residue provides a handle for achieving the desired degree of selectivity (Singh, J., Petter, R. C., Kluge, A. F., Curr. Opin. Chem. Biol., 2010, 14, 1-6; Cohen, M. S., Zhang, C., Shokat, K. M., Taunton, J., Science, 2005, 308, 1318-1321; Leproult, E., Barluenga, S., Moras, D., Wurtz, J. M., Winssinger, N., J. Med. Chem., 2011, 54, 1347-1355).
Reversible kinase inhibitors interact with the ATP-binding site. As the ATP-binding sites are highly conserved among kinases, it is difficult to develop a reversible inhibitor that selectively inhibits a desired kinase. Thus with reversible kinase inhibitors, it is difficult to achieve broad therapeutic window. Generating potent, selective, oral BTK inhibitors using covalent, irreversible and electrophilic compounds is feasible approach. However, the irreversible inhibitors exhibit toxicity due to covalent boding with off-target macromolecules. Thus to overcome undesirable off-target effects, it is essential to develop irreversible BTK inhibitors that covalently bind with BTK enzyme, without binding to off-target polypeptides.
Several BTK inhibitors are being developed as therapeutic agents for various indications. Among these, the covalent inhibitor Ibrutinib (Pharmacyclics) was developed as a selective and irreversible inhibitor of BTK, targeting the cysteine-481 residue in the active site. Ibrutinib is a potent nanomolar inhibitor of BTK and exhibited promising activity in preclinical models of BCR-driven B-lineage lymphoma and clinical testing in lymphoma patients (Pan, Z., Scheerens, H., Li, S. J., Schultz, B. E., Sprengeler, P. A., Burrill, L. C., Mendonca, R. V., Sweeney, M. D., Scott, K. C., Grothaus, P. G., Jeffery, D. A., Spoerke, J. M., Honigberg, L. A., Young, P. R., Dalrymple, S. A and Palmer, J. T., Chem. Med. Chem., 2007, 2, 58-61; Honigberg, L. A., Smith, A. M., Sirisawad, M., Verner, E., Loury, D., Chang, B., Li, S., Pan, Z., Thamm, D. H., Miller, R. A and Buggy, J. J., Proc. Natl. Acad. Sci. USA., 2010, 107, 13075-13080). Likewise, dianilinopyrimidine-based irreversible BTK inhibitors with micromolar activity were developed and two lead compounds, AVL-101 and AVL-291 (Avila Therapeutics) showed promising in vitro activity against lymphoma cells (Evans, E., Ponader, S., Karp, R., et al., Clin. Lymphoma Myeloma Leuk., 2011, 11 Suppl 2, S173-S174). Ibrutinib is a covalent BTK inhibitor, recently approved for the treatment of patients with various B-cell malignancies. Thus inhibition of BTK is emerging as a promising mechanism for targeting B-cell malignancies (Harrison, C., Nat. Rev. Drug Discov., 2012, 11(2), 96-97).
We herein disclose novel heterocyclic compounds of general formula (I) which are selective BTK inhibitors for the prevention and treatment of disease states mediated by BTK, including cancer and inflammation. More particularly, embodiments of the present invention describe irreversible kinase inhibitors including inhibition of BTK, that are useful as therapeutics in the treatment of a variety of pathological conditions including cancer, lymphoma, auto-immune diseases, heteroimmune diseases, inflammatory diseases and neurodegenerative diseases or conditions.
SUMMARY OF THE INVENTION
The present invention discloses heterocyclic compounds as defined by the general formula (I) that are selective BTK inhibitors for the prevention and treatment of disease states mediated by BTK. The compounds of the present invention are useful in the treatment of human or animal body, by inhibition of BTK. The compounds of this invention are therefore suitable for the prevention and treatment of disease states mediated by BTK.
EMBODIMENT(S) OF THE INVENTION
An embodiment of the present invention provides novel heterocyclic compounds represented by the general formula (I), their tautomeric forms, their enantiomers, their diastereoisomers, their stereoisomers, their pharmaceutically acceptable salts and pharmaceutical compositions containing them or their mixtures thereof.
In a further embodiment of the present invention is provided pharmaceutical compositions containing compounds of the general formula (I), their tautomeric forms, their enantiomers, their diastereoisomers, their stereoisomers, their pharmaceutically acceptable salts, or their mixtures in combination with suitable carriers, solvents, diluents and other media normally employed in preparing such compositions.
In a still further embodiment is provided the use of heterocyclic compounds of the present invention as selective BTK inhibitors, by administering a therapeutically effective and non-toxic amount of compounds of general formula (I) or their pharmaceutically acceptable compositions to the mammals.
In a still further embodiment is provided a process for preparing the novel compounds of the present invention.


DESCRIPTION OF THE INVENTION
Accordingly, the present invention relates to the compounds of the general formula (I) represented below and their pharmaceutically acceptable salts, enantiomers and their diastereomers;




Wherein, V, W, X, Y & Z independently represents, ‘C’ or ‘N’; R1, represents groups selected from hydrogen, keto, halogen, unsubstituted or substituted groups selected from cyano, alkyl, haloalkyl, aryl, alkoxy, acyloxy, aryloxy, arylalkyl, heteroaryl, heterocyclyl, heterocycloalkyl, cycloalkyl, cycloalkylalkyl, aryloxyaryl, aryloxyalkyl, aryloxyheteroaryl groups;
R2 represent the following ring system:







Wherein R3 at each occurrence is independently selected from hydrogen, haloalkyl, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, aryl, cycloalkyl, heterocycloalkyl, cycloalkyl(C1-7)alkyl, heterocycloalkyl(C1-7)alkyl, C(O)NH(C1-7)alkyl, C(O)—CH═CH2, C(O)—CH═CH—R4, C(O)—C(CN)═CH2, C(O)—C(CN)═CH—R4, SO2—NH(C1-7)alkyl, SO2—CH═CH2, SO2—CH═CH—R4 groups;
R4 is selected from —(CH2)n-NR5R6; wherein, n=0-7 and each of R5 and R6 are independently selected from hydrogen, haloalkyl, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, aryl, cycloalkyl, carbocycle, heterocycloalkyl, cycloalkyl(C1-7)alkyl, heterocycloalkyl(C1-7)alkyl; ‘U’ represent unsubstituted or substituted groups selected from alkyl, alkenyl, alkynyl, alkoxy, acyloxy, aryl, aryloxy, arylalkyl, cycloalkyl, cycloalkylalkyl, biaryl, heteroaryl, heterocycle, heterocycloalkyl, O-aryl, O-cycloalkyl, O-heteroaryl, O-heterocycle, O-heterocycloalkyl, aryloxyaryl, aryloxyalkyl, aryloxyheteroaryl, heteroaryloxyaryl, heteroaryloxyalkyl, heteroaryloxyheteroaryl, Ph-CO—N(R7R8), Ph-N(R9)—CO—R10, wherein, R7, R8 and R10 are independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy; aryl, cycloalkyl, heteroaryl, heterocycloalkyl; further substituted with halogen, alkyl, alkoxy, haloalkoxy groups and R9 are independently selected from hydrogen, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl.
In a preferred embodiment, the groups, radicals described above may be selected from:
“Alkyl”, as well as other groups having the prefix “alk”, such as alkoxy and alkanoyl, means a carbon chain which may further be substituted with an oxygen atom as is well understood by a skilled artisan, which may further be either linear or branched, and combinations thereof, unless the carbon chain is defined otherwise. Examples of alkyl group include but not are limited to methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert.-butyl, pentyl, hexyl etc. Where the specified number of carbon atoms permits e.g. from C3-10, the term alkyl also includes cycloalkyl groups, and combinations of linear or branched alkyl chains combined with cycloalkyl structures. When no number of carbon atoms is specified, C1-6 is intended.
“Alkenyl” means carbon chains which contain at least one carbon-carbon double bond, and which may be linear or branched or combinations thereof, unless the carbon chain is defined otherwise. Examples of alkenyl include vinyl, allyl, isopropenyl, hexenyl, pentenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl etc. Where the specified number of carbon atoms permits, e. g., from C5-10, the term alkenyl also includes cycloalkenyl groups and combinations of linear, branched and cyclic structures. When no number of carbon atoms is specified, C(2-6) is intended.
“Alkynyl” means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3-methyl-1-pentynyl etc. When no number of carbon atoms is specified, C(2-6) is intended.
As used herein, “carbocycle” or “carbocyclic residue” is intended to mean any stable monocyclic or bicyclic or tricyclic ring, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin). In a broader perspective, the term carbocycle is intended to include, wherever applicable, the groups representing cycloalkyl, phenyl and other saturated, partially saturated or aromatic residues;
“Cycloalkyl” is the subset of alkyl and means saturated carbocyclic ring having a specified number of carbon atoms, preferably 3-6 carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc. A cycloalkyl group generally is monocyclic unless otherwise stated. Cycloalkyl groups are saturated unless and otherwise stated.
The “alkoxy” refers to the straight or branched chain alkoxides of the number of carbon atoms specified.
“Aryl” means a mono- or polycyclic aromatic ring system containing carbon ring atoms. The preferred aryls are monocyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryls.
The terms “Heterocycle” or “heterocyclyl” refer to saturated or unsaturated non-aromatic rings or ring systems containing at least one heteroatom selected from O, S, N further optionally including the oxidized forms of sulfur, namely SO & SO2. Examples of heterocycles include tetrahydrofuran (THF), dihydrofuran, 1,4-dioxane, morpholine, 1,4-dithiane, piperazine, piperidine, 1,3-dioxolane, imidazoline, imidazolidine, pyrrolidine, pyrroline, tetrahydropyran, dihydropyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane, oxathiane, thiomorpholine, etc. The term “heterocycloalkyl” refers to a heterocyclic group as defined above connected to an alkyl group as defined above;
“Heteroaryl” means an aromatic or partially aromatic heterocycle that contains at least one ring heteroatom selected from O, S and N. Heteroaryls thus include heteroaryls fused to the other kinds of rings, such as aryls, cycloalkyls, and heterocycles that are not aromatic. Examples of heteroaryl groups include; pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, thienyl, pyrimidyl, benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzothiadiazolyl, dihydrobenzofuranyl, indolinyl, pyridazinyl, indazolyl, isoindolyl, dihydrobenzothienyl, indolinyl, pyridazinyl, indazolyl, isoindolyl, dihydrobenzothienyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, napthyridinyl, carbazolyl, benzodioxolyl, quinoxalinyl, purinyl, furazanyl, isobenzylfuranyl, benzimidazolyl, benzofuranyl, benzothienyl, quinolyl, indolyl, isoquinolyl, dibenzofuranyl etc. For heterocyclyl and heteroaryl groups, rings and ring systems containing from 3-15 carbon atoms are included, forming 1-3 rings.
An “aryloxy” group used either alone or in combination with other radicals, is selected from groups containing an aryl radical, as defined above, attached directly to an oxygen atom, more preferably groups selected from phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenyloxy, and the like;
“Cycloalkylalkyl” means an alkyl radical substituted with cycloalkyl group as defined herein. cycloalkylalkyl groups include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and the like.
An “arylalkyl” group as used herein is an aromatic substituent that is linked to an alkyl group having from one to about six carbon atoms. examples of arylalkyl groups include benzyl group, phenethyl and the like.
The “acyloxy” group used either alone or in combination with other radicals, is selected from a suitable acyl group, directly attached to an oxygen atom; more preferably such groups are selected from acetyloxy, propionyloxy, butanoyloxy, iso-butanoyloxy, benzoyloxy and the like;
The term “Haloalkyl” means a alkyl structure in which at least one hydrogen is replaced with a halogen atom. In certain embodiments in which two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are all the same as one another.
In certain other embodiment in which two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are not all the same as one another.
“Aryloxyalkyl” means an alkyl radical substituted with aryloxy group as defined herein.
“Aryloxyaryl” means an aryl radical substituted with aryloxy group as defined herein.
“Aryloxyheteroaryl” means a heteroaryl radical substituted with aryloxy group as defined herein.
“Halo/Halogen” refers to fluorine, chlorine, bromine, iodine. Chlorine and fluorine are generally preferred.
Suitable groups and substituents on the groups may be selected from those described anywhere in the specification.
The term “substituted,” as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. The term “substituted,” as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
“Pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include mineral or organic acid salts of the basic residues. Such conventional non-toxic salts include those derived from inorganic and organic acids selected from 1, 2-ethanedisulfonic, 2-acetoxybenzoic, 2-hydroxyethanesulfonic, acetic, ascorbic, benzenesulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodide, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methanesulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicyclic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, and toluenesulfonic.
The term ‘optional’ or ‘optionally’ means that the subsequent described event or circumstance may or may not occur, and the description includes instances where the event or circumstance occur and instances in which it does not. For example, ‘optionally substituted alkyl’ means either ‘alkyl’ or ‘substituted alkyl’. Further an optionally substituted group includes an unsubstituted group.
Unless otherwise stated in the specification, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
Particularly useful compounds may be selected from the following:









TABLE 1





Compd
Structures
IUPAC Names

















1




1-(5-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1- yl)hexahydrocyclopenta[c]pyrrol-2(1H)- yl)prop-2-en-1-one


 


2




1-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-1H- pyrazolo[3,4-d]pyrimidin-1- yl)hexahydrocyclopenta[c]pyrrol-2(1H)- yl)prop-2-en-1-one


 


3




1-(5-(5-((4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1- yl)methyl)pyridin-2- yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)prop-2-en-1-one


 


4




1-(5-(2-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1- yl)ethyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)prop-2-en-1-one


 


5




1-(5-(4-amino-3-(2-methylbenzo[d]thiazol-6- yl)-1H-pyrazolo[3,4-d]pyrimidin-1- yl)hexahydrocyclopenta[c]pyrrol-2(1H)- yl)prop-2-en-1-one


 


6




1-(5-(4-amino-3-(benzo[b]thiophen-5-yl)-1H- pyrazolo[3,4-d]pyrimidin-1- yl)hexahydrocyclopenta[c]pyrrol-2(1H)- yl)prop-2-en-1-one


 


7




1-(5-(4-amino-3-(2,3- dihydrobenzo[b]thiophen-5-yl)-1H- pyrazolo[3,4-d]pyrimidin-1- yl)hexahydrocyclopenta[c]pyrrol-2(1H)- yl)prop-2-en-1-one


 


8




1-(5-(4-amino-3-(dibenzo[b,d]furan-3-yl)-1H- pyrazolo[3,4-d]pyrimidin-1- yl)hexahydrocyclopenta[c]pyrrol-2(1H)- yl)prop-2-en-1-one


 


9




N-(6-(1-(2- acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-1H-pyrazolo[3,4-d]pyrimidin-3- yl)benzo[d]thiazol-2-yl)acetamide


 


10




1-(5-(4-amino-3-(2-methoxybenzo[d]thiazol- 6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1- yl)hexahydrocyclopenta[c]pyrrol-2(1H)- yl)prop-2-en-1-one


 


11




1-(5-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1- yl)hexahydrocyclopenta[c]pyrrol-2(1H)- yl)prop-2-yn-1-one


 


12




1-(5-(4-amino-3-(3-methoxy-4- phenoxyphenyl)-1H-pyrazolo[3,4- d]pyrimidin-1- yl)hexahydrocyclopenta[c]pyrrol-2(1H)- yl)prop-2-en-1-one


 


13




4-(1-(2- acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)- N-(pyridin-2-yl)benzamide


 


14




1-(5-(4-amino-3-(2-phenylbenzo[d]thiazol-6- yl)-1H-pyrazolo[3,4-d]pyrimidin-1- yl)hexahydrocyclopenta[c]pyrrol-2(1H)- yl)prop-2-en-1-one


 


15




1-(5-(4-amino-3-(benzo[d][1,3]dioxol-5-yl)- 1H-pyrazolo[3,4-d]pyrimidin-1- yl)hexahydrocyclopenta[c]pyrrol-2(1H)- yl)prop-2-en-1-one


 


16




1-(5-(4-amino-3-(4-(5-methyl-1,3,4-oxadiazol- 2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1- yl)hexahydrocyclopenta[c]pyrrol-2(1H)- yl)prop-2-en-1-one


 


17




1-(5-(4-amino-3-(benzo[d]oxazol-6-yl)-1H- pyrazolo[3,4-d]pyrimidin-1- yl)hexahydrocyclopenta[c]pyrrol-2(1H)- yl)prop-2-en-1-one


 


18




3-(4-phenoxyphenyl)-1-(2- (vinylsulfonyl)octahydrocyclopenta[c]pyrrol- 5-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine


 


19




1-(5-(4-amino-3-(2-phenylbenzo[d]oxazol-6- yl)-1H-pyrazolo[3,4-d]pyrimidin-1- yl)hexahydrocyclopenta[c]pyrrol-2(1H)- yl)prop-2-en-1-one


 


20




1-(5-(4-amino-3-(2-phenoxybenzo[d]thiazol- 6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1- yl)hexahydrocyclopenta[c]pyrrol-2(1H)- yl)prop-2-en-1-one


 


21




1-(5-(4-amino-3-(4-(1-methyl-1H-pyrazol-4- yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1- yl)hexahydrocyclopenta[c]pyrrol-2(1H)- yl)prop-2-en-1-one


 


22




1-(5-(4-amino-3-(benzo[d]oxazol-5-yl)-1H- pyrazolo[3,4-d]pyrimidin-1- yl)hexahydrocyclopenta[c]pyrrol-2(1H)- yl)prop-2-en-1-one


 


23




1-(5-(4-amino-3-(2-phenylbenzo[d]oxazol-5- yl)-1H-pyrazolo[3,4-d]pyrimidin-1- yl)hexahydrocyclopenta[c]pyrrol-2(1H)- yl)prop-2-en-1-one


 


24




(E)-1-(5-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1- yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 4-(dimethylamino)but-2-en-1-one


 


25




9-(2-acryloyloctahydrocyclopenta[c]pyrrol-5- yl)-6-amino-7-(4-phenoxyphenyl)-5,7- dihydro-4H-purin-8(9H)-one


 


26




1-(5-(4-amino-3-(4-(5-(pyridin-2-yl)-1,3,4- oxadiazol-2-yl)phenyl)-1H-pyrazolo[3,4- d]pyrimidin-1- yl)hexahydrocyclopenta[c]pyrrol-2(1H)- yl)prop-2-en-1-one


 


27




1-(5-(4-amino-6-bromo-5-(4-phenoxyphenyl)- 7H-pyrrolo[2,3-]pyrimidin-7- yl)hexahydrocyclopenta[c]pyrrol-2(1H)- yl)prop-2-en-1-one


 


28




(E)-2-(5-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1- yl)octahydrocyclopenta[c]pyrrole-2- carbonyl)-3-cyclopropylacrylonitrile


 


29




4-(1-(2- acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)- 2-methoxy-N-(4-methylpyridin-2- yl)benzamide


 


30




4-(1-(2- acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)- N-(4-methylpyridin-2-yl)benzamide


 


31




1-(5-(4-amino-5-(4-phenoxyphenyl)-7H- pyrrolo[2,3-d]pyrimidin-7- yl)hexahydrocyclopenta[c]pyrrol-2(1H)- yl)prop-2-en-1-one


 


32




N-(4-(1-(2- acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-1H-pyrazolo[3,4-d]pyrimidin-3- yl)phenyl)picolinamide


 


33




6-amino-7-(4-phenoxyphenyl)-9-(2- (vinylsulfonyl)octahydrocyclopenta[c]pyrrol- 5-yl)-7H-purin-8(9H)-one


 


34




4-(1-(2- acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)- N-(benzo[d]thiazol-2-yl)benzamide


 


35




N-(4-(1-(2- acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-1H-pyrazolo[3,4-d]pyrimidin-3- yl)phenyl)pyrazine-2-carboxamide


 


36




1-(5-(4-amino-3-(2,2- difluorobenzo[d][1,3]dioxol-5-yl)-1H- pyrazolo[3,4-d]pyrimidin-1- yl)hexahydrocyclopenta[c]pyrrol-2(1H)- yl)prop-2-en-1-one


 


37




4-(1-(2- acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)- N-(pyrazin-2-yl)benzamide


 


38




N-(4-(1-(2- acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-1H-pyrazolo[3,4-d]pyrimidin-3- yl)phenyl)benzamide


 


39




1-(5-(4-amino-3-(4-(5-(pyridin-2-yl)-1,3,4- thiadiazol-2-yl)phenyl)-1H-pyrazolo[3,4- d]pyrimidin-1- yl)hexahydrocyclopenta[c]pyrrol-2(1H)- yl)prop-2-en-1-one


 


40




4-(1-(2- acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)- N-(4-(trifluoromethyl)pyridin-2- yl)benzamide


 


41




(Z)-methyl 4-(1-(2- acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)- N-(4-methylpyridin-2-yl)benzimidate


 


42




6-(1-(2- acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)- N-(4-methylpyridin-2-yl)nicotinamide


 


43




1-(5-(4-amino-3-(4-(pyridin-2-yloxy)phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-1- yl)hexahydrocyclopenta[c]pyrrol-2(1H)- yl)prop-2-en-1-one


 


44




(E)-4-(4-amino-1-(2-(4-(dimethylamino)but-2- enoyl)octahydrocyclopenta[c]pyrrol-5-yl)- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N- (pyridin-2-yl)benzamide


 


45




(E)-4-(4-amino-1-(2-(4-(dimethylamino)but-2- enoyl)octahydrocyclopenta[c]pyrrol-5-yl)- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4- methypyridin-2-yl)benzamide


 


46




1-(5-(4-amino-3-(4-(5-(pyrazin-2-yl)-1,3,4- thiadiazol-2-yl)phenyl)-1H-pyrazolo[3,4- d]pyrimidin-1- yl)hexahydrocyclopenta[c]pyrrol-2(1H)- yl)prop-2-en-1-one


 


47




(E)-1-(5-(4-amino-3-(4-(pyridin-2- yloxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin- 1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)- yl)-4-(dimethylamino)but-2-en-1-one


 


48




(E)-1-(5-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1- yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 4-(dimethylamino)but-2-en-1-one


 


49




(E)-4-(4-amino-1-(2-(4-(dimethylamino)but-2- enoyl)octahydrocyclopenta[c]pyrrol-5-yl)- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N- (pyrazin-2-yl)benzamide


 


50




(Z)-methyl 4-(4-amino-1-(2-((E)-4- (dimethylamino)but-2- enoyl)octahydrocyclopenta[c]pyrrol-5-yl)- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4- methylpyridin-2-yl)benzimidate


 


51




(E)-4-(4-amino-1-(2-(4-(dimethylamino)but-2- enoyl)octahydrocyclopenta[c]pyrrol-5-yl)- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4- (trifluoromethyl)pyridin-2-yl)benzamide


 


52




1-(5-(4-amino-3-(4-(pyridin-3-yloxy)phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-1- yl)hexahydrocyclopenta[c]pyrrol-2(1H)- yl)prop-2-en-1-one


 


53




(E)-1-(5-(4-amino-3-(4-(pyridin-3- yloxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin- 1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)- yl)-4-(dimethylamino)but-2-en-1-one


 


54




4-(1-(2- acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)- N-methyl-N-(4-methylpyridin-2- yl)benzamide


 


55




(E)-4-(4-amino-1-(2-(4-(dimethylamino)but-2- enoyl)octahydrocyclopenta[c]pyrrol-5-yl)- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N- methyl-N-(4-methylpyridin-2-yl)benzamide


 


56




(E)-1-(5-(4-amino-3-(4-(5-(pyrazin-2-yl)-1,3,4- thiadiazol-2-yl)phenyl)-1H-pyrazolo[3,4- d]pyrimidin-1- yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 4-(dimethylamino)but-2-en-1-one


 


57




(E)-1-(5-(4-amino-3-(4-(5-(pyridin-2-yl)-1,3,4- oxadiazol-2-yl)phenyl)-1H-pyrazolo[3,4- d]pyrimidin-1- yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 4-(dimethylamino)but-2-en-1-one









or pharmaceutically acceptable salts of any of the compounds above.

Following is a list of abbreviations used in the description of the preparation of the compounds of the present invention:

ALL: Acute lymphoblastic leukemia

ATP: Adenosine triphosphate

BTK: Bruton's Tyrosine Kinase

bs: broad singlet

CLL: Chronic lymphocytic leukemia

CDCl3: Deuterated chloroform

CHCl3: Chloroform

d: doublet

dd: doublet of doublet

dt: doublet of triplet

DCM: Dichloromethane

DMAC: N,N-(Dimethylacetamide)

DMAP: 4-(Dimethylamino) pyridine

DMF: N,N-Dimethyl formamide

DMSO: Dimethyl sulfoxide

EDTA: Ethylenediaminetertraacetic acid

EtOAc: Ethyl acetate

EtOH: Ethanol

HCl(g): Hydrogen chloride (gas)

K2CO3: Potassium carbonate

MeOH: Methanol

m: multiplet

mmol: millimoles

□g: microgram

MS: Mass spectrum

NHL: Non-Hodgkin's lymphoma

Na2CO3: Sodium carbonate

ng: nanogram

NIS: N-iodosuccinimide

1H NMR: Proton nuclear magnetic resonance

Pet ether: Petroleum ether, boiling range (60-80° C.)

POCl3: Phosphorylchloride

s: singlet

t: Triplet

td: triplet of doublet

THF: Tetrahydrofuran

TLC: Thin layer chromatography

The novel compounds of the present invention can be prepared using the reactions and techniques described below, together with conventional techniques known to those skilled in the art of organic synthesis, or variations thereon as appreciated by those skilled in the art.

The reactions can be performed in solvents appropriate to the reagents and materials employed and suitable for the transformations being affected. Preferred methods include those described below, where all symbols are as defined earlier unless and otherwise defined below.
The compounds of the formula (I) can be prepared as described in schemes below along with suitable modifications/variations which are well within the scope of a person skilled in the art.




Wherein ‘U’, R2 and R3 are as defined earlier. Compound of formula (I) can be prepared by variety of methods familiar to those skilled in art. Compound of formula (i) was transformed into compound (ii) by reacted with hydrazine hydrate (Scheme-I). Compound of formula (ii) was cyclized using formamide to afford the compound of formula (iii). Compound (iii) was reacted with N-iodosuccinimide to get compound (iv). Compound (iv) reacted with compound (v) using different base to furnish the compound of formula (vi). Compound (vi) can subjected to Suzuki type of reaction, with compound (vii) using suitable catalysts, base and appropriate solvents to obtain compound of formula (viii). The deprotection of compound (viii) gives compound (ix). Compound (ix) is reacted with optionally substituted acid chlorides (x) to obtain compounds of formula (I).
The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and methods of preparing such compounds. In the following examples molecules with a single chiral center, unless otherwise noted, exist as a racemic mixture. Those molecules with two or more chiral centers, unless otherwise noted, exist as a racemic mixture of diastereomers. Single enantiomers/diastereomers may be obtained by methods known to those skilled in the art.
The compounds of formula (I) may also be synthesized as described in Scheme II. wherein ‘U’, R2 and R3 are as defined earlier. Compound (i) may be continently prepared by variety of methods familiar to those skilled in art. Compound (i) was transformed into compound (ii) by reacting with dibenzyl amine using different bases. Compound of formula (ii) was reacted with different protected cycloalkyl amines (iii) using suitable bases to furnish compound (iv). Compound (iv) was reduced to amine to afford the compound (v). Compound (v) was reacted with Triphosgene to get the compound (vi). Compound (vi) was deprotected to using Pd(OH)2 to afford compound (vii). Compound (vii) was reacted with different Boronic acid to obtain compound (viii). Compound (viii) was deproted using suitable acid to get the compound (ix). Compound (ix) was reacted with optionally substituted acid chlorides using base to obtain compound of formula (I).




The compounds of formula (I) may also be synthesized as described in Scheme III. wherein ‘U’, R2 and R3 are as defined earlier. Compound (i) may be continently prepared by variety of methods familiar to those skilled in art. Compound (i) was transformed into compound (ii) using Ammonia. Compound (ii) reacted with compound (iii) using different base to furnish the compound of formula (iv). Compound (iv) can be subjected to Suzuki type of reaction, with compound (v) using suitable catalysts, base and appropriate solvents to obtain compound of formula (vi). Compound (vi) can be halogenated to afford compound (vii). The deprotection of compound (vii) gives compound (viii). Compound (viii) is reacted with optionally substituted acid chlorides to obtain compounds of formula (I).




Compounds of the present invention can be isolated either as free amine form or as a salt corresponding to the acid used such as trifluoroacetic acid, hydrochloric acid, hydrobromic acid, oxalic acid, maleic acid, fumeric acid, succinic acid, p-toluene sulfonic acid or benzene sulfonic acid. The compounds can be purified where ever required, by recrystallization, trituration, precipitation, preparative thin layer chromatography, flash chromatography or by preparative HPLC method. The compounds of the present invention can be used either alone or in combination with one or more therapeutic agents or pharmaceutically acceptable salts thereof. Such use will depend on the condition of the patient being treated and is well within the scope of a skilled practitioner.
The invention is further illustrated by the following examples which describe the preferred way of carrying out the present invention. These are provided without limiting the scope of the present invention in any way.
1H NMR spectral data given in the examples (vide infra) are recorded using a 400 MHz spectrometer (Bruker AVANCE-400) and reported in 6 scale. Until and otherwise mentioned the solvent used for NMR is CDCl3 using TMS as the internal standard.
Example: 1
Synthesis of 1-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one (compound No: 1)
Synthesis of titled compound was carried out, as described in Scheme-IV and step-wise procedure is described below.




Step-1: Synthesis of tert-butyl 5-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta [c]pyrrole-2(1H)-carboxylate (3)




Intermediate 1 (2.0 g, 7.66 mmol), prepared as per general process disclosed in US 2012/0088912 and triphenylphosphine (6.53 g) were mixed together, in THF (20 mL). Tert-butyl 5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate 2 (3.47 g, 15.32 mmol) was added to the mixture followed by the addition of diisopropyl diazodicarboxylate (2.26 mL, 11.49 mmol). The reaction mixture was stirred at room temperature overnight, filtered and concentrated. The residue obtained was purified by flash chromatography (CH2Cl2/MeOH=98/2) to get intermediate 3 as a white solid (2.75 g, 76% Yield). 1H NMR (DMSO-d6, 400 MHz) δ ppm: 1.40 (s, 9H), 1.94-2.00 (m, 2H), 2.17-2.24 (m, 2H), 2.82-3.00 (m, 2H), 3.10-3.14 (m, 2H), 3.45-3.50 (m, 2H), 5.27-5.30 (m, 1H), 8.29 (s, 1H). MS (ESI-MS): m/z 471.10 (M+H)+.
Step-2: Synthesis of tert-butyl5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (5)




To a stirred solution Intermediate 3 (2.7 g, 5.74 mmol), dissolved in dry DMF (27 mL), PdCl2(PPh3)2(0.4 g, 0.57 mmol), 4-phenoxyphenylboronicacid 4 (1.84 g, 8.61 mmol) and KHCO3 (3.44 g, 34.46 mmol) was added. The reaction mixture was heated at 90° C. for 2 hrs, under N2 atmosphere. Mixture was cooled to room temperature, diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layer was washed with water (2×25 mL) and brine solution (25 mL), dried over Na2SO4, and concentrated to dryness. The residue obtained was purified by column chromatography (using 0-5% methanol in DCM as a mobile phase) to obtain Intermediate 5 as an off white solid (2.2 g, 74% Yield). 1H NMR (DMSO-d6, 400 MHz) δ ppm: 1.48 (s, 9H), 1.98-2.04 (m, 2H), 2.27-2.34 (m, 2H), 2.89 (s, 2H), 3.13-3.17 (m, 2H), 3.47 (q, 2H, J=8.0 Hz), 5.36 (q, 1H, J=8.0 Hz), 7.10-7.14 (m, 4H), 7.144-7.20 (m, 1H), 7.40-7.43 (m, 2H), 7.65-7.68 (m, 2H), 8.23 (s, 1H). ESI-MS (ESI-MS): m/z 535.23 (M+Na)+.
Step-3: Synthesis of 1-(octahydrocyclopenta[c]pyrrol-5-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (6)




To a solution of Intermediate 5 (2.1 g, 4.09 mmol) in CH2Cl2 (40 mL) was added TFA (1.25 mL, 16.37 mmol). After stirring 2 hrs at room temperature, the solvent was removed and the residues were dissolved in a mixture of ethyl acetate (50 mL) and dilute aq. K2CO3. The organic layer was separated, dried over MgSO4, filtered and concentrated to provide Intermediate 6 as a white solid (1.2 g, 71% Yield). 1H NMR (400 MHz) δ ppm: 1.92-1.96 (m, 2H), 2.31-2.39 (m, 2H), 2.74-2.78 (m, 2H), 2.89-2.30 (m, 2H), 3.12-3.20 (m, 2H), 5.43-5.37 (m, 1H), 7.11-7.20 (m, 5H), 7.41-7.45 (m, 2H), 7.64-7.66 (m, 2H), 8.24 (s, 1H); MS (ESI-MS): m/z 413.20 (M+H)+.
Step-4: Synthesis of 1-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one, compound No: 1




To a solution of Intermediate 6 (1.1 g, 2.66 mmol), dissolved in CH2Cl2 (30 mL), tri-ethyl amine (1.11 mL, 8.00 mmol) was added followed by addition of acryl chloride (0.2 mL, 2.53 mmol). The reaction was stopped after 2 hrs. The reaction mixture was washed with water and then with brine. The organic layer was separated, dried over MgSO4, filtered and concentrated. Residue obtained was purified by flash chromatography (using CH2Cl2/MeOH=25/1, as a mobile phase) to get compound 1 as a white solid (0.75 g, 60% Yield). 1H NMR: (CDCL3, 400 MHz): δ 8.36 (S, 1H), 7.66-7.62 (m, 2H), 7.37-7.41 (m, 2H), 7.13-7.20 (s, 3H), 7.07-7.09 (m, 2H), 6.36-6.50 (m, 2H), 5.68-5.71 (m, 1H), 5.53-5.59 (m, 3H), 3.82-3.87 (m, 2H), 3.45-3.53 (m, 2H), 3.10-3.21 (m, 2H), 2.50-2.58 (m, 2H), 2.11-2.17 (m, 2H); ESI-MS: (+ve mode) 467.20 (M+H)+ (100%); UPLC: 98.09%.
Example: 2
Synthesis of 4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(pyridin-2-yl)benzamide (compound No: 13)
Synthesis of titled compound was carried out, as described in Scheme-V and step-wise procedure is described below.




Step-1: Synthesis of tert-butyl 5-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocylcopenta[c]pyrrole-2(1H)-carboxylate (3)




Intermediate 1 (0.22 g, 0.851 mmol) and triphenylphosphine (0.71 g) were mixed together in THF (10 mL). Tert-butyl 5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate 2 (0.38 g, 1.7 mmol) was added to the reaction mixture followed by the addition of diisopropyl diazodicarboxylate (0.24 mL, 1.22 mmol). The reaction mixture was stirred at room temperature overnight, filtered and concentrated. The residue obtained was purified by flash chromatography (CH2Cl2/MeOH=98/2) to get intermediate 3 as a white solid (0.3 g, 76% Yield). 1H NMR (DMSO-d6, 400 MHz) δ ppm: 1.40 (s, 9H), 1.94-2.00 (m, 2H), 2.17-2.24 (m, 2H), 2.82-3.00 (m, 2H), 3.10-3.14 (m, 2H), 3.45-3.50 (m, 2H), 5.27-5.30 (m, 1H), 8.29 (s, 1H). MS (ESI-MS): m/z 471.10 (M+H)+.
Step-2: Synthesis of tert-butyl 5-(4-amino-3-(4-(pyridin-2-ylcarbamoyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (5)




To a stirred solution of intermediate 3 (0.3 g, 0.638 mmol), dissolved in dry DMF (3 mL) were added PdCl2(PPh3)2(0.089 g, 0.127 mmol), (4-(pyridin-2-ylcarbamoyl)phenyl)boronic acid 4 (0.31 g, 0.95 mmol) and KHCO3 (0.340 g, 3.56 mmol). The reaction mixture was heated at 90° C. for 2 hrs, under N2 atmosphere. Mixture was cooled to room temperature, diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layer was washed with water (2×25 mL) and brine solution (25 mL), dried over Na2SO4 and concentrated to dryness. The residue obtained was purified by column chromatography (silica gel, 0-5% methanol in DCM) to obtain intermediate 5 as an off white solid (0.25 g, 72.56% Yield). 1H NMR (DMSO-d6, 400 MHz) δ ppm: 1.59 (s, 9H), 2.11-2.17 (m, 2H), 2.49-2.57 (m, 2H), 3.07-3.09 (m, 2H), 3.28 (bs, 2H), 3.64 (bs, 2H), 5.55 (q, 1H, J=8.0 Hz), 7.11 (q, 1H, J=8.0 Hz), 7.78-7.81 (m, 1H), 7.82 (m, 2H), 8.10 (d, 2H, J=8.0 Hz), 8.35 (m, 1H), 8.41-8.43 (m, 2H), 8.63 (s, 1H). ESI-MS (ESI-MS): m/z 541.41 (M+H)+.
Step-3: Synthesis of 4-(4-amino-1-(octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(pyridin-2-yl)benzamide (6)




To a solution of Intermediate 5 (0.25 g, 0.462 mmol) in CH2Cl2 (10 mL), TFA (1.0 mL, 15.87 mmol) was added and the reaction mixture was stirred for 2 hrs at room temperature. The solvent was removed and the residue obtained was dissolved in a mixture of ethyl acetate (50 mL) and dilute aq. K2CO3. The organic layer was dried over MgSO4, filtered and concentrated to get Intermediate 6 as a white solid (0.13 g, 63.85% Yield). 1H NMR (DMSO-d6, 400 MHz) δ ppm: 1.15-1.23 (m, 2H), 2.32-2.37 (m, 2H), 2.54-2.58 (m, 2H), 2.93-2.97 (m, 2H), 3.24-3.29 (m, 2H), 5.33-5.37 (m, 1H), 7.16-7.19 (m, 1H), 7.77 (q, 2H, J=12.0 Hz), 7.84-7.88 (m, 1H), 8.18-8.20 (m, 2H), 8.22-8.24 (m, 1H), 8.25-8.30 (m, 1H), 8.40-8.41 (m, 1H), 10.83 (s, 1H); MS (ESI-MS): m/z 441.15 (M+H)+.
Step-4: Synthesis of 4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(pyridin-2-yl)benzamide; compound No: 13




To a solution of Intermediate 6 (0.13 g, 0.295 mmol), dissolved in CH2Cl2 (30 mL) and tri-ethyl amine (0.090 g, 0.886 mmol), acryl chloride (0.026 g, 0.295 mmol) was added and the reaction mixture was stirred for 2 hrs. The reaction mixture was washed with water and brine solution. The organic layer was dried over MgSO4, filtered, concentrated and residue obtained was purified by flash chromatography, using CH2Cl2/MeOH (25/1) to get compound 13 as a white solid (0.03 g, 20.58% Yield). 1H NMR: (CDCl3, 400 MHz): δ 8.72 (s, 1H), 8.43 (d, 1H, J=6.4 Hz), 8.39 (s, 1H), 8.35-8.34 (m, 1H), 8.13 (d, 2H, J=8.4 Hz), 7.88 (d, 2H, J=8.4 Hz), 7.83-7.79 (m, 1H), 7.14-7.11 (m, 1H), 6.49 (dd, 1H, J1=10.0 Hz, J2=16.8 Hz), 6.42 (dd, 1H, J1=2.4 Hz, J2=16.8 Hz), 5.72 (dd, 1H, J1=2.8 Hz, J2=10.0 Hz), 5.61-5.55 (m, 3H), 3.89-3.84 (m, 2H), 3.57-3.47 (m, 2H), 3.24-3.21 (m, 1H), 315-3.12 (m, 1H), 2.60-2.52 (m, 2H), 2.21-2.14 (m, 1H); ESI-MS: (+ve mode) 495.4 (M+H)+ (100%); HPLC: 99.09.
Example: 3
Compound 2: (1-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one




1H NMR: (CDCl3, 400 MHz): δ 9.11 (s, 1H), 8.41 (s, 1H), 8.34-8.30 (m, 2H), 7.87 (dd, 1H, J1=1.6 Hz, J2=8.4 Hz), 6.49 (dd, 1H, J1=9.6 Hz, J2=16.8 Hz), 6.42 (dd, 1H, J1=2.8 Hz, J2=16.8 Hz), 5.72 (dd, 1H, J1=2.4 Hz, J2=9.6 Hz), 5.64-5.57 (m, 1H), 5.50 (bs, 2H), 3.89-3.84 (m, 2H), 3.57-3.47 (m, 2H), 3.25-3.20 (m, 1H), 3.17-3.11 (m, 1H), 2.62-2.54 (m, 2H), 2.22-2.13 (m, 2H); ESI-MS: (+ve mode) 431.9 (M+H)+ (100%); HPLC: 96.04%.
Example: 4
Compound 3: 1-(5-(5-((4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyridin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-2-en-1-one




1H NMR: (DMSO-d6, 400 MHz): δ 8.27 (S, 1H), 8.11-8.09 (m, 1H), 7.63-7.61 (m, 2H), 7.44-7.40 (m, 1H), 7.48-7.44 (m, 2H), 7.19-7.17 (m, 1H), 7.13-7.09 (m, 5H), 6.56-6.49 (m, 1H), 6.44-6.41 (m, 1H), 6.11-6.06 (m, 1H), 5.64-5.61 (m, 1H), 5.39 (s, 2H), 4.41-4.39 (m, 2H), 3.81-3.80 (m, 1H), 3.64-3.57 (m, 2H), 3.46-3.45 (m, 2H), 3.19-3.16 (m, 2H); ESI-MS: (+ve mode) 559.35 (M+H)+ (100%); HPLC: 95.82%.
Example: 5
Compound 4: 1-(5-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-2-en-1-one




1H NMR: (CDCl3, 400 MHz): δ 8.37 (s, 1H), 7.65 (dd, 2H, J1=2.0 Hz, J2=6.4 Hz), 7.40 (t, 2H, J=4.4 Hz), 7.18-7.13 (m, 3H), 7.09 (d, 2H, J=7.6 Hz), 6.37-6.27 (m, 2H), 5.61 (dd, 1H, J1=3.6 Hz, J2=9.2 Hz), 5.41 (bs, 2H), 3.79-3.68 (m, 2H), 3.35 (dd, 1H, J1=4.8 Hz, J2=12.8 Hz), 3.27 (dd, 1H, J1=4.8 Hz, J2=10.4 Hz), 3.08-3.05 (m, 1H), 2.96 (t, 1H, J=6.0 Hz), 2.89-2.86 (m, 1H), 2.77-2.75 (m, 1H), 2.70-2.57 (m, 4H); ESI-MS: (+ve mode) 496.15 (M+H)+ (100%); HPLC: 96.62%.
Example: 6
Compound 5: 1-(5-(4-amino-3-(2-methylbenzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one




1H NMR: (CDCl3, 400 MHz): δ 8.40 (s, 1H), 8.19 (d, 1H, J=2.0 Hz), 8.12 (d, 1H, J=8.4 Hz), 7.77 (dd, 1H, J1=2.0 Hz, J2=8.4 Hz), 6.49 (dd, 1H, J1=10.0 Hz, J2=16.8 Hz), 6.42 (dd, 1H, J1=2.8 Hz, J2=16.8 Hz), 5.72 (dd, 1H, J1=2.4 Hz, J2=9.6 Hz), 5.61-5.57 (m, 1H), 5.31 (bs, 2H), 3.89-3.83 (m, 2H), 3.56-3.47 (m, 2H), 3.24-3.22 (m, 1H), 3.14-3.12 (m, 1H), 2.91 (s, 3H), 2.59-2.55 (m, 2H), 2.19-2.14 (m, 2H); ESI-MS: (+ve mode) 446.0 (M+H)+ (100%); HPLC: 95.09%.
Example: 7
Compound 6: 1-(5-(4-amino-3-(benzo[b]thiophen-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one




1H NMR: (DMSO, 400 MHz): δ 8.24 (s, 1H), 8.16 (dd, 2H, J1=6.0 Hz, J2=4.4 Hz), 7.85 (d, 1H, J=5.6 Hz), 7.65 (dd, 1H, J=8.4 Hz, J2=1.6 Hz), 7.56 (d, 1H, J=5.2 Hz), 7.62 (dd, 1H, J1=10.4 Hz, J2=16.8 Hz), 6.14 (dd, 1H, J1=16.8 Hz, J2=2.4 Hz), 5.67 (dd, 1H, J1=10.0 Hz, J2=2.4 Hz), 5.45-5.41 (m, 1H), 3.81-3.76 (m, 1H), 3.66-3.60 (m, 1H), 3.54-3.50 (m, 1H), 3.42-3.35 (m, 1H), 3.00-3.08 (m, 1H), 23.00-2.98 (m, 1H), 2.38-2.31 (m, 2H), 2.09-2.04 (m, 2H); ESI-MS: (+ve mode) 431.0 (M+H)+ (100%), 453.2 (M+Na)+ (25%); UPLC: 98.53%.
Example: 8
Compound 7: 1-(5-(4-amino-3-(2,3-dihydrobenzo[b]thiophen-5-yl)-1H-pyrazolo [3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one




1H NMR (DMSO-d6, 400 MHz) δ ppm: 8.22 (s, 1H), 7.55-7.51 (m, 2H), 7.42-7.38 (m, 2H), 6.65-6.58 (m, 1H), 6.16-6.11 (dd, 1H, J1=2.8 Hz, J2=17.2 Hz), 5.68-5.66 (m, 1H), 5.64-5.39 (m, 1H), 3.42-3.40 (m, 1H), 3.39-3.37 (m, 1H), 3.35-3.35 (m, 1H), 3.32-3.30 (m, 3H), 3.10-2.83 (m, 2H), 2.82-2.80 (m, 2H), 2.33-2.29 (m, 3H), 2.04-2.03 (m, 2H); (ESI-MS): (+ve mode) 433.05 (M+H)+. (100%), UPLC: 95.80%.
Example: 9
Compound 8: 1-(5-(4-amino-3-(dibenzo[b,d]furan-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one




1H NMR: (DMSO, 400 MHz): δ 8.30-8.28 (m, 1H), 8.26 (s, 1H), 8.22-8.20 (m, 1H), 7.92 (d, 1H, J=0.8 Hz), 7.75-7.69 (m, 2H), 7.58-7.54 (m, 1H), 7.46-5.43 (m, 1H), 6.66-6.59 (m, 1H), 6.14 (dd, 1H, J1=2.4 Hz, J2=16.8 Hz), 5.67 (dd, 1H, J1=2.4 Hz, J2=10.4 Hz), 5.46-5.43 (m, 1H), 3.82-3.77 (m, 1H), 3.65-3.61 (m, 1H), 3.55-3.51 (m, 1H), 3.39-3.35 (m, 1H), 3.17-2.92 (m, 2H), 2.41-2.33 (m, 2H), 2.11-2.05 (m, 2H); ESI-MS: (+ve mode) 465.1 (M+H)+ (100%), 487.3 (M+Na)+ (10%); UPLC: 95.50.
Example: 10
Compound 9: N-(6-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo [3,4-d]pyrimidin-3-yl)benzo[d]thiazol-2-yl)acetamide




1H NMR: (DMSO, 400 MHz): δ 12.41 (s, 1H), 8.24 (s, 2H), 8.87-8.85 (m, 1H), 7.69-7.67 (m, 1H), 6.65-6.58 (m, 1H), 6.14 (dd, 1H, J1=2.4 Hz, J2=14.4 Hz), 5.66 (dd, 1H, J1=1.2 Hz, J2=10.4 Hz), 5.44-5.41 (m, 1H), 3.81-3.38 (m, 3H), 3.40-3.33 (m, 1H), 3.11-2.99 (m, 2H), 2.50-2.37 (m, 2H), 2.20 (s, 3H), 2.12-1.90 (m, 2H); ESI-MS: (+ve mode) 489.3 (M+H)+ (100%), 511.0 (M+Na)+(10%); UPLC: 95.29%.
Example: 11
Compound 10: 1-(5-(4-amino-3-(2-methoxybenzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d] pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one




1H NMR (DMSO-d6, 400 MHz) δ ppm: 8.23 (s, 1H), 8.17 (s, 1H), 7.79 (m, 1H, J=8.4 Hz), 7.67-7.65 (m, 1H), 6.64-6.58 (m, 1H), 6.30-6.11 (dd, 1H, J1=2.4 Hz, J2=16.8 Hz), 5.70-5.65 (dd, 1H, J1=2.4 Hz, J2=10.4 Hz), 5.45-5.42 (m, 1H), 4.19 (s, 3H), 3.80-3.76 (m, 1H), 3.62-3.53 (m, 1H), 3.40-3.38 (m, 1H), 3.10-2.83 (m, 1H), 2.82-2.80 (m, 2H), 2.36-2.32 (m, 2H), 2.06-2.05 (m, 2H); (ESI-MS): (+ve mode) 462.05 (M+H)+. (100%), UPLC: 95.22%, Ret. time=3.09 min.
Example: 12
Compound 11: 1-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-yn-1-one




1H NMR: (DMSO-d6, 400 MHz): δ 8.23 (s, 1H), 7.67-7.64 (m, 2H), 7.44-7.40 (m, 2H), 7.19-7.10 (m, 5H), 5.4 (s, 1H), 4.21-4.18 (m, 1H), 3.83-3.74 (m, 1H), 3.65-3.61 (m, 2H), 3.05-3.03 (m, 2H), 2.34-2.31 (m, 2H), 2.05-2.03 (m, 2H); ESI-MS: (+ve mode) 465.50 (M+H)+ (100%); HPLC: 99.12%.
Example: 13
Compound 12: 1-(5-(4-amino-3-(3-methoxy-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one




1H NMR: (CDCl3, 400 MHz): δ 8.38 (s, 1H), 7.37-7.33 (m, 3H), 7.22 (dd, 1H, J1=8.0 Hz, J2=2.0 Hz), 7.14-7.08 (m, 2H), 7.03 (d, 2H, J=8.0 Hz), 6.51-6.37 (m, 2H), 5.70 (dd, 1H, J1=10.0 Hz, J2=2.4 Hz), 5.65 (bs, 2H), 5.60-5.53 (m, 1H), 3.95 (s, 3H), 3.89-3.84 (m, 2H), 3.55-3.51 (m, 2H), 3.24-3.21 (m, 1H) 3.15-3.11 (m, 1H), 2.63-2.54 (m, 2H), 2.21-2.12 (m, 2H); ESI-MS: (+ve mode) 497.1 (M+H)+ (100%), 519.25 (M+Na)+ (50%); UPLC: 95.90%.
Example: 14
Compound 14: 1-(5-(4-amino-3-(2-phenylbenzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one




1H NMR: (CDCl3, 400 MHz): δ 8.41 (s, 1H), 8.27 (d, 1H, J=1.6 Hz), 8.23 (d, 1H, J=8.0 Hz), 8.15-8.13 (m, 2H), 7.82 (dd, 1H, J1=8.0 Hz, J2=2.0 Hz), 7.56-7.53 (m, 3H), 6.52-6.38 (m, 2H), 5.70 (dd, 1H, J1=10.0 Hz, J2=2.0 Hz), 5.63-5.59 (m, 1H), 5.49 (bs, 2H), 3.90-3.84 (m, 2H), 3.57-3.48 (m, 2H), 3.25-3.22 (m, 1H), 3.17-3.14 (m, 1H), 2.63-2.55 (m, 2H), 2.22-2.13 (m, 2H); ESI-MS: (+ve mode) 507.6 (M+H)+ (100%), 530.1 (M+Na)+ (30%); UPLC: 97.51%.
Example: 15
Compound 15: 1-(5-(4-amino-3-(benzo[d] [1,3]dioxol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one




1H NMR: (DMSO-d6, 400 MHz): δ 8.21 (s, 1H), 7.15-7.13 (m, 1H), 7.12-7.10 (m, 1H), 7.09-7.07 (m, 1H), 6.65-6.58 (m, 1H), 6.16-6.12 (m, 1H), 6.11 (s, 2H), 5.68-5.64 (m, 1H), 5.42-5.35 (m, 1H), 3.83-3.81 (m, 1H), 3.80-3.75 (m, 1H), 3.65-3.60 (m, 1H), 3.50-3.49 (m, 1H), 3.08-3.06 (m, 1H), 2.99-2.96 (m, 1H), 2.36-2.82 (m, 2H), 2.07-2.04 (m, 2H); ESI-MS: (+ve mode) 419.58 (M+H)+ (100%); HPLC: 96.33%.
Example: 16
Compound 16: 1-(5-(4-amino-3-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one




1H NMR: (DMSO-d6, 400 MHz): δ 8.25 (s, 1H), 8.13-8.11 (d, 2H, J=8.0 Hz), 7.89-7.87 (d, 2H, J=8.0 Hz), 6.65-6.58 (m, 1H), 6.16-6.11 (dd, 1H, J1=2.8 Hz, J2=16.8 Hz), 5.68-6.65 (dd, 1H, J1=2.4 Hz, J2=20 Hz), 5.46-5.41 (m, 1H), 3.78-3.76 (m, 1H), 3.64-3.61 (m, 1H), 3.54-3.50 (m, 1H), 3.39-3.34 (m, 1H), 3.23-3.08 (m, 1H), 3.07-3.00 (m, 1H), 2.61 (s, 3H), 2.38-2.32 (m, 2H), 2.07-2.05 (m, 2H); ESI-MS: (+ve mode) 457.10 (M+H)+ (100%); UPLC: 95.87%.
Example: 17
Compound 17: 1-(5-(4-amino-3-(benzo[d]oxazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one




1H NMR: (CDCl3, 400 MHz): δ 8.40 (s, 1H), 8.22 (s, 1H), 7.99-7.97 (m, 2H), 7.74-7.72 (m, 1H), 6.47-6.42 (m, 1H), 5.73-5.70 (m, 1H), 5.78-5.60 (m, 2H), 3.86-3.84 (m, 2H), 3.57-3.55 (m, 2H), 3.22-3.19 (m, 2H), 2.56-2.54 (m, 2H), 2.18-2.16 (m, 2H); ESI-MS: (+ve mode) 416.78 (M+H)+ (100%); HPLC: 96.12%.
Example: 18
Compound 18: 3-(4-phenoxyphenyl)-1-(2-(vinylsulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine




1H NMR: (DMSO, 400 MHz): δ 8.24 (s, 1H), 7.64 (dd, 2H, J1=6.8 Hz, J2=2.0 Hz), 7.44-7.40 (m, 2H), 7.19-7.10 (m, 5H), 6.94-6.87 (m, 1H), 6.21 (d, 1H, J=10.0 Hz), 6.15 (d, 1H, J=16.8 Hz), 5.41-65.30 (m, 1H), 3.29-3.24 (m, 2H), 3.04-3.01 (m, 4H), 2.34-2.32 (m, 2H), 2.10-1.90 (m, 2H); ESI-MS: (+ve mode) 503.15 (M+H)+ (100%); UPLC: 95.16%.
Example: 19
Compound 19: 1-(5-(4-amino-3-(2-phenylbenzo[d]oxazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one




1H NMR: (CDCl3, 400 MHz): δ 8.41 (s, 1H), 8.32-8.30 (m, 2H), 7.96-7.93 (m, 2H), 7.73-7.70 (m, 1H), 7.59-7.57 (m, 3H), 6.52-6.43 (m, 1H), 5.72-5.69 (m, 1H), 5.62-5.59 (m, 1H), 5.50-5.49 (m, 1H), 3.90-3.84 (m, 2H), 3.58-3.48 (m, 2H), 3.23-3.19 (m, 2H), 2.60-2.58 (m, 2H), 2.20-2.17 (m, 2H); ESI-MS: (+ve mode) 492.35 (M+H)+ (100%); HPLC: 95.63%.
Example: 20
Compound 20: 1-(5-(4-amino-3-(2-phenoxybenzo[d]thiazol-6-yl)-1H-pyrazolo [3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one




1H NMR (DMSO-d6, 400 MHz) δ ppm: 8.22 (s, 1H), 7.82 (d, 1H, J=8.4 Hz), 7.70-7.68 (m, 1H), 7.56-7.53 (m, 2H), 7.49-7.47 (m, 2H), 7.42-7.40 (m, 1H), 6.65-6.61 (m, 1H), 6.16 (dd, 1H, J1=2.4 Hz, J2=14.4 Hz), 5.68 (dd, 1H, J1=2.4 Hz, J2=10.4 Hz), 5.64-5.40 (m, 1H), 3.58-3.50 (m, 1H), 3.38-3.36 (m, 1H), 3.35-3.33 (m, 1H), 3.25-2.84 (m, 2H), 2.82-2.80 (m, 2H), 2.36-2.32 (m, 2H), 2.08-2.00 (m, 2H); (ESI-MS): (+ve mode) 524.15 (M+H)+. (100%), UPLC: 95.74%.
Example: 21
Compound 21: 1-(5-(4-amino-3-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)-1H-pyrazolo [3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one




1H NMR (DMSO-d6, 400 MHz) δ ppm: 8.38 (s, 1H), 7.86-7.83 (m, 1H), 7.71-7.70 (m, 3H), 7.69-7.63 (m, 2H), 6.51-6.37 (m, 2H), 5.72-5.69 (m, 1H), 5.59-5.44 (m, 2H), 3.99 (s, 1H), 3.50-3.46 (m, 2H), 3.23-3.14 (m, 2H), 2.57-2.55 (m, 2H), 2.18-2.14 (m, 2H), 1.68-1.59 (m, 2H); (ESI-MS): (+ve mode) 455.10 (M+H)+. (100%), HPLC: 95.98%.
Example: 22
Compound 22: 1-(5-(4-amino-3-(benzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one




1H NMR: (DMSO-d6, 400 MHz): δ 8.84 (s, 1H), 8.24 (s, 1H), 8.01 (s, 1H), 7.93-7.91 (d, 1H, J=8.0 Hz), 7.73-7.71 (d, 1H, J=8.0 Hz), 6.65-6.58 (m, 1H), 6.16-6.11 (dd, 1H, J1=2.8 Hz, J2=16.8 Hz), 5.68-5.65 (dd, 1H, J1=2.4 Hz, J2=11.2 Hz), 5.44-5.41 (m, 1H), 3.78-3.66 (m, 2H), 3.63-3.60 (m, 2H), 3.53-3.50 (m, 1H), 3.40-3.38 (m, 1H), 3.15-2.85 (m, 2H), 2.07-2.05 (m, 2H); ESI-MS: (+ve mode) 416.10 (M+H)+ (100%); UPLC: 95.64%.
Example: 23
Compound 23: (5-(4-amino-3-(2-phenylbenzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one




1H NMR: (DMSO-d6, 400 MHz): δ 8.24-8.27 (m, 3H), 8.02-8.01 (d, 1H, J=4.0 Hz), 7.95-7.93 (d, 1H, J=8.0 Hz), 7.73-7.70 (m, 1H), 7.67-7.63 (m, 3H), 6.66-6.59 (m, 1H), 6.16-6.12 (m, 1H), 5.68-5.65 (m, 1H), 5.45-5.42 (m, 1H), 3.81-3.66 (m, 1H), 3.64-3.61 (m, 1H), 3.55-3.50 (m, 1H), 3.39-3.35 (m, 1H), 3.10-3.00 (m, 2H), 2.44-2.31 (m, 2H), 2.09-2.04 (m, 2H); ESI-MS: (+ve mode) 492.05 (M+H)+ (100%); UPLC: 97.40%.
Example: 24
Compound 24: (E)-1-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-(dimethylamino)but-2-en-1-one




1H NMR: (D2O, 400 MHz): δ 8.38 (s, 1H), 7.65 (d, 2H, J=6.8 Hz), 7.62-7.47 (m, 2H), 7.46-7.45 (m, 1H), 7.29-7.16 (m, 2H), 6.81-6.69 (m, 2H), 5.56-5.52 (m, 1H), 3.99-3.91 (m, 3H), 3.80 (dd, 1H, J1=8.4 Hz, J2=13.2 Hz), 3.63 (dd, 1H, J1=4.4 Hz, J2=11.2 Hz), 3.50 (dd, 1H, J1=4.8 Hz, J2=13.2 Hz), 3.20-3.11 (m, 2H), 2.93 (s, 6H), 2.47-2.41 (m, 2H), 2.23-2.16 (m, 2H); ESI-MS: (+ve mode) 525.7 (M+H)+ (100%); HPLC: 97.25%.
Example: 25
Compound 25: 9-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-6-amino-7-(4-phenoxyphenyl)-5,7-dihydro-4H-purin-8(9H)-one




1H NMR (DMSO-d6, 400 MHz) δ ppm: 8.12 (s, 1H), 7.45-7.41 (m, 4H), 7.20-7.17 (m, 1H), 7.15-7.11 (m, 1H), 6.63-6.56 (m, 1H), 6.15 (dd, 1H, J1=4.0 Hz, J2=16.0 Hz), 5.74-5.72 (m, 2H), 5.97-5.64 (m, 1H), 5.01-4.93 (m, 1H), 3.62-3.46 (m, 3H), 3.40-3.35 (m, 2H), 3.20-2.90 (m, 3H), 1.90-1.97 (m, 2H); (ESI-MS): (+ve mode) 483.10 (M+H)+. (100%); HPLC: 98.02%.
Example: 26
Compound 26: 1-(5-(4-amino-3-(4-(5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one




1H NMR: (DMSO-d6, 400 MHz): δ 8.84-8.83 (d, 1H, J=4.0 Hz), 8.31-8.26 (m, 4H), 8.12-8.08 (m, 1H), 7.95-7.93 (d, 2H, J=8.0 Hz), 7.69-7.66 (m, 1H), 6.65-6.59 (m, 1H), 6.16-6.12 (dd, 1H, J1=2.4 Hz, J2=16.8 Hz), 5.65-5.68 (dd, 1H, J1=2.4 Hz, J2=10.4 Hz), 5.47-5.44 (m, 1H), 3.81-3.77 (m, 1H), 3.65-3.61 (m, 1H), 3.55-3.50 (m, 1H), 3.39-3.33 (m, 1H), 3.12-2.90 (m, 2H), 2.42-2.31 (m, 2H), 2.09-2.07 (m, 2H); ESI-MS: (+ve mode) 520.20 (M+H)+ (85%); UPLC: 95.96%.
Example: 27
Compound 27: 1-(5-(4-amino-6-bromo-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one




1H NMR (DMSO-d6, 400 MHz) δ ppm: 8.13 (s, 1H), 7.46-7.41 (m, 4H), 7.21-7.19 (m, 1H), 7.15-7.13 (m, 2H), 7.11-7.09 (m, 2H), 6.65-6.54 (m, 1H), 6.16 (dd, 1H, J1=2.4 Hz, J2=16.8 Hz), 5.68 (dd, 1H, J1=2.4 Hz, J2=10.4 Hz), 5.35-5.33 (m, 1H), 3.52-3.50 (m, 1H), 3.38-3.34 (m, 1H), 3.33-3.31 (m, 1H), 3.12-2.83 (m, 1H), 2.81-2.80 (m, 1H), 2.67-2.65 (m, 2H), 2.37-2.35 (m, 1H), 2.33-2.00 (m, 2H); (ESI-MS): (+ve mode) 546.15 (M+H)+. (100%); UPLC: 95.60%.
Example: 28
Compound 28: 2-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)octahydrocyclopenta[c]pyrrole-2-carbonyl)-3-cyclopropylacrylonitrile




1H NMR: (CDCl3-d1, 400 MHz): δ 8.38 (s, 1H), 7.67-7.65 (m, 2H), 7.42-7.32 (m, 2H), 7.19-7.15 (m, 3H), 7.11-7.09 (m, 2H), 6.87-6.84 (d, 1H, J=11.6 Hz), 5.59-5.53 (m, 1H), 5.41 (s, 2H), 4/05-3.88 (m, 2H), 3.68-3.54 (m, 2H), 3.23-3.12 (m, 2H), 2.62-2.52 (m, 2H), 2.17-2.08 (m, 2H), 1.44-1.26 (m, 2H), 0.98-0.93 (m, 2H), 0.89-0.87 (m, 1H); ESI-MS: (+ve mode) 532.25 (M+H)+ (100%); UPLC: 95.05%.
Example: 29
Compound 29: 4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxy-N-(4-methylpyridin-2-yl)benzamide




1H NMR: (DMSO, 400 MHz): δ 10.42 (s, 1H), 8.26 (s, 1H), 8.23-8.21 (m, 1H), 8.16-8.10 (m, 1H), 8.07 (d, 1H, J=8.0 Hz), 7.45-7.42 (m, 2H), 7.03-7.02 (m, 1H), 6.66-6.59 (m, 1H), 6.15 (dd, 1H, J1=2.4 Hz, J2=16.4 Hz), 5.67 (dd, 1H, J1=2.8 Hz, J2=10.4 Hz), 5.46-5.42 (m, 1H), 4.08 (s, 3H), 3.85-3.75 (m, 1H), 3.70-3.57 (m, 1H), 3.56-3.45 (m, 2H), 3.15-2.90 (m, 2H), 2.45-2.38 (m, 5H), 2.18-2.06 (m, 2H); ESI-MS: (+ve mode) 539.2 (M+H)+ (100%); UPLC: 96.93%.
Example: 30
Compound 30: 4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)benzamide




1H NMR: (CDCl3, 400 MHz): δ 8.59 (bs, 1H), 8.39 (s, 1H), 8.26 (s, 2H), 8.19 (d, 1H, J=5.2 Hz), 8.11 (d, 2H, J=8.0 Hz), 7.87 (d, 2H, J=8.0 Hz), 6.95 (d, 1H, J=5.2 Hz), 6.48 (dd, 1H, J1=10.0 Hz, J2=16.8 Hz), 6.40 (dd, 1H, J1=2.4 Hz, J2=16.8 Hz), 5.70 (dd, 1H, J1=2.4 Hz, J2=12.4 Hz), 5.60-5356 (m, 1H), 5.44 (bs, 2H), 3.88-3.83 (m, 2H), 3.56-3.46 (m, 2H), 3.23-3.21 (m, 1H), 3.14-3.12 (m, 1H), 2.59-2.54 (m, 2H), 2.43 (s, 3H), 2.20-2.09 (m, 2H); ESI-MS: (+ve mode) 509.1 (M+H)+ (100%); HPLC: 96.67%.
Example: 31
Compound 31: 1-(5-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one




1H NMR (DMSO-d6, 400 MHz) δ ppm: 8.16 (s, 1H), 7.45-7.41 (m, 3H), 7.15-7.13 (m, 2H), 6.70-6.66 (m, 5H), 6.86-6.59 (m, 1H), 6.16 (dd, 1H, J1=2.8 Hz, J2=10.4 Hz), 5.68 (dd, 1H, J1=2.4 Hz, J2=10.4 Hz), 5.30-5.24 (m, 1H), 3.80-3.78 (m, 1H), 3.66-3.51 (m, 2H), 3.51-3.35 (m, 1H), 3.10-2.95 (m, 1H), 2.37-2.34 (m, 1H), 2.32-2.25 (m, 3H), 2.07-2.05 (m, 2H); (ESI-MS): (+ve mode) 466.05 (M+H)+. (100%); UPLC: 97.65%.
Example: 32
Compound 32: N-(4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)picolinamide




1H NMR: (DMSO-d6, 400 MHz): δ10.82 (s, 1H), 8.77-8.76 (m, 1H), 8.23 (s, 1H), 8.18-8.12 (m, 1H), 8.11-8.09 (m, 3H), 7.71-7.65 (m, 3H), 6.65-6.59 (m, 1H), 6.16-6.11 (m, 1H), 5.68-5.65 (m, 1H), 5.43-5.41 (m, 1H), 3.82-3.79 (m, 1H), 3.76-3.73 (m, 1H0, 3.50-3.48 (m, 1H), 3.37-3.35 (m, 1H), 3.23-3.19 (m, 2H), 2.35-2.32 (m, 2H), 2.08-2.04 (m, 2H); ESI-MS: (+ve mode) 495.15 (M+H)+ (100%); HPLC: 98.31%.
Example: 33
Compound 33: 6-amino-7-(4-phenoxyphenyl)-9-(2-(vinylsulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)-7H-purin-8(9H)-one




1H NMR: (DMSO, 400 MHz): δ 8.12 (s, 1H), 7.45-7.40 (m, 4H), 7.21-7.19 (m, 1H), 7.17-7.13 (m, 4H), 6.94-6.87 (m, 1H), 6.21-6.12 (m, 2H), 5.71 (m, 1H), 4.97 (m, 1H), 3.34-3.33 (m, 1H), 3.00-2.96 (m, 4H), 2.61-2.59 (m, 2H), 1.86-1.81 (m, 2H); ESI-MS: (+ve mode) 519.15 (M+H)+ (100%); 541.35 (M+Na)+ (10%); UPLC: 95.21%.
Example: 34
Compound 34: 4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(benzo[d]thiazol-2-yl)benzamide




1H NMR: (DMSO-d6, 400 MHz): δ 13.0 (s, 1H), 8.32-8.30 (m, 2H), 8.26 (s, 1H), 8.19-8.17 (m, 1H), 7.86-7.84 (m, 2H), 7.82-7.80 (m, 1H), 7.49-7.47 (m, 1H), 7.36-7.34 (m, 1H), 6.66-6.59 (m, 1H), 6.17-6.12 (m, 1H), 5.68-5.65 (m, 1H), 5.49-5.47 (m, 1H), 3.83-3.81 (m, 1H), 3.76-3.73 (m, 1H), 3.09-3.06 (m, 1H), 2.45-2.44 (m, 2H), 2.37-2.35 (m, 2H); ESI-MS: (+ve mode) 551.78 (M+H)+ (100%); HPLC: 97.74%.
Example: 35
Compound 35: N-(4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)pyrazine-2-carb oxamide




1H NMR: (DMSO-d6, 400 MHz): δ 10.92 (s, 1H), 9.32 (s, 1H), 8.95 (s, 1H), 8.84-8.83 (m, 1H), 8.23 (s, 1H), 8.11-8.09 (d, 2H, J=8.0 Hz), 7.69-7.67 (d, 2H, J=8.0 Hz), 6.65-6.59 (m, 1H), 6.16-6.11 (dd, 1H, J1=2.8 Hz, J2 16.8 Hz), 5.68-5.43 (dd, 1H, J1=2.4 Hz, J2=10.4 Hz), 5.43-5.40 (m, 1H), 3.81-3.76 (m, 1H), 3.66-3.61 (m, 1H), 3.54-3.50 (m, 1H), 3.38-3.34 (m, 1H), 3.10-3.08 (m, 1H), 3.00-2.98 (m, 1H), 2.37-2.32 (m, 2H), 2.08-2.03 (m, 2H); ESI-MS: (+ve mode) 496.15 (M+H)+ (100%); UPLC: 95.55%.
Example: 36
Compound 36: 1-(5-(4-amino-3-(2,2-difluorobenzo[d] [1,3]dioxol-5-yl)-1H-pyrazolo [3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one




1H NMR: (DMSO-d6, 400 MHz): δ 8.19 (s, 1H), 7.21-7.19 (m, 1H), 7.17-7.14 (m, 1H), 7.07-7.05 (m, 1H), 6.59-6.55 (m, 1H), 6.15-6.12 (m, 1H), 5.67-5.64 (m, 1H), 5.40-5.32 (m, 1H), 3.81-3.79 (m, 1H), 3.78-3.75 (m, 1H), 3.59-3.57 (m, 1H), 3.51-3.48 (m, 1H), 3.03-3.00 (m, 1H), 2.97-2.93 (m, 1H), 2.36-2.82 (m, 2H), 2.02-2.00 (m, 2H); ESI-MS: (+ve mode) 455.78 (M+H)+ (100%); HPLC: 96.22%.
Example: 37
Compound 37: 4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(pyrazin-2-yl)benzamide




1H NMR: (DMSO-d6, 400 MHz): δ 11.22 (s, 1H), 9.45 (s, 1H), 8.50-8.49 (m, 1H), 8.44-8.43 (m, 1H), 8.23-8.22 (m, 2H), 7.83-7.81 (m, 2H), 6.66-6.59 (m, 1H), 6.16-6.12 (m, 1H), 5.68-5.65 (m, 1H), 5.47-5.44 (m, 1H), 3.81-3.80 (m, 1H), 3.79-3.76 (m, 1H), 3.54-3.53 (m, 1H), 3.39-3.38 (m, 2H), 3.08-3.01 (m, 2H), 2.39-2.31 (m, 2H), 2.09-2.06 (m, 2H); ESI-MS: (+ve mode) 496.25 (M+H)+ (100%); HPLC: 96.38%.
Example: 38
Compound 38: N-(4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)benzamide




1H NMR: (DMSO-d6, 400 MHz): δ 10.44 (s, 1H), 8.24 (s, 1H), 7.98 (d, 4H, J=8.0 Hz), 7.65 (d, 2H, J=8.4 Hz), 7.60-7.53 (m, 3H), 6.62 (dd, 1H, J1=16.8 Hz, J2=10.2 Hz), 6.14 (dd, 1H, J1=16.8 Hz, J2=2.4 Hz), 5.67 (dd, 1H, J1=10.2 Hz, J2=2.4 Hz), 5.42-5.38 (m, 1H), 3.78-3.75 (m, 1H), 3.66-3.60 (m, 1H), 3.55-3.50 (m, 1H), 3.37-3.33 (m, 1H), 3.10-3.06 (m, 1H), 3.01-2.98 (m, 1H), 2.37-2.32 (m, 2H), 2.08-2.05 (m, 2H); ESI-MS: (+ve mode) 494.1 (M+H)+ (100%); UPLC: 96.83%.
Example: 39
Compound 39: 1-(5-(4-amino-3-(4-(5-(pyridin-2-yl)-1,3,4-thiadiazol-2-yl)phenyl)-1H-pyrazolo [3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one




1H NMR: (DMSO-d6, 400 MHz): δ 8.74-8.76 (m, 1H), 8.33-8.35 (m, 1H), 8.22-8.26 (m, 3H), 8.08-8.15 (m, 1H), 7.87-7.89 (m, 2H), 7.62-7.64 (m, 1H), 6.59-6.66 (m, 1H), 6.12-6.17 (dd, 1H, J1=2.4 Hz, J2=16.8 Hz), 5.65-5.68 (m, 1H), 5.41-5.48 (m, 1H), 3.75-3.90 (m, 1H), 3.58-3.68 (m, 1H), 3.55-3.58 (m, 1H), 3.35-3.37 (m, 1H), 2.90-3.10 (m, 2H), 2.35-2.37 (m, 2H), 2.07-2.08 (m, 2H); ESI-MS: (+ve mode) 536.05 (M+H)+ (100%); UPLC: 97.81%.
Example: 40
Compound 40: 4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide




1H NMR: (CDCl3, 400 MHz): δ 9.02 (bs, 1H), 8.73 (s, 1H), 8.51 (d, 1H, J=5.2 Hz), 8.39 (s, 1H), 8.14 (d, 2H, J=8.4 Hz), 7.89 (d, 2H, J=8.4 Hz), 7.33 (dd, 1H, J1=0.8 Hz, J2=5.2 Hz), 6.48 (dd, 1H, J1=10.0 Hz, J2=16.8 Hz), 6.40 (dd, 1H, J1=2.4 Hz, J2=16.8 Hz), 5.69 (dd, 1H, J1=2.4 Hz, J2=9.6 Hz), 5.60-5.56 (m, 3H), 3.87-3.83 (m, 2H), 3.56-3.47 (m, 2H), 3.25-3.20 (m, 1H), 3.18-3.09 (m, 1H), 2.57-2.53 (m, 2H), 2.18-2.15 (m, 2H); ESI-MS: (+ve mode) 563.3 (M+H)+ (100%); HPLC: 99.55%.
Example: 41
Compound 41: (1-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one




1H NMR: (CDCl3, 400 MHz): δ 8.47 (d, 2H, J=8.4 Hz), 8.32 (s, 2H), 7.75 (d, 2H, J=8.4 Hz), 7.53 (d, 1H, J=6.4 Hz), 6.52-6.45 (m, 2H), 6.42 (dd, 1H, J1=2.4 Hz, J2=16.8 Hz), 5.72 (dd, 1H, J1=2.8 Hz, J2=10.0 Hz), 5.59-5.55 (m, 1H), 3.91 (s, 3H), 3.87-3.83 (m, 2H), 3.56-3.47 (m, 2H), 3.26-3.21 (m, 1H), 3.16-3.11 (m, 1H), 2.58-2.53 (m, 2H), 2.36 (s, 3H), 2.19-2.15 (m, 2H); ESI-MS: (+ve mode) 523.2 (M+H)+ (100%); HPLC: 98.58%.
Example: 42
Compound 42: 6-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)nicotinamide




1H NMR: (DMSO-d6, 400 MHz): δ 10.77 (s, 1H), 8.26-8.25 (m, 2H), 8.19-8.17 (m, 2H), 8.08 (m, 1H), 7.80-7.78 (m, 2H), 7.03-7.02 (m, 1H), 6.66-6.59 (m, 1H), 6.16-6.12 (m, 1H), 5.68-5.65 (m, 1H), 5.48-5.43 (m, 1H), 3.81-3.79 (m, 1H), 3.77-3.74 (m, 1H), 3.61-3.58 (m, 1H), 3.22-3.18 (m, 2H), 3.13-3.07 (m, 2H), 2.35 (s, 3H), 2.08-2.06 (m, 2H); ESI-MS: (+ve mode) 509.35 (M)+ (100%); HPLC: 97.99%.
Example: 43
Compound 43: 1-(5-(4-amino-3-(4-(pyridin-2-yloxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one




1H NMR: (DMSO-d6, 400 MHz): δ 8.24 (s, 1H), 8.20-8.18 (dd, 1H, J1=8.0 Hz, J2=8.0 Hz), 7.90-7.86 (m, 1H), 7.71-7.69 (d, 2H, J=8.0 Hz), 7.29-7.27 (d, 2H, J=16 Hz), 7.18-7.15 (m, 1H), 7.11-7.09 (d, 1H, J=8.0 Hz), 6.65-6.58 (m, 1H), 6.16-6.11 (dd, 1H, J1=4.0 Hz, J2=8.0 Hz), 5.68-5.65 (dd, 1H, J1=2.4 Hz, J2=10 Hz), 5.44-5.40 (m, 1H), 3.80-3.76 (m, 1H), 3.65-3.50 (m, 3H), 3.08-3.07 (m, 1H), 3.00-2.97 (m, 1H), 2.38-2.32 (m, 2H), 2.08-2.03 (m, 2H); ESI-MS: (+ve mode) 468.00 (M+H)+ (100%); UPLC: 95.99%.
Example: 44
Compound 44: (E)-4-(4-amino-1-(2-(4-(dimethylamino)but-2-enoyl) octahydrocyclopenta [c]pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(pyridin-2-yl) benzamide




1H NMR (DMSO-d6, 400 MHz) δ ppm: 10.89 (s, 1H), 9.83-9.81 (m, 1H), 8.35-8.29 (m, 1H), 8.28-8.23 (m, 1H), 8.22-8.20 (m, 3H), 7.89-7.81 (m, 1H), 7.80-7.78 (m, 1H), 6.72-6.70 (m, 1H), 6.66-6.64 (m, 1H), 5.53-5.50 (m, 1H), 3.91-3.89 (m, 2H), 2.79 (d, 6H, J=4.4 Hz); (ESI-MS): (+ve mode) 552.40 (M+H)+. (100%); UPLC: 98.02%.
Example: 45
Compound 45: (E)-4-(4-amino-1-(2-(4-(dimethylamino)but-2-enoyl)octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl) benzamide




1H NMR: (D2O, 400 MHz): δ 8.47 (s, 1H), 8.34 (d, 1H, J=6.4 Hz), 8.23 (d, 2H, J=8.4 Hz), 7.96 (d, 2H, J=8.4 Hz), 7.59-7.56 (m, 2H), 6.83-6.70 (m, 2H), 5.64-5.51 (m, 1H), 4.01-3.95 (m, 3H), 3.83 (dd, 1H, J1=8.4 Hz, J2=13.2 Hz), 3.67 (dd, 1H, J1=4.8 Hz, J2=11.2 Hz), 3.55 (dd, 1H, J1=4.8 Hz, J2=13.2 Hz), 3.27-3.23 (m, 1H), 3.21-3.18 (m, 1H), 2.91 (s, 6H), 2.65 (s, 3H), 2.54-2.47 (m, 2H), 2.30-2.24 (m, 2H); ESI-MS: (+ve mode) 566.3 (M+H)+ (100%); HPLC: 96.24%.
Example: 46
Compound 46: 1-(5-(4-amino-3-(4-(5-(pyrazin-2-yl)-1,3,4-thiadiazol-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one




1H NMR: (DMSO-d6, 400 MHz): δ 9.53 (s, 1H), 8.87-8.85 (m, 2H), 8.27-8.25 (m, 3H), 7.90-7.88 (d, 2H, J=8.0 Hz), 6.66-6.59 (m, 1H), 6.17-6.12 (m, 1H), 5.68-5.65 (m, 1H), 5.47-5.42 (m, 1H), 3.80-3.78 (m, 1H), 3.56-3.52 (m, 1H), 3.37-3.33 (m, 1H), 3.10-2.90 (m, 3H), 2.39-2.32 (m, 2H), 2.10-2.07 (m, 2H); ESI-MS: (+ve mode) 537.20 (M+H)+ (100%); HPLC: 97.71%.
Example: 47
Compound 47: (E)-1-(5-(4-amino-3-(4-(pyridin-2-yloxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-(dimethylamino)but-2-en-1-one




1H NMR: (DMSO-d6, 400 MHz): δ 8.24 (s, 1H), 8.21-8.19 (m, 1H), 7.90-7.86 (m, 1H), 7.71-7.69 (m, 2H), 7.30-7.28 (m, 2H), 7.19-7.15 (m, 1H), 7.12-7.10 (d, 1H, J=8.0 Hz), 6.66-6.60 (m, 1H), 6.42-6.38 (d, 1H, J=16 Hz), 5.44-5.41 (m, 1H), 3.77-3.74 (m, 1H), 3.62-3.59 (m, 1H), 3.52-3.48 (m, 1H), 3.37-3.36 (m, 1H), 3.09-2.99 (m, 4H), 2.36-2.31 (m, 2H), 2.15 (s, 6H), 2.08-2.04 (m, 2H); ESI-MS: (+ve mode) 525.45 (M+H)+ (100%); HPLC: 96.91%.
Example: 48
Compound 48: (E)-1-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-(dimethylamino)but-2-en-1-one




1H NMR: (CD3OD, 400 MHz): δ 8.43 (s, 1H), 8.09 (d, 2H, J=6.4 Hz), 7.45-7.41 (m, 2H), 7.22-7.16 (m, 3H), 7.13-7.11 (m, 2H), 6.87 (d, 1H, J=15.2 Hz), 6.77 (dd, 1H, J1=6.8 Hz, J2=14.0 Hz), 5.69-5.64 (m, 1H), 3.98 (d, 2H, J=6.8 Hz), 3.97-3.92 (m, 1H), 3.83-3.78 (m, 1H), 3.67-3.64 (m, 4H), 3.54 (dd, 1H, J1=4.8 Hz, J2=13.2 Hz), 3.32-3.28 (m, 1H), 3.21-3.17 (m, 1H), 2.93 (s, 6H), 2.55-2.50 (m, 2H), 2.24-2.19 (m, 2H); ESI-MS: (+ve mode) 524.3 (M+H)+ (100%); HPLC: 97.39%.
Example: 49
Compound 49: (E)-4-(4-amino-1-(2-(4-(dimethylamino)but-2-enoyl) octahydrocyclopenta [c] pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(pyrazin-2-yl)benzamide




1H NMR: (DMSO-d6, 400 MHz): δ 11.25 (s, 1H), 9.45 (s, 1H), 8.51-8.50 (m, 1H), 8.44 (m, 1H), 8.26 (s, 1H), 8.23-8.21 (m, 2H), 7.83-7.81 (m, 2H), 6.64-6.61 (m, 1H), 6.43-6.39 (m, 1H), 5.48-5.45 (m, 1H), 3.81-3.78 (m, 1H), 3.76-3.72 (m, 1H), 3.68-3.62 (m, 1H), 3.20-3.18 (m, 1H), 3.04-3.02 (m, 3H), 2.99-2.97 (m, 1H), 2.37-2.15 (m, 2H), 2.15 (m, 6H), 2.08 (m, 2H); ESI-MS: (+ve mode) 553.45 (M+H)+ (100%); HPLC: 95.44%.
Example: 50
Compound 50: (Z)-methyl 4-(4-amino-1-(2-((E)-4-(dimethylamino)but-2-enoyl)octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methyl pyridin-2-yl) benzimidate




1H NMR: (CD3OD, 400 MHz): δ 8.73 (d, 1H, J=6.4 Hz), 8.47 (s, 1H), 8.31 (d, 2H, J=8.4 Hz), 8.13 (s, 1H), 7.98 (d, 2H, J=8.4 Hz), 7.77-7.76 (m, 1H), 6.87 (d, 1H, J=15.2 Hz), 6.78 (dd, 1H, J1=6.8 Hz, J2=13.6), 5.72-5.68 (m, 1H), 4.31 (s, 3H), 3.98 (d, 2H, J=7.2 Hz), 3.96-3.93 (m, 1H), 3.81 (dd, 1H, J1=8.0 Hz, J2=12.8 Hz), 3.68 (dd, 1H, J1=4.8 Hz, J2=11.2 Hz), 3.53 (dd, 1H, J1=4.8 Hz, J2=13.2 Hz), 3.31-3.26 (m, 2H), 2.70 (s, 3H), 2.57-2.52 (m, 2H), 2.26-2.24 (m, 2H); ESI-MS: (+ve mode) 580.5 (M+H)+ (100%); HPLC: 96.62%.
Example: 51
Compound 51: (E)-4-(4-amino-1-(2-(4-(dimethylamino)but-2-enoyl)octahydrocyclopenta [c] pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-(trifluoromethyl) pyridine-2-yl)benzamide




1H NMR: (CD3OD, 400 MHz): δ 8.68 (d, 1H, J=5.6 Hz), 8.55 (s, 1H), 8.48 (s, 1H), 8.30 (d, 2H, J=8.4 Hz), 7.94 (d, 2H, J=8.4 Hz), 7.65 (dd, 1H, J1=1.2 Hz, J2=5.6 Hz), 6.9 (d, 1H, J=15.2 Hz), 6.80-6.75 (m, 1H), 5.69-5.66 (m, 1H), 4.09 (d, 2H, J=7.2 Hz), 4.00-3.94 (m, 1H), 3.81 (dd, 1H, J1=8.0 Hz, J2=12.8 Hz), 3.69 (dd, 1H, J1=4.4 Hz, J2=11.2 Hz), 3.53 (dd, 1H, J1=4.4 Hz, J2=13.2 Hz), 3.32-3.27 (m, 2H), 2.93 (s, 6H), 2.57-2.52 (m, 2H), 2.28-2.23 (m, 2H); ESI-MS: (+ve mode) 620.4 (M+H)+ (100%); HPLC: 97.87%.
Example: 52
Compound 52: 1-(5-(4-amino-3-(4-(pyridin-3-yloxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one




1H NMR: (CDCl3-di, 400 MHz): δ 8.50-8.46 (m, 2H), 8.35 (s, 1H), 7.70-7.68 (d, 2H, J=8.0 Hz), 7.43-7. 7.34 (m, 2H), 7.21-7.19 (d, 2H, J=8.0 Hz), 6.47-6.39 (m, 2H), 5.73-5.70 (m, 1H), 5.59-5.55 (m, 1H), 3.88-3.83 (m, 2H), 3.61-3.47 (m, 4H), 3.23-3.13 (m, 2H), 2.57-2.52 (m, 2H), 2.18-2.16 (m, 2H); ESI-MS: (+ve mode) 468.15 (M+H)+ (100%); HPLC: 95.64%.
Example: 53
Compound 53: (E)-1-(5-(4-amino-3-(4-(pyridin-3-yloxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-(dimethylamino)but-2-en-1-one




1H NMR: (DMSO-d6, 400 MHz): δ 8.47-8.48 (m, 1H), 8.41-8.39 (m, 1H), 8.23 (s, 1H), 7.70-7.67 (m, 2H), 7.58-7.55 (m, 1H), 7.48-7.45 (m, 1H), 7.23-7.21 (m, 2H), 6.64-6.59 (m, 1H), 6.42-6.38 (m, 1H), 5.43-5.40 (m, 1H), 3.77-3.74 (m, 1H), 3.64-3.61 (m, 1H), 3.52-3.49 (m, 1H), 3.09-2.96 (m, 5H), 2.35-2.30 (m, 2H), 2.15 (s, 6H), 2.06-2.04 (m, 2H); ESI-MS: (+ve mode) 525.45 (M+H)+ (100%); HPLC: 95.44%.
Example: 54
Compound 54: 4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-N-(4-methylpyridin-2-yl)benzamide




1H NMR: (DMSO-d6, 400 MHz): δ 8.23 (s, 1H), 8.21-8.20 (m, 1H), 7.58 (d, 1H, J=8.4 Hz), 7.12-7.10 (m, 1H), 7.04-7.02 (m, 1H), 6.65-6.58 (m, 1H), 6.16-6.11 (m, 1H), 5.40-5.38 (m, 1H), 3.77-3.75 (m, 1H), 3.62-3.59 (m, 1H), 3.53-3.49 (m, 1H), 3.43 (s, 3H), 3.11-3.08 (m, 1H), 2.98-2.96 (m, 1H), 2.34-2.29 (m, 3H), 2.21 (s, 3H), 2.06-2.03 (m, 2H); ESI-MS: (+ve mode) 523.35 (M+H)+ (100%); HPLC: 98.29%.
Example: 55
Compound 55: (E)-4-(4-amino-1-(2-(4-(dimethylamino)but-2-enoyl) octahydrocyclopenta [c] pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-N-(4-methyl pyridin-2-yl)benzamide




1H NMR: (DMSO-d6, 400 MHz): δ 8.22 (s, 1H), 8.20 (d, 1H, J=8.4 Hz), 7.57-7.55 (m, 2H), 7.43-7.41 (m, 2H), 7.11-7.09 (m, 1H), 7.03-7.02 (m, 1H), 6.63-6.59 (m, 1H), 6.41 (m, 1H), 5.39 (m, 1H), 3.79-3.72 (m, 1H), 3.59-3.57 (m, 2H), 3.43-3.42 (m, 2H), 3.08 (s, 3H), 3.05-3.03 (m, 2H), 2.32-2.30 (m, 2H), 2.16-2.09 (m, 3H), 2.09-2.06 (m, 3H), 2.04-2.02 (m, 6H); ESI-MS: (+ve mode) 580.55 (M+H)+ (100%); HPLC: 96.27%.
Example: 56
Compound 56: (E)-1-(5-(4-amino-3-(4-(5-(pyrazin-2-yl)-1,3,4-thiadiazol-2-yl) phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-(dimethylamino)but-2-en-1-one




1H NMR: (DMSO-d6, 400 MHz): δ 9.54 (S, 1H), 8.88-8.86 (m, 2H), 8.27-8.25 (m, 3H), 7.90-7.88 (d, 2H, J=8.0 Hz), 6.66-6.59 (m, 1H), 6.43-6.39 (d, 2H, J=16 Hz), 5.47-5.43 (m, 1H), 3.80-3.75 (m, 1H), 3.65-3.60 (m, 1H), 3.53-3.51 (m, 1H), 3.83-3.33 (m, 1H), 3.09-3.00 (m, 4H), 2.40-2.32 (m, 2H), 2.15 (s, 6H), 2.09-2.07 (m, 2H); ESI-MS: (+ve mode) 594.40 (M+H)+ (100%); HPLC: 97.57%.
Example: 57
Compound 57: (E)-1-(5-(4-amino-3-(4-(5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-(dimethylamino)but-2-en-1-one




1H NMR: (DMSO-d6, 400 MHz): δ 8.85-8.84 (m, 1H), 8.32-8.27 (m, 4H), 8.13-8.09 (m, 1H), 7.95-7.93 (m, 2H), 7.69-7.67 (m, 1H), 6.50-6.61 (m, 1H), 6.43-6.39 (m, 1H), 5.47-5.44 (m, 1H), 3.77-3.75 (m, 1H), 3.62-3.60 (m, 1H), 3.52-3.50 (m, 1H), 3.17-3.03 (m, 5H), 2.37-2.32 (m, 2H), 2.15 (s, 6H), 2.12-2.08 (m, 2H); ESI-MS: (+ve mode) 577.55 (M+H)+ (100%); HPLC: 99.24%.
Using the above procedures, following compounds (Table-2) can be prepared, using different boronic acids and finally reacting with optionally substituted acid chlorides.









TABLE 2





Compd
Structures
IUPAC Names

















58




1-(5-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-5,6- dihydrocyclopenta[c]pyrrol-2(1H,3H,4H)-yl)prop- 2-en-1-one


 


59




2-acryloyl-5-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-2,3- dihydrocyclopenta[c]pyrrole-4,6(1H,5H)-dione


 


60




2-acryloyl-5-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-5,6- dihydrocyclopenta[c]pyrrole-1,3(2H,4H)-dione


 


61




1-(5-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1- yl)hexahydrocyclopenta[b]pyrrol-1(2H)-yl)prop-2- en-1-one


 


62




1-(4-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-2,3,5,6- tetrahydrocyclopenta[b]pyrrol-1(4H)-yl)prop-2-en- 1-one


 


63




1-(6-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)hexahydro-1H- cyclopenta[c]pyridin-2(3H)-yl)prop-2-en-1-one


 


64




1-(5-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-4,5,6,7-tetrahydro- 1H-isoindol-2(3H)-yl)prop-2-en-1-one


 


65




1-(6-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3- azabicyclo[3.2.0]heptan-3-yl)prop-2-en-1-one


 


66




1-(3-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-6- azabicyclo[3.2.0]heptan-6-yl)prop-2-en-1-one


 


67




N-(5-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)octahydropentalen- 2-yl)acrylamide


 


68




1-(5-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4,6,7-tetrahydro- 1H-cylcopenta[c]pyridin-2(5H)-yl)prop-2-en-1-one


 


69




1-(5-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)hexahydro-1H- isoindol-2(3H)-yl)prop-2-en-1-one


 


70




1-(4-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1- yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2- en-1-one


 


71




1-(4-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1- yl)hexahydrocyclopenta[b]pyrrol-1(2H)-yl)prop-2- en-1-one


 


72




1-(5-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-2,3,5,6- tetrahydrocyclopenta[b]pyrrol-1(4H)-yl)prop-2-en- 1-one


 


73




1-(4-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-5,6- dihydrocyclopenta[c]pyrrol-2(1H,3H,4H)-yl)prop- 2-en-1-one


 


74




1-(6-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)octahydro-1H- cyclopenta[b]pyridin-1-yl)prop-2-en-1-one


 


75




1-(5-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-2,3,4,5,6,7- hexahydro-1H-cyclopenta[b]pyridin-1-yl)prop-2- en-1-one


 


76




1-(7-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-2,3,4,5,6,7- hexahydro-1H-cyclopenta[b]pyridin-1-yl)prop-2- en-1-one


 


77




1-(6-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4,6,7-tetrahydro- 1H-cyclopenta[c]pyridin-2(5H)-yl)prop-2-en-1-one


 


78




1-(7-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4,6,7-tetrahydro- 1H-cyclopenta[c]pyridin-2(5H)-yl)prop-2-en-1-one


 


79




1-(7-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-2,3,4,5,6,7- hexahydro-1H-cyclopenta[b]pyridin-1-yl)prop-2- en-1-one


 


80




1-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-5,6- dihydrocylcopenta[c]pyrrol-2(1H,3H,4H)-yl)prop- 2-en-1-one


 


81




2-acryloyl-5-(4-amino-3-(benzo[d]thiazol-6-yl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-2,3- dihydrocyclopenta[c]pyrrole-4,6(1H,5H)-dione


 


82




2-acryloyl-5-(4-amino-3-(benzo[d]thiazol-6-yl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-5,6- dihydrocyclopenta[c]pyrrole-1,3(2H,4H)-dione


 


83




1-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-1H- pyrazolo[3,4-d]pyrimidin-1- yl)hexahydrocyclopenta[b]pyrrol-1(2H)-yl)prop-2- en-1-one


 


84




1-(4-(4-amino-3-(benzo[d]thiazol-6-yl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-2,3,5,6- tetrahydrocyclopenta[b]pyrrol-1(4H)-yl)prop-2-en- 1-one


 


85




1-(6-(4-amino-3-(benzo[d]thiazol-6-yl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)hexahydro-1H- cyclopenta[c]pyridin-2(3H)-yl)prop-2-en-1-one


 


86




1-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-4,5,6,7-tetrahydro- 1H-isoindol-2(3H)-yl)prop-2-en-1-one


 


87




1-(6-(4-amino-3-(benzo[d]thiazol-6-yl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3- azabicyclo[3.2.0]heptan-3-yl)prop-2-en-1-one


 


88




1-(3-(4-amino-3-(benzo[d]thiazol-6-yl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-6- azabicyclo[3.2.0]heptan-6-yl)prop-2-en-1-one


 


89




N-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)octahydropentalen- 2-yl)acrylamide


 


90




1-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4,6,7-tetrahydro- 1H-cyclopenta[c]pyridin-2(5H)-yl)prop-2-en-1-one


 


91




1-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)hexahydro-1H- isoindol-2(3H)-yl)prop-2-en-1-one


 


92




1-(4-(4-amino-3-(benzo[d]thiazol-6-yl)-1H- pyrazolo[3,4-d]pyrimidin-1- yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2- en-1-one


 


93




1-(4-(4-amino-3-(benzo[d]thiazol-6-yl)-1H- pyrazolo[3,4-d]pyrimidin-1- yl)hexahydrocyclopenta[b]pyrrol-1(2H)-yl)prop-2- en-1-one


 


94




1-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-2,3,5,6- tetrahydrocyclopenta[b]pyrrol-1(4H)-yl)prop-2-en- 1-one


 


95




1-(4-(4-amino-3-(benzo[d]thiazol-6-yl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-5,6- dihydrocyclopenta[c]pyrrol-2(1H,3H,4H)-yl)prop- 2-en-1-one


 


96




1-(6-(4-amino-3-(benzo[d]thiazol-6-yl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)octahydro-1H- cyclopenta[b]pyridin-1-yl)prop-2-en-1-one


 


97




1-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-2,3,4,5,6,7- hexahydro-1H-cyclopenta[b]pyridin-1-yl)prop-2- en-1-one


 


98




1-(7-(4-amino-3-(benzo[d]thiazol-6-yl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-2,3,4,5,6,7- hexahydro-1H-cyclopenta[b]pyridin-1-yl)prop-2- en-1-one


 


99




1-(6-(4-amino-3-(benzo[d]thiazol-6-yl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4,6,7-tetrahydro- 1H-cyclopenta[c]pyridin-2(5H)-yl)prop-2-en-1-one


 


100




1-(7-(4-amino-3-(benzo[d]thiazol-6-yl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4,6,7-tetrahydro- 1H-cylcopenta[c]pyridin-2(5H)-yl)prop-2-en-1-one


 


101




1-(7-(4-amino-3-(benzo[d]thiazol-6-yl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-2,3,4,5,6,7- hexahydro-1H-cyclopenta[b]pyridin-1-yl)prop-2- en-1-one


 


102




1-(5-(4-amino-3-(benzo[b]thiophen-5-yl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-5,6- dihydrocyclopenta[c]pyrrol-2(1H,3H,4H)-yl)prop- 2-en-1-one


 


103




1-(6-(4-amino-3-(benzo[b]thiophen-5-yl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)hexahydro-1H- cyclopenta[c]pyridin-2(3H)-yl)prop-2-en-1-one


 


104




1-(6-(4-amino-3-(benzo[b]thiophen-5-yl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3- azabicyclo[3.2.0]heptan-3-yl)prop-2-en-1-one


 


105




N-(5-(4-amino-3-(benzo[b]thiophen-5-yl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)octahydropentalen- 2-yl)acrylamide


 


106




1-(5-(4-amino-3-(benzo[b]thiophen-5-yl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4,6,7-tetrahydro- 1H-cyclopenta[c]pyridin-2(5H)-yl)prop-2-en-1-one


 


107




1-(5-(4-amino-3-(2,3-dihydrobenzo[b]thiophen-5- yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5,6- dihydrocyclopenta[c]pyrrol-2(1H,3H,4H)-yl)prop- 2-en-1-one


 


108




1-(6-(4-amino-3-(2,3-dihydrobenzo[b]thiophen-5- yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydro- 1H-cyclopenta[c]pyridin-2(3H)-yl)prop-2-en-1-one


 


109




1-(6-(4-amino-3-(2,3-dihydrobenzo[b]thiophen-5- yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3- azabicyclo[3.2.0]heptan-3-yl)prop-2-en-1-one


 


110




N-(5-(4-amino-3-(2,3-dihydrobenzo[b]thiophen-5- yl)-1H-pyrazolo[3,4-d]pyrimidin-1- yl)octahydropentalen-2-yl)acrylamide


 


111




1-(5-(4-amino-3-(2,3-dihydrobenzo[b]thiophen-5- yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4,6,7- tetrahydro-1H-cyclopenta[c]pyridin-2(5H)- yl)prop-2-en-1-one


 


112




N-(6-(1-(2-acryloyl-1,2,3,4,5,6- hexahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H- pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]thiazol-2- yl)acetamide


 


113




N-(6-(1-(2-acryloyloctahydro-1H- cyclopenta[c]pyridin-6-yl)-4-amino-1H- pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]thiazol-2- yl)acetamide


 


114




N-(5-(3-(2-acetamidobenzo[d]thiazol-6-yl)-4- amino-1H-pyrazolo[3,4-d]pyrimidin-1- yl)octahydropentalen-2-yl)acrylamide


 


115




(E)-1-(5-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-5,6- dihydrocylcopenta[c]pyrrol-2(1H,3H,4H)-yl)-4- (dimethylamino)but-2-en-1-one


 


116




(E)-1-(6-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)hexahydro-1H- cyclopenta[c]pyridin-2(3H)-yl)-4- (dimethylamino)but-2-en-1-one


 


117




(E)-1-(6-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3- azabicyclo[3.2.0]heptan-3-yl)-4- (dimethylamino)but-2-en-1-one


 


118




(E)-1-(5-(4-amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4,6,7-tetrahydro- 1H-cyclopenta[c]pyridin-2(5H)-yl)-4- (dimethylamino)but-2-en-1-one


 


119




(E)-1-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-1H- pyrazolo[3,4-d]pyrimidin-1- yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl-4- (dimethylamino)but-2-en-1-one


 


120




(E)-1-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-5,6- dihydrocyclopenta[c]pyrrol-2(1H,3H,4H)-yl)-4- (dimethylamino)but-2-en-1-one


 


121




(E)-1-(6-(4-amino-3-(benzo[d]thiazol-6-yl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)hexahydro-1H- cyclopenta[c]pyridin-2(3H)-yl)-4- (dimethylamino)but-2-en-1-one


 


122




(E)-1-(6-(4-amino-3-(benzo[d]thiazol-6-yl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3- azabicyclo[3.2.0]heptan-3-yl)-4- (dimethylamino)but-2-en-1-one


 


123




(E)-1-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4,6,7-tetrahydro- 1H-cyclopenta[c]pyridin-2(5H)-yl)-4- (dimethylamino)but-2-en-1-one


 


124




1-(5-(4-amino-3-(4-benzoylphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1- yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2- en-1-one


 


125




4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-1H-pyraozlo[3,4-d]pyrimidin-3-yl)-N- phenylbenzamide


 


126




4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N- methyl-N-phenylbenzamide


 


127




4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2- methyl-N-phenylbenzamide


 


128




4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2- methoxy-N-phenylbenzamide


 


129




4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N,2- dimethyl-N-phenylbenzamide


 


130




4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2- methoxy-N-methyl-N-phenylbenzamide


 


131




4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2- methyl-N-(pyridin-2-yl)benzamide


 


132




4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2- methoxy-N-(pyridin-2-yl)benzamide


 


133




4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2- methyl-N-(4-methylpyridin-2-yl)benzamide


 


134




4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2- methyl-N-(4-(trifluoromethyl)pyridin-2- yl)benzamide


 


135




4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2- methoxy-N-(4-(trifluoromethyl)pyridin-2- yl)benzamide


 


136




4-(7-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-6-chloro-7H-pyrrolo[2,3-d]pyrimidin-5- yl)-N-phenylbenzamide


 


137




4-(7-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-6-fluoro-7H-pyrrolo[2,3-d]pyrimidin-5- yl)-N-phenylbenzamide


 


138




4-(7-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-6-bromo-7H-pyrrolo[2,3-d]pyrimidin-5- yl)-N-phenylbenzamide


 


139




4-(7-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-6-(difluoromethyl)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)-N-phenylbenzamide


 


140




4-(7-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-6-(trifluoromethyl)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)-N-phenylbenzamide


 


141




4-(7-(2-acryloyloctahydrocylcopenta[c]pyrrol-5-yl)- 4-amino-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-5- yl)-N-phenylbenzamide


 


142




4-(7-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N- phenylbenzamide


 


143




4-(7-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N- methyl-N-phenylbenzamide


 


144




4-(7-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N- (pyridin-2-yl)benzamide


 


145




4-(7-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N- methyl-N-(pyridin-2-yl)benzamide


 


146




4-(7-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-(4- methylpyridin-2-yl)benzamide


 


147




4-(7-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N- methyl-N-(4-methylpyridin-2-yl)benzamide


 


148




4-(7-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N- methyl-N-(4-(trifluoromethyl)pyridin-2- yl)benzamide


 


149




4-(7-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-(4- (trifluoromethyl)pyridin-2-yl)benzamide


 


150




4-(7-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2- methyl-N-phenylbenzamide


 


151




4-(7-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2- methoxy-N-phenylbenzamide


 


152




4-(7-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N,2- dimethyl-N-phenylbenzamide


 


153




4-(7-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2- methoxy-N-methyl-N-phenylbenzamide


 


154




4-(7-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2- methyl-N-(pyridin-2-yl)benzamide


 


155




4-(7-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2- methoxy-N-(pyridin-2-yl)benzamide


 


156




4-(7-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N,2- dimethyl-N-(pyridin-2-yl)benzamide


 


157




4-(7-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2- methoxy-N-methyl-N-(pyridin-2-yl)benzamide


 


158




4-(7-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2- methyl-N-(4-methylpyridin-2-yl)benzamide


 


159




4-(7-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2- methoxy-N-(4-methylpyridin-2-yl)benzamide


 


160




4-(7-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N,2- dimethyl-N-(4-(trifluoromethyl)pyridin-2- yl)benzamide


 


161




4-(7-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2- methoxy-N-methyl-N-(4-(trifluoromethyl)pyridin- 2-yl)benzamide


 


162




4-(7-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2- methyl-N-(4-(trifluoromethyl)pyridin-2- yl)benzamide


 


163




4-(7-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2- methoxy-N-(4-(trifluoromethyl)pyridin-2- yl)benzamide


 


164




4-(3-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 8-aminoimidazo[1,5-a]pyrazin-1-yl)-N- phenylbenzamide


 


165




4-(3-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 8-aminoimidazo[1,5-a]pyrazin-1-yl)-N-methyl-N- phenylbenzamide


 


166




4-(3-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 8-aminoimidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2- yl)benzamide


 


167




4-(3-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 8-aminoimidazo[1,5-a]pyrazin-1-yl)-N-(4- (trifluoromethyl)pyridin-2-yl)benzamide


 


168




4-(3-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 8-aminoimidazo[1,5-a]pyrazin-1-yl)-2-methoxy-N- (4-(trifluoromethyl)pyridin-2-yl)benzamide


 


169




4-(9-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 6-amino-8-oxo-8,9-dihydro-7H-purin-7-yl)-N- phenylbenzamide


 


170




4-(9-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 6-amino-8-oxo-8,9-dihydro-7H-purin-7-yl)-N- methyl-N-phenylbenzamide


 


171




4-(9-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 6-amino-8-oxo-8,9-dihydro-7H-purin-7-yl)-N- (pyridin-2-yl)benzamide


 


172




4-(9-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 6-amino-8-oxo-8,9-dihydro-7H-purin-7-yl)-N-(4- methylpyridin-2-yl)benzamide


 


173




4-(9-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 6-amino-8-oxo-8,9-dihydro-7H-purin-7-yl)-N-(4- (trifluoromethyl)pyridin-2-yl)benzamide


 


174




4-(9-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 6-amino-8-oxo-8,9-dihydro-7H-purin-7-yl)-2- methoxy-N-(4-(trifluoromethyl)pyridin-2- yl)benzamide


 


175




4-(1-(2-acryloyl-1,2,3,4,5,6- hexahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H- pyrazolo[3,4-d]pyrimidin-3-yl)-N- phenylbenzamide


 


176




4-(1-(1-acryloyloctahydrocyclopenta[b]pyrrol-5- yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N- phenylbenzamide


 


177




4-(4-amino-1-(2- (vinylsulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N- phenylbenzamide


 


178




(E)-4-(4-amino-1-(2-(4-(dimethylamino)but-2- enoyl)octahydrocyclopenta[c]pyrrol-5-yl)-1H- pyrazolo[3,4-d]pyrimidin-3-yl)-N- phenylbenzamide


 


179




(E)-4-(4-amino-1-(2-(4- (cyclopropyl(methyl)amino)but-2- enoyl)octahydrocyclopenta[c]pyrrol-5-yl)-1H- pyrazolo[3,4-d]pyrimidin-3-yl)-N- phenylbenzamide


 


180




(Z)-4-(4-amino-1-(2-(2-cyano-3- cyclopropylacryloyl)octahydrocyclopenta[c]pyrrol- 5-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N- phenylbenzamide


 


181




4-(7-(2-acryloyl-1,2,3,4,5,6- hexahydrocyclopenta[c]pyrrol-5-yl)-4-amino-7H- pyrrolo[2,3-d]pyrimidin-5-yl)-N-phenylbenzamide


 


182




4-(7-(1-acryloyloctahydrocyclopenta[b]pyrrol-5- yl)-4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N- phenylbenzamide


 


183




4-(4-amino-7-(2- (vinylsulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)- 7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N- phenylbenzamide


 


184




(E)-4-(4-amino-7-(2-(4-(dimethylamino)but-2- enoyl)octahydrocyclopenta[c]pyrrol-5-yl)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)-N-phenylbenzamide


 


185




(E)-4-(4-amino-7-(2-(4- (cyclopropyl(methyl)amino)but-2- enoyl)octahydrocyclopenta[c]pyrrol-5-yl)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)-N-phenylbenzamide


 


186




(Z)-4-(4-amino-7-(2-(2-cyano-3- cyclopropylacryloyl)octahydrocyclopenta[c]pyrrol- 5-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N- phenylbenzamide


 


187




4-(3-(2-acryloyl-1,2,3,4,5,6- hexahydrocyclopenta[c]pyrrol-5-yl)-8- aminoimidazo[1,5-a]pyrazin-1-yl)-N- phenylbenzamide


 


188




4-(3-(1-acryloyloctahydrocyclopenta[b]pyrrol-5- yl)-8-aminoimidazo[1,5-a]pyrazin-1-yl)-N- phenylbenzamide


 


189




4-(8-amino-3-(2- (vinylsulfonyl)octahydrocyclopenta[c]pyrrol-5- yl)imidazo[1,5-a]pyrazin-1-yl)-N- phenylbenzamide


 


190




(E)-4-(8-amino-3-(2-(4-(dimethylamino)but-2- enoyl)octahydrocyclopenta[c]pyrrol-5- yl)imidazo[1,5-a]pyrazin-1-yl)-N- phenylbenzamide


 


191




(E)-4-(8-amino-3-(2-(4- (cyclopropyl(methyl)amino)but-2- enoyl)octahydrocyclopenta[c]pyrrol-5- yl)imidazo[1,5-a]pyrazin-1-yl)-N- phenylbenzamide


 


192




(Z)-4-(8-amino-3-(2-(2-ayno-3- cyclopropylacryloyl)octahydrocyclopenta[c]pyrrol- 5-yl)imidazo[1,5-a]pyrazin-1-yl)-N- phenylbenzamide


 


193




4-(9-(2-acryloyl-1,2,3,4,5,6- hexahydrocyclopenta[c]pyrrol-5-yl)-6-amino-8- oxo-8,9-dihydro-7H-purin-7-yl)-N- phenylbenzamide


 


194




4-(9-(1-acryloyloctahydrocyclopenta[b]pyrrol-5- yl)-6-amino-8-oxo-8,9-dihydro-7H-purin-7-yl)-N- phenylbenzamide


 


195




4-(6-amino-8-oxo-9-(2- (vinylsulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)- 8,9-dihydro-7H-purin-7-yl)-N-phenylbenzamide


 


196




(E)-4-(6-amino-9-(2-(4-(dimethylamino)but-2- enoyl)octahydrocyclopenta[c]pyrrol-5-yl)-8-oxo- 8,9-dihydro-7H-purin-7-yl)-N-phenylbenzamide


 


197




(E)-4-(6-amino-9-(2-(4- (cyclopropyl(methyl)amino)but-2- enoyl)octahydrocyclopenta[c]pyrrol-5-yl)-8-oxo- 8,9-dihydro-7H-purin-7-yl)-N-phenylbenzamide


 


198




(Z)-4-(6-amino-9-(2-(2-cyano-3- cyclopropylacryloyl)octahydrocyclopenta[c]pyrrol- 5-yl)-8-oxo-8,9-dihydro-7H-purin-7-yl)-N- phenylbenzamide


 


199




1-(5-(4-amino-3-(4-(5-phenyl-1,3,4-oxadiazol-2- yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1- yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2- en-1-one


 


200




1-(5-(4-amino-6-chloro-5-(4-phenoxyphenyl)-7H- pyrrolo[2,3-d]pyrimidin-7- yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2- en-1-one


 


201




1-(5-(4-amino-6-(difluoromethyl)-5-(4- phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2- en-1-one


 


202




1-(5-(8-amino-1-(4-phenoxyphenyl)imidazo[1,5- a]pyrazin-3-yl)hexahydrocyclopenta[c]pyrrol- 2(1H)-yl)prop-2-en-1-one


 


203




1-(4-phenoxyphenyl)-3-(2- (vinylsulfonyl)octahydrocyclopenta[c]pyrrol-5- yl)imidazo[1,5-a]pyrazin-8-amine


 


204




7-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4- amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3- d]pyrimidine-6-carboxylic acid


 


205




4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(5- chloropyridin-2-yl)benzamide


 


206




1-(5-(4-aminio-3-(4-(morpholinomethyl)phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-1- yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2- en-1-one


 


207




1-(5-(4-amino-3-(4-(piperidin-1-ylmethyl)phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-1- yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2- en-1-one


 


208




1-(5-(4-amino-3-(4-((3,4-dihydroisoquinolin-2(1H)- yl)methyl)phenyl)-1H-pyrazolo[3,4-d]pyrimdiin-1- yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2- en-1-one


 


209




1-(5-(4-amino-3-(4-((tetrahydrofuran-2- yl)oxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1- yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2- en-1-one


 


210




1-(5-(4-amino-3-(4-(1-morpholinoethyl)phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-1- yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2- en-1-one


 


211




1-(5-(4-amino-3-(4-(pyrrolidin-1-ylmethyl)phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-1- yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2- en-1-one


 


212




1-(5-(4-amino-3-(4- ((dimethylamino)methyl)phenyl)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol- 2(1H)-yl)prop-2-en-1-one


 


213




N-(4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5- yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3- yl)benzyl)acetamide


 


214




1-(5-(4-amino-3-(4-(2-morpholinoethoxy)phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-1- yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2- en-1-one


 


215




2-(4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5- yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3- yl)benzyl)isoindoline-1,3-dione


 


216




1-(5-(4-amino-3-(4-((3,4-dihydroisoquinolin-2(1H)- yl)methyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1- yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2- en-1-one


 


217




1-(5-(4-amino-3-(4-(azepan-1-ylmethyl)phenyl)-1H- pyrazolo[3,4-d]pyrimidin-1- yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2- en-1-one


 


218




1-(5-(4-amino-3-(4-((hexahydro-1H-isoindol-2(3H)- yl)methyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1- yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2- en-1-one


 


219 




1-(5-(4-amino-3-(4- (thiomorpholinomethyl)phenyl)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol- 2(1H)-yl)prop-2-en-1-one


 


220




1-(5-(4-amino-3-(4-((1,1-dioxidobenzo[d]isothiazol- 2(3H)-yl)methyl)phenyl)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol- 2(1H)-yl)prop-2-en-1-one


 


221




2-(4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5- yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3- yl)benzyl)isoindolin-1-one


 


222




9-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-6- amino-7-(benzo[d]thiazol-6-yl)-7H-purin-8(9H)- one


 


223




4-(9-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 6-amino-8-oxo-8,9-dihydro-7H-purin-7-yl)-N- methyl-N-(4-methylpyridin-2-yl)benzamide


 


224




9-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-6- amino-7-(4-((methyl(4-methylpyridin-2- yl)amino)methyl)phenyl)-7H-purin-8(9H)-one


 


225




4-(9-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 6-amino-8-oxo-8,9-dihydro-7H-purin-7-yl)-N- (pyridin-2-yl)benzamide


 


226




9-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-6- amino-7-(4-benzoylphenyl)-7H-purin-8(9H)-one









Testing of Compounds of the Invention

Biological Studies:

In vitro BTK Inhibitory Activity Assay:

In vitro BTK inhibitory activity of test compounds were screened using BTK kinase assay on ADP Glo platform (Li, H., Totoritis, R. D., Lor, L. A., Schwartz, B., Caprioli, P., Jurewicz, A. J and Zhang, G., Assay Drug Dev. Technol., 2009, 7(6), 598-605). Briefly, fixed amount of recombinant purified human BTK (3 ng/reaction from SignalChem, USA) were incubated with increasing concentration of test compounds, in 1× kinase reaction buffer (40 mM Tris-Cl, pH7.5, 20 mM MgCl2, 2 mM MnCl2, 0.1 mg/ml BSA and 50 μM DTT). Enzymatic reaction was initiated by adding a substrate cocktail containing 50 M of ATP (final concentration) and 5 g of polyGln4Tyr1 (Signal Chem) in total 25 μl of reaction, in round bottom white 96 well plate. The reaction mixture was incubated at room temperature for 2 hr. After 2 hr of incubation, 10 μl of the reaction mix was mixed with 10 t of ADP Glo reagent, in another round bottom white 96 well plate and incubated at room temperature for 40 min. This was followed by addition of kinase detection reagent (20 μl per reaction) and incubation at room temperature for 30 min. Finally, plate was read for luminescence at an integration time of 500 millisecond per well. Data were plotted taking Enzyme with no inhibitor set as the 100% kinase activity and for dose response curve, % Kinase activity was plotted against conc on Log scale and IC50 was determined by non linear curve fitting method using GraphPad Prism software 6. The in vitro BTK inhibitory activity (IC50) for representative compounds are listed in







TABLE 3







Table 3: Invitro (IC50) BTK inhibitory & CYP inhibition


data of representative compounds










In-vitro BTK



compd
inhibitory
CYP inhibition @ 10   M concn














No.
activity: IC50 (nM)
1A2
2C8
2C9
2C19
2D6
3A4

















1
1.3
A
A
A
A
A
A


2
1.1
A
A
A
A
A
A


3
8
A
A
B
A
A
A


4
2
A
A
A
A
A
A


5
8
A
A
A
A
A
B


6
1.7
A
A
A
A
A
A


7
6
A
A
B
A
A
B


8
4
A
A
A
B
A
A


9
28
A
B
B
A
A
B


10
25
A
B
A
A
B
B


11
13
A
A
A
A
A
A


12
37
A
B
B
A
A
B


13
1.8
A
A
A
B
A
A


14
1.4
A
A
A
A
A
A


15
18
A
A
A
A
A
B


16
1.7
A
A
A
A
A
A


17
5
A
A
A
A
A
B


18
218
A
B
B
A
A
B


19
4
A
A
A
A
A
A


20
223
A
B
B
A
A
B


21
50
B
A
A
A
A
A


22
40
A
A
A
A
B
A


23
48
A
B
B
A
A
B


24
2.5
A
A
A
A
A
A


25
5
A
A
A
A
A
A


26
1.1
A
A
A
A
A
A


27
1.6
A
A
A
A
A
A


28
16
A
A
B
A
A
B


29
1.2
A
A
A
A
A
A


30
6
A
A
A
A
A
A


31
0.6
A
A
A
A
A
A


32
4
A
A
A
A
A
B


33
1.5
A
A
A
A
A
A


34
359
B
A
A
B
A
B


35
1.2
A
A
A
A
A
A


36
1.1
A
A
A
A
A
A


37
1
A
A
A
A
A
A


38
17
A
A
A
A
B
A


39
1.4
A
A
A
A
A
A


40
6
B
A
B
A
A
A


41
3.5
A
A
A
A
A
B


42
0.1
A
A
A
A
A
A


43
2
A
A
A
A
A
A


44
1.4
A
A
A
A
A
A


45
10
B
A
A
A
A
A


46
1
A
A
A
A
A
A


47
3
A
A
A
A
A
A


48
50
B
A
A
A
A
B


49
2.5
A
A
A
A
A
A


50
19
A
A
A
A
B
B


51
100
A
B
B
A
A
B


52
162
B
A
A
B
A
B


53
10
A
A
A
A
A
B


54
0.1
A
A
A
A
A
A


55
80
A
B
B
B
A
B


56
50
B
B
B
A
A
B


57
100
A
B
B
A
A
B





A: <50% CYP inhibition @ 10   M concentrations;


B: >50% CYP inhibition @ 10   M concentrations






CYP Inhibition Studies:

CYP inhibition studies were performed with test compounds, at two concentrations (2 M and 10 μM), using human liver microsomes (Yao, M., Zhu, M., Sinz, M. W., Zhang, H., Humphreys, W. F., Rodrigues, A. D and Dai, R., Journal of Pharmaceutical and Biomedical Analysis, 2007, 44, 211-223; Walsky, R. L and Obach, R. S., Drug Metab. Dispos., 2004, 32, 647-660). Human liver microsomes were mixed with 100 mM phosphate buffer (pH 7.4) and probe substrate and warmed to 370 in microcentrifuge tubes. Aliquots of this mixture (499 μL) were transferred to each pre-labeled microcentrifuge tubes, followed by addition of the 1 μL of inhibitors (test compound/CYP-specific positive control inhibitor) or control solvent (DMSO). Aliquots of this mixture (90 μL) were transferred to each pre-labeled microcentrifuge tubes in duplicate. Final solvent concentrations were 0.2% (v/v) or less. Incubations were commenced with the addition of 10 μL NADPH stock (assay concentration, 1 mM) to a final incubation volume of 100 μL and incubated in shaking water bath (at 37° C. and 100 rpm), for the period defined in Tables 1. Incubations were terminated by addition of 400 μL of termination solvent (CH3CN) containing internal standard. The terminated samples were vortex-mixed, centrifuged at 10000 rpm for 5 min and supernatant transferred into HPLC vials for LC-MS/MS analysis to monitor metabolites produced by marker CYP reactions. CYP inhibitory activity (% inhibition) of test compounds is listed in Table 3.

In Vivo Efficacy Studies:

Demonstration of in vivo efficacy of test compounds in rats mice, oral routes of administration.

Animals

All the animal experiments were carried out in female rats and mice, bred in-house. Animals were housed in groups of 6 animals per cage, for a week, in order to habituate them to vivarium conditions (25±4° C., 60-65% relative humidity, 12: 12 h light: dark cycle, with lights on at 7.30 am). All the animal experiments were carried out according to the internationally valid guidelines following approval by the ‘Zydus Research Center animal ethical committee’.
SCW Arthritis
Female Sprague dawley (SD) rats were primed with an intra-articular injection of 20 μl of peptidoglycan polysaccharide (PGPS), at 0.5 mg/ml of rhamnose in the right ankle. At 2 weeks the paw swelling were measured using a plethysmometer and rats assigned to groups based on initial paw swelling. On day 14 after model initiation, rats were dosed orally (po) with the test compounds. Following the dose administration, 1 h later, the rats received a booster dose of 0.5 ml of PGPS (0.5 mg/ml of rhamnose) via i.v. injection using their tail vein. Compounds were dosed for the following two more days and their paw volumes were measured for 3 more days. The efficacy of the compound was determined as percentage inhibition of paw swelling verses the control (untreated) group. Representative data of some of the test compounds are listed in Table-4.
Diffused Large B Cell Lymphoma Xenografts Using TMD-8 Cell Line
Female SCID mice were inoculated sc with 10×106 TMD-8 cells in 0.1 mL of PBS to the right flank. Animals were observed twice weekly for occurrence of tumor. Once the tumors became palpable (around 100 mm3) around 14 days after injection, treatment was initiated via oral route. Tumor volume was determined every alternate day using digital calipers and the tumor volume was calculated using the formula: [length/2]×[width2]. Body weights of the animals were also recorded 3 times a week as a measure of treatment related side effect. Treatment was continued for two more weeks and inhibition of tumor volume compared to vehicle control was considered as efficacy endpoint. Representative data of some of the test compounds are listed in Table-4.
Protocol for Collagen Induced Arthritis (CIA) Study in Mice
CIA is a frequently used animal model of human RA (Courtenay, J. S., Dallman, M. J., Dayan, A. D., Martin, A. and Mosedale, B., Nature, 1980, 283, 666-668; Bevaart, L., Vervoordeldonk, M. J., Tak, P. P., Methods Mol. Biol., 2010, 602, 181-192). Following 7 days acclimation, mice were randomly assigned to groups according body weight. Mice were immunized subcutaneously in the tail using bovine type II collagen mix in complete Freund's adjuvant (CFA). Twenty-one days after the first immunization, mice were given booster dose of collagen in incomplete Freund's adjuvant (IFA). Mice were monitored every other day after the booster dose for the development of arthritis. Mice were recruited for the study once clinical signs were visible. Eight animals were assigned each of three groups [vehicle, positive control and test compounds] and treatment was continued for four weeks and percentage inhibition in clinical score is recorded as per graded score. Body weights of the animals were also recorded 3 times a week as a measure of treatment related side effect, paw thickness measured twice a week and blood serum are collected at termination for cytokines profile. Representative data of some of the test compounds are listed in Table-4.







TABLE 4







Invivo efficacy data of representative compounds











% inhibition





of paw



inflammation,
% Inhibition in
% inhibition of


Compounds
Day-16, in
tumor volume, Day-
clinical score, Day-


(Dose: 10
SCW Arthritis
16, in TMD-8
28, in CIA Arthritis


mpk, po)
Model
Xenografts Model
Model













25
69.6 ± 12.7
 50.2 ± 10.1
90.1 ± 6.3  


32
75.3 ± 6.2 
56.1 ± 8.2
100 ± 3.9 


42
51.3 ± 9.7 
62.2 ± 8.8
100 ± 4.2 


46
81.8 ± 11.2
54.3 ± 9.1
88 ± 7.1


54
89.2 ± 10.3
 92.1 ± 13.1
98 ± 4.5





Date represent Mean ± SD, n = 8 animals in each group






The novel compounds of the present invention can be formulated into suitable pharmaceutically acceptable compositions by combining with suitable excipients by techniques and processes and concentrations as are well known.
The compounds of formula (I) or pharmaceutical compositions containing them are useful as a medicament for the inhibition of BTK activity and suitable for humans and other warm blooded animals, and may be administered either by oral, topical or parenteral administration.
Thus, a pharmaceutical composition comprising the compounds of the present invention may comprise a suitable binder, suitable bulking agent &/or diluent and any other suitable agents as may be necessary. Optionally, the pharmaceutical composition may be suitably coated with suitable coating agents.
The compounds of the present invention (I) are BTK inhibitors and are useful in the treatment of disease states mediated by BTK enzyme, preferably cancer, arthritis and related disorders.
In one of the embodiments the present invention of formula (I) in combination with one or more suitable pharmaceutically active agents selected from following therapeutic agents in any combination. Immunosuppressants (e.g., Methotrexate, mercaptopurine, cyclophosphamide), glucocorticoids, non-steroidal anti-inflammatory drugs, Cox-2 specific inhibitors, TNF- binding proteins (eg., Infliximab, etanercept), interferon-13, interferon-, interleukin-2, antihistamines, beta-agonist, anticolinergics, anti-cancer agents or their suitable pharmaceutically acceptable salts. Further examples of anticancer agents for use in combination with BTK inhibitors include chemotherapy or a targeted therapy, alkylating agents, platinum compounds, DNA altering agents, Topoisomerase inhibitors, microtubule modifiers, antimetabolites, anticancer antibiotics, hormones, Aromatase inhibitors, antibodies, cytokines, vaccines, drug conjugates, inhibitors of mitogen-activated protein kinase signaling (ex: BAY 43-9006), Syk inhibitors, mTOR inhibitors, antibodies (Rituxan), other anticancer agents that can be employed in combination include, Vinblastin, Bleomycin, Cisplatin, Acivicin, Azacitidine, Decitabine, Doxorubicin, Enloplatin, Flurouracil, Methotrexate, Vinblastin, Vincristine and BCR/ABL antagonist
The quantity of active component, that is, the compounds of Formula (I) according to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the particular application method, the potency of the particular compound and the desired concentration. Generally, the quantity of active component will range between 0.5% to 90% by weight of the composition.

## Claims

1. Compound having the structure of general formula (I)



and their pharmaceutically acceptable salts, enantiomers and their diastereomers, Bicyclic ring A-B is selected from the group consisting of:




Wherein
R2 is selected from the following ring system:







R3 at each occurrence is independently selected from C(O)NH(C1-7)alkyl, C(O)—CH═CH2, C(O)—CH≡C—R11, C(O)—CH═CH—R4, C(O)—C(CN)═CH2, C(O)—C(CN)═CH—R4, SO2—NH(C1-7)alkyl, SO2—CH═CH2, SO2—CH═CH—R4 groups; wherein, R11 is independently selected from hydrogen and alkyl group;
R4 at each occurrence is selected from —(CH2)n-NR5R6; wherein, n=0-7 and each of R5 and R6 are independently selected from hydrogen, haloalkyl, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, aryl, cycloalkyl, carbocycle, heterocycloalkyl, cycloalkyl(C1-7)alkyl, heterocycloalkyl(C1-7)alkyl;
‘U’ is selected from unsubstituted or substituted groups selected from heteroaryl, heterocycle, heterocycloalkyl, aryloxyaryl, aryloxyalkyl, aryloxyheteroaryl, heteroaryloxyaryl, heteroaryloxyalkyl, heteroaryloxyheteroaryl, Ph-CO—N(R7R8), Ph-N(R9)—CO—R10, wherein, R7, R8 and R10 are independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, aryl, cycloalkyl, heteroaryl, heterocycloalkyl and wherein each of the alkyl, haloalkyl, alkoxy, aryl, cycloalkyl, heteroaryl, heterocycloalkyl groups are when substituted are further substituted with halogen, alkyl, alkoxy, haloalkoxy groups; R9 are independently selected from hydrogen, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl.

2. A compound as claimed in claim 1 selected from the group comprising of:
1-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
1-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
1-(5-(4-amino-3-(2-methylbenzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
1-(5-(4-amino-3-(benzo[b]thiophen-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
1-(5-(4-amino-3-(2,3-dihydrobenzo[b]thiophen-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
1-(5-(4-amino-3-(dibenzo[b,d]furan-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
N-(6-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]thiazol-2-yl)acetamide;
1-(5-(4-amino-3-(2-methoxybenzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
1-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-yn-1-one;
1-(5-(4-amino-3-(3-methoxy-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(pyridin-2-yl)benzamide;
1-(5-(4-amino-3-(2-phenylbenzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
1-(5-(4-amino-3-(benzo[d] [1,3]dioxol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
1-(5-(4-amino-3-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
1-(5-(4-amino-3-(benzo[d]oxazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
3-(4-phenoxyphenyl)-1-(2-(vinylsulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine;
1-(5-(4-amino-3-(2-phenylbenzo[d]oxazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
1-(5-(4-amino-3-(2-phenoxybenzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
1-(5-(4-amino-3-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
1-(5-(4-amino-3-(benzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
1-(5-(4-amino-3-(2-phenylbenzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
(E)-1-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-(dimethylamino)but-2-en-1-one;
1-(5-(4-amino-3-(4-(5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
(E)-2-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)octahydrocyclopenta[c]pyrrole-2-carbonyl)-3-cyclopropylacrylonitrile;
4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxy-N-(4-methylpyridin-2-yl)benzamide;
4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)benzamide;
N-(4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)picolinamide;
4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(benzo[d]thiazol-2-yl)benzamide;
N-(4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)pyrazine-2-carboxamide;
1-(5-(4-amino-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(pyrazin-2-yl)benzamide;
N-(4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)benzamide;
1-(5-(4-amino-3-(4-(5-(pyridin-2-yl)-1,3,4-thiadiazol-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide;
Z)-methyl 4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)benzimidate;
6-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)nicotinamide;
1-(5-(4-amino-3-(4-(pyridin-2-yloxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
(E)-4-(4-amino-1-(2-(4-(dimethylamino)but-2-enoyl)octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(pyridin-2-yl)benzamide;
(E)-4-(4-amino-1-(2-(4-(dimethylamino)but-2-enoyl)octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)benzamide;
1-(5-(4-amino-3-(4-(5-(pyrazin-2-yl)-1,3,4-thiadiazol-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
(E)-1-(5-(4-amino-3-(4-(pyridin-2-yloxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-(dimethylamino)but-2-en-1-one;
(E)-1-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-(dimethylamino)but-2-en-1-one;
(E)-4-(4-amino-1-(2-(4-(dimethylamino)but-2-enoyl)octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(pyrazin-2-yl)benzamide;
(Z)-methyl 4-(4-amino-1-(2-((E)-4-(dimethylamino)but-2-enoyl)octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)benzimidate;
(E)-4-(4-amino-1-(2-(4-(dimethylamino)but-2-enoyl)octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide;
1-(5-(4-amino-3-(4-(pyridin-3-yloxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
(E)-1-(5-(4-amino-3-(4-(pyridin-3-yloxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-(dimethylamino)but-2-en-1-one;
4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-N-(4-methylpyridin-2-yl)benzamide;
(E)-4-(4-amino-1-(2-(4-(dimethylamino)but-2-enoyl)octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-N-(4-methylpyridin-2-yl)benzamide;
(E)-1-(5-(4-amino-3-(4-(5-(pyrazin-2-yl)-1,3,4-thiadiazol-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-(dimethylamino)but-2-en-1-one; or
(E)-1-(5-(4-amino-3-(4-(5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-(dimethylamino)but-2-en-1-one.

3. A compound as claimed in claim 1 selected from the group comprising of:
1-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
1-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
1-(5-(5-((4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyridin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-2-en-1-one;
1-(5-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-2-en-1-one;
1-(5-(4-amino-3-(2-methylbenzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
1-(5-(4-amino-3-(benzo[b]thiophen-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
1-(5-(4-amino-3-(2,3-dihydrobenzo[b]thiophen-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
1-(5-(4-amino-3-(dibenzo[b,d]furan-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
N-(6-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]thiazol-2-yl)acetamide;
1-(5-(4-amino-3-(2-methoxybenzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
1-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-yn-1-one;
1-(5-(4-amino-3-(3-methoxy-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(pyridin-2-yl)benzamide;
1-(5-(4-amino-3-(2-phenylbenzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
1-(5-(4-amino-3-(benzo[d][1,3]dioxol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
1-(5-(4-amino-3-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
1-(5-(4-amino-3-(benzo[d]oxazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
3-(4-phenoxyphenyl)-1-(2-(vinylsulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine;
1-(5-(4-amino-3-(2-phenylbenzo[d]oxazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
1-(5-(4-amino-3-(2-phenoxybenzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
1-(5-(4-amino-3-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
1-(5-(4-amino-3-(benzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
1-(5-(4-amino-3-(2-phenylbenzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
(E)-1-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-(dimethylamino)but-2-en-1-one;
1-(5-(4-amino-3-(4-(5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
(E)-2-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)octahydrocyclopenta[c]pyrrole-2-carbonyl)-3-cyclopropylacrylonitrile;
4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxy-N-(4-methylpyridin-2-yl)benzamide;
4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)benzamide;
N-(4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)picolinamide;
4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(benzo[d]thiazol-2-yl)benzamide;
N-(4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)pyrazine-2-carboxamide;
1-(5-(4-amino-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(pyrazin-2-yl)benzamide;
N-(4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)benzamide;
1-(5-(4-amino-3-(4-(5-(pyridin-2-yl)-1,3,4-thiadiazol-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide;
Z)-methyl 4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)benzimidate;
6-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)nicotinamide;
1-(5-(4-amino-3-(4-(pyridin-2-yloxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
(E)-4-(4-amino-1-(2-(4-(dimethylamino)but-2-enoyl)octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(pyridin-2-yl)benzamide;
(E)-4-(4-amino-1-(2-(4-(dimethylamino)but-2-enoyl)octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)benzamide;
1-(5-(4-amino-3-(4-(5-(pyrazin-2-yl)-1,3,4-thiadiazol-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
(E)-1-(5-(4-amino-3-(4-(pyridin-2-yloxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-(dimethylamino)but-2-en-1-one;
(E)-1-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-(dimethylamino)but-2-en-1-one;
(E)-4-(4-amino-1-(2-(4-(dimethylamino)but-2-enoyl)octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(pyrazin-2-yl)benzamide;
(Z)-methyl 4-(4-amino-1-(2-((E)-4-(dimethylamino)but-2-enoyl)octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)benzimidate;
(E)-4-(4-amino-1-(2-(4-(dimethylamino)but-2-enoyl)octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide;
1-(5-(4-amino-3-(4-(pyridin-3-yloxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
(E)-1-(5-(4-amino-3-(4-(pyridin-3-yloxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-(dimethylamino)but-2-en-1-one;
4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-N-(4-methylpyridin-2-yl)benzamide;
(E)-4-(4-amino-1-(2-(4-(dimethylamino)but-2-enoyl)octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-N-(4-methylpyridin-2-yl)benzamide;
(E)-1-(5-(4-amino-3-(4-(5-(pyrazin-2-yl)-1,3,4-thiadiazol-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-(dimethylamino)but-2-en-1-one;
(E)-1-(5-(4-amino-3-(4-(5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-(dimethylamino)but-2-en-1-one;
1-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5,6-dihydrocyclopenta[c]pyrrol-2(1H,3H,4H)-yl)prop-2-en-1-one;
2-acryloyl-5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,3-dihydrocyclopenta[c]pyrrole-4,6(1H,5H)-dione;
2-acryloyl-5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5,6-dihydrocyclopenta[c]pyrrole-1,3 (2H,4H)-dione;
1-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[b]pyrrol-1(2H)-yl)prop-2-en-1-one;
1-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,3,5,6-tetrahydrocyclopenta[b]pyrrol-1(4H)-yl)prop-2-en-1-one;
1-(6-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydro-1H-cyclopenta[c]pyridin-2(3H)-yl)prop-2-en-1-one;
1-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1l-yl)-4, 5,6,7-tetrahydro-1H-isoindol-2(3H)-yl)prop-2-en-1-one;
1-(6-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-azabicyclo[3.2.0]heptan-3-yl)prop-2-en-1-one;
1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-6-azabicyclo[3.2.0]heptan-6-yl)prop-2-en-1-one;
N-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)octahydropentalen-2-yl)acrylamide;
1-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1l-yl)-3,4,6,7-tetrahydro-1H-cyclopenta[c]pyridin-2(5H)-yl)prop-2-en-1-one;
1-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydro-1H-isoindol-2(3H)-yl)prop-2-en-1-one;
1-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
1-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[b]pyrrol-1(2H)-yl)prop-2-en-1-one;
1-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,3,5,6-tetrahydrocyclopenta[b]pyrrol-1(4H)-yl)prop-2-en-1-one;
1-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1l-yl)-5,6-dihydrocyclopenta[c]pyrrol-2(1H,3H,4H)-yl)prop-2-en-1-one;
1-(6-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)octahydro-1H-cyclopenta[b]pyridin-1-yl)prop-2-en-1-one;
1-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[b]pyridin-1-yl)prop-2-en-1-one;
1-(7-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[b]pyridin-1-yl)prop-2-en-1-one;
1-(6-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1l-yl)-3,4,6,7-tetrahydro-1H-cyclopenta[c]pyridin-2(5H)-yl)prop-2-en-1-one;
1-(7-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1l-yl)-3,4,6,7-tetrahydro-1H-cyclopenta[c]pyridin-2(5H)-yl)prop-2-en-1-one;
1-(7-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[b]pyridin-1-yl)prop-2-en-1-one;
1-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5,6-dihydrocyclopenta[c]pyrrol-2(1H,3H,4H)-yl)prop-2-en-1-one;
2-acryloyl-5-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,3-dihydrocyclopenta[c]pyrrole-4,6(1H,5H)-dione;
2-acryloyl-5-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5,6-dihydrocyclopenta[c]pyrrole-1,3 (2H,4H)-dione;
1-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[b]pyrrol-1(2H)-yl)prop-2-en-1-one;
1-(4-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,3,5,6-tetrahydrocyclopenta[b]pyrrol-1(4H)-yl)prop-2-en-1-one;
1-(6-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydro-1H-cyclopenta[c]pyridin-2(3H)-yl)prop-2-en-1-one;
1-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-4, 5,6,7-tetrahydro-1H-isoindol-2(3H)-yl)prop-2-en-1-one;
1-(6-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-azabicyclo[3.2.0]heptan-3-yl)prop-2-en-1-one;
1-(3-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-6-azabicyclo[3.2.0]heptan-6-yl)prop-2-en-1-one;
N-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)octahydropentalen-2-yl)acrylamide;
1-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4,6,7-tetrahydro-1H-cyclopenta[c]pyridin-2(5H)-yl)prop-2-en-1-one;
1-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydro-1H-isoindol-2(3H)-yl)prop-2-en-1-one;
1-(4-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
1-(4-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[b]pyrrol-1(2H)-yl)prop-2-en-1-one;
1-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,3,5,6-tetrahydrocyclopenta[b]pyrrol-1(4H)-yl)prop-2-en-1-one;
1-(4-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5,6-dihydrocyclopenta[c]pyrrol-2(1H,3H,4H)-yl)prop-2-en-1-one;
1-(6-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)octahydro-1H-cyclopenta[b]pyridin-1-yl)prop-2-en-1-one;
1-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[b]pyridin-1-yl)prop-2-en-1-one;
1-(7-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[b]pyridin-1-yl)prop-2-en-1-one;
1-(6-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4,6,7-tetrahydro-1H-cyclopenta[c]pyridin-2(5H)-yl)prop-2-en-1-one;
1-(7-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4,6,7-tetrahydro-1H-cyclopenta[c]pyridin-2(5H)-yl)prop-2-en-1-one;
1-(7-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[b]pyridin-1-yl)prop-2-en-1-one;
1-(5-(4-amino-3-(benzo[b]thiophen-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5,6-dihydrocyclopenta[c]pyrrol-2(1H,3H,4H)-yl)prop-2-en-1-one;
1-(6-(4-amino-3-(benzo[b]thiophen-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydro-1H-cyclopenta[c]pyridin-2(3H)-yl)prop-2-en-1-one;
1-(6-(4-amino-3-(benzo[b]thiophen-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-azabicyclo[3.2.0]heptan-3-yl)prop-2-en-1-one;
N-(5-(4-amino-3-(benzo[b]thiophen-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)octahydropentalen-2-yl)acrylamide;
1-(5-(4-amino-3-(benzo[b]thiophen-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4,6,7-tetrahydro-1H-cyclopenta[c]pyridin-2(5H)-yl)prop-2-en-1-one;
1-(5-(4-amino-3-(2,3-dihydrobenzo[b]thiophen-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5,6-dihydrocyclopenta[c]pyrrol-2(1H,3H,4H)-yl)prop-2-en-1-one;
1-(6-(4-amino-3-(2,3-dihydrobenzo[b]thiophen-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydro-1H-cyclopenta[c]pyridin-2(3H)-yl)prop-2-en-1-one
1-(6-(4-amino-3-(2,3-dihydrobenzo[b]thiophen-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-azabicyclo[3.2.0]heptan-3-yl)prop-2-en-1-one;
N-(5-(4-amino-3-(2,3-dihydrobenzo[b]thiophen-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)octahydropentalen-2-yl)acrylamide;
1-(5-(4-amino-3-(2,3-dihydrobenzo[b]thiophen-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4,6,7-tetrahydro-1H-cyclopenta[c]pyridin-2(5H)-yl)prop-2-en-1-one;
N-(6-(1-(2-acryloyl-1,2,3,4,5,6-hexahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]thiazol-2-yl)acetamide;
N-(6-(1-(2-acryloyloctahydro-1H-cyclopenta[c]pyridin-6-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]thiazol-2-yl)acetamide;
N-(5-(3-(2-acetamidobenzo[d]thiazol-6-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)octahydropentalen-2-yl)acrylamide;
(E)-1-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5,6-dihydrocyclopenta[c]pyrrol-2(1H,3H,4H)-yl)-4-(dimethylamino)but-2-en-1-one;
(E)-1-(6-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydro-1H-cyclopenta[c]pyridin-2(3H)-yl)-4-(dimethylamino)but-2-en-1-one;
(E)-1-(6-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-azabicyclo[3.2.0]heptan-3-yl)-4-(dimethylamino)but-2-en-1-one;
(E)-1-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4,6,7-tetrahydro-1H-cyclopenta[c]pyridin-2(5H)-yl)-4-(dimethylamino)but-2-en-1-one;
(E)-1-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-(dimethylamino)but-2-en-1-one;
(E)-1-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5,6-dihydrocyclopenta[c]pyrrol-2(1H,3H,4H)-yl)-4-(dimethylamino)but-2-en-1-one;
(E)-1-(6-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydro-1H-cyclopenta[c]pyridin-2(3H)-yl)-4-(dimethylamino)but-2-en-1-one;
(E)-1-(6-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-azabicyclo[3.2.0]heptan-3-yl)-4-(dimethylamino)but-2-en-1-one;
(E)-1-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4,6,7-tetrahydro-1H-cyclopenta[c]pyridin-2(5H)-yl)-4-(dimethylamino)but-2-en-1-one;
1-(5-(4-amino-3-(4-benzoylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-phenylbenzamide;
4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-N-phenylbenzamide;
4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methyl-N-phenylbenzamide
4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxy-N-phenylbenzamide;
4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N,2-dimethyl-N-phenylbenzamide;
4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxy-N-methyl-N-phenylbenzamide;
4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methyl-N-(pyridin-2-yl)benzamide;
4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxy-N-(pyridin-2-yl)benzamide;
4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methyl-N-(4-methylpyridin-2-yl)benzamide;
4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methyl-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide;
4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxy-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide;
4-(1-(2-acryloyl-1,2,3,4, 5,6-hexahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-phenylbenzamide;
4-(1-(1-acryloyloctahydrocyclopenta[b]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-phenylbenzamide;
4-(4-amino-1-(2-(vinylsulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-phenylbenzamide;
(E)-4-(4-amino-1-(2-(4-(dimethylamino)but-2-enoyl)octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-phenylbenzamide;
(E)-4-(4-amino-1-(2-(4-(cyclopropyl(methyl)amino)but-2-enoyl)octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-phenylbenzamide;
(Z)-4-(4-amino-1-(2-(2-cyano-3-cyclopropylacryloyl)octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-phenylbenzamide;
1-(5-(4-amino-3-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(5-chloropyridin-2-yl)benzamide;
1-(5-(4-amino-3-(4-(morpholinomethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
1-(5-(4-amino-3-(4-(piperidin-1-ylmethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
1-(5-(4-amino-3-(4-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
1-(5-(4-amino-3-(4-((tetrahydrofuran-2-yl)oxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
1-(5-(4-amino-3-(4-(1-morpholinoethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
1-(5-(4-amino-3-(4-(pyrrolidin-1-ylmethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
1-(5-(4-amino-3-(4-((dimethylamino)methyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
N-(4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)acetamide;
1-(5-(4-amino-3-(4-(2-morpholinoethoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
2-(4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)isoindoline-1,3-dione;
1-(5-(4-amino-3-(4-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
1-(5-(4-amino-3-(4-(azepan-1-ylmethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
1-(5-(4-amino-3-(4-((hexahydro-1H-isoindol-2(3H)-yl)methyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
1-(5-(4-amino-3-(4-(thiomorpholinomethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one;
1-(5-(4-amino-3-(4-((1,1-dioxidobenzo[d]isothiazol-2(3H)-yl)methyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; or
2-(4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)isoindolin-1-one.

4. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) as claimed in claim 1 and optionally one or more pharmaceutically acceptable carriers, diluents or excipients.

5. A method of treating autoimmune and/or allergic disorders selected from rheumatoid arthritis, systemic lupus erythromatosis, scleroderma, asthma, allergic rhinitis, allergic eczema, B-cell lymphoma, multiple sclerosis, juvenile rheumatoid arthritis, juvenile idiopathic arthritis, inflammatory bowel disease, graft versus host disease, psoriatic arthritis, ankylosing spondylitis and uveritis, B cell lymphoma, multiple sclerosis, diffuse large B-cell lymphoma, follicular lymphoma or chronic lymphocytic leukemia and B-cell prolymphocytic leukemia, the method comprising:
administering to a patient in need the compound of Formula (I) of claim 1, and a suitable pharmaceutically acceptable agent selected from anti-cancer and anti-inflammatory agents or their pharmaceutically acceptable salts for the treatment of the autoimmune and/or allergic disorders.

6. A method of treating autoimmune and/or allergic disorders selected from rheumatoid arthritis, systemic lupus erythromatosis, scleroderma, asthma, allergic rhinitis, allergic eczema, B-cell lymphoma, multiple sclerosis, juvenile rheumatoid arthritis, juvenile idiopathic arthritis, inflammatory bowel disease, graft versus host disease, psoriatic arthritis, ankylosing spondylitis and uveritis, B cell lymphoma, multiple sclerosis, diffuse large B-cell lymphoma, follicular lymphoma or chronic lymphocytic leukemia and B-cell prolymphocytic leukemia, the method comprising:
administering to a patient in need the pharmaceutical composition of claim 4, and a suitable pharmaceutically acceptable agent selected from anti-cancer and anti-inflammatory agents or their pharmaceutically acceptable salts for the treatment of autoimmune and/or allergic disorders.