OA17875A - Heterocyclic compounds. - Google Patents

Heterocyclic compounds. Download PDF

Info

Publication number
OA17875A
OA17875A OA1201600264 OA17875A OA 17875 A OA17875 A OA 17875A OA 1201600264 OA1201600264 OA 1201600264 OA 17875 A OA17875 A OA 17875A
Authority
OA
OAPI
Prior art keywords
amino
pyrazolo
pyrimidin
pyrrol
prop
Prior art date
Application number
OA1201600264
Inventor
Rajesh Bahekar
Ranjit C. Desai
Dipam Patel
Kiran Shah
Original Assignee
Cadila Healthcare Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cadila Healthcare Limited filed Critical Cadila Healthcare Limited
Publication of OA17875A publication Critical patent/OA17875A/en

Links

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, ________________________________________________________________________________________________________________________ 26 pharmaceutical compositions containing the compounds and their use as selective Bruton's Tyrosine Kinase (BTK) inhibitors.

Description

NOVEL HETEROCYCLIC COMPOUNDS
FIELD OF INVENTION
The présent invention relates to novel heterocyclic compounds of the general formula (I) their pharmaceutically acceptable salts, pharmaceutically acceptable solvatés, enantiomers, diastereomers, and polymorphs. The invention also relates to processes for the préparation of the compounds of invention, pharmaceutical compositions containing the compounds and their use as sélective 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 wellcharacterized rôle 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 ail 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-κΒ 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 tum, BTK phosphorylâtes and activâtes 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, prolifération and différentiation of B-lineage lymphoid cells. BTK is an upstream activator of multiple antiapoptotic signaling molécules and networks, including the signal transducer and activator of transcription 5 (STAT5) protein, phosphatidylinositol (PI) 3kinase/AKT/mammalian target of rapamycin (mTOR) pathway, and nuclear factor kappa B (NFkB) (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 molécule that govems normal B-cell development, différentiation and functioning and has also been implicated in initiation, survival and progression of mature B-cell lymphoproliférative 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 4mediated activation and prolifération. Furthermore, BTK plays a rôle in B-cell antigen processing and présentation (Satterthwaite, A.B., Witte, O.N., Immunol. Rev., 2000, 175, 120127). 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 sérum Ig. Thus, BTK is a uniquely attractive kinase target for sélective B-cell inhibition and small molécule based BTK inhibitors offers therapeutic benefit in the treatment of lymphoma and autoimmune diseases (Vâliaho, J., Smith, C.I., Vihinen, M., Hum. Mutât., 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 irréversible 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., Vemer, E., Loury, D., Chang, B., Li, S., Pan, Z., Thamm, D. H., Miller, R.A., Buggy, J.J., Proc. Natl. Acad. Sci., U S A., 2010, 107(29), 1307513080).
Thus BTKs are important in the régulation of many cellular processes including cell cycle régulation, prolifération, survival, apoptosis and motility and are significant components of the molecular mechanisms of diseases such as cancer, diabètes 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, W02008/039218, W02008/054827, WO2008/121742, WO2010/009342,
WO2011/046964, WO2014/078578 and WO2011/153514, by Pharmacyclics Inc, discloses pyrazolo-pyrimidin-amine dérivatives 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, W02010/122038, US2010/273768, WO2012/020008, US2012/040949, WO2010/000633, US2010/004231, WO2010/006947, US2010/016301, W02014/064131, W02014/076104, WO2014/083026, W02014/090715), Biogen Idée Inc (WO2011/029046, US2012/157443, WO2011/029043, US2012/157442), CGI Pharmaceuticals Inc (W02006/099075, US2006/229337, WO2009/137596, US2011/118233, WO2010/056875, US2011/301145, W02010/068788), 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 (W02013/010380, WO2014/093230) and Cellular Genomics Inc (W02005/005429, US2005/101604) discloses diverse class of heterocyclic compounds as BTK inhibitors. BASF (W02001/019829 and W02002/080926) 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 W02014/064131 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 compétitive inhibitor having sufficient selectivity. A lack of selectivity of an inhibitor for BTK over these kinases could potentially hâve négative conséquences. 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 (Cys4gi 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 dépendent 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).
Réversible kinase inhibitors interact with the ATP-binding site. As the ATP-binding sites are highly conserved among kinases, it is difficult to develop a réversible inhibitor that selectively inhibits a desired kinase. Thus with réversible kinase inhibitors, it is difficult to achieve broad therapeutic window. Generating potent, sélective, oral BTK inhibitors using covalent, irréversible and electrophilic compounds is feasible approach. However, the irréversible inhibitors exhibit toxicity due to covalent boding with off-target macromolecules. Thus to overcome undesirable off-target effects, it is essential to develop irréversible 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 sélective and irréversible 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., Vemer, E., Loury, D., Chang, B., Li, S., Pan, Z., Thamm, D.H., Miller, R.A and Buggy, J.J., Proc. Natl. Acad. Sci. U S A., 2010, 107, 13075-13080). Likewise, dianilinopyrimidine-based irréversible 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. DrugDiscov., 2012, 11(2), 96-97).
We herein disclose novel heterocyclic compounds of general formula (I) which are sélective BTK inhibitors for the prévention and treatment of disease states mediated by BTK, including cancer and inflammation. More particularly, embodiments of the présent invention describe irréversible kinase inhibitors includinginhibition 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 présent invention discloses heterocyclic compounds as defined by the general formula (I) that are sélective BTK inhibitors for the prévention and treatment of disease states mediated by BTK. The compounds of the présent 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 prévention and treatment of disease states mediated by BTK.
EMBODIMENT(S) OF THE INVENTION
An embodiment of the présent 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 présent 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 furthei' embodiment is provided the use of heterocyclic compounds of the présent invention as sélective 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 présent invention.
DESCRIPTION OF THE INVENTION
Accordingly, the présent invention relates to the compounds of the general formula (I) represented below and their pharmaceutically acceptable salts, enantiomers and their diastereomers;
R2-R3 (ï)
Wherein, V, W, X, Y & Z independently represents, ‘C’ or ‘N’; Ri, represents groups selected from hydrogen, keto, halogen, unsubstituted or substituted groups selected from cyano, 5 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(Ci_7)alkyl, heterocycloalkyl(C1.7)alkyl, C(O)NH(Ci_7)alkyl, C(O)-CH=CH2, C(0)-CH=CH-R4, C(O)C(CN)=CH2, C(O)-C(CN)=CH-R4, SO2-NH(Ci-7)alkyl, SO2-CH=CH2, SO2-CH=CH-R4 groups;
R4 is selected from -(CfLjn-NRsRô; wherein, n=0-7 and each of R5 and Rg are independently selected from hydrogen, haloalkyl, C1.7 alkyl, C2-7 alkenyl, C2.7 alkynyl, aryl, cycloalkyl, carbocycle, heterocycloalkyl, cycloalkyl(Ci_7)alkyl, heterocycloalkyl(Ci_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-Rio, wherein, R7j Rs and Rio are independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy; aryl, cycloalkyl, heteroaryl, heterocycloalkyl; further substituted with halogen, alkyl, alkoxy, haloalkoxy groups and Rg are independently selected from hydrogen, Ci_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 prefïx “alk”, such as alkoxy and alkanoyl, means a carbon chain which may fùrther 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, ier/.-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, Ci_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, 1propenyl, 2-butenyl, 2-methyl-2-butenyl etc. Where the specified number of carbon atoms permits, e. g., from C5.jo, 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-l-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, thiomoipholine, 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, rio-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 ail 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 ail 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 spécification.
The term substituted, as used herein, means that any one or more hydrogens on the designated atom is replaced with a sélection 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 sélection 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 dérivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts includemineral or organic acid salts of the basic residues. Such conventional non-toxic salts includethose 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 subséquent 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 spécification, 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 Naines
1 nh, H JL -N l-(5-(4-amino-3-(4-phenoxyphenyl)-l 1Ipy razolo[3,4-d]pyrimidin-'l yl )hexahydrocyclopenta[c] py rrol-2( 111)y 1 ) pro p-2-en-1 -one
2 l-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-l 11pvrazolo[3,4-d]pvrimidin-lyl )hexahydrocyclopenta[c] pyrrol-2(111)yl)prop-2-en-l-onc
3 F~S NH; A n __ 1-(5-( 5-((4-amino-3-(4-phenoxvphenv 1)-111- pyrazolo[3,4-d]pyrimidin-l- yl)methyl)pvridin-2- yl)hexahydropyrrolo[3,4-c]pyrrol-2(llI)vl)prop-2-en-l-one
4 ''ta' jrV Nl% u ' ’N V-N N-., B L'M 1 -(5-(2-(4-ammo-3-(4-phenoxyphenyl)-l Hpyrazol o[3,4-d]pyrimidin-1 y!)ethyl)hexahydropjTTolo[3,4-c]pyrrol2( 1 H)-vl Jprop-2-en-l -one
5 fVS NI h . A^ J uA/ \ b l-(5-(4-amino-3-(2-methylbenzo[d]thiazol-6yl)-lH-pyrazolo[3,4-d]pyrimidm-lyl )hexahydrocy clopenta[c]pyTTol-2( 1 H) yl)prop-2-en-l -one
6 ε / ?. (fV Ml!, \-_-J \ '^r-4 A. % l-(5-(4-amino-3-(benzo[b]thiophen-5-yl)-lHpvrazol o[3,4-d jpyrimid in-1 yl)hexahydrocydopenta[c]pyrrol-2( 1H)yi)prop-2-en- ! -one
7 S-, (‘V χ>' J N V'''1' /-’ \-X L ) *K 0 1 -(5-(4-amino- 3-(2,3- dihydrobenzo[bjthiophen-5-yl)-lHpyrazolo[3,4-d]pyrimidin-1yl)hexahydrocydopenta[cjpyrrol-2(lH)y I) prop-2-en-1 -one
8 P ,·7'Χ.-ό Nil· V-V 0 l-(5-(4-ammo-3-(dibenzo[b,d]furan-3-yl)-lHpyrazol o[3,4-d jpyrimidin-1 yl)hexahydrocyclopenta[c]pyrrol-2(lH)yl)prop-2-en-1 -one
9 rV NIL·, y U srX--L Ί ; N N v> -N N-(6-(l-(2- acryioyloctahydrocyciopenta[c]pyrrol-5-yï)4-amino-1 H-pyrazolo[3,4-d]pyrimid in-3yl)benzo[d]thiazol-2-yl)acetamide
10 Ά<-r p t τ$· 'N S y/ l-(5-(4-amino-3-(2-methoxybenzo[d]thiazol6-yl)-l H-pyrazolo[3y4-d]pyrimidin-l y 1 )hexahy drocy dopenta[c]pyrrol-2( 1 H)yl)prop-2-en-1 -one
11 Μ. Λ Mli, X-J n'Sa μ* 1”Ν ί' 1 -(5-(4-amino-3-(4-phenoxypheny t)-1Hpyrazolo[3,4-d)p_yrimidin-lyl)hexahydrocyclopenta[c]pyrrol-2( 1 H) yl)prop-2-yn-l-one
12 /-Y Y-y ί’Λ -c ΜΙ, \---' J/M. μ .. > k-e-y ζ> c' 1 -(5-(4-amino-3-(3-methoxy-4phenaxyphenyl)-! H-pyrazolo[3,4djpyrimidin-1yl)hexahydrocyclopenta[cjpyrrol-2('lH)yî)prop-2-en-l -one
13 ο η y-xn r x™ y.·' 'ô'^ û kl 4-(1-(2- acryloyloctahydrocydopenta[c]pyrrol-5-yl)- 4-am ino-1 H-py razol cj[3, 4-d jpyri mi d in-3-y 1 )- N-(pyridm-2-yl)benzamide
14 k ’ NH, 1 x l· ‘K L >·-.. x- N > b m l-(5-(4-amino-3-{2-pheny!benzo[d]thiazoI-6yl )-1H -pyrazolo[3,4-d Jpyrimid in-1 y[)hexaliydrocydopenta[cJpynOl-2(!H)vl)prop-2-en-l -one
15 fl-, ί* V*3 r-- y I . x N’ N s S zy/ l-(5-(4-amino-3-(benzo[d][l,3]dioxol-5-yl)lH-pyrazoIo[3,4-d]pyrimidin-lyl )hexahydrocydopenta[c]pyrrol-2( 1H)yl) prop-2-en-1 -one
16 k n i X-.N y Nil· \s^ N-b-4 1 -N xn---n /- \-À > cK 1- (5-(4-amino-3-(4-(5-methyI-l,3,4-oxadiazol- 2- yl}phenyl)-lH-pyrazoIo[3,4-d]pyrimidin-l- v i )hexahy d rocy clopen ta [ cjpyrrol-2( I H) yl) prop-2-en-1 -one
17 Λ-η .rv· 14'·'·«-- ü l-n? ί.Ί l-(S(4-amino-3-(benzo[d]oxazol-6-yl)-lHpyrazol o[3,4-d jpyrimidïn-1 yl)hexahydrocydopenta[c]pyrrol-2(lH)y 1) prop-2-en-1 -one
13 , o / c? Mit, y=; ' M < VA> 1-/ T'ft 3-(4-phenoxvphenyl)-l -(2(vinylsulfonyi)octahydrocyclopenta[c]pynOl5-y 1)-1 H-pyrazolo [3,4-d ]pyrimidin-4-amine
19 *i ·* N rO NH; V-7 :l _i N •n^-n <Λ l-n z l·rt' i-(5-(4-amino-3-(2-phenylbenzo[d]oxazol-6yl)-lH-pyrazolo[3,4-djpyrimidin-lyl)hexahydrocydopenta[c]pyrrol-2( 1H)y l) prop-2-en-1 -one
20 nu. 'V--7 Ά/ 0Ί η ~Ν 7 l-(5-(4-amino-3-(2-phenoxybenzo[d]thiazol- 6-yl)-I H-pyrazolo [3,4-dJpyrimidin-lyl )hexahyd rocy dopenta {cjpv rrol-2( 1 H) vl)prop-2-en-l-one
21 Μ-Μ ? Γ> Ν1ί< \---··' ΧΜ'; »' 7. 7— C 1 -(5-(4-aniino-3-(4-( 1 -methyl-1 H-pyrazol-4yl)phenyl)-l H-pyrazolo[3,4-d]pyrîmidin-lyl)hexahydrocydopenta(c]pyTTol-2(lH)y ljprop-2-en-1 -one
22 Π—, (V κιι: y---NÀ>--y ι „ Λ XV-N .Λ- Cl l-(5-(4-ammo-3-(benzo[d]oxazol-5-yl)-lHpyrazol o[3,4-dJpyrinûd in-1 yl)hexahyd rocydopenta [c]pyrrol-2( 1 H) vl)prop-2-en-1 -one
23 ο f’Ç-N Mlij V^·' 1 ,J Μ Μ Μ ’'Ν 7 l-(5-(4-amino-3-(2-phenylbenzo[d]oxazoÎ-5y 1)-1 H-pyrazolo[3,4-d Jpyrimidin-1 yi)hexahydrocydopenta[c)pyrrol-2(lH)y I)prop-2-en-l -one
24 fV •f MI, \x--·' u (E)- i -(5-(4-ammo-3-(4-phenoxyphenyl)-1Hpvrazol o[3,4-d Jpyrimid in-1 yl)hexahydrocydopenta[c]pyrrol-2(lH)-yI)4-(dimethylamino)but-2-en-'l-one
25 /''N ‘P'XJ·' À Mil, y--:v-r A Y-\ W 7 O 9-(2-acryloyloctahydrocydopenta[c]pyrrol-5yl)-6-amino-7-(4-phenoxyphenyi)-5,7dihydro-4H-purin-8(9H)-one
26 T'*-·'·, v./ J--N <Vn Λ NH; M'L, ·.--.$. J J N -•n-n ù 1 -(5- (4-am ino-3-(4-(5-(pyrid in-2-yI)-1,3,4oxadiazol-2-yl)phenyl)-lH-pyrazolo[3,4d|pyrimidin-l- y l jhexahy drocydopenta [c]pvrrol-2( 1 H) yl)prop-2-en-1 -one
27 /-Ύ p-VY A Ml; I i; Tr %'X-N A U l-(5-(4-amino-6-bromo-5-(4-phenoxyphenyl)- 7H-pyi’rolo[2,3-d]pyrimidin-7yI)hexahydrocydopenta[cjpyrrol-2(lH)vl)prop-2-en-1 -one
28 Μ A Mk AS b (E)-2-(5-(4-amino-3-(4-phenoxyphenyl)-lHpyrazol o[3,4-d jpyriniid in-1 yl)octahydrocyclopenta[c]pyrrnle-2carbonyl}-3-cyclopropylacrylanitrile
29 rvn ; 4-(1-(2-
w „ acryioylociahydrocy’clopenta[c]pyrrol-5-yI)-
?= K „ 4-amino-lH-pyrazolo[3,4-d]pyrimidin-3-y!)-
< x>'”\ Mîk \=y 2-methoxy-N-(4-methylpyridin-2-
j •••Ab u b Γ« yl)benzamide
30 Va 4-(1-(2-
V=N · ! acryloyloctahydrocydopenta[c]pyrrol-5-yl)-
4-amino-lH-pyrazolo[3..4-d jpyrimidin-3-yi)-
Kl I, 1/ Ί b’b N-(4-methy!pyTidin-2-yl)benzamide
/ · ''-A
31 J' l-(5-(4-amino-5-(4-phenoxyphenyI)-7H-
ί“Κ pyrrolo[2,3-d]pyrimidin-7-
s.11, \=R yI)hexahydrcicycIopenta[c]pyrrol-2( 1 H)-
Λ A A i! y A-·-'· y 1) prop-2-en-1 -one
32 y.-v «y -¼.. / À \w. y.--' K·· ; V V\ ·-V N-(4-(l-(2- acryk>yloctahydrocyclopenta[c]pyrrol-5-yl)4-amino-lH-pyTazolo[3,4-djpyrimïdin-3yl)phenyl jpicofmamide
33 ;=-\ p-V Ml; \=--'' i «1*ί l-· !/'*“< Q Cî‘o 6-amino-7-(4-phenoxyphenyl)-9-(2(vinyl5ulfonyl)octahydrocyclapenta[c]pyrrol5-yl)-7H-purin-8(9H)-one
34 N sj.-S y<51 rs mu y-- ''•x**'* S δ, -x cf 4-(1-(2- acryloyloctahydrocycloperita[c]pyrrol-5-yI)4-amina-lH-pyrazolo[3,4-d]pyrimidin-3-yI)N-(ben.zo[djthiazol-2-yl)benzamide
35 y\ v< k'Â rs Mk \=v s-U. i L > ••e r <Z ; Y-y “•S n N-(4-(l-(2- acryloyloctaliydroQTlopenta[c]pyrrol-5-yl)4-aniino-lH-pyrazolo[3,4-d]pyrimîdin-3yl)phenyl)pyrazine-2-carboxamide
36 T F O-.l·' f i NE. n\--L 1 .1 > fe 1 -(5-(4-amino-3-(2.,2difluorobenzo [d] [ l,3]dioxol-5-y i)-l HpyTazolo[3,4-djpyrimidin-ly0hexahydrocyclopenta(cJpyrrol-2( 1H)yl) prop-2-en-1 -one
37 ’V-MI rS Kllj \ =,^ x ·+--( fe c 4-(1-(2- acryloyloctahydrocyclopenta[c]pyrrol-5-yî)4-amino-lH-pyrazolo[3,4-d]pyrimidin-3-yl)- N-(pyrazin-2-yl)benzamide
38 ,.ί·\ w .ΓΛ NH. ^-v^-i « -.-7 N '> fe 0 N-(4-(l-(2- acryloyloctahydrocydopenta[c]pynOl-5-yi)4-amïno-lH-pyrazolo[3,4-d]pyrimidin-3yl)phenyl)benzam.ide
39 Vf rfe >n3 y-1 '* ' ÎT \ \--^ /--- V\ Ύ U 1 -(5- (4-amino-3-(4-(5-( pyridin-2-y l)-l ,3,4thiadiazol-2-yl)phenyl)-lH-pyraznlo[3,4djpyrimidin-lyl)hexahydrocydopenta[c]pyrrol-2(lH)yl)prop-2-en-l-one
40 ΓΤ %-^Γ ,Ά ) Ύ'Χ '•---χ ) -Λ 4-(1-(2- acryloyloctahydrocyclopentajc]pyrrol-5-yl)- 4-amino-lH-pvrazolo[3? 4-d Jpyrimidin-3-yl)- N-(4-(trifluoromethyl)pyridin-2- yl)benzamide
41 .' 'Xr-N η. y Wl; V·'· νγκ /-- < , <. ) a (Z)-methyl 4-(1-(2- acryloyloctahydroq,’clopenta[c]pyrrol-5-yl)4-amino-lH-pyTazolo[3,4-dJpyrimidin-3-yl)N-(4-methyipyridin-2-yl)benzÎmidate
42 >Λ c Ύ' ^-ΜΙΙ ,τΛ •sai. \χ--\· i •V S n 6-(1-(2- acryloyloctahydroc\'clopenta[c]pyrrrol-5-yI)- 4-amino-lH-pyrazolo[3,4-djpyrimidin-3-yl)- N-(4-methylpyridin-2-yl)nicotinamide
43 A .r% NU, 'yxV 1 -( 5-(4-amino-3- (4-(pyridïn-2-yloxy Jphenyl)- 1 H-pyrazolo[3,4-d ] pyrimidin-1 yl)hexahydrocydopenta[c]pyrrol-2(lH)yl)prop-2-en- l-one
44 Y (Γ •1 J h2\ Ύ” ù *\ V Γ T v..-\ ·» * > N— 7 (E)-4-(4-aniino-l-(2-{4-(dimethylamino)but-2enoyl)tKtahydrocyclopenta[c]pyrrol-5-yl)lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N.'(pyridin-2-yl)benzamide
45 y J (E)-4-(4-amino-l-(2-(4-(dimethylamino)but-2-
j_ enoyl)octahydrocyclopenta[c]pyTrol-5-yl)lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-
?·- U. J 7ΙΛ M, \ *nl ,·' il ÿ·— K \_ methylpyridin-2-yl)benzamide
VS v v-\ Al
46 ' ‘J 1-(5-(4-amino-3-(4-(5-(pyrazin-2-y 1)-1,3,4-
thiadîazol-2-yl)phenyl)-lH-pyrazolo[3,4-
J djpyrimidin-l-
Ml, % J'' yl )hexahydrocyclopenta[cjpyrrol-2( 1 H)-
. -k. J ·- i> t_- s /... V—·. > ιΎ y l)prop-2-en-1 -one
47 K Y il ! (E)-l-(5-(4-ainino-3-(4-(pyridin-2-
Γι'* •sis’·’ t yloxy)phenyl)-lH-pyrazolo[3,4-d]pyrimidîri-
..y l-yl)hexahydrocyclopenta[c]pyrrol-2(lH)-
ΛΑ yl)-4-(dimethylamino)but-2-en-l-one
d’
48 Ο l1 .1 η;ν γ·- Ν' Τ * 'i Jf Ν A SA >- * k # ΰ' (E)-l-(5-(4-aniino-3-(4-phenoxyplienyl)-lHpvrazolo[3, 4-d jpyrimidin-1 yl)hexahydrocyclapenta[c]pyrrol-2(lH)-yl)4-(dimethylamino)but-2-en-l-one
49 A n*. γ-' < ' >-. V> \'y ' (E)-4-(4-ammo-'l-(2-{4-(dimethylamino)but-2enoy l)octahyd rocy cl open ta [ c jpyrrol -5-vl)1 H-pyrazolo[3,4-d ]pyrimidin-3-y 1)-N( pyrazin-2-y l)benzamide
50 ν _Ν • V %-··* Λ G η.ν y SA ν ι-χ / z 0 (Zj-methyl 4-(4-amino-1 -(2-((E)-4(dïmethylammo)but-2enoyl)octahydrocyclopenta[c]pyrrol-5-yl)IH-p}'razolo[3,4-d]p}TÎmidin-3-yl)-N-{4methylpyridin-2-yl)benzimidate
51 M A / 1* X^·-· Xlk \z-J \ • --Λ N Ά-, S> v (E)-4-(4-amino-l-(2-(4-(dimethylammo)but-2enoyl)octahydrocyclopenta[cjpyrrol-5-yl)1 H-pyrazoio[3,4-d Jpyrimi din-3-y l)-N-(4(trifluorornethyl)pyridin-2-yl)benzamide
52 .7 vu ν' V-? ft. l-(5-(4-amino-3-(4-(pyridin-3-yloxyjphenyl)- 1 H-pyrazo!o[3,4-d]pyrimidïn-1 yl)hexahydrocyclopenta[c)pyrrol-2( 1H)y 1) prop-2-en-1 -one
53 ... ·ζ=·' , ' \ '> (E)-l-(5-(4-amino-3-(4-(pyrïdm-3-
Ml, / ) A yloxy)phenyl)-lH-pyrazolo[3,4-d]pyTÎmidin-
-1 \ 1 -yljhexahy drocy clopen ta [c] pyrro l-2( 1 H)-
/'X (ft 1 σ^··.^···...·Κ yl)-4-(dimethylamino)but-2-en-l-one
54 Va, 4-(1-(2-
\=n aciyloyloctahydri>cyclopenta[c]pyrrol-5-yi)-
s\ ' 4-amino-lH-pyrazolo[3,4-cljpyrimidin-3-yl)-
KH; î\’-methyl-N-(4-methylpyridin-2-
x ^--4 1' ., > '·' !.. / '> ‘•♦x* yl)benzamide
55 >Λ (E)-4-(4-amino-l -(2-(4-(dimethylamino)but-2-
e VA enoyl)octahydrocydopenta[c]pyrrol-5-vl)-
r\ 1 H-pyrazolo[3,4-d ]pyrim.idm-3-yl)-N-
,Γ\\ Ml, X^-J < ->·. .Λ X -· r A U-? ft .+ methyl-Î\-(4-methylpyridin-2-yl)benzamide
56 S. <-· ;j υ * NH. V-'·' s [ Si ’S'? i > · -./=' s l. ( E )-1 -(5-( 4- amino-3-(4-(5-(pyrazin-2-v !)-1,3,4thiadiazol-2-vl)phenyl)-lH-pyrazolo[3,4djpyrinndin-lyl)hexahydrocyclopenta[c]pyrrol-2(lH)-yl)4-(dimethylamino)but-2-en-l-one
57 .%·'···-<· ’N MJ W' .J·. .* \ *·' / ' V-, T '-V A. a (E)-l-(5-(4-amino-3-(4-(5-(pyridin-2-yl)-'1,3,4oxadiazol-2-yl)phenyl)-'lH-pyrazolo[3,4djpyrimidin-lyl)hexahydrocycloper«ta[c]pyrrol-2(lH)-yl)4-(dimethyl amino)bu t-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 préparation of the compounds of the présent invention:
ALL: Acute lymphoblastic leukemia
ATP: Adenosine triphosphate
BTK: Bruton’s Tyrosine Kinase bs: broad singlet
CLL: Chronic lymphocytic leukemia
CDCfi: Deuterated chloroform
CHC13: Chloroform d: doublet dd: doublet of doublet dt: doublet of triplet
DCM: Dichloromethane
DMAC: N,N-(Dimethylacetamide)
DMAP: 4-(Dimethylamino) pyridine
DMF: 2V,MDimethyl 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 *H NMR: Proton nuclear magnetic résonance
Pet ether: Petroleum ether, boiling range (60-80 °C)
POCI3 : Phosphorylchloride s: singlet t: Triplet td: triplet of doublet
THF: Tetrahydrofuran
TLC: Thin layer chromatography
The novel compounds of the présent 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 ail 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.
Hydrazine hydrate (i)
Formamide (ii)
NH2 (m)
(iv)
Xxpg NH, 1 I J
(y) ιίΎ A
Base, DMF N
(vi) R,-Pg
R3-C1 (X) (vü)
U-B(OH)2
TEA/DCM
(I)
Scheme I:
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 fumish the compound of formula (vi). Compound (vi) can subjected to Suzuki 10 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 préparations provided below further illustrate and exemplify the 15 compounds of the présent invention and methods of preparing such compounds. In the following examples molécules with a single chiral center, unless otherwise noted, exist as a racemic mixture. Those molécules 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 fumish 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).
Scheme II
TEA DCM
Triphosgene
U-B(OH)2 >=O
Cl-R >o
TEA/DCM
DIPEA DMAP THF
H2,Pd(OH)2/C
MeOH
Fe,NH4CI
EtOH/H2O
V=O ' ' Deprotection R2-Pg viii
TEA, dioxane R2-Pg R2-Pg
Cu(OAc)2, Py DMF r2-R3
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 fumish 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).
(i)
(ü)
(iv)
Deprotection
NH3-H2O
Dioxane
Scheme III
Compounds of the présent invention can be isolated either as free amine form or as a sait corresponding to the acid used such as trifluoroacetic acid, hydrochloric acid, hydrobromic acid, oxalic acid, maleic acid, fumerie acid, succinic acid, p-toluene sulfonic acid or benzene sulfonic 10 acid. The compounds can be purified where ever required, by recrystallization, trituration, précipitation, préparative thin layer chromatography, flash chromatography or by préparative HPLC method.
The compounds of the présent invention can be used either alone or in combination with one or more therapeutic agents or pharmaceutically acceptable salts thereof. Such use will 15 dépend 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 présent invention. These are provided without limiting the scope of the présent invention in any way.
(Η NMR spectral data given in the examples (vide infra) are recorded using a 400 MHz spectrometer (Bruker AVANCE-400) and reported in δ scale. Until and otherwise mentioned the solvent used for NMR is CDCI3 using TMS as the internai standard.
Example: 1
Synthesis ofl-(5-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-lyl)hexahydrocyclopenta[c]pyrrol-2(lH)-yl)prop-2-en-l-one (compound No: 1)
Synthesis of titled compound was carried out, as described in Scheme-IV and step-wise 10 procedure is described below.
Scheme-IV:
Step-1: Synthesis of tert-butyl 5-(4-amino-3-iodo-lH-pyrazolo[3,4-d]pyrimidin-lyl)hexahydrocyclopenta [c]pyrrole-2(lH)-carboxylate (3)
Boc
Intennediate 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(lH)-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 température 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). ’H NMR (DMSO-dô, 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)-lH-pyrazolo[3,4-d]pyrimidin-lyl)hexahydrocyclopenta[c]pyrrole-2( 1 H)-carboxylate (5)
Boc
To a stirred solution Intennediate 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 atmosphère. Mixture was cooled to room température, diluted with water (50 mL) and extracted with EtOAc (3 x 50mL). The combined organic layer was washed with water (2 x 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). ’H NMR (DMSO-dô, 400 MHz) δ ppm: 1.48 (s, 9H), 1.98-2.04 (m, 2H), 2.27-2.34 (m, 2H), 2.89 (s, 2 H), 3.13-3.17 (m, 2 H), 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, 1 H). ESI-MS (ESI-MS): m/z 535.23 (M+Na)+.
Step-3: Synthesis of l-(octahydrocyclopenta[c]pyrrol-5-yl)-3-(4-phenoxyphenyl)-lHpyrazolo[3,4-d]pyrimidin-4-amine (6)
To a solution of Intermediate 5 (2.1 g, 4.09 mmol) in CH2CI2 (40 mL) was added TFA (1.25 mL, 16.37 mmol). After stirring 2 hrs at room température, 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 MgSCfr, filtered and concentrated to provide Intermediate as a white solid (1.2 g, 71% Yield). XH 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 l-(5-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-lyl)hexahydrocyclopenta[c]pyrrol-2(lH)-yl)prop-2-en-l-one, compound No: 1
To a solution of Intermediate 6 (1.1 g, 2.66 mmol), dissolved in CH2C12 (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 MgSCU, filtered and concentrated. Residue obtained was purified by flash chromatography (using CH2C12/MeOH=25/l, 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), 6.366.50 (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), 3.103.21 (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-1 H-pyrazolo[3,4d]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.
Scheme-V:
Step-1: Synthesis of tert-butyl 5-(4-amino-3-iodo-lH-pyrazolo[3,4-d]pyrimidin-lyl)hexahydrocyclopenta [c]pyrrole-2(lH)-carboxylate (3)
Intermediate 1 (0.22 g, 0.S51 mmol) and triphenylphosphine (0.71 g) were mixed together in THF (10 mL). Tert-butyl 5-hydroxyhexahydrocyclopenta[c] pyrrole-2(lH)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 température ovemight, filtered and concentrated. The residue obtained was purified by flash chromatography (CHiCL/MeOH = 98/2) to get intermediate 3 as a white solid (0.3 g, 76% Yield). ‘H 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)-lHpyrazolo[3,4-d]pyrimidin-l-yl)hexahydrocyclopenta[c]pyrrole-2(lH)-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 (0.31 g, 0.95 mmol) and KHCO3 (0.340 g, 3.56 mmol). The reaction mixture was heated at 90 °C for 2hrs, under N2 atmosphère. Mixture was cooled to room température, diluted with water (50 mL) and extracted with EtOAc (3 x 50mL). The combined organic layer was washed with water (2 x 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). Ή NMR (DMSOd6, 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, 2 H), 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=8.0Hz), 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-l-(octahydrocyclopenta[c]pyrrol-5-yl)-lH-pyrazolo[3,4d]pyrimidin-3-yl)-N-(pyridin-2-yl)benzamide (6)
To a solution of Intermediate 5 (0.25 g, 0.462 mmol) in CH2CI2 (10 mL), TFA (1.0 mL, 15.87 mmol) was added and the reaction mixture was stirred for 2 hrs at room température. 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). 'H NMR (DMSO-dô, 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=12.0Hz), 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-(l-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-lHpyrazolo[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 CH2CI2 (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 MgSCU, filtered, concentrated and residue obtained was purified by flash chromatography, using CFLCL/MeOH (25/1) to get compound 13 as a white solid (0.03 g, 20.58 % Yield). *H NMR: (CDC13, 400 MHz): δ 8.72 (s, 1H), 8.43 (d, 1H, J = 6A 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, Λ = 10.0 Hz, J2 = 16.8 Hz), 6.42 (dd, 1H, Λ = 2.4 Hz, J2 = 16.8 Hz), 5.72 (dd, 1H, Jx = 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: (l-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-lH-pyrazolo[3,4-d] pyrimidin-1yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one
’H NMR: (CDC13,400 MHz): δ 9.11 (s, 1H), 8.41 (s, 1H), 8.34-8.30 (m, 2H), 7.87 (dd, 1H, Λ =
1.6 Hz, J2 = 8.4 Hz), 6.49 (dd, 1H, Λ = 9.6 Hz, J2 = 16.8 Hz), 6.42 (dd, 1H, Jx = 2.8 Hz, J2 =
16.8 Hz), 5.72 (dd, 1H, Λ = 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, 5 2H) ; ESI-MS: (+ve mode) 431.9 (M+H)+ (100 %); HPLC: 96.04 %.
Example:4
Compound 3: l-(5-(5-((4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin -1yl)methyl)pyridin-2-yl)hexahydropynOlo[3,4-c]pyiTol-2(lH)-yl)prop-2-en-l-one
'H NMR: (DMSO-d6, 400 MHz): δ 8.27 (S, 1H), 8.11-8.09 (m,lH), 7.63-7.61 (m, 2H), 7.447.40 (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), 6.446.41 (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 15 (M+H)+ (100 %); HPLC: 95.82 %.
Example: 5 Compound 4: 1 -(5-(2-(4-amino-3-(4-phenoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 -
yl)ethy!)hexahydropyrrolo[3,4-c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one
’H NMR: (CDC13,400 MHz): δ 8.37 (s, 1H), 7.65 (dd, 2H, Jx = 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, Λ =
3.6 Hz, J2 = 9.2 Hz), 5.41 (bs, 2H), 3.79-3.68 (m, 2H), 3.35 (dd, 1H, Λ = 4.8 Hz, J2 = 12.8 Hz), 3.27 (dd, 1H, Λ = 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: l-(5-(4-amino-3-(2-methylbenzo[d]thiazol-6-yI)-lH-pyrazolo[3,4-d] pyrimidin-1yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one
’H NMR: (CDCI3, 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, Λ = 2.0 Hz, J2 = 8.4 Hz), 6.49 (dd, 1H, f = 10.0 Hz, J2 = 16.8 Hz), 6.42 (dd, 1H, Λ = 2.8 Hz, J2 = 16.8 Hz), 5.72 (dd, 1H, Λ = 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: l-(5-(4-amino-3-(benzo[b]thiophen-5-yl)-lH-pyrazolo[3,4-d] pyrimidin-1yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one
’ll NMR: (DMSO, 400 MHz): δ 8.24 (s, 1H), 8.16 (dd, 2H, J7= 6.0 Hz, J2 = 4.4 Hz), 7.85 (d, 1H, J = 5.6 Hz), 7.65 (dd, 1H, Js= 8.4 Hz, J2 = 1.6 Hz), 7.56 (d, 1H, J= 5.2 Hz), 7.62 (dd, 1H, J7= 10.4 Hz, J2 = 16.8 Hz), 6.14 (dd, 1H, J7= 16.8 Hz, J2 = 2.4 Hz),
5.67 (dd, 1H, J7= 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: l-(5-(4-amino-3-(2,3-dihydrobenzo[b]thiophen-5-yl)-lH-pyrazolo [3,4d]pyrimidin-1 -yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one
*H NMR (DMSO-dô, 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, J7 = 2.8Hz, J2 = 17.2 Hz ), 5.68-5.66 (m, 1H), 5.6440
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), 3.102.83 (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: l-(5-(4-amino-3-(dibenzo[b,d]furan-3-yl)-lH-pyrazolo[3,4-d] pyrimidin-1yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1-one
’H 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, Ji = 2.4 Hz, J2 = 16.8 Hz), 5.67 (dd, 1H, Ji = 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-(l -(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1 H-pyrazolo
[3,4-d]pyrimidin-3-yl)benzo[d]thiazol-2-yl)acetamide
’H 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, Λ = 2.4 Hz, J2 = 14.4 Hz), 5.66 (dd, 1H, J! = 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: l-(5-(4-amino-3-(2-methoxybenzo[d]thiazol-6-yl)-lH-pyrazolo[3,4-d] pyrimidin
-1 -yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one
Tl NMR (DMSO-dô, 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, Ji = 2.4 Hz, J2 = 16.8 Hz ), 5.70-5.65 (dd, 1H, = 2.4 Hz, J2 = 10.4 Hz ), 5.45-5.42 (m, 1H), 4.19 (s, 3H), 3.80-3.76 (m, 1H), 3.6215 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:
-(5-(4-amino-3-(4-phenoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-yn-1 -one
’H NMR: (DMSO-dé, 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: l-(5-(4-amino-3-(3-methoxy-4-phenoxyphenyl)-lH-pyrazolo[3,4-d] pyrimidin1 -yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one
Ή NMR: (CDC13, 400 MHz): δ 8.38 (s, 1H), 7.37-7.33 (m, 3H), 7.22 (dd, 1H, J! = 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, Jj = 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: l-(5-(4-amino-3-(2-phenylbenzo[d]thiazol-6-yl)-lH-pyrazolo[3,4-d]pyrimidin1 -yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one
NMR: (CDC13, 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, = 8.0 Hz, J2 = 2.0 Hz), 7.56-7.53 (m, 3H), 6.52-6.38 (m, 2H),
5.70 (dd, 1H, Ji = 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: l-(5-(4-amino-3-(benzo[d][l,3]dioxol-5-yl)-lH-pyrazolo[3,4-d] pyrimidin-1 yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one
NMR: (DMSO-dô, 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: l-(5-(4-amino-3-(4-(5-methyl-l,3,4-oxadiazol-2-yl)phenyl)-lH-pyrazolo[3,4d]pyrimidin-1 -yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one
'H NMR: (DMSO-dô, 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, Ji = 2.8 Hz, J2 = 16.8 Hz), 5.68-6.65 (dd, 1H,
Λ = 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: l-(5-(4-amino-3-(benzo[d]oxazol-6-yl)-lH-pyrazolo[3,4-d]pyrimidin -1yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one
Ή 'H NMR: (CDC13,400 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)-l-(2-(vinylsulfonyl)octahydrocyclopenta[c] pyrrol-5-yl)1 H-pyrazolo[3,4-d]pyrimidin-4-amine
Ή NMR: (DMSO, 400 MHz): δ 8.24 (s, 1H), 7.64 (dd, 2H, J! = 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: l-(5-(4-amino-3-(2-phenylbenzo[d]oxazol-6-yl)-lH-pyrazolo[3,4-d]pyrimidin1 -yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one
’ll NMR: (CDC13, 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 : l-(5-(4-amino-3-(2-phenoxybenzo[d]thiazol-6-yl)-lH-pyrazolo [3,4d]pyrimidin-1 -yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one
Example: 21
Compound 21: l-(5-(4-ammo-3-(4-(l-methyl-lH-pyrazol-4-yl)phenyl)-lH-pyrazolo [3,4djpyrimidin-1 -yl)hexahydrocyclopenta[c]pyrrol-2( lH)-yl)prop-2-en-1 -one
'H NMR (DMSO-dô, 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), 3.5015 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); (ESIMS): (+ve mode) 455.10 (M+H)+.(100%), HPLC: 95.98%.
Example: 22
Compound 22: l-(5-(4-amino-3-(benzo[d]oxazol-5-yl)-lH-pyrazolo[3,4-d]pyrimidin -1yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one
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, Λ = 2.8 Hz, J2 =
16.8 Hz), 5.68-5.65 (dd, 1H, Jj = 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)-lH-pyrazolo[3,4-d]pyrimidin-lyl)hexahydrocyclopenta[c]pyirol-2( 1 H)-yl)prop-2-en-1 -one
’H NMR: (DMSO-d6, 400 MHz): δ 8.24-8.27 (m, 3H), 8.02-8.01 (d, 1H, 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)-l-(5-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d] pyrimidin-1yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)-4-(dimethylamino)but-2-en-1 -one
Ή NMR: (D2O, 400 MHz): δ 8.38 (s, 1H), 7.65 (d, 2H, J = 6.8 Hz), 7.62-7.47 (m, 2H), 7.467.45 (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, Λ = 8.4 Hz, J2 = 13.2 Hz), 3.63 (dd, 1H, f = 4.4 Hz, J2 = 11.2 Hz), 3.50 (dd, 1H, Λ =
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
’H NMR (DMSO-dâ, 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, Jj = 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: l-(5-(4-amino-3-(4-(5-(pyridin-2-yl)-l,3,4-oxadiazol-2-yl)phenyl)-lHpyrazolo[3,4-d]pyrimidin-1 -yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one
’H NMR: (DMSO-dé, 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, Ji = 2.4 Hz, J2=16.8 Hz), 5.65-5.68 (dd, 1H, J, = 2.4 Hz, J2 = 10.4 Hz), 5.47-5.44 (m, 1H), 3.813.77 (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), 2.422.31 (m, 2H), 2.09-2.07 (m, 2H); ESI-MS: (+ve mode) 520.20 (M+H)+ (85 %); UPLC: 95.96 %.
Example:27
Compound 27: l-(5-(4-amino-6-bromo-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d] pyrimidin-7yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one
’H NMR (DMSO-dâ, 400 MHz) δ ppm: 8.13 (s, 1H),7.46-7.41 (m, 4H), 7.21-7.19 (m, 1H), 7.157.13 (m, 2H), 7.11-7.09 (m, 2H), 6.65-6.54 (m, 1H), 6.16 (dd, 1H, J) = 2.4 Hz, J2 = 16.8 Hz),
5.68 (dd, 1H, Λ = 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)-lH-pyrazolo[3,4-d]pyrimidin-l-
yl)octahydrocyclopenta[c]pyrrole-2-carbonyl)-3-cyclopropylacrylonitrile
NMR: (CDCl3-di, 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-(l-(2-acryloyloctahydrocyclopenta[c]pynOl-5-yl)-4-amino-lH-pyrazolo[3,4d]pyrimidm-3-yl)-2-methoxy-N-(4-methylpyridin-2-yl)benzamide
HN
ΧΗ 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, Λ = 2.4 Hz, J2 = 16.4 Hz), 5.67 (dd, 1H, Λ = 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-(l-(2-acryloyloctahydrocyclopenta[c]pyirol-5-yl)-4-amino-lH-pyrazolo[3,4d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)benzamide
Ή NMR: (CDC13, 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, Λ = 10.0 Hz, J2 = 16.8 Hz), 6.40 (dd, 1H, Jx = 2.4 Hz, J2 = 16.8 Hz), 5.70 (dd, 1H, Λ = 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 10 mode) 509.1 (M+H)+ (100 %); HPLC: 96.67 %.
Example:31
Compound
31:
l-(5-(4-amino-5-(4-phenoxyphenyl)-7H-pyirolo[2,3-d]pyrimidin-7yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one
’H NMR (DMSO-dô, 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, Ji = 2.8 Hz, J2 = 10.4 Hz ), 5,68 (dd, 1H,
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): (+vemode) 466.05 (M+H)+.(100%); UPLC: 97.65%.
Example:32
Compound 32 : N-(4-(l -(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1Hpyrazolo[3,4-d]pyrimidin-3-yl)phenyl)picolinamide
’HNMR: (DMSO-dô, 400 MHz): Ô10.82 (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)octahydrocyclo penta[c]pyrrol-5-yl)-7H-purin-8(9H)-one
Ή 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-(l-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-lH-pyrazolo[3,4d]pyrimidin-3-yl)-N-(benzo[d]thiazol-2-yl)benzamide
’H NMR: (DMSO-dâ, 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]pynOl-5-yl)-4-amino-1 H-
pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)pyrazine-2-carboxamide
’H 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, 7/ = 2.8 Hz, J2 = 16.8 Hz), 5.68-5.43 (dd, 1H, J! = 2.4 Hz, J2 =10.4 Hz), 5.435.40 (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), 3.103.08 (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: l-(5-(4-amino-3-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)-lH-pyrazolo [3,4djpyrimidin-1 -yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one
*H NMR: (DMSO-d6, 400 MHz): δ 8.19 (s, 1H), 7.21-7.19 (m, 1H), 7.17-7.14 (m, 1H), 7.077.05 (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), 3.813.79 (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), 2.972.93 (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-(l-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-lH-pyrazolo[3,4d]pyrimidin-3 -yl)-N - (pyrazin-2-yl)b enzamide
'HNMR: (DMSO-de, 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-(l-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-lHpyrazolo[3,4-d]pyrimidin-3-yl)phenyl)benzamide
’H NMR: (DMSO-rfe, 400 MHz): δ 10.44 (s, 1H), 8.24 (s, 1H), 7.98 (d, 4H, 8.0 Hz), 7.65 (d,
2H, J= 8.4 Hz ), 7.60-7.53 (m, 3H), 6.62 (dd, 1H, Ji = 16.8 Hz, J2 = 10.2 Hz), 6.14 (dd, 1H, Λ =
16.8 Hz, J2 = 2.4 Hz), 5.67 (dd, 1H, Ji = 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: l-(5-(4-amino-3-(4-(5-(pyiidin-2-yl)-l,3,4-thiadiazol-2-yl)phenyl)-lH-pyrazolo [3,4-d]pyrimidin-1 -yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one
NMR: (DMSO-dô, 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, 7/=2.4 Hz, 7)=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-(l-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-lH-pyrazolo[3,4d]pyrimidin-3-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide
*H NMR: (CDC13, 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, 7 = 8.4 Hz), 7.89 (d, 2H, J= 8.4 Hz), 7.33 (dd, 1H, Jv = 0.8 Hz, J2 = 5.2 Hz),
6.48 (dd, 1H, 7j = 10.0 Hz, J2 = 16.8 Hz), 6.40 (dd, 1H, 7j = 2.4 Hz, J2 = 16.8 Hz), 5.69 (dd, 1H,
Λ = 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: (l-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-lH-pyrazolo[3,4-d] pyrimidin-115 yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one
Tl NMR: (CDCI3, 400 MHz): δ 8.47 (d, 2H, 7 = 8.4 Hz), 8.32 (s, 2H), 7.75 (d, 2H, J= 8.4 Hz),
7.53 (d, 1H, 7= 6.4 Hz), 6.52-6.45 (m, 2H), 6.42 (dd, 1H, Λ = 2.4 Hz, J2 = 16.8 Hz), 5.72 (dd,
1Η, Λ = 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-(l-(2-acryloyloctahydrocyclopenta[c]pynOl-5-yl)-4-amino-lH-pyrazolo[3,4d]pyrimidm-3-yl)-N-(4-methylpyridin-2-yl)nicotmamide
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: l-(5-(4-amino-3-(4-(pyridin-2-yloxy)phenyl)-lH-pyrazolo[3,4-d] pyrimidin-1yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one
’H NMR: (DMSO-dô, 400 MHz): δ 8.24 (s, 1H), 8.20-8.18 (dd, 1H, Λ = 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, Ji = 4.0Hz, J2 =8.0
Hz), 5.68-5.65 (dd, 1H, Λ = 2.4 Hz, J2 = 10 Hz), 5.44-5.40 (m, 1H), 3.80-3.76 (m, 1H), 3.653.50 (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); ESIMS: (+ve mode) 468.00 (M+H)+ (100 %); UPLC: 95.99 %.
Example: 44
Compound 44: (E)-4-(4-amino-l-(2-(4-(dimethylamino)but-2-enoyl) octahydrocyclo penta [c]pyrrol-5-yl)-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(pyridin-2-yl) benzamide
’H NMR (DMSO-dô, 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, 4.4 Hz); (ESI-MS):
(+vemode) 552.40 (M+H)+.(100%); UPLC: 98.02%.
Example: 45
Compound 45 : (E)-4-(4-amino-1 -(2-(4-(dimethylamino)but-2-enoyl)octahydrocyclo penta[c]pyrrol-5-yl)-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl) benzamide
’H 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, Λ = 8.4 Hz, J2 = 13.2 Hz), 3.67 (dd, 1H, Jx = 4.8 Hz, J2 = 11.2 Hz), 3.55(dd, 1H, J, = 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: l-(5-(4-amino-3-(4-(5-(pyrazin-2-yl)-l,3,4-thiadiazol-2-yl)phenyl)- 1Hpyrazolo[3,4-d]pyrimidin-1 -yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one
’H NMR: (DMSO-d6, 400 MHz): δ 9.53 (s, 1H), 8.87-8.85 (m, 2H), 8.27-8.25 (m, 3H), 7.907.88 (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)-l-(5-(4-amino-3-(4-(pyridin-2-yloxy)phenyl)-lH-pyrazolo[3,4-d] pyrimidin1 -yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)-4-(dimethylamino)but-2-en-1 -one
’H 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), 2.082.04 (m, 2H); ESI-MS: (+ve mode) 525.45 (M+H)+ (100 %); HPLC: 96.91 %.
Example:48
Compound 48: (E)-l-(5-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d] pyrimidin-1yl)hexahydrocyclopenta[c]pynOl-2( 1 H)-yl)-4-(dimethylamino)but-2-en-1 -one
’H NMR: (CD3OD, 400 MHz): δ 8.43 (s, 1H), 8.09 (d, 2H, J= 6.4 Hz), 7.45-7.41 (m, 2H), 7.227.16 (m, 3H), 7.13-7.11 (m, 2H), 6.87 (d, 1H, J = 15.2 Hz), 6.77 (dd, 1H, Λ = 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), 3.673.64 (m ,4H), 3.54 (dd, 1H, Λ = 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-l-(2-(4-(dimethylamino)but-2-enoyl) octahydrocyclo penta [c ] pyrrol-5-yl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(pyrazin-2-yl)benzamide
’H 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), 5.485.45 (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), 3.043.02 (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-l-(2-((E)-4-(dimethylamino)but-2-enoyl)octa hydrocycIopenta[c]pyrroI-5-yI)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methyl pyridin-2-yI) benzimidate
’H NMR: (CD3OD, 400 MHz): δ 8.73 (d, 1H, J= 6.4 Hz), 8.47 (s, 1H), 8.31 (d, 2H, 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, Λ = 6.8 Hz, Λ = 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, Λ = 8.0 Hz, J2 = 12.8 Hz), 3.68 (dd, 1H, Λ = 4.8 Hz, J2 = 11.2 Hz), 3.53 (dd, 1H, Λ = 4.8 Hz, Λ = 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-l-(2-(4-(dimethylamino)but-2-enoyl)octahydrocyclo penta [c] pyrrol-5-yl)-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-(trifluoromethyl) pyridine-2-yl)benzamide
’H 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, J{ = 1.2 Hz, Λ = 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, Λ = 8.0 Hz, J2 = 12.8 Hz), 3.69 (dd, 1H, Λ = 4.4 Hz, J2 = 11.2 Hz), 3.53 (dd, 1H, Λ = 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: l-(5-(4-amino-3-(4-(pyridin-3-yloxy)phenyl)-lH-pyrazolo[3,4-d] pyrimidin-1yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one
'il 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)-l-(5-(4-amino-3-(4-(pyridin-3-yloxy)phenyl)-lH-pyrazolo[3,4-d) pyrimidin1 -yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)-4-(dimethylamino)but-2-en-1 -one
*H NMR: (DMSO-dô, 400 MHz): δ 8.47-8.48 (m, 1H), 8.41-8.39 (m, 1H), 8.23 (s, 1H), 7.707.67 (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), 6.426.38 (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-(l-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-lH-pyrazolo[3,4d]pyrimidin-3-yl)-N-methyl-N-(4-methylpyridin-2-yl)benzamide
’H NMR: (DMSO-dô, 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-l-(2-(4-(dimethylamino)but-2-enoyl) octahydrocyclo penta [c] pyrrol-5-yl)-lH-pyrazolo[3,4-d]pyriniidm-3-yl)-N-methyl-N-(4-methyl pyridin-2-yl)benzamide
’H NMR: (DMSO-dé, 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)-l-(5-(4-amino-3-(4-(5-(pyrazin-2-yl)-l,3,4-thiadiazol-2-yl) phenyl)-lHpyrazolo[3,4-d]pyrimidin-1 -yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)-4-(dimethylamino)but-
2-en-l-one
’H NMR: (DMSO-d6, 400 MHz): δ 9.54 (S, 1H), 8.88-8.86 (m, 2H), 8.27-8.25 (m, 3H), 7.907.88 (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)-l-(5-(4-amino-3-(4-(5-(pyridin-2-yl)-l,3,4-oxadiazol-2-yl)phenyl)-lHpyrazolo[3,4-d]pyrimidin-1 -yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)-4-(dimethylamino)but-
2-en-l-one
NMR: (DMSO-dô, 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 p-V _4 ,.Ç X HH, \= = '’ H ''•s--/ K ····„--« À'z O i'. 1 - (5-(4-amino-3-(4-pherioxyp henyl )-1Hpyrazolo[3,4-djpyrimidin-l-yl)-5,6dihydrocyciopenta[c]pyrrol-2(lH,3H,4H)-yl)prop2-en-l-one
59 P'Vj· HH, V .1. ·' V’A > '-n' A-. Q‘ 7, 2-acryloyl-5-(4-amino-3-(4-phe‘noxyphenyl)-lHpyrazolo[3,4-d Jpyrimidin-1 -yl )-2,3dihydrocydopenta[c]pyrrole-4,6( 1 H,5H)-dione
60 .-4 ,7 HHa X M. V·* ( ’’ ST' > fi Λ·o” ΐ. 2-acrylûyl-5-(4-amirio-3-(4-phenaxyphenyl)-lHpyrazolo[3,4-d]pyrimidin-l-yl)-5,6dihydrocydopenta[c]pyrrole-l,3(2H,4H)-dione
61 P A / l-(5-(4-amino-3-(4-phenoxyphenyl)-lH-
pv razolo[3,4-d JpyTiniidin-l -
NHj X-.-J yl)hexahydrocyclopenta[b]pyrrol-l(2H)-yl)prop-2-
H C. -Γ en- l-one
62 l-(4-(4-amino-3-(4-phenoxyphenyl)-lH-
rS pyrazolo[3,4-d]pyritnidin-l-yl)-2,3,5,6-
tjHj tetrahydrocyclopenta[b]pyrrol-l(4H)-yl)prop-2-en-
i:V'··*· r-p -rs 1-one
63 PV '·' 1-(6-(4-amino-3-(4-phenoxyphenyi)-l H-
fS pyrazolo[3,4-d]pyrimidin-l-yl)hexahydro-lH-
khj y= 1.·-^·^-y, νΝΛ«’ ί y-% Y-À-. ii N· a cyclopenta[c]pyridin-2(3H)-yl)prap-2-en-l-one
64 Ô ο -*·χ y 1-(5-(4-amino-3-(4-phenoxyphenyl)-'l H-
A pyrazolo[3,4-d]pyrimidm-l-yl)-4,5,6,7-tetrahydro-
NH, \==·’ -TY ( '. --O V N. O lH-isoindo!-2(3H)-yl)prop-2-en-l-one
65 ί'Κ bH Χ=--·' r, • N V·' <3 1 - (6-(4-amino-3-(4-phenoxy p henyl)-1Hpyrazolo[3,4-d]pyrimidm-1 -yl)-3az.abicyclo[3.2.0]heptan-3-yl)prop-2-en-1 -one
66 Γ=Γ\ 0 ~\J' „0 t'T> V·» ό r · \.h*. XV. η ·< O 1 - (3-(4-amino-3-(4-phenoxy p henyl)- '1Hpyrazolo[3,4-d]pyrimidin-l-yl)-6azabicyclo[3.2.0]heptan-6-yl)prop-2-en-l-one
67 o-4 _·ί ,rA w, ν’ Ÿ> HH-^° N-(5-(4-amino-3-(4-p henoxypheny 1) -1Hpyrazolo[3,4-d]pyrjmidin-l-yl)octahydropentalen2-yl)acrylamide
68 Λ~\ o Mb \--·· ΆΛ ‘‘K h a 1 -(5-(4-amino-3-(4-phenoxyp henyl)-1Hpyrazo lo[3,4-d]py rimidin-1 -y 1)-3,4,6,7-tetrahydrolH-cyclopenta(cJpyridin-2(5H)-yi)prop-2-en-l-one
69 a-\_/ Mb v=/ _ .:··. ./ *· rx -yr-κ· A. 0 l-(5-(4-amino-3-(4-phenoxyphenyl)-lH- pyrazolo[3,4-d]pyrimidin-l-yl)hexahydro-'lH- isoindol-2(3H)-yl)prop-2-en-Î-one
70 r’X p-\J' NHs 'y-·' -h -y 0 I. M 1 -(4-(4-amino-3-(4-phenoxyphenyl)-l H- pvr azo I o[ 3,4-d ] pyrimidin-1 yl)hexahydrocyclopenta(c]pyrrol-2( 1 H)-yl)prop-2en-l-one
71 .''X o-y j i '% W, \x-·' Vti 'N -M' ΓΓ> /° l-(4-(4-amino-3-(4-phenoxyphenyl)-lHpyrazolo[3,4-d]pyrimidi.n-lyl)hexahydrocvdopenta[b]pyrral-l(2H)-yl)prop-2en-l-one
72 o P‘V ,.„,0 •·η·~ν S----A r? N / </ \ ... . l-(5-(4-amino-3-(4-phenoxyphenyl)-lHpvr azolo[3,4~d]pyrimidin-'l-yl}-2,3,5,6tetrahydrocyclopenta[b]pyrrol-l(4H}-yl)prop-2-en1-one
73 C-\\ / l v--» o ,Γ> L 1 Sr n CO1-/- 1- (4-(4-amino-3-(4-phenoxyphenyl)-lH- pyrazolo[3,4-d]pyrimidin-1 -yl)-5,6dihydrocydopenta[c]pyrrol-2(lH,3H,4H)-yI)prop- 2- en-l-one
74 p-y./ rS blJ, ^--1 l. ] St-n a t l-(6-(4-amino-3-(4-phenoxyphenyI)-lHpyrazcdo[3,4-d]pyrimidin-l-yl)octahydro-lHcydopenta[b]pyridin-‘l -yl)prop-2-en-l -one
75 p-y./ i. ,> y nh2 \==>’* H’ N b’O cA-** 1 - (5-(4-amino-3-(4-phenoxypheny 1)-1 Hpyrazolo[3,4-d]pyrimidin-l-yl)-2,3,4,5,6,7hexahydro-lH-cyclopenta[b]pyridin-l-yl)piOp-2en-l-one
76 p-O ό hUj y- Γ Γ>^.....-.,. Ό. a <-U l-(7-(4-amino-3-(4-phenoxyphenyl)-lHpyTazolo[3>4-d]pj'TÎmidin-l-yl)-2,3,4,5,6,7hexahydro-1 H-cycl openta [b] pyridin-1 -y l) prop-2en-l-one
77 ? 'S.s HHj \r='' Ό ':H ·”·Ν b... <ï 0 l-(6-(4-amino-3-(4-phenoxyphenyl)-!H- pyrazolo[3,4-d]pyrimidin-l-yl)-3,4,6,7-tetrahydrolH-cydapenta[c]pyridÎn-2(5H)-yI)prop-2-en-l-ane
78 •'Ά ,fÀ NH; y--·' ΓιΛ V -n : /--γ^'Ν-^Οι CO l-(7-(4-amino-3-(4-phenoxyphenyl)-lHpyrazolo[3,4-d]pyrîmidin-1 -y 1)-3,4,6,7-tetrahydrolH-cydopenta[c]pyridin-2(5H)-yl)prop-2-en-l-one
79 ,r==X 0-¼ _ J A ’ hh3 LxO J-. C ,1 Ί ΐ Toy V-n i ZvS 1 - (7-(4-amino-3-(4-phenoxypheny 1)-1Hpyrazolo[3,4-d]pyrïmidin-l-yl)-2,3,4,5,6,7hexahvdro-1 H-cyclopenta[b]pyridin- l-yljprop-2en-l-one
80 κ.=. ,rÇs hh, ''y-h ^'>-4 k k* -h- -h C ; > ’-N >-. C ’), 1- (5-(4-amino-3-(benzo[d]thiazol-6-yl)-lHpyrazolo[3,4-d]pyrimidin-'l-yl)-5,6dihydrocydopentaJc]pyrrol-2(lH,3H,4H)-yl)prop- 2- en-l-one
81 N.-., Ml, V il > --n'-n 10 F 2-acryloyl-5-(4-aminci-3-(benzo[d]thiazol-6-yl)-lHpyrazolo[3,4-d]pyrîmidin-l-yl)-2,3dihydroqT.'dopenta[c]pyrroIe-4/6(î H,5H)-dione
82 N-, V* h L > U. c^-h „Λ-τ, c V. 2-acr}'loyI-5-(4-amino-3-(benzo[d]ihiazoI-6-yl)-'lHpyrazolo[3,4-d ]pv rimidin-1 -yl)-5,6dihvdrocydopenta[c]pyrrcile-l,3(2H,4H)-dione
83 h-. rV hhj L-1' JL.' 'Q-l l-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-lHpyrazolo[3,4-d]pyrimidin-lyl)hexahydrocyclopenta[b]pyrrol-l(2H)-yl)prop-2en-l-one
84 Nx-, rv W= VA4 Γ ΊΝ y-h rP l-n Fl l-(4-(4-amino-3-(benzo[d]thiazol-6-yl)-lHpyrazolo[3,4-d]pyrimidin-'l-yl)-2,3,5,6tetrahydrocvclopenta[b]pyrral-'l (4H )-yl )prop-2-en1-one
85 h =. Γ$·έ S-- & h v-~a π V Q 1 -(6-(4-ammo-3-(benzo[d]thiazol-6-yl)-l H- pyrazolo[3,4-d]pyTÎmidin-l-yl)hexahydro-lHcydapenta[c]pyridin-2(3H)-yl)prop-2-en-l-one
86 H=-, rV3 y- iM t, i j-. vv l-(5-(4-amino-3-(benzo[d]th.iazol-6-yl)-lHpyrazolo[3,4-d]pyrimidiri-l-yl)-4,5.,6,7-tetrahydrt>IH-isoindoI-2(3H)-yl)prop-2-en-l-one
87 Æ Ntt y- Ar·4··^ y. 0 1 - (6-(4-amino-3-(benzo [d] thiazol-6-yl)-1Hpyrazolo[3,4-d]pyrimidin-i-yl}-3azabicyclo[3.2.0]heptan-3-yl)prop-2-en-l-one
88 H-, / --v* NH; V·'' N- N /-i VN.. £ ~ l-(3-(4-amino-3-(benzo[d]thiazol-6-yl)-'lHpyrazoIo[3,4-d]pyrimidîn-l-yl)-6az-abicyclo[3.2.0]heptan-6-yl)prop-2-en-l-one
89 Νη rV y? Κ'Υ[Λ ïA 2> HN·^·0 N-(5-(4-amino-3-(benzo [ d ]thiazol-6-yl)-l Hpyrazolo[3z4-d]pyrimidîn-l-yl)octahydropentater.2-yl)acrylamide
90 N:. / ί y3 b.H3 '•A <ΧΊ. ·' · v· G l-(5-(4-amino-3-(benzo[d]tliiazol-6-yl)-lHpyrazolo[3,4-d]pyrimidin-'l-yl)-3,4,6,7-tetrahydro1 H-cydopenta(c]pyTÎdin-2(5H)-y l)prop-2-en-1 -one
91 A /AA Hfe A J' •Ά Cb V N h*‘ b. Ô l-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-lHpy razo lo[3,4-d Jpyrimid in-1 -yl)hexahydro-1Hisoindo!-2(3H)-yl)prop-2-en-l-one
92 A, rO NH; V* NYÀ CO C l-(4-(4-amino-3-(benzo[d]thiazol-6-yl)-] Hpyrazolo[3,4-d]pyrirnidin-lyl)hexahydrocydopenta[c]pyrrol-2(IH)-yi)prop-2en-l-one
93 Ml·· v ryA V <x> /=0 'Λ 1 - (4-(4-amino-3-(benzo [d] thiazol-6-yl )-l Hpy razolo[3,4-d]pyrimidin-l yl)hexahydrocydopenta[b]pyrrol-l(2H)-yl)prop-2en-l-one
94 k== hk3 Y ΑΎ Ù c 1 - (5-(4-amino-3-(benzo [d] thiazol-6-yl )-l Hpyrazolo[3,4-d]pyrimidin-l-yl)-2,3,5,6tetrahydrocydopenta [b]pyrrol-l (4H)-yi)pr op-2-en- 1-one
95 N-., ,·Ύ Η.Η2 V-·' ”.Ί5 'N·· 'N 1 -(4-(4-amino-3-(benzo[d]thiazol-6-yl)-l H- pyrazolo[3,4-d]pyrnnidin-l-yl)-5,6- dihydrocy'clopenta[cJpyrrol-2(lH,3H,4H)-yl)prop2-en-l-one
96 .· 1 ,-=\ <J ; ?r- Ι,Ι.;, \ J' VA Λ| ç Y υ-Ά v...·· 1 - (6-(4-amino-3-(benzo [d ] thi azol-6-yl)-l Hpyrazolo[3,4-d]pyrimidin-l -y])octahydro-l Hcy,,c!openta[b]pyTidin-l-yl)prop-2-en-l-one
97 K=- V-‘ M ‘‘V’·* i-. '-V l-(5-(4-amino-3-(benzo[d]thiazoI-6-yl)-lHpyrazolo[3,4-d]pyrimidin-l-y] )-2,3,4,5,6,7hexahydro-1 H-cyclopenta[b]pvTÎdin-1 -yl)prop-2en-l-one
98 K=. .. , rt-ys y V ΤΆ··*·· -N--r > - OO 1 -(7-(4-ammo-3-(benzo[d]thiazol-6-yl)-l HpyTazolo[3,4-d]pjTimidin-l-yl)-2,3,4,5,6,7hexahydro-lH-cyclopenta[b]pyridin-l-yi)prop-2en-l-one
99 H-., ,r--\ JS m. V'r m-h J·-., A k.»i p l-(6-(4-amino-3-(benzo[d]thiazol-6-yl)-lHpyrazolo[3,4-d]pyrimidin-l-y])-3,4,6,7-tetrahydrc>lH-cydopenta[c]pyridin-2(5H)-yt)prap-2-en-l-one
100 KMj A ’Ύ ., <ΧΓΏ ]-(7-(4-amino-3-(benzo[d]thiazol-6-yl)-iHpyrazolo[3,4-d]pyrimidin-l-yl)-3,4,6,7-tetrahydrolH-cyclopenta[c]pyridin-2(5H)-yi)prop-2-en-l-one
101 /A-·* «4, V' N'/X w l-(7-(4-amino-3-(benzo[d]thiazol-6-yl)-'lHpyrazolo[3,4-d]pyrimidin-l-yl)-2,3,4,5,6,7hexahydro-1 H-cyclopenta[b]pyridin-! -vl)prop-2en-l-one
102 fi »„,0 V-N n -N R'î 1 -(5-(4-amïno-3-(benzo[b] thiophen-5-yl)-1Hpyrazolo[3,4-d Jpyrimidin-1 -vl)-5,6dihydrocyclopenta[c]pyrrol-2(lH,3H,4H)-yl)prop2-en-l-one
103 /S C-*. ή’ NH; %=-' V’ff Y-N, T Y'S 0 1 - (6-(4- amino-3-(benzo [b] thiophen-5-yl)-l Hpyrazolo[3,4-d]pyrimidin-l-yl)hexahydro-lHcycIopenta|c]pyridin-2(3H)-yl}prop-2-en-l-one
104 n ,îA NH, \7 .1. Z i: > V'« X^N Û 1 - (6-(4- amino-3-(benzo [b] thiophen-5-yl )-1Hpyrazolo[3,4-d]pyTimidin-l-yl)-3azabicyclo[3.2.0]heptan-3-yI)prop-2-en-l-one
105 Cf bH2 \=~' «fA νΛ-Η' k. u if . i\‘-(5-(4-ammo-3-(benzo[b]thÎophen-5-yl)-lHpyrazolo[3z4-d]pyrimidin-'l-yl)octahydropentalen2-yl)acrylamide
106 7s H W-, y.--·· Ν' ''χ—-h /-t·''·-·' c 1 - (5-(4-amino-3-(benzo [b] thiophen-5-y 1)- 1Hpyrazolo[3,4-d]pyrîmidin-I-yl)-3z4,D,7-tetrahydrolH-cydopenta[cjpyridin-2(5H)-yÎ)prop-2-en-l-one
107 A Mb /4 ΰ ο'Λ7'. 1 - (5-(4-amino-3-(2,3-di hy drobenzo[b ] thiophen-5yl)-lH-pyrazoIo[3,4-d]pyrimidin-l-yl)-5,6dihydrocydopenta[c]pyrrol-2(lHz3H,4H)-yl)prop2-en-I-one
108 O MH. V-‘ t ' F N:'r« ;N' N L / S---\ 'Ά-Λ 0 1 - (6-(4-amino-3-(2,3-dïhydrobenzo[b]thiophen-5- yl)-lH-pyrazoIo[3,4-d]pjTÎmidin-l-yl)hexahydrolH-cydopenta[cjpyridin-2(3H)-yI)prop-2-en-l-one
109 z-s n NH- \----‘ Vv d 1 - (6-(4-amino-3-(2,3-dihyd roberszofb ] thiophen-5yl)-lH-pyrazoIo[3,4-d]pyrimidin-l-yl)-3azab icv do [3.2.0]heptan-3-y l }prop-2-en-1 -one
110 c? r‘\ < Nt-a Y®· N |Î k u <_/ N-(5-{4-amino-3-(2,3-dihydrobenzo[b]thiophen-5yl}-lH-pyrazoio[3,4-d]pyriinidin-lyl)octahydropentaien-2-yl)acrylamide
111 \-< NH. \=J ζϊ> CCy Q 1 - (5-(4-amino-3-(2, 3-d i hyd robenzo [b ] thi op hen-5yl )-1 H-pyrazoio[3,4-d]pyrimidm-1 -vl)-3,4,6,7tetrahydro-lH-cydopenta[c]pyridin-2(5H}yl)prop-2-en-l -one
112 rU ° nh, y J F rS '•N'· < σ v, K-(6-( 1 -(2-acryloyI-l,2,3,4,5,6hexahydrocydopenta[c]pyrroî-5-yl)-4-amino-1Hpyrazolo[3,4-d]pyrimidin-3-yl)benzo[dJthiazol-2vl)acetamide
113 Μ H Ύ Ν·=< V, rS-À ° rw2 V-1’ -M. 'M'’ -fl ’X.-N., ÿ* v. a N’-(6-{ 1 -(2-acryloy Iactahydro-1 Hcydopenta[c]pyridin-6-yl)-4-am.ino-lHpyrazoln[3,4-d]pyTimidin-3-yl)benzo[d]thiazoI-2vljacetamide
114 r V /--M c m-j y/ Vvy h χ l-h-f* r<-(5-(3-{2-acetamidobenzo[d]thiazol-6-yl)-4amino-lH-pyrazola[3,4-d]pyriinidin-lyl)octahydropentalen-2-yi)acrylamide
115 rîîrx‘ï 0 J -J-.. Ü Z' H»1 'f' .L. A N4- ΐ « sAv <A 1 1 --N «V ~·>. Ü ' - λ y (E)-l -(5-(4-amino-3-(4-phenoxyphenyl)-1Hpyrazolo[3,4-d]pyrimidin-l-yl)-5,6dîhydrocydopenta[c]pyrrol-2(lH,3H,4H)-yl)-4(dimethylamino)but-2-en-1-one
116 kWj V·.·' to Ç_, -, & > - (E)-l-(6-(4-amino-3-(4-phenoxyphenyl)-lHpyrazolo[3,4-d]pyrimidin-1 -yl)hexahydro-1Hcyciopen ta[c]p yridin-2(3H )-y 1 )-4- (dimethy lamino)but-2-en-1 -one
117 M4. À=J v·b-, O (E)-'I -(6-(4-amino-3-(4-phenoxvpheny l)-’l Hpyrazolo[3,4-d]pyrimidin-l-yl)-3azabicvclo[3-2.0]heptan-3-yl}-4(dimethylamino)buÈ-2-en-l-one
118 f-~\ oA # rS ’ hh2 \==/ Ά-4 •br'· n' to. ,^N. & ? (E)-'l-(5-(4-amino-3-(4-phenoxyphenyl)-lHpyrazolo[3,4-d]pyrimidin-l-yl)-3,4?6z7-tetrahydrolH-cyclopenta[c]pyridin-2(5H)-yl)-4(dimethylamino)but-2-en-l -one
119 cY IfcN '· N'tyfS ‘V-y. J ‘. UN /Λ_ n - (E)-l-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-lHpyrazolo[3,4-d]pyrimidin-l- y])hexahydrocyclopenta[c]pyrrol-2(lH)-yl)^l(dimethylaminolbut-2-en-1 -one
120 F* · A U .ii hg r hhr -=,. /'-N h >-> ¥> '-h /K ,h- (E)-l-(5-(4-arnino-3-(benzo[d]thiazol-6-yl)-lH- pyrazoIo[3,4-d]pyrimidin-l-yl)-5,6- dihydrocydopenta[c]pyrrol-2(lHi3H,4H)-yl)-4- (dimethylamino)but-2-en-1-one
121 h Λ -< S 1·-- V Η,Ν V V'\ <A : · '--.χΚ ·γ'·· ··ΐ^···τ, ·' i 1 (E)-l-(6-(4-amÎno-3-(benzo[d]thiazoI-6-yl)-lHpjTazolo[3,4-d]pyrimidin-l-yl)hexahydro-lHcydopenta[c]pyridin-2(3H)-yl)-4- (d i me thy 1 amino)bu t-2-en-1 -one
122 _/A fvs NHj VI VA 4>'i O 1 (E)-1 -(6-(4-amino-3-(benzo [d ] thiazol-6-y 1)-1 Hpyrazolo[3,4-d]pyrim.idin-l-yl)-3azabicydo[3.2.0]heptan-3-yl)-4(dimethylamino)but-2-en-l -one
123 h f'M M*a h ΑΧ d-y c (E)-l-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-lHpyrazolo[3,4-d]pyrimidin-l-yl)-3,4,6,7-tetrahydrolH-cydopenta[c]pyridin-2(5H)-yl)-4(dimethylamino)but-2-en-l-one
124 1 V J > ' z-fc * >-· VS A /2 c Ί -(5-(4- amino-3-(4-benzoylphenyI)- 1Hpyrazolo[3,4-d]pyrimidin-lvl)hexahydrocydopenta[c]pyrrol-2( l H)-yl)prop-2en-l-one
125 .Ά HHj W VXN-« N ' Ν Α-_ b Οζ ’Λ 4-( 1-(2-acryloyloctahy drocyclopenta [c] pyrrol-5-y ï)- 4-amino-lH-pyrazolo[3,4-d]pyrimidin-3-yi)-Nphenylbenzamide
126 A rs Mfe H^r’4 ·:Κ··^·1ί S A 4-(l-(2-acryloylc)ctahydrocyciopenta[c]pyrrol-5-yi)- 4-amino-lH-pyrazolo[3,4-djpyrirnidin-3-yi)-Nme thy i-Ν' -pheny ibenzami d e
127 %-NH rV NH, \-V tS'À f- À 4-(l-(2-aoyloyloctahydrocyciopenta[c]pyrrol-5-yl)- 4-anüno-lH-pjTrazolo[3,4-d]pyrimidin-3-y!)-2- methyl-N'-phenylbenzamide
128 O 0· -’ '‘V-MH ,f '\--OCH, nh2 V AA / ':· XA *N λ-.-. o ·.·. 4-('l-(2-aciyloyloctahydrocycïopenta[c]pyrrol-5-yl)- 4-amino-l H-pyrazolo[3,4-d]pyrimidin-3-yl)-2methoxy-N-phenylbenzamide
129 Ο Α· «ΐ y--' Cà ; / Ν λ— Ο 4-(L-(2-acryloyloctahydn>cy'dopenta[c]pyrrol-5-yI)- 4-amino-lH-pyrazolo[3,4-d]p’;Timidin-3-yl)-.N/2dimethyl-N'-phenylbenzamide
130 “”Λ\ <ι · c V' ^Μ ,r \ fK-CCHi MJ. n^fSj “Ν' ”N -N 4- (l-(2-acry loyl octahydrocy dopen ta [c] pyrrol -5-y I) - 4- am ino-1 H-pyrazolo(3,4- d ] pyrimi d i n-3-y l)-2methoxy-I\’-methyl-N-phenylbenzamtde
131 f/ ( 7' N-, \s=·' λ J MΊΛ V'·*' A v’\ 4- (1 -(2-acryloyl octahydrocy dopenta [c] pyrrol -5-y 1) 4-amino-l H-pyrazolo[3,4-d ]pyrimidin-3-yI)-2methyl-N.'-(pyridin-2-yl)benzamide
132 c W w .fV-CCHj NH. VJ η^'Ά l-m 7-J. 4- ( l-(2-acryloyl octahvdrocvdopen ta [c] pyrrol-5-y I) - 4-amtno-l H-pyrazolo[3,4-d]pyrimidin-3-y!)-2rne thoxy-\’-(pyrîd in-2-y l)benzamide
133 Ry-fX A.μί y/ A •'•-k _A-n U '4 4-(1-(2-acryloyloctahv drocy clopenta [c]pyrroI-5-y E )- 4-amino-lH-pyTazolo[3,4-d]pyrimidin-3-yl)-2methyl-N'-(4-methylpyridin-2-yl)benzamide
134 cf3 ' %«· À- y y.· h A--\ L T.,-K f. ’ k C\ '*r/ 4-(l-(2-aCTyloyloctahydrocyclopenta[c]pyrrol-5-yl)4-amino-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-2me thv l-N'-(4-( tri fluoromethyl)py rid in-2yljbenzamide
135 r'x.CTFi, m J %-NH W, \=-‘ «y-y rir -h >... < ; 4- (1 -(2-acry loyloctahydrocv clopen ta [c] pyrrol-5-y!) 4-amino-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-2methoxy-N-(4-(trifluoromethyl)pyridin-2yljbenzamide
136 ‘X %-w ('X hh3 \==· •^c >. / I \A '•rf <F. 4- (7-(2-acry loyl octahydrocy ciopenta [c] pyrrol-5-y I) - 4-amino-6-chloro-7H-pyTrolo[2,3-d]pyrimidin-5- yl)-N-p heny lbenzam ide
137 A4. ''N »i ά y ··*--. C’ ’v. 4-(7-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)- 4-amino-6-fluoro-7H-pyrrolo[2,3-d]pyrimidin-5yl)-N-phenylbenzamide
138 ,ry νΓ r$ y yv ï‘V& y -n *N A. Q’z ΐ 4-(7-(2-aCTyloyloctahydrocyclopenta[c]pyrrol-5-yI)- 4-aminD-6-bromo-7H-pyrrolo[2,3-d]pyriniidin-5yl)-N-phenylbenzamide
139 0 o. V NK A hh2 V' ”^f-VCHF, y- h U 0¾ 4-(7-(2-acryIoyloctahydrocy’clopenta[c]pyrrol-5-yl)- 4-amino-6-(difluoromethyl)-7H-pyrrolo[2/3- d]pyrimidin-5-yl)-N-phenylbenzamide
140 i K y ., .u t ï V«b %î -·« k. f * v-\ y 0 % 4-(7-(2-acryloyloctahydrocy'clopenta[c]pyrrol-5-yI)- 4-amino-6-(trifluoromethyl)-7H-pyrrolo[X3- d]p}TÎmidin-5-yl)-N-phenyIbenzamide
141 rs c V rS r,-M t h * v-\ i_-N' F, 4- (7- (2-acry loyl octahydrocy ci open ta [ c] pyrrol -5-y I) - 4-amino-6-methyI-7H-pyrrolo[2,3-d]pyrimidin-5y])-N-phenyIbenzamide
142 %-HI» U, Xz=.·' .1 .'' tr> *N* * i.. U . X ’-N λ-_ 4-(7-(2-acryloyloctahydrocyc!openta[c]pyrrol-5-yl)- 4-amino-7H-pyrrolo[2,3-d}pyrinndin-5-yi)-Nphenylbenz amide
143 rv ÿ'V M-z X_-=- Xs A--11 À -v o W 4-(7-(2-acryrloyloctahydrocydopenta[c]pyrrol-5-yl)- 4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-bI- me thy l-N'-phenylbenzami d e
144 Ms.J %. NH fS Ntt \-zs· wA-À 1 i > S^-N /-w / i •-i/ F. 4- (7-(2- acryloyl octahy drocyciopen ta [c] pyrrol-5-y 1) - 4-ammo-7H-pyrro]o[2,3-d]pyrimidin-5-yl}-N- (pyridin-2-yl)benzamide
145 r.-N W ./ À ' NH, -••·ν··--ν· ι-/ Ο V. 4-(7-(2-aa‘yloyloctahydrocyclopenta[c]pyrrol-5-yl)4-amino-7H-pyrrolo[2,3-djpyrimîdin-5-yÎ}-Nme thy l-N-(py ridin-2-y l)benzamide
146 Ο °y4JH rS ΗΗ, Ύ=·' »*γΐ ''ν·χ·ν'' Ζ·Ί 0 X. ο \ 4- (7-(2-acry loyl octahydrocyclopenta [c] pyrrol-5-y I) 4-amino-7H-p)TTol o[2z3-d j pyrimid in-5-yI )-N-(4methyIpyridin-2-yl)benzamide
147 ,ι'Γ·^ν— Ν^-; ΟΧ-Ν, .À νη2 ν; πΛ Ά Λ--. < ! A 0 ΐ, 4-(7-(2-aŒyloyloctahvdrocyclopenta[c]pyrrol-5-yI)- 4-amino-7H-pyrrolo(2,3-d]pyrimidin-5-yl)-Nmethyi-\'-(4-methylpyridin-2-yl)benzamide
148 ff %.--CFa 1,1¼ V /-> A L / K Tl C A 4-(7-(2-acryloyloctahydrocycIoperita[c]pyrrol-5-yI)- 4-amino-7H-pyrrolo[2/3-d]pyrimidin-5-yl)-Nmethvl-N-(4-(trifluoromethyl)pyridin-2yl)benzamide
149 ,çV.Cf3 C^-H4 A MT, s?-> /'Ί \ *““N A 4-(7-(2-atTyloylociahydrocyclopenta[c]pyTrol-5-yl)4-amino-7H-pynOlo[2,3-d) pyrimid in-5-y! )-N-( 4(trilluoromethyl)pyridiri-2-yl)benzainide
150 o °V-NH rVγη N ô Q o 4-(7-(2-acryloyloctahydrocyciopenta[c]pyrrol-5-yl)- 4-amîno-7H-pynOlo(2/3-djpj<rimidin-5-yl)-2- methyl-N'-phenylbenzamide
151 α M S-Ν' ;Ç %-CCF., M-a V-·’' i'-i A 4-(7-(2-acrj''Ioyloctahydrocj'clopenta[c]pyrrol-5-yl)- 4-amina-7H-pyrrola[2,3-d]pyrirnidin-5-yI)-2- methoxy-N’-phenylberizamide
152 ΓΧ \-=· V\ /S- y1 Ό 'KJ h f- ’v-'X 4-(7-(2-acryloyloctahydrocydopenta[c]pyrrol-5-yl)- 4- amino-7H-pyrrol o[2,3-d ] pvrimid in-5-y ! )-N, 2dimethyl-X'-phenvlbenzamide
153 νΓ ,1; '^ΰΟ-3 κπ5 y·-· . / •''Ν L. / ’ λ -’h' 4- (7-(2-acrv loyl octahvdrocydopenta [c] pyrrol-5-y 1) - 4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-y!)-2- methoxy-N’-methyl-N-phenylbenzamide
154 rx GyW ήy Nrf'-Â A'-h' C. , ) *M 4- (7-(2-acryloyloctahvdrocy clopenta [c] pyrrol -5-y I) - 4-amino-7H-pyrrolo[2,3-d]pyrimidiri-5-yi)-2- methyl-N-(pyridin-2-yl)benzamide
155 O o ·’’ y « hh r'K-ccH, NH, V-·./ tM %-N f v-\ i ? *‘ N Λ 4- (7-(2-acryloyl octahydrocy dopenta [c] pyrrol-5-yl) 4-am ino-7 H-pyrrol o[2,3-d ] pyrimi d in-5-y 1 )-2methoxy-N-(pyridin-2-yl)benzamide
156 X--- °y\ (V w. y-· a Q C» v. 4- (7-(2-aCTy loyl octahydrocy dopenta [c] pyrrol-5-y 1) - 4-amino-7H-pyrrolo[2,3-d]pyriinidin-5-yl)-bI,2- dimethyl-I\'-(pyridin-2-yl)benzamide
157 ç Ά. n nh2 ..x·. .·! t S'· N -h' À, 4-(7-(2-acryloyloctahydrocycIopenta[c]pyrrol-5-yl)- 4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-y[)-2- me thoxy-N-methyl-NH pyTidin-2-yl)benzarnide
158 *î '“V-* AV A-W' ,rV- WL; W 1 J / ν^’Ά SA ή y-x, ‘-ν' 4-(7-(2-acryloyloctahydrocyclopenta[c]pyrroI-5-yI)- 4-amina-7H-pyrrolo[2,3-djpyrimidin-5-yl)-2- methyl-Î\-(4-metliylpyridin-2-yl)benzamide
159 \X fX-CCHa NH; »·'γΥ <;n--'{ Çs -N /-¾ 4-(7-(2- acryloyloctahydroc)rclopenta[c]pyrTol-5-yl)4-amino-7H-pyïTol o[2,3~d jpyrimid in-5-yl )-2methcixy-N'-(4-methylpyridin-2-yl)benzamide
160 .fX-CFi H ___,' v< A.üG vu K H J-. G ? *~N o ·,·, 4- (7-(2-acry loyloctahydrocy clopenta [c] pyrrol-5-y I) 4-amino-7H-pyrrolo[2/3-dJp\Timidin-5-y!)-N,2dimethyl-N--(4-(trifluoramethyl)pyridin-2yljbenzamide
161 rycP, i'V-œH, '4 y7 V * h. vx -H or ?, 4- (7-(2-acryloyl octahy drocy dopen ta [ c] pyrrol-5-yl) 4- am t no-7H-pv rrol o[2,3-d ] pyrim îdin-5-yi)-2methoxy-î\-methy]-N-{4-(ti’iHuoromethyl)pyridin2-yl)benzamide
162 n, fÇ nh2 y-' “5 · \ v»' C --N* 4- (7-(2-acry loyl octahydrocycloperi ta [c] pyrrol-5-yl) 4-amtno-7H-pyrrolo[2,3-d}pyrimidin-5-yI)-2niethyI-N-(4-(trifluDromethyl)pyridin-2yljbenzamide
163 ÇrCFi %-NH J'Vv-OCH, HH. \r=·'' Ή v cr ‘Â 4-(7-(2-aayloyloctahydrocycIopenta[c]pyrrol-5-yI)- 4-amino-7H-pyrrolo[2/3-d)pyrimidin-5-yt)-2methoxy-!\'-(4-(ti’ifluoromethyl)pyridir>-2yljbenzamide
164 .Q KH MH. \==/ ! * »· T 7% Ci υ /y 4- (3-(2-acryIoyloctahydrocy'dopenta[c]pyrrol-5-yI)- 5- aminoimidazo[ l,5-a]pyrazin-l -yl)-Nphenylbenzamide
165 vP (Λ tJHa >==' «F 4-(3-(2-acryloyloctahydriK:yck)penta[c]pyrrol-5-yi)- 8-aminoimidazo[ l,5-a]pyrazin-l -yl)-N-methyl-N’phenylbenzamide
166 rs. Nw‘ ’V-NH Λ WJ. “3> G ; > *”N Λ. 4- (3-(2-acryloyl octahydrocydopen ta [c] pyrrol-5-y I) - 8-aminoimidazo[l,5-a]pyraziri-l-yi)-N-(pyridîn-2yl)benzamide
167 O3 ο Γ ^-NH Λ HH, 'V-·1 N5Y> 'fe oF. 4-(3-(2-acryloyIoctahydrocj'dopenta[c]pyrrol-5-yI'j- 8-aminoimidazo[l,5-a]pjTazin-l-yl)-N-(4- (trifluoromethyl)pyridin-2-yl)benzarnide
168 c Ύ ym fY«Hj NHj V^’ η'Μ< -¾. .H-.ÿ- ’ y ΊΛ U’M c? ’v. 4- (3-(2-acryloyloctahydrocydopenta [c] pyrrol-5-yl) 8-aminoimidazo[l,5-a]p yrazin-1 -yi)-2-methoxy-b.'(4-(tri fluoromethy l)pyridin-2-y l)benza mi d e
169 Ο A NHj \=W ^n-'-n T 4- (9-(2-acry loyl octahy drocvdopenta [ c] pyrrol-5-y !)- 6-amino-S-oxo-8,9-dihydro-7H-purin-7-y[)-Nphenylbenzamide
170 /A \-·· V< Μ-, W A'-\c XV·*' ù \ f ’-N A 4-(9-(2-acry’loyloctahydrocydopenta[c]pyrrol-5-yI)- 6-amino-8-oxo-8,9-dihydro-7H-purin-7-yl)-Nmethyl-X'-phenylbenzamide
171 <7 Mh ,r\ Wj V-ΓγΆ •H' 'N Cl T’ \ -N' Λ-, 0 4- (9- (2-acryloyloctahydrocyclopenta [c] pyrrol-5-y !) - 6-amino-8-oxo-8,9-d.ihydro-7H-purin-7-yl)-N(pyridin-2-yl)benzamide
172 Αχ fin J •7 HH, KA-M 1: >·<. h'h, ta À 4- (9-(2-acry loyl octahy drocy clopenta [c] pyrrol-5-y 1) - 6-amino-8-oxo-8,9-dihydro-7H-purin-7-yl)-bI-(4methyIpyridin-2-yi)benzaTnide
173 %·ΝΗ /'S 'F=/ «M L >=û Vu .>-. t ; \-\ c··’’’:·. 4-(9-(2-acryloyloctahydrocycIopenta[c]p\Trol-5-yI)6-amtno-8-oxo-8,9-d i hy dro-7H-purm-7-y 1)-N-(4(trifIuoromethy])pyridin-2-yl)benzamide
174 r>a V .vÀ-aa-t, 1SH3 \=-! u <·^. .Λ i. 'Vh, S 7’> 4-(9-(2-acryloylnctahydrocyclopenta[c]pyrrol-5-yl)- 6-amino-8 -oxo-8,9-dihydro-7H-purin-7-yl)-2methoxy-N'-(4-(trifluoiOmethyl)pyridtn-2yl)benzamide
175 o y«y-HH ,fÀ, Nft 'y-·'' H ! W 1 i > •V-h y **-N* <Λ·. 4-fl-(2-acryloyl-l,2,3,4,5,6- hexahydrocyclopenta[c]pyrroI-5-yl)-4-amino-lH- pyrazolo[3,4-d]pyrimidin-3-yl)-Nphenylbenzamide
176 rv ^y-NH i ί’Λ nu, y-* <v L-^ 5 4-(1-( 1 -acryloyloctahydr ocyclopenta[b]pyrrol-5yl)-4-amino-lH-pyrazoIo[3,4-d]pyrimidm-3-yl)-Nphenylbenz-amide
177 ο %-ΜΗ ,f4 νη2 V·'' y-y V·-·*! »,, k-x ; > Cf-'T 4- (4-amino-1 -(2- (vinylsulfonyl)octahydrocyclapenta[c]pyrrol-5-yI)lH-pyrazolo[3,4-d]pyrimidin-3-yl)-Nrphenylbenzamide
178 /-¾ O X y-NH NH- f \ W A 4 0- A A (E)-4-(4-amino-l-(2-(4-(dimethylaniino)but-2enoyl)octahydr ocyclopen ta [ c] pyrro 1-5-y 1 )-1Hpyrazolo[3,4-d]pyrimidin-3-yl)-Nphenylbenzamide
179 C. C) . Λ'ΚΗ f i K---\ F '> y-i ''P ^'1 Λ V (E)-4-(4-amino-'l -(2-(4- (cyclopropyl(methyl)amino)but-2enoy 1 Joctahydr ocy cl open ta [ c] pyrro 1- 5-y 1 )-1H pyrazolo[3,4-d]pyrîmidin-3-yl)-Nphenylbenzamide
ISO ,Α hKs v=;' tT/ SXn L. / 2 '-À. -< ,CK α λ y v (Z)-4-(4-amino-1-(2-(2-cyano-3- c\'c!opropyiacr}4oy0octahydrocy'clopenta[c]p\Trol- 5-y 1 )- ! H-pyrazo!o[3,4-d]pyrimidin-3-y I)-Nphenylbenzamide
181 T~ \ Xi»! rS NH, \,iMX-Î V-N 6 A 4-(7-(2-acryloy]-l,2,3,4,5,6- hexahydrocycl open ta [c] pyrrol-5-y l)-4-amino-7Hpyrrolo[2,3-d]pyrimidin-5-yl)-Î\-phenyIbenzamide
182 O a > v Nb / r\ M-3y-’ nrs •'V h ό 1-00, 4- (7-( 1-acryloyl octahy drocyciopen ta [b] pyrrol -5yl)-4-amino-7H-pyrro!o[2,3-d]pyrimidin-5-yl)-Nphenylbenzamide
183 /0 °y- kh i'0 hh. fri -N' 'H. s-° °SV. 4-(4-amino-7-(2- (vinyLsulfonyI)octahydrocyclopenta[c]pyrrol-5-yl)7H-pyrrolo[2,3-d]pyrimidin-5-yl)-Nphenylbenzamide
184 /Λ 9. /-ΜΗ NH; / i Y Λ' N-V λ <* > \ 4 .·' ' ΊΝ ..Α.. (E)-4-(4-amino-7-(2-(4-(dimethylamino)but-2enoyl)octahydrocyclopenta[c]p)Trol-5-yl)-7HpyrrolofS^’djpyrimidin-S-ylj-N-phenyibenzamide
185 ,··?’ ''a Q. > b' > ·ΗΗ NH. «À W A \ / t S H’ o'A b v (E)-4-(4-amino-7-(2-(4- (cydopropyl(metliyl)amino)but-2enoyl)odahydrocydopenta [c] pyrro l-5-yl)-7H pynOlo[2,3-d]pyrimidin-5-yl)-i\'-phenyIbenzamide
186 Oo γΜ-Ι J l NH, V=/ A- b ΐ r ti L-, YS (Z)-4-(4-amino-7-(2-(2-cyano-3cydopropylacrylay!)octahydrocydopenta[c]pyrrol5-y]}-7H-pyrrolo[2j3-d]pyrimidin-5-yl)-Nphenylbenzamide
187 ,ί'Λ c V A NH; V-J N*V\, U P -N A. 4- (3-(2-acry loyl-1,2,3,4,5,6hexahydrocyclopenta[c]pyrroi-5-yl)-8aminoimid azo[l,5-a]pyrazi n-1 -yl )-Nphenylbenzamide
188 V °^-WH ό NH.: V-- NPj U/ 4-(3-( I-acryloyloctahydrocy ciopenta[b]pyrrol-5yl)-S-aminoimidazo[l,5-a]pyTazin-l-yl)-Nphenylbenzamide
189 P V-NH r\ NH; X*-W kPP1 P N. Λ 4-(8-amino-3-(2- (vÎnylsutfonyl)actahydrocycIopenta[c]pyrrol-5yl)imidazo[l,5-a]pyrazin-l-yl)-Nphenylbenzamide
190
191
(E)-4-(8-amjno-3-(2-(4-(dimethylamino)but-2enoyl joctahyd rocycl open ta [c] pyrra 1-5yl)imidazo[ l,5-a]pyrazin-l -yi)-Nphenylbenzamide (E)-4-(8-amîno-3-(2-(4(cyclopropyl(methyl)amino)but-2enoyl)octahyd rocycl open ta [ cjpyrro 1-5yl)inudazo[l,5-a]pyrazin-l -yl )-Nphenylbenzamide
192 ,ί'Ά q V’’y-NN ;Γ% NH; \^' AJ N · γτ-- ··. i N -¾.. ..N-.y ù CN ÿ-·/ o y (Z)-4-(8-amino-3-(2-(2-cyano-3- <yclopropylacryIoyI)octahydrocydopenta[c]pyTrol- 5-yl)imidazo[ l(5-a]pyrazin-1 -yl)-N- pheny Ibertzamide
193 ir\ V-' r4 NH; V--''' rA-<_ L J. SrA -N /λ 4-(9-(2-acryloyl-1,2,3,4,5,6hexahydrocyclopenta[c]pyrrot-5-yl)-6-amino-8oxo-8,9-d i hydro-7H -purin-7-y 1}- Nphenylbenzamide
194 O - 'r~ y-NH rS wAt-n U* ü Va 4-(9-(l-acTyloyloctahydrocydopenta[b]pyrrol-5yl)-6-amino-8-oxo-8,9-dihydro-7H-purin-7-yl)-Nphenylbenzamide
195 V °y-NH ,Ά NH; nA-À t Ή’ N S b-.O CT---S 4-(6-amino-8-oxo-9-(2- (vinylsulfonyI)octahydrocyclope'nta[c]pyrrol-5-y!)- 8/9-dihydro-7H-purin-7-yl)-N-phenyibenzamide
196 W O y-NH rS MH; V-J Λ« <λ . J ”N N — / (E)-4-(6-amino-9-(2-(4-(dirnethylamirio)but-2enoyl)<ictahydrocydoperita[c]pyrroI-5-yl)-8-oxo8,9-dihydro-7H-purin-7-yl)-\‘-phenylbenzamide
197 o ·' y-NH ,.fA ? V-7 nA-V u 1/-·° Ν' ’Ν Ο .Λν (E)-4-(6-aniino-9-(2-(4- (cydopropyl(methyl)amino)but-2enoyljoctahydrocycl open ta [ c] pyrrol-5-yl)-8-oxo8,9-dihydro-7H-purin-7-yl)-ï\'-phenylbenzamide
100
198 Ο NH; U-ç-° Ci Q « Af (Z)-4-(6-amino-9-(2-(2-cyano-3cydopropylaayk)yl}octahydrocyd<:>penta[c]pyrral5-yl}-8-oxo-8,9-dihydro-7H-puriri-7-yl)-i\·phenylbenzamide
199 ο ο'Ύ Χ.----Ν ι À NH; ''N -'N. Ù V l-(5-(4-amino-3-(4-(5-phenyl-li3,4-oxadiazol-2- yl)phenyl)-lH-pyrazoîo[3.,4-d]pyrimidin-lyl)hexahydrocydopenta[cjpyirol-2(lH)-yI)prop-2en-l-one
200 ίΛ ' NHj u >-7 Cl Ν’ N c l-(5-(4-amino-6-chtoro-5-(4-phenoxyphenyl)-7H- pyrrolo[2,3-d]pyrimidin-7- yl)hexahydrocydopenta[c]pyrrol-2(lH)-yl)prop-2en-l-one
101
201 p-V_.·/ C NHn W * / ·> chf2 'V'-»' V ’N' 7“-·, Ο 'ύ l-(5-(4-amino-6-(difluoromethv 1)-5-(4phenoxypheny 1) -7H-pyrrolo[2,3-d ] pyrimid in-7yl)hexahydrocydapenta[c]pyrrol-2(lI-I)-yl)prop-2en-l-one
202 p-\J' rv MH, %----/ φ> -'NJ ° \\ l-(5-(S-amiiTO-l-(4-phenoxyphenyl)imidazo[l,5ajpyrazin-3-yl)hexahydrocyclopenta[c]pyrrol2( 1 H)-yl)prop-2-en-l -one
203 VA pv A NH, ; N ^_.··Ν-Γ ù Ap A 1 - (4-phenoxyphenyI )-3-(2(vinylsulfonyl)octahydrocyclopenta[c]p\Trol-5yl}imidazo[l,5-ajpyrazîn-8-amine
204 rN o-\_ i1 rS v'jrVw* A o M O \\ 7-(2-acryloyloctahydrocydopenta[c]pyrrol-5-yl)-4amino-5-(4-phenoxyphenyl)-7H-pyTTolo[2?3d]pyrimidine-6-carboxylic add
102
2Û5 P ί\ Μ V° ρ U ν _>-ζ ο 4-(l-(2-acryloyloctahydrocydopenta[c]pyrrol-5-yl)- 4-amino-1 H-pyTazolo[3/l-dJpyrimidin-3-yl)-N-(5diloiOpyridin-2-yl)benzamide
206 ,.Ο χ NHa y/ h -'.y : Ή <' ’ νΛ ‘•-ν' A-. o l-(5-(4-amino-3-(4-(morpholinomethyl)phenyl)lH-pyrazolo[3,4-d]pyrimidin-ly])hexahydrocydoperita|c]pyrrol-2( 1 H)-yI)prop-2en-'l-one
207 /X -N .· X.--’ f Wj X-- ’Π'Λ S ίΊ ή O ,f l-(5-(4-ammo-3-(4-(pipertdin-'l-ylmethyl)phenyl)lH-pyrazolo[3,4-d]pyrimidin-lyl)hexahydrocydopenta[cjpyrrol-2(lH)-yI)prop-2en-l-one
208 r-\ j'X rS w NH, \x=? fTS 0 - -k < J 9 Λ--, ο 7, l-(5-(4-amino-3-(4-((3,4-dihydroisoquinolin-2(lH)yl}methyl)pheriyl)-lH-pyrazoIo[3,4-d]pyrimidin-lyl)hexahydrocydcipenta[cjpyrrol-2(lH)-yi)prop-2en-I-one
103
209 □A A KHj 05 N N <Ί 9 X_, Ο Λ l-(5-(4-am.ino-3-(4-((tetrahydrofuran-2- y 1 )oxy )p heny 1)-1 H-pyrazol o[3,4-d ] pyrimidin-1 yl)hexahydrocyclopenta[c}pyrrol-2( 1 H)-yl)prop-2en-l-one
210 y Ο •y 'n NHa · N V« > *A A 1- (5-(4-amino-3-(4-( 1 -morpholinoethyl)phenyl)lH-pyrazolo[3,4-d]pyrimidin-lyl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-vl)prop-2en-l-one
211 rO A RW, \--.· AÀ λΝ - ‘N Ci Q Ci l-(5-(4-amino-3-(4-(pyrrolidin-l-ylmethyl)phenyl)- lH-pyrazülo[3,4-djpyrimidin-lyl)hexahydroCTclopenta[cJpyrrol-2( 1 H)-v!)prop-2en-l-one
212 ,X .r\ w, y-u Ylf Ci C’y, 1 - (5- (4-amino-3-(4- ((dimethy laminojmethyl )pheny 1)-1 H-pyrazolo [3,4d ] pyri midin-1 -y 1) hexahydrocyclopen ta [c] pyrrol2( 1 H)-yl)prop-2-en-1 -one
213 °ν- ^-WH Af% Mb V'’ Ά 4 : r\ e-w Λ-„ Cl' 7. N-(4-(l-(2-acryloyloctahydrocyclopenta[cJpyrrol-5yl)-4-amino-lH-pyrazoto[3,4-d]pyrimidin-3yl)benzyl)acetamide
104
214 ,-H \ / < -J p ' ,··Ά, NHs \=·’ V'-w Z*-. < ‘ fc'N' (A· 1-(5-(4- amino-3-(4-(2-morpholinoethoxy Jphenyl}lH-pyrazolo[3,4-djpyrimidin-lyl)hexahydrocyrclopenta[c]pyrrol-2( 1 H)-yl)prop-2en-l-one
215 Va·, f S ° nh2 >=-* AS **N ”’N G, *··ν’ ΟΛ î. 2-(4-( l-(2-acryloyloctahydrocyclopenta[c]p}TroI-5yl)-4-amino-1 H-pyrazolo[3,4-d]pyrimïdin-3yl)benzyl)isoïndaline-l,3-dione
216 v K X 0 ?, l-(5-(4-amino-3-(4-((3,4-dihydroi5oqumolin-2(lH)- yl)metliyl)phenyl)-lH-pyrazolo[3,4-d]pyTÎmidin-lyl)hexahydrocydaperita[c]pyrrol-2(lH)-yt)prop-2en-l-one
217 NHa «Mn V'N /'·> H ‘•N À 1 -(5-(4-amino-3-(4-(azepan-1 -yimethyl)phenyl)-l Hpyrazolo[3,4-d]pyriTnidin-lyl)hexahydrocyclcipenta[c]pyrrol-2(lH)-yl)prop-2en-l-one
105
218 Γ'^ NHa V** κίΊΛ •H'--N v--., % <A l-(5-(4-amino-3-(4-((hexahydro-lH-isoindol-2(3H)yl)inethyl)phenyl)-lH-pyrazolo[3,4-d]pyrimidin-lyl)hexahydrocyclopenta[c]pyrrül-2(lH)-yl)prop-2en-l-one
219 „-O rs ««□ V*’ lV-N yy •-N Λ-. 0 ·), l-(5-(4-amino-3-(4- (tliiomorpholinomethyi)phenyl)-lH-pyrazolo[3,4d]pyrimidin-l-vl)hexahydrocyclopenta[c]pyrrol2(lH)-yI)prop-2-en-'l-one
220 .·- -/'y ,- H .AL : .3’ _ o'ü NH; w 2 N V’N < , VA '’-N‘ c/’7\ l-(5-(4-ammo-3-(4-((l,l-dioxidobenzo[d]isotI-ûazol- 2(3H)-yl)methyl)phenyl)-l H-pyrazo!o[3,4djpyrimidin-l -yl)hexahydrocyclopenta[c] pyrrol2( lH)-yl)prop-2-en-l -one
221 ,-H J.X y ί X 0 NH; ^'x\ *N^-W Cl· -n' <A 2-(4-(l-(2-acryloyloctahydrocyclopenta[c]pyrrol-5yl)-4-amino-lH-pyrazolo[3,4-d]pyrimidin-3y 1 jbenzyl jisoind olin-1 -one
106
222 Nx, (V NH, Va'-Vo ’n'-H s , ? •H L. 0' ‘Α. 9-(2-aayIoyloctahydroc\'cl<)penta[cjpyrrol-5-yl)-6amino-7-(benzo[d]thiazol~6-yl)-7H-purin-8{9H)one
223 ΓΑ a HH, V1 -F 'V H \-x . Z ’H 6* 'v 4-(9-(2-acryloyloctahydrtxyclopenta[c]pyrrol-5-yl)- 6-amino-8-oxo-8,9-dihydro-7H-purin-7-yl)-N- methyl-b>'-(4-methylpyridin-2-yl)benzamide
224 Va V» A Wj V’' -'Ma V’M A- 'T -H 9-(2-acryIoyloctahydrocydopenta[c]pyrrol-5-yl)-ûamino-7-(4-((methyl(4-methylpyridin-2yl)amino)methyl)phenyl)-7H-purin-8{9H)-one
225 X t',' '*· K °y< A KHj V-' ......k -R 4-(9-(2-acry loyl octahydrocyclopenta [ c] pyrrol-5-y 1) - 6-amino-8-oxo-8,9-dihydro-7H-purin-7-yl)-N- (pyridin-2-yl)benzamide
226 h'''T Ky_o 0 ’-t» 9-(2-acryioyloctahydracydopenta[c]pyriOl-5-yl)-6animo-7-(4-benzoylphenyl)-7H-purin-S(9H)-one
Testins of Compounds of the invention
107
Biological studies:
Invitro 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., 5 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 IX kinase reaction buffer (40 mM Tris-Cl, pH7.5, 20 mM MgCl2, 2 mM MnCl2, O.lmg/ml BSA and 50 μΜ DTT). Enzymatic reaction was initiated by adding a substrate cocktail containing 50μΜ of ATP (final 10 concentration) and 5pg of polyGln4Tyrl (Signal Chem) in total 25μ1 of reaction, in round bottom white 96 well plate. The reaction mixture was incubated at room température for 2 hr. After 2 hr of incubation, 10μ1 of the reaction mix was mixed with 10μ of ADP Glo reagent, in another round bottom white 96 well plate and incubated at room température for 40 min. This was followed by addition of kinase détection reagent (20μ1 per reaction) and incubation at room 15 température for 30 min. Finally, plate was read for luminescence at an intégration 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 invitro BTK inhibitory activity (IC50) for représentative compounds are listed in Table 3.
Table 3: Invitro (IC50) BTK inhibitory & CYP inhibition data of représentative compounds
compd No. In-vitro BTK inhibitory activity: IC50 (nM) CYP inhibition @10 ©>M concn
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
108
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
109
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 concentrations; B: >50% CYP inhibition @10 concentrations
CYP inhibition studies:
CYP inhibition studies were performed with test compounds, at two concentrations (2 μΜ and μΜ), using human liver microsomes (Yao, M., Zhu, M., Sinz, M.W., Zhang, H., Humphreys, 5 W. F., Rodrigues, A. D and Dai, R., Journal of Pharmaceutical and Biomédical 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 37° in microcentrifuge tubes. Aliquots of this mixture (499 pL) were transferred to each pre-labeled microcentrifuge tubes, followed by addition of the 1 pL of inhibitors (test 10 compound / CYP-specific positive control inhibitor) or control solvent (DMSO). Aliquots of this
110 mixture (90 pL) 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 pL NADPH stock (assay concentration, 1 mM) to a final incubation volume of 100 pL 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 pL of termination solvent (CH3CN) containing internai standard. The terminated samples were vortex-mixed, centrifuged at 10000 rpm for 5 min and supematant transferred into HPLC vials for LC-MS/MS analysis to monitor métabolites produced by marker CYP reactions. CYP inhibitory activity (% inhibition) of test compounds is listed in Table 3.
In vivo efficacy studies:
Démonstration of in vivo efficacy of test compounds in rats mice, oral routes of administration.
Animais
Ail the animal experiments were carried out in female rats and mice, bred in-house. Animais were housed in groups of 6 animais 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). Ail the animal experiments were carried out according to the intemationally 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 20pl 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. Représentative data of some of the test compounds are listed in Table-4.
111
Diffused large B cell lymphoma Xenografts using TMD-8 cell line
Female SCID mice were inoculated sc with 10 x 106 TMD-8 cells in 0.1 mL of PBS to the right flank. Animais 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 altemate day using digital calipers and the tumor volume was calculated using the formula: [length/2] x [width2]. Body weights of the animais 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. Représentative data of some of the test compounds are listed in Table-4.
Protocol for Collagen Induced Arthritis (CIA) Study in Mice
CIA is a ffequently 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 complété Freund’s adjuvant (CFA). Twenty-one days after the first immunization, mice were given booster dose of collagen in incomplète 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 animais 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 animais were also recorded 3 times a week as a measure of treatment related side effect, paw thickness measured twice a week and blood sérum are collected at termination for cytokines profile. Représentative data of some of the test compounds are listed in Table-4.
Table-4: Invivo efficacy data of représentative compounds
Compounds (Dose: 10 mpk, po) % inhibition of paw inflammation, Day-16, in SCW Arthritis % Inhibition in tumor volume, Day16, in TMD-8 % inhibition of clinical score, Day28, in CIA Arthritis
112
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 animais in each group
The novel compounds of the présent 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 médicament for the inhibition of BTK activity and suitable for humans and other warm blooded animais, and may be administered either by oral, topical or parentéral administration.
Thus, a pharmaceutical composition comprising the compounds of the présent 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 présent 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 présent 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 spécifie inhibitors, TNF-o 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
113 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 (8)

  1. We claim:
    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
    10 R2 is selected from the following ring system:
    115
    Ο
    R3 at each occurrence is independently selected from, C(O)NH(Ci_7)alkyl, C(O)CH=CH2, C(O)-CH=C-Rlb C(O)-CH=CH-R4, C(O)-C(CN)=CH2, C(O)-C(CN)=CH-R4, 5 SO2-NH(Ci_7)alkyl, SO2-CH=CH2, SO2-CH=CH-R4 groups; wherein, Ru is independently selected from hydrogen and alkyl group;
    R4 at each occurrence is selected from -(CH2)n-NR5Râ; wherein, n=0-7 and each of R5 and Rô are independently selected from hydrogen, haloalkyl, C1.7 alkyl, C2_7 alkenyl, C2-7 alkynyl, aryl, cycloalkyl, carbocycle, heterocycloalkyl, cycloalkyl(Ci_7)alkyl, 10 heterocycloalkyl(C i_7)alkyl;
    ‘U’ is selected from unsubstituted or substituted groups selected from heteroaryl, heterocycle, heterocycloalkyl, aryloxyaryl, aryloxyalkyl, aryloxyheteroaryl, heteroaryloxyaryl, heteroaryloxyalkyl, heteroaryloxyheteroaryl, Ph-CO-N(R7Rg), PhNfRçj-CO-Rio, wherein, R7, Rg and Rio are independently selected from hydrogen, 15 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.
    116
  2. 2. A compound as claimed in claim 1 selected from the group comprising of:
    1 -(5-(4-amino-3-(4-phenoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    l-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-lH-pyrazolo[3,4-d]pyrimidin-lyl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    l-(5-(4-amino-3-(2-methylbenzo[d]thiazol-6-yl)-lH-pyrazolo[3,4-d]pyrimidin-lyl)hexahydrocyclopenta[c]pynOl-2( 1 H)-yl)prop-2-en-1 -one;
    l-(5-(4-amino-3-(benzo[b]thiophen-5-yl)-1 H-pyrazolo[3,4-d]pyrimidin-1 yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    l-(5-(4-amino-3-(2,3-dihydrobenzo[b]thiophen-5-yl)-lH-pyrazolo[3,4-d]pyrimidin-lyl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    1 -(5-(4-amino-3-(dibenzo[b,d]furan-3-yl)-1 H-pyrazolo[3,4-d]pyrimidin-1 yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    N-(6-( 1 -(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1 H-pyrazolo[3,4d]pyrimidin-3-yl)benzo[d]thiazol-2-yl)acetamide;
    l-(5-(4-amino-3-(2-methoxybenzo[d]thiazol-6-yl)-lH-pyrazolo[3,4-d]pyrimidin-lyl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    1 -(5-(4-amino-3-(4-phenoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-yn-1 -one;
    1 -(5-(4-amino-3-(3 -methoxy-4-phenoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    4-(l-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-lH-pyrazolo[3,4d]pyrimidin-3-yl)-N-(pyridin-2-yl)benzamide;
    l-(5-(4-amino-3-(2-phenylbenzo[d]thiazol-6-yl)-1 H-pyrazolo[3,4-d]pyrimidin-1yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    1 -(5-(4-amino-3-(benzo[d][ 1,3]dioxol-5-yl)-1 H-pyrazolo[3,4-d]pyrimidin-1 yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    1 -(5-(4-amino-3-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-1 H-pyrazolo[3,4d]pyrimidin-1 -yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    l-(5-(4-amino-3-(benzo[d]oxazol-6-yl)-lH-pyrazolo[3,4-d]pyrimidin-lyl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    117
  3. 3- (4-phenoxyphenyl)-1 -(2-(vinylsulfonyl)octahydrocyclopen.ta[c]pyrrol-5-yl)-1Hpyrazolo[3,4-d]pyrimidin-4-amine;
    l-(5-(4-amino-3-(2-phenylbenzo[d]oxazol-6-yl)-lH-pyrazolo[3,4-d]pyrimidin-lyl)hexahydrocyclopenta[c]pyirol-2( 1 H)-yl)prop-2-en-1 -one;
    l-(5-(4-amino-3-(2-phenoxybenzo[d]thiazol-6-yl)-lH-pyrazolo[3,4-d]pyrimidin-lyl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    1 -(5-(4-amino-3-(4-( 1 -methyl-1 H-pyrazol-4-yl)phenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1-one;
    l-(5-(4-amino-3-(benzo[d]oxazol-5-yl)-lH-pyrazolo[3,4-d]pyrimidin-lyl)hexahydrocyclopenta[c]pyiTol-2( 1 H)-yl)prop-2-en-1 -one;
    1 -(5-(4-amino-3-(2-phenylbenzo[d]oxazol-5-yl)-1 H-pyrazolo[3,4-d]pyrimidin-1yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    (E)-1 -(5-(4-amino-3 -(4-phenoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)-4-(dimethylamino)but-2-en-1 -one; l-(5-(4-amino-3-(4-(5-(pyridin-2-yl)-l,3,4-oxadiazol-2-yl)phenyl)-lH-pyrazolo[3,4djpyrimidin-1 -yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    (E)-2-(5-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-lyl)octahydrocyclopenta[c]pyrrole-2-carbonyl)-3-cyclopropylacrylonitrile;
  4. 4- (l-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-lH-pyrazolo[3,4d]pyrimidin-3-yl)-2-methoxy-N-(4-methylpyridin-2-yl)benzamide;
    4-(l-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-lH-pyrazolo[3,4d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)benzamide;
    N-(4-( 1 -(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1 H-pyrazolo[3,4d]pyrimidin-3-yl)phenyl)picolinamide;
    4-( 1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1 H-pyrazolo[3,4d]pyrimidin-3-yl)-N-(benzo[d]thiazol-2-yl)benzamide;
    N-(4-( 1 -(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1 H-pyrazolo[3,4d]pyrimidin-3-yl)phenyl)pyrazine-2-carboxamide;
    l-(5-(4-amino-3-(2,2-difluorobenzo[d] [ 1,3]dioxol-5-yl)- lH-pyrazolo[3,4-d]pyrimidin-1 yl)hexahydrocyclopenta[c]pynOl-2( 1 H)-yl)prop-2-en-1 -one;
    118
    4-(l-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-lH-pyrazolo[3,4d]pyrimidin-3-yl)-N-(pyrazin-2-yl)benzamide;
    N-(4-( 1 -(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1 H-pyrazolo[3,4d]pyrimidin-3 -yl)phenyl)benzamide;
    l-(5-(4-amino-3-(4-(5-(pyridin-2-yl)-l,3,4-thiadiazol-2-yl)phenyl)-lH-pyrazolo[3,4d]pyrimidin-1 -yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    4-(l-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-lH-pyrazolo[3,4d]pyrimidin-3-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide;
    Z)-methyl 4-(l-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-lH-pyrazolo[3,4d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)benzimidate;
    6-(l-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-lH-pyrazolo[3,4d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)nicotinamide;
    1 -(5-(4-amino-3-(4-(pyridin-2-yloxy)phenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    (E)-4-(4-amino-l-(2-(4-(dimethylamino)but-2-enoyl)octahydrocyclopenta[c]pyrrol-5-yl)lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(pyridin-2-yl)benzamide;
    (E)-4-(4-amino-l-(2-(4-(dimethylamino)but-2-enoyl)octahydrocyclopenta[c]pyrrol-5-yl)lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)benzainide;
    l-(5-(4-amino-3-(4-(5-(pyrazin-2-yl)-l,3,4-thiadiazol-2-yl)phenyl)-lH-pyrazolo[3,4d]pyrimidin-1 -yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    (E)-1 -(5-(4-amino-3-(4-(pyridin-2-yloxy)phenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)-4-(dimethylamino)but-2-en-1 -one;
    (E)-1 -(5-(4-amino-3-(4-phenoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)-4-(dimethylamino)but-2-en-1 -one;
    (E)-4-(4-amino-l-(2-(4-(dimethylamino)but-2-enoyl)octahydrocyclopenta[c]pyrrol-5-yl)lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(pyrazin-2-yl)benzamide;
    (Z)-methyl 4-(4-amino-1 -(2-((E)-4-(dimethylamino)but-2enoyl)octahydrocyclopenta[c]pyrrol-5-yl)-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4methylpyridin-2-yl)benzimidate;
    (E)-4-(4-amino-l-(2-(4-(dimethylamino)but-2-enoyl)octahydrocyclopenta[c]pyrrol-5-yl)lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide;
    119
    1 -(5-(4-amino-3-(4-(pyridin-3-yloxy)phenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 yl)hexahydrocyclopenta[c]pyiTol-2( 1 H)-yl)prop-2-en-1 -one;
    (E)-1 -(5-(4-amino-3-(4-(pyridin-3-yloxy)phenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 yl)hexahydrocyclopenta[c]pynOl-2( 1 H)-yl)-4-(dimethylamino)but-2-en-1 -one;
    4-(l-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-lH-pyrazolo[3,4d]pyrimidin-3-yl)-N-methyl-N-(4-methylpyridin-2-yl)benzamide;
    (E)-4-(4-amino-l-(2-(4-(dimethylamino)but-2-enoyl)octahydrocyclopenta[c]pyrrol-5-yl)lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-N-(4-methylpyridin-2-yl)benzamide;
    (E)-l-(5-(4-amino-3-(4-(5-(pyrazin-2-yl)-l,3,4-thiadiazol-2-yl)phenyl)-lH-pyrazolo[3,4djpyrimidin-1 -yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-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)-1 H-pyrazolo[3,4djpyrimidin-1 -yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)-4-(dimethylamino)but-2-en-1 one.
    3. A compound as claimed in claim 1 selected from the group comprising of: l-(5-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-lyl)hexahydrocyclopenta[c]pyxrol-2( 1 H)-yl)prop-2-en-1 -one;
    1 -(5-(4-amino-3-(benzo[d]thiazol-6-yl)-1 H-pyrazolo[3,4-d]pyrimidin-1 yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    l-(5-(5-((4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-lyl)methyl)pyridin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one; l-(5-(2-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-lyl)ethyl)hexahydropyrrolo[3,4-c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    1 -(5-(4-amino-3-(2-methylbenzo[d]thiazol-6-yl)-1 H-pyrazolo[3,4-d]pyrimidin-1 yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    l-(5-(4-amino-3-(benzo[b]thiophen-5-yl)-lH-pyrazolo[3,4-d]pyrimidin-lyl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    l-(5-(4-amino-3-(2,3-dihydrobenzo[b]thiophen-5-yl)-lH-pyrazolo[3,4-d]pyrimidin-lyl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    120 l-(5-(4-amino-3-(dibenzo[b,d]furan-3-yl)-lH-pyrazolo[3,4-d]pyrimidin-lyl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    N-(6-( 1 -(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1 H-pyrazolo[3,4d]pyrimidin-3-yl)benzo[d]thiazol-2-yl)acetamide;
    l-(5-(4-amino-3-(2-methoxybenzo[d]thiazol-6-yl)- lH-pyrazolo[3,4-d]pyrimidin-1 yl)hexahydrocyclopenta[c]pynOl-2( 1 H)-yl)prop-2-en-1 -one;
    1 -(5-(4-amino-3-(4-phenoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-yn-1 -one;
    1 -(5-(4-amino-3-(3-methoxy-4-phenoxyphenyl)- lH-pyrazolo[3,4-d]pyrimidin-1 yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    4-(l-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-lH-pyi’azolo[3,4d]pyrirnidin-3-yl)-N-(pyridin-2-yl)benzarnide;
    l-(5-(4-amino-3-(2-phenylbenzo[d]thiazol-6-yl)-1 H-pyrazolo[3,4-d]pyrimidin-1 yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    l-(5-(4-amino-3-(benzo[d][l ,3]dioxol-5-yl)- lH-pyrazolo[3,4-d]pyrimidin-1 yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    1 -(5-(4-amino-3-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-1 H-pyrazolo[3,4d]pyrimidin-1 -yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    l-(5-(4-amino-3-(benzo[d]oxazol-6-yl)-lH-pyrazolo[3,4-d]pyrimidin-lyl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    3-(4-phenoxyphenyl)-1 -(2-(vinylsulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)-1Hpyrazolo[3,4-d]pyrimidin-4-amine;
    l-(5-(4-amino-3-(2-phenylbenzo[d]oxazol-6-yl)-lH-pyrazolo[3,4-d]pyrimidin-lyl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    1-(5-(4-amino-3-(2-phenoxybenzo[d]thiazol-6-yl)-1 H-pyrazolo[3,4-d]pyrimidin-1yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    l-(5-(4-amino-3-(4-(l-methyl-lH-pyrazol-4-yl)phenyl)-lH-pyrazolo[3,4-d]pyrimidin-lyl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    l-(5-(4-amino-3-(benzo[d]oxazol-5-yl)-lH-pyrazolo[3,4-d]pyrimidin-lyl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    121 l-(5-(4-amino-3-(2-phenylbenzo[d]oxazol-5-yl)-lH-pyrazolo[3,4-d]pyrimidin-lyl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    (E)-1 -(5-(4-amino-3-(4-phenoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 yl)hexahydrocyclopenta[c]pynOl-2( 1 H)-yl)-4-(dimethylamino)but-2-en-1 -one; l-(5-(4-amino-3-(4-(5-(pyridin-2-yl)-l,3,4-oxadiazol-2-yl)phenyl)-lH-pyrazolo[3,4djpyrimidin-1 -yl)hexahydrocyclopenta[c]pyiTol-2( 1 H)-yl)prop-2-en-1 -one;
    (E)-2-(5-(4-amino-3 -(4-phenoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 yl)octahydrocyclopenta[c]pyrrole-2-carbonyl)-3-cyclopropylacrylonitrile;
    4-(l-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-lH-pyrazolo[3,4d]pyrimidin-3-yl)-2-methoxy-N-(4-methylpyridin-2-yl)benzamide;
    4-(l-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-lH-pyrazolo[3,4d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)benzamide;
    N-(4-( 1 -(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1 H-pyrazolo[3,4d]pyrimidin-3-yl)phenyl)picolinamide;
    4-( 1 -(2-acryloyloctahydrocyclopenta[c]pynOl-5-yl)-4-amino-1 H-pyrazolo[3,4d]pyrimidin-3-yl)-N-(benzo[d]thiazol-2-yl)benzamide;
    N-(4-( 1 -(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1 H-pyrazolo[3,4d]pyrimidin-3-yl)phenyl)pyrazine-2-carboxamide;
    1 -(5-(4-amino-3-(2,2-difluorobenzo[d] [ 1,3]dioxol-5-yl)-1 H-pyrazolo[3,4-d]pyrimidin-1 yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    4-(l-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-lH-pyrazolo[3,4d]pyrimidin-3-yl)-N-(pyrazin-2-yl)benzamide;
    N-(4-( 1 -(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-aniino-1 H-pyrazolo[3,4d]pyrimidin-3-yl)phenyl)benzamide;
    l-(5-(4-amino-3-(4-(5-(pyridin-2-yl)-l,3,4-thiadiazol-2-yl)phenyl)-lH-pyrazolo[3,4djpyrimidin-1 -yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    4-(l-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-lH-pyrazolo[3,4d]pyrimidin-3-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide;
    Z)-methyl 4-(l-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-lH-pyrazolo[3,4d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)benzimidate;
    122
    6-(l-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-lH-pyrazolo[3,4d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)nicotinamide;
    1 -(5-(4-amino-3-(4-(pyridin-2-yloxy)phenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    (E)-4-(4-amino-l-(2-(4-(dimethylamino)but-2-enoyl)octahydrocyclopenta[c]pyrrol-5-yl)lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(pyridin-2-yl)benzamide;
    (E)-4-(4-amino-l-(2-(4-(dimethylamino)but-2-enoyl)octahydrocyclopenta[c]pyrrol-5-yl)lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)benzamide;
    l-(5-(4-amino-3-(4-(5-(pyrazin-2-yl)-l,3,4-thiadiazol-2-yl)phenyl)-lH-pyrazolo[3,4d]pyrimidin-1 -yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    (E)-l-(5-(4-amino-3-(4-(pyridin-2-yloxy)phenyl)-lH-pyrazolo[3,4-d]pyrimidin-lyl)hexahydrocyclopenta[c]pynOl-2( 1 H)-yl)-4-(dimethylamino)but-2-en-1-one;
    (E)-1 -(5-(4-amino-3-(4-phenoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)-4-(dimethylamino)but-2-en-1 -one;
    (E)-4-(4-amino-l-(2-(4-(dimethylamino)but-2-enoyl)octahydrocyclopenta[c]pyrrol-5-yl)lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(pyrazin-2-yl)benzamide;
    (Z)-methyl 4-(4-amino-1 -(2-((E)-4-(dimethylamino)but-2enoyl)octahydrocyclopenta[c]pyrrol-5-yl)-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4methylpyridin-2-yl)benzimidate;
    (E)-4-(4-amino-l-(2-(4-(dimethylamino)but-2-enoyl)octahydrocyclopenta[c]pyrrol-5-yl)lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide;
    l-(5-(4-amino-3-(4-(pyridin-3-yloxy)phenyl)-lH-pyrazolo[3,4-d]pyrimidin-lyl)hexahydrocyclopenta[c]pynOl-2( 1 H)-yl)prop-2-en-1 -one;
    (E)-1 -(5-(4-amino-3 -(4-(pyridin-3-yloxy)phenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)-4-(dimethylamino)but-2-en-1 -one; 4-(l-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-lH-pyrazolo[3,4d]pyrimidin-3-yl)-N-methyl-N-(4-methylpyridin-2-yl)benzamide;
    (E)-4-(4-amino-l-(2-(4-(dimethylamino)but-2-enoyl)octahydrocyclopenta[c]pyrrol-5-yl)lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-N-(4-methylpyridin-2-yl)benzamide;
    123 (E)-l-(5-(4-amino-3-(4-(5-(pyrazin-2-yl)-l,3,4-thiadiazol-2-yl)phenyl)-lH-pyrazolo[3,4djpyrimidin-1 -yl)hexahydrocyclopenta[c]pyiTol-2( 1 H)-yl)-4-(dimethylamino)but-2-en-1 one;
    (E)-l-(5-(4-amino-3-(4-(5-(pyridin-2-yl)-l,3,4-oxadiazol-2-yl)phenyl)-lH-pyrazolo[3,4djpyrimidin-1 -yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)-4-(dimethylamino)but-2-en-1 one;
    1- (5-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)-5,6dihydrocyclopenta[c]pyrrol-2( 1 H,3H,4H)-yl)prop-2-en-1 -one;
    2- acryloyl-5-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)-2,3dihydrocyclopenta[c]pyrrole-4,6(lH,5H)-dione;
    2-acryloyl-5-(4-amino-3 -(4-phenoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)-5,6dihydrocyclopenta[c]pyrrole-1,3 (2H,4H)-dione;
    l-(5-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-lyl)hexahydrocyclopenta[b]pyiTol-1 (2H)-yl)prop-2-en-1 -one;
    l-(4-(4-amino-3-(4-phenoxyphenyl)-lH-pyr azolo[3,4-d]pyrimidin-l-yl)-2,3,5,6tetrahydrocyclopenta[b]pyrrol-1 (4H)-yl)prop-2-en-1 -one;
    1 -(6-(4-amino-3-(4-phenoxyphenyl)-1 H-pyrazolo [3,4-d]pyrimidin-1 -yl)hexahydro-1Hcyclopenta[c]pyridin-2(3H)-yl)prop-2-en-1 -one;
    l-(5-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)-4,5,6,7tetrahydro-1 H-isoindol-2(3H)-yl)prop-2-en-1 -one;
    1 -(6-(4-amino-3 -(4-phenoxyphenyl)-1 H-pyrazolo [3,4-d]pyrimidin-1 -yl)-3 azabicyclo[3.2.0]heptan-3-yl)prop-2-en-1 -one;
    l-(3-(4-amino-3-(4-phenoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)-6azabicyclo[3.2.0]heptan-6-yl)prop-2-en-l-one;
    N-(5-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-lyl)octahydropentalen-2-yl)acrylamide;
    l-(5-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)-3,4,6,7tetrahydro-1 H-cyclopenta[c]pyridin-2(5H)-yl)prop-2-en-1 -one;
    1 -(5-(4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-d]pyrimidin-1 -yl)hexahydro- 1Hisoindol-2(3H)-yl)prop-2-en-l-one;
    124
    1 -(4-(4-amino-3-(4-phenoxyphenyl)-1 H-pyrazolo [3,4-d]pyrimidin-1 yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    1 -(4-(4-amino-3-(4-phenoxyphenyl)-1 H-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)-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)-2,3,5,6tetrahydrocyclopenta[b]pyrrol-1 (4H)-yl)prop-2-en-1 -one;
    l-(4-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)-5,6dihydrocyclopenta[c]pyrrol-2( 1 H,3H,4H)-yl)prop-2-en-1 -one;
    1-(6-(4-amino-3-(4-phenoxyphenyl)-1 H-pyrazolo [3,4-d]pyrimidin-1-yl)octahydro-1Hcyclopenta[b]pyridin-1 -yl)prop-2-en-1 -one;
    l-(5-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)-2,3,4,5,6,7hexahydro-1 H-cyclopenta[b]pyridin-1 -yl)prop-2-en-1 -one;
    l-(7-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)-2,3,4,5,6,7hexahydro-1 H-cyclopenta[b]pyridin-1 -yl)prop-2-en-1 -one;
    l-(6-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)-3,4,6,7tetrahydro-1 H-cyclopenta[c]pyridin-2(5H)-yl)prop-2-en-1 -one;
    l-(7-(4-amino-3-(4-phenoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)-3,4,6,7tetrahydro-1 H-cyclopenta[c]pyridin-2(5H)-yl)prop-2-en-1 -one;
    l-(7-(4-amino-3-(4-phenoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)-2,3,4,5,6,7hexahydro-1 H-cyclopenta[b]pyridin-1 -yl)prop-2-en-1 -one;
    1- (5-(4-amino-3-(benzo[d]thiazol-6-yl)-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)-5,6dihydrocyclopenta[c]pyrrol-2( 1 H,3H,4H)-yl)prop-2-en-1 -one;
    2- acryloyl-5-(4-amino-3-(benzo[d]thiazol-6-yl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)-2,3dihydrocyclopenta[c]pyrrole-4,6(lH,5H)-dione;
    2-acryloyl-5-(4-amino-3-(benzo[d]thiazol-6-yl)-lH-pyrazolo[3,4-d]pyriniidin-l-yl)-5,6dihydrocyclopenta[c]pyrrole-1,3 (2H,4H)-dione;
    l-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-lH-pyrazolo[3,4-d]pyrimidin-lyl)hexahydrocyclopenta[b]pyrrol-1 (2H)-yl)prop-2-en-1 -one;
    l-(4-(4-amino-3-(benzo[d]thiazol-6-yl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)-2,3,5,6tetrahydrocyclopenta[b]pyrrol-1 (4H)-yl)prop-2-en-1 -one;
    125 l-(6-(4-amino-3-(benzo[d]thiazol-6-yl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)hexahydrolH-cyclopenta[c]pyridin-2(3H)-yl)prop-2-en-l-one;
    l-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)-4,5,6,7tetrahydro-lH-isoindol-2(3H)-yl)prop-2-en-l-one;
    l-(6-(4-amino-3-(benzo[d]thiazol-6-yl)-lH-pyrazolo[3,4-d]pyriinidin-l-yl)-3azabicyclo[3.2.0]heptan-3-yl)prop-2-en-l-one;
    1 -(3-(4-amino-3-(benzo[d]thiazol-6-yl)-1 H-pyrazolo[3,4-d]pyrimidin- l-yl)-6azabicyclo[3,2.0]heptan-6-yl)prop-2-en-1 -one;
    N-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-lH-pyrazolo[3,4-d]pyrimidin-lyl)octahydropentalen-2-yl)acrylamide;
    l-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)-3,4,6,7tetrahydro-1 H-cyclopenta[c]pyridin-2(5H)-yl)prop-2-en-1 -one;
    l-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)hexahydrolH-isoindol-2(3H)-yl)prop-2-en-1 -one;
    l-(4-(4-amino-3-(benzo[d]thiazol-6-yl)-lH-pyrazolo[3,4-d]pyrirnidin-lyl)hexahydrocyclopenta[c]pynOl-2( 1 H)-yl)prop-2-en-1 -one;
    1 -(4-(4-amino-3-(benzo[d]thiazol-6-yl)-1 H-pyrazolo[3,4-d]pyrimidin-1 yl)hexahydrocyclopenta[b]pyrrol-1 (2H)-yl)prop-2-en-1 -one;
    l-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-lH-pyrazolo[3,4-d]p yrimidin-l-yl)-2,3,5,6tetrahydrocyclopenta[b]pyrrol-1 (4H)-yl)prop-2-en-1 -one;
    l-(4-(4-amino-3-(benzo[d]thiazol-6-yl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)-5,6dihydrocyclopenta[c]pyrrol-2( 1 H,3H,4H)-yl)prop-2-en-1 -one;
    1 -(6-(4-amino-3-(benzo[d]thiazol-6-yl)-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)octahydro-1Hcyclopenta[b]pyridin-1 -yl)prop-2-en-1 -one;
    l-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)-2,3,4,5,6,7hexahydro-1 H-cyclopenta[b]pyridin-1 -yl)prop-2-en-1 -one;
    l-(7-(4-amino-3-(benzo[d]thiazol-6-yl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)-2,3,4,5,6,7hexahydro-1 H-cyclopenta[b]pyridin-1 -yl)prop-2-en-1 -one;
    l-(6-(4-amino-3-(benzo[d]thiazol-6-yl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)-3,4,6,7tetrahydro-1 H-cyclopenta[c]pyridin-2(5H)-yl)prop-2-en-1 -one;
    126 l-(7-(4-amino-3-(benzo[d]1fciazol-6-yl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)-3,4,6,7tetrahydro-1 H-cyclopenta[c]pyridin-2(5H)-yl)prop-2-en-1 -one;
    l-(7-(4-ammo-3-(benzo[d]thiazol-6-yl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)-2,3,4,5,6,7hexahydro-1 H-cyclopenta[b]pyridin-1 -yl)prop-2-en-1 -one;
    l-(5-(4-amino-3-(benzo[b]thiophen-5-yl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)-5,6dihydrocyclopenta[c]pyrrol-2( 1 H,3H,4H)-yl)prop-2-en-1-one;
    l-(6-(4-amino-3-(benzo[b]thiophen-5-yl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)hexahydrolH-cyclopenta[c]pyridin-2(3H)-yl)prop-2-en-l-one;
    l-(6-(4-amino-3-(benzo[b]thiophen-5-yl)-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)-3azabicyclo[3.2.0]heptan-3-yl)prop-2-en-l-one;
    N-(5-(4-amino-3-(benzo[b]thiophen-5-yl)-1 H-pyrazolo[3,4-d]pyrimidin-1 yl)octahydropentalen-2-yl)acrylamide;
    l-(5-(4-amino-3-(benzo[b]thiophen-5-yl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)-3,4,6,7tetrahydro-1 H-cyclopenta[c]pyridin-2(5H)-yl)prop-2-en-1 -one;
    l-(5-(4-amino-3-(2,3-dihydrobenzo[b]thiophen-5-yl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)5,6-dihydrocyclopenta[c]pyirol-2(lH,3H,4H)-yl)prop-2-en-l-one;
    l-(6-(4-amino-3-(2,3-dihydrobenzo[b]thiophen-5-yl)-1 H-pyrazolo[3,4-d]pyrimidin-1 yl)hexahydro-1 H-cyclopenta[c]pyridin-2(3H)-yl)prop-2-en-1 -one l-(6-(4-ammo-3-(2,3-dihydrobenzo[b]thiophen-5-yl)-lH-pyrazolo[3,4-d]pyrimidin-l-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)-lH-pyrazolo[3,4-d]pyrimidin-lyl)octahydropentalen-2-yl)acrylamide;
    l-(5-(4-amino-3-(2,3-dihydrobenzo[b]thiophen-5-yl)-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)3,4,6,7-tetrahydro-lH-cyclopenta[c]pyridin-2(5H)-yl)prop-2-en-l-one;
    N-(6-( 1 -(2-acryloyl-1,2,3,4,5,6-hexahydrocyclopenta[c]pyrrol-5-yl)-4-amino- 1Hpyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]thiazol-2-yl)acetaniide;
    N-(6-( 1 -(2-acryloyloctahydro-1 H-cyclopenta[c]pyridin-6-yl)-4-amino-1 H-pyrazolo[3,4d]pyrimidin-3 -yl)b enzo [d] thiazol-2-yl) acetamide;
    N-(5-(3-(2-acetamidobenzo[d]thiazol-6-yl)-4-amino-lH-pyrazolo[3,4-d]pyrimidin-lyl)octahydropentalen-2-yl)acrylamide;
    127 (E)-1 -(5-(4-amino-3 -(4-phenoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)-5,6dihydrocyclopenta[c]pyrrol-2(lH,3H,4H)-yl)-4-(dimethylamino)but-2-en-l-one;
    (E)-1 -(6-(4-amino-3 -(4-phenoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)hexahydrolH-cyclopenta[c]pyridin-2(3H)-yl)-4-(dimethylamino)but-2-en-l-one;
    (E)-1-(6-(4-amino-3-(4-phenoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)-3azabicyclo[3.2.0]heptan-3-yl)-4-(dimethylamino)but-2-en-l-one;
    (E)-1 -(5-(4-amino-3 -(4-phenoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)-3,4,6,7tetrahydro-1 H-cyclop enta[c]pyridin-2(5H)-yl)-4-(dimethylamino)but-2-en-1 -one;
    (E)-1 -(5-(4-amino-3-(benzo[d]thiazol-6-yl)- lH-pyrazolo[3,4-d]pyrimidin-1 yl)hexahydrocyclopenta[c]pyiTol-2( 1 H)-yl)-4-(dimethylamino)but-2-en-1 -one;
    (E)-l-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)-5,6dihydrocyclopenta[c]pyrrol-2(lH,3H,4H)-yl)-4-(dimethylaniino)but-2-en-l-one;
    (E)-l-(6-(4-amino-3-(benzo[d]thiazol-6-yl)-lH-pyrazolo[3,4-d]pyrimidin-lyl)hexahydro-1 H-cyclopenta[c]pyridin-2(3H)-yl)-4-(dimethylamino)but-2-en-1 -one;
    (E)-1 -(6-(4-amino-3-(benzo[d]thiazol-6-yl)-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)-3azabicyclo[3,2.0]heptan-3-yl)-4-(dimethylamino)but-2-en-1 -one;
    (E)-l-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)-3,4,6,7tetrahydro-lH-cyclopenta[c]pyridin-2(5H)-yl)-4-(dimethylamino)but-2-en-l-one;
    l-(5-(4-amino-3-(4-benzoylphenyl)-lH-pyrazolo[3,4-d]pyrimidin-lyl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    4-(l-(2-acryloyloctahydrocyclopenta[c]pynOl-5-yl)-4-ainino-lH-pyrazolo[3,4d]pyrimidin-3-yl)-N-phenylbenzamide;
    4-(l-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-lH-pyrazolo[3,4d]pyrimidin-3-yl)-N-methyl-N-phenylbenzamide;
    4-(l-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-lH-pyrazolo[3,4d]pyrimidin-3-yl)-2-methyl-N-phenylbenzamide
    4-( 1 -(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1 H-pyrazolo[3,4d]pyrimidin-3-yl)-2-methoxy-N-phenylbenzamide;
    4-( 1 -(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1 H-pyrazolo[3,4d]pyrimidin-3-yl)-N,2-dimethyl-N-phenylbenzamide;
    128
    4-(l-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-lH-pyrazolo[3,4d]pyrimidin-3-yl)-2-methoxy-N-methyl-N-phenylbenzamide;
    4-(l-(2-acryloyloctahydrocyclopenta[c]pynOl-5-yl)-4-amino-lH-pyrazolo[3,4d]pyrimidin-3-yl)-2-methyl-N-(pyridm-2-yl)benzamide;
    4-( 1 -(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1 H-pyrazolo[3,4d]pyrimidin-3-yl)-2-methoxy-N-(pyridin-2-yl)benzaniide;
    4-(l-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-lH-pyrazolo[3,4d]pyrimidin-3-yl)-2-methyl-N-(4-methylpyridin-2-yl)benzamide;
    4-(l-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-lH-pyrazolo[3,4d]pyrimidin-3-yl)-2-methyl-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide;
    4-( l-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1 H-pyrazolo[3,4d]pyrimidin-3-yl)-2-methoxy-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide;
    4-(l-(2-acryloyl-l,2,3,4,5,6-hexahydrocyclopenta[c]pyrrol-5-yl)-4-amino-lHpyrazolo[3,4-d]pyrimidin-3-yl)-N-phenylbenzamide;
    4-( 1-( 1-acryloyloctahydrocyclopenta[b]pyrrol-5-yl)-4-amino-1 H-pyrazolo[3,4d]pyrimidin-3-yl)-N-phenylbenzamide;
    4-(4-amino-1 -(2-(vinylsulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)-1 H-pyrazolo[3,4d]pyrimidin-3-yl)-N-phenylbenzamide;
    (E)-4-(4-amino-l-(2-(4-(dimethylamino)but-2-enoyl)octahydrocyclopenta[c]pyrrol-5-yl)lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-phenylbenzamide;
    (E)-4-(4-amino-1 -(2-(4-(cyclopropyl(methyl)amino)but-2enoyl)octahydrocyclopenta[c]pyrrol-5-yl)-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-Nphenylbenzamide;
    (Z)-4-(4-amino-l-(2-(2-cyano-3-cyclopropylacryloyl)octahydrocycIopenta[c]pyrrol-5yl)-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-N-phenylbenzamide;
    l-(5-(4-amino-3-(4-(5-phenyl-l,3,4-oxadiazol-2-yl)phenyl)-lH-pyrazolo[3,4d]pyrimidin-1 -yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    4-(l-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-lH-pyrazolo[3,4d]pyrimidin-3-yl)-N-(5-chloropyridin-2-yl)benzamide;
    l-(5-(4-amino-3-(4-(morpholinomethyl)phenyl)- lH-pyrazolo[3,4-d]pyrimidin-1 yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    129 l-(5-(4-amino-3-(4-(piperidin-1 -ylmethyl)phenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    1 -(5-(4-amino-3-(4-((3,4-dihydroisoquinolin-2( 1 H)-yl)methyl)phenyl)-1 H-pyrazolo[3,4d]pyrimidin-1 -yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    l-(5-(4-amino-3-(4-((tetrahydrofuran-2-yl)oxy)phenyl)-lH-pyrazolo[3,4-d]pyrimidin-lyl)hexahydrocyclopenta[c]pynOl-2(lH)-yl)prop-2-en-1 -one;
    l-(5-(4-amino-3-(4-(l-morpholinoethyl)phenyl)-lH-pyrazolo[3,4-d]pyrimidin-lyl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    1 -(5-(4-amino-3-(4-(pyrrolidin-1 -ylmethyl)phenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 yl)hexahydrocyclopenta[c]pyiTol-2( 1 H)-yl)prop-2-en-1 -one;
    l-(5-(4-amino-3-(4-((dimethylamino)methyl)phenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    N-(4-( 1 -(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1 H-pyrazolo[3,4d]pyrimidin-3 -yl)b enzyl) acetamide;
    1- (5-(4-amino-3-(4-(2-morpholinoethoxy)phenyl)-lH-pyrazolo[3,4-d]pyrimidin-lyl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    2- (4-(l-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-lH-pyrazolo[3,4d]pyrimidin-3-yl)benzyl)isoindoline-1,3-dione;
    l-(5-(4-amino-3-(4-((3,4-dihydroisoquinolin-2(lH)-yl)methyl)phenyl)-lH-pyrazolo[3,4djpyrimidin-1 -yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    1 -(5-(4-amino-3-(4-(azepan-1 -ylmethyl)phenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    l-(5-(4-amino-3-(4-((hexahydro-lH-isoindol-2(3H)-yl)methyl)phenyl)-lH-pyrazolo[3,4djpyrimidin-1 -yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    1- (5-(4-amino-3-(4-(thiomorpholinomethyl)phenyl)-lH-pyrazolo[3,4-d]pyrimidin-lyl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    1 -(5-(4-amino-3-(4-(( 1,1 -dioxidobenzo[d]isothiazol-2(3H)-yl)methyl)phenyl)-1Hpyrazolo[3,4-d]pyrimidin-1 -yl)hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)prop-2-en-1 -one;
    2- (4-( 1 -(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1 H-pyrazolo[3,4d]pyrimidin-3-yl)benzyl)isoindolin-1 -one.
    130
    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. 5. The pharmaceutical composition of a compound of Formula (I) as claimed in claim 1 which is useful for treating a disease, disorder or condition, which would benefit from inhibition of tyrosine kinase (s), such as BTK activity to provide clinical benefit in diseases such as autoimmune disorders, an inflammatory disease, or an allergy disease selected from rheumatoid arthritis or lupus erythromatosis, asthma, allergie rhinitis, B-cell proliférative disorder such as B-cell lymphoma, multiple sclerosis, mantle cell lymphoma, chronic lymphocytic lymphoma / leukemia, diffuse large B-cell lymphoma, Follicular lymphoma or chronic lymphocytic leukemia, B-cell prolymphocytic leukemia.
  6. 6. Use of a compound of Formula (I) according to any of the preceding claims or its suitable pharmaceutical composition for the treatment of a disease, disorder or condition, which would benefit from inhibition of tyrosine kinase (s), such as BTK activity.
  7. 7. A medicine for the treatment of a disease, disorder or condition, which would benefit from inhibition of tyrosine kinase (s), such as BTK activity, which comprises administering a therapeutically effective amount of compound of Formula (I) or its pharmaceutical composition as defined in any of the preceding claims to a patient or subject in need thereof.
  8. 8. Use of the compound of formula (I) as claim in 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 autoimmune and allergie disorders, such as rheumatoid arthritis, systemic lupus erythromatosis, scleroderma, asthma, allergie rhinitis, allergie eczema, B-cell lymphoma, multiple sclerosis, juvénile rheumatoid arthritis, juvénile 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.
OA1201600264 2014-02-03 2015-02-02 Heterocyclic compounds. OA17875A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN362/MUM/2014 2014-02-03
IN2271/MUM/2014 2014-07-11

Publications (1)

Publication Number Publication Date
OA17875A true OA17875A (en) 2018-02-16

Family

ID=

Similar Documents

Publication Publication Date Title
EP3102579B1 (en) Heterocyclic compounds
USRE48239E1 (en) Heteroaryl pyridone and aza-pyridone compounds
CN113024547B (en) Bicyclic heterocycles as FGFR4 inhibitors
TWI478714B (en) N-containing heteroaryl derivatives as jak3 kinase inhibitors
US9266883B2 (en) Ring-fused bicyclic pyridyl derivatives as FGFR4 inhibitors
KR101792837B1 (en) Imidazopyrazines for use as kinase inhibitors
DK3050882T3 (en) PIPERIDIN-4-YL-AZETIDINE DERIVATIVES AS JAK1 INHIBITORS
JP2021518395A (en) SHP2 Inhibitors and Their Use
TW202000669A (en) Indazole compounds and uses thereof
KR20100113567A (en) 3h-[1,2,3]triazolo[4,5-d]pyrimidine compounds, their use as mtor kinase and pi3 kinase inhibitors, and their syntheses
MX2014008605A (en) 3,5-disubstituted alkynylbenzene compound and salt thereof.
AU2006297351A1 (en) Deazapurines useful as inhibitors of janus kinases
JP5832664B2 (en) Inhibitor of breton-type tyrosine kinase
AU2012266941A1 (en) Substituted pyridopyrazines as novel Syk inhibitors
CA2708783A1 (en) Triazolotriazines and triazolopyrazines and the use thereof
US10961238B2 (en) Modulators of hedgehog (Hh) signaling pathway
JP6960064B2 (en) 7H-pyrrolo [2,3-d] pyrimidine-4-amine derivative
OA17875A (en) Heterocyclic compounds.
RU2785126C2 (en) New compounds and their pharmaceutical compositions for treatment of inflammatory diseases
RU2796605C2 (en) 7h-pyrrolo[2,3-d]pyrimidine-4-amine derivative
KR20160095167A (en) Heterocyclic compounds
TW202411229A (en) Novel compounds and pharmaceutical compositions thereof for the treatment of inflammatory disorders
NZ624021B2 (en) Heteroaryl pyridone and aza-pyridone compounds as inhibitors of btk activity