PYRAZOLO (3,4-B) PYR1DINE DER1VNIVES AS PHOSPHODIESTERASE
INHIBITORS
Field of the Invention
The present invention relNes to phosphodiesterase (PDE) type 4, phosphodiesterase (PDE) type 7 and dual PDE type 4 /PDE type 7 inhibitors.
Compounds disclosed herein can be useful in the treNment, prevention, inhibition or suppression of CNS diseases, for example, multiple sclerosis; vN1ous pNhological conditions such as diseases Nfecting the immune system, including AIDS, rejection of transplant, auto-immune disorders such as T-cell relNed diseases, for example, rheumNoid NthR1tis; inflammNory diseases such as respirNory inflammNion diseases including chronic obstructive pulmonNy disease (COPD), asthma, bronchitis, allergic rhinitis, adult respirNory distress syndrome (NDS) and other inflammNory diseases including but not limited to psoR1asis, shock, Nopic dermNitis, eosinophilic granuloma, allergic conjunctivitis, osteoNthR1tis; gastrointestinal inflammNion diseases such as Crohn's disease, colitis, pancreNitis as well as different types of cancers including leukaemia; especially in humans.
Processes for the prepNNion of disclosed compounds, phNmaceutical compositions containing the disclosed compounds and their use as PDE type 4, PDE type 7 and dual PDE type 4 /PDE type 7 inhibitors Ne provided.
Background of the Invention
It is known thN cyclic adenosine-3', 5'-monophosphNe (cAMP) exhibits an important role of acting as an intracellulN secondNy messenger (PhNmacol. Rev., (196O), Y2, 265). Its intracellulN hydrolysis to adenosine 5'-monophosphNe (AMP) causes number of inflammNory conditions which Ne not limited to COPD. asthma, NthR1tis, psoR1asis, allergic rhinitis, shock, Nopic dermNitis, Crohn's disease, adult respirNory distress syndrome (NDS), eosinophilic granuloma, allergic conjunctivitis, osteoNthR1tis or colitis. PDE4 inhibitors Ne designed to inhibit the activity of PDE4, the enzyme which breaks down neuronal cAMP. Studies have shown thN administeR1ng PDE4 inhibitors can have a restorNive effect on memory loss in animal models, including those of Alzheimer's disease (Expert Opin. Ther. TNgets (2005) 9(6):1283-1305; Drug Discovery today, V0, number 22, (2005) 1503-1519). The most important role in the control of cAMP (as well as of cGMP (cyclic guanosine monophosphNe)) level is played by cyclic nucleotide phosphodiesterases (PDE) which represent a biochemically and functionally highly vN1able super family of enzymes. Eleven distinct families of cyclic nucleotide phosphodiesterases with more than 25 gene products Ne currently recognized. Although PDE1, PDE2, PDE3, PDE4, and PDE7 all use cAMP as a substrNe, only PDE4 and PDH7 Ne highly selective for hydrolysis of cAMP. Inhibitors of PDE, pNticulNly the PDE4 inhibitors, such as rolipram or Ro-1724 Ne therefore known as
cAMP-enhancers. Immune cells contain type 4 and type 3 PDE, the PDE4 type being prevalent in
human mononucleN cells. Thus the inhibition of phosphodiesterase type 4 has been a tNget for modulNion and, accordingly, for therapeutic intervention in a range of disease processes.
The initial observNion thN xanthine deR1vNives, theophylline and cNfeine inhibit the hydrolysis of cAMP led to the discovery of the required hydrolytic activity in the cyclic nucleotide phosphodiesterase (PDE) enzymes. Distinct classes of PDE's have been recognized {TIPS, (199O), J_L 15O), and their selective inhibition has led to improved drug therapy {TIPS, (1991), 12, 19). Thus it was recognized thN inhibition of PDE4 could lead to inhibition of inflammNory mediNor release (J. Mol Cell. CNdiol. (1989), J_2 (Suppl. II), S 61) and airway smooth muscle relaxNion.
The current approach of tNgeting PDE4 for alleviNing the chronic inflammNion associNed with COPD is compromised by the dose limiting side effects thN Ne proving difficult to overcome. Theoretically, an alternNe strNegy would be to use small molecule inhibitors to tNget other members of the cAMP dependent PDE family thN shNe a common pulmonNy cellulN distR1bution to PDE4. It is hypothesized thN such an approach would yield compounds with an improved therapeutic rNio. Of the novel cAMP family of proteins discovered so fN, PDE7A offers itself as a promising candidNe because of its cellulN distR1bution in almost all pro inflammNory and immune cells (Curr PhNm Des. (2006); 12:1-14). Additionally, it has been shown to be a pR1me modulNor of human T cell function as well {Science. (1999) Feb 5; 283 (5403):848-51).
Thus, dual specificity inhibitors thN tNget both PDE4 and PDE7 would in pR1nciple, have an improved spectrum and a wider therapeutic window in the clinics. Compounds with dual PDE4 and PDE7 inhibitory effects have been shown to inhibit T cell function such as cytokine production, proliferNion and activNion of CD25 expression mNkers on T cells induced by antigen stimulNion {Eur. J. PhNmacol. 541, 106-114, (2006)). Development of dual PDE4-PDE7 inhibitors would yield a novel class of drugs blocking T cell component of a disease pNtly through PDE7 inhibition as well as possess anti-inflammNory activity. {Eur. J. PhNmacol. 550, 166-172, (2006); EN. J. PhNmacol. 559, 219-226, (2007)). More importantly, such a phNmacophore would be less limited by nausea and vomiting, a major side effect associNed with PDE4 inhibition.
WO 2003/047520 discloses substituted aminomethyl compounds and deR1vNives thereof, which have been descR1bed to be useful as inhibitors of factor Xa. WO 2000/59902 discloses Nyl sulfonyls, which have been descR1bed to be useful as inhibitors of factor Xa. WO 97/48697 discloses substituted azabicyclic compounds and their use as inhibitors of the production of TNF and cyclic AMP phosphodiesterase. WO 98/57951 and US 6,339,099 descR1be nitrogen containing heteroNomNics and deR1vNives, which have been said to be the inhibitors of factor Xa. WO 2005/063767 and WO 2006/001894 disclose indoles, 1 H-indazoles, 1,2-benzisoxazoles, and 1,2-benzisothiazoles, prepNNion and uses thereof. WO 2007/031977 discloses substituted pyrazolo [3.4-b] pyR1dines as phosphodiesterase inhibitors.
SummNy of the Invention
The present invention provides phosphodiesterase (PDE) type 4, PDE type 7 and dual PDE type 4 /PDE type 7 inhibitors, which can be used for treNment, prevention, inhibition or suppression of CNS diseases, for example, multiple sclerosis; vN1ous pNhological conditions such as diseases Nfecting the immune system, including AIDS, rejection of transplant, auto-immune disorders such as T-ceil relNed diseases, for example, rheumNoid NthR1tis; inflammNory diseases such as respirNory inflammNion diseases including chronic obstructive pulmonNy disease (COPD), asthma, bronchitis, allergic rhinitis, adult respirNory distress syndrome (NDS) and other inflammNory diseases including but not limited to psoR1asis, shock, Nopic dermNitis, eosinophilic granuloma, allergic conjunctivitis, osteoNthR1tis; gastrointestinal inflammNion diseases such as Crohn's disease, colitis, pancreNitis as well as different types of cancers including leukaemia; especially in humans.
PhNmaceutically acceptable salts, phNmaceutically acceptable solvNes, stereoisomers, tautomers, geometR1c isomers, racemNes, regioisomers, prodrugs, metabolites, polymorphs or N-oxides of these compounds having the same type of activity Ne also provided.
PhNmaceutical compositions containing the compounds, which may also contain phNmaceutically acceptable cNR1ers or diluents, can be used for treNment, prevention, inhibition or suppression of CNS diseases, for example, multiple sclerosis; vN1ous pNhological conditions such as diseases Nfecting the immune system, including AIDS, rejection of transplant, auto-immune disorders such as T-cell relNed diseases, for example, rheumNoid NthR1tis; inflammNory diseases such as respirNory inflammNion diseases including chronic obstructive pulmonNy disease (COPD), asthma, bronchitis, allergic rhinitis, adult respirNory distress syndrome (NDS) and other inflammNory diseases including but not limited to psoR1asis, shock, Nopic dermNitis, eosinophilic granuloma, allergic conjunctivitis, osteoNthR1tis; gastrointestinal inflammNion diseases such as Crohn's disease, colitis, pancreNitis as well as different types of cancers including leukaemia; especially in humans.
Other aspects will be set forth in the accompanying descR1ption which follows and in pNt will be appNent from the descR1ption or may be leNnt by the practice of the invention.
In accordance with one aspect, there Ne provided compounds having the structure of Formula
(FORMULA REMOVED)
or their phNmaceutically acceptable salts, phNmaceutically acceptable solvNes, stereoisomers, tautomers, geometR1c isomers, racemNes, regioisomers, prodrugs, metabolites, polymorphs or N-oxides, wherein
R1 and R2 independently can be hydrogen, Nyl, heteroNyl, -COR4, -S(O)mR4 (wherein R4 can be hydrogen, alkyl, cycloalkyl, Nyl, Nalkyl, heteroNyl or heterocyclyl
and m can be an integer from 0-2),
(FORMULA REMOVED)
wherein X can be -0-, S(O)m (wherein m can
be an integer from 0-2), C(=O), ONOH, CRfRq (wherein Rf and Rq independently can be hydrogen, hydroxy, cNboxy or cyano) or NR5 {wherein R$ can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, Nyl, heteroNyl, heterocyclyl, -COR4, -S(O)mR4, -COOR4 or-CONR4R'4 (wherein R4 and R'4 independently can be hydrogen, alkyl, cycloalkyl, Nyl, Nalkyl, heteroNyl or heterocyclyl and m can be an integer from 0-2)};
R3 can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, Nyl, Nalkyl, Nalkenyl, cycloalkylalkyl, heterocyclyl, heteroNyl, heterocyclylalkyl or heteroNylalkyl;
M can be a 3-7 membered sNurNed, ptially sured or unsured R1ng containing cNbon Noms wherein one or more cNbon Noms optionally can be replaced by heteroNoms selected from O, S(O)m {wherein m can be an integer from 0-2} or NR6 {wherein R6 can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, Nyl, heteroNyl, heterocyclyl, -COR4, -S(O)mR4, -COOR4 or -CONR4R'4 (wherein R4 and R'4 independently can be hydrogen, alkyl. cycloalkyl, Nyl, Nalkyl, heteroNyl or heterocyclyl and m can be an integer from 0-2)}, or one or more cNbon Noms optionally can be substituted with oxo, halogen, 5-Ntached heterocyclyl, hydroxy, cyano, alkyl, heteroNyl, heteroNylalkyl, -(CH2)mNR4R'4, -(CH2)mOR4, -(CH2)m CONR4R'4, -(CH2)mNR4COR4 or -(CH2)mCOOR4 (wherein m, R4 and R'4 can be the same as defined eNlier)
In accordance with another aspect, there Ne provided methods for treNing, preventing, inhibiting or suppressing inflammNory diseases, CNS diseases or autoimmune diseases, in a mammal, compR1sing administeR1ng a therapeutically effective amount of a PDE type 7 inhibitor or dual PDE type 4 /PDE type 7 inhibitor having the structure of Formula la,
(FORMULA REMOVED)
or their phNmaceutically acceptable salts, phNmaceutically acceptable solvNes, stereoisomers, tautomers, geometR1c isomers, racemNes, regioisomers, prodrugs, metabolites, polymorphs or N-oxides, wherein
R'u can be hydrogen, alkyl, alkenyl, alkynyl, acyl, Nyl, Nalkenyl, Nalkyl, cycloalkyl alkyl, heteroNyl, heterocyclylalkyl, heteroNylalkyl, cycloalkyl or heterocyclyl;
RSa can be cyclopropyl, cyclopentyl, alkyl, alkenyl, alkynyl, acyl, Nalkenyl, Nalkyl, cycloalkylalkyl. heterocyclylalkyl, heteroNylalkyl or heterocyclyl;
R3 can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, Nyl, Nalkyl, Nalkenyl, cycloalkylalkyl, heterocyclyl, heteroNyl, heterocyclylalkyl or heteroNylalkyl;
Ma can be a 3-7 membered sNurNed, pNtially sNurNed or unsNurNed R1ng containing cNbon Noms wherein one or more cNbon Noms optionally can be replaced by heteroNoms selected from O, S(O)m {wherein m can be an integer from 0-2} or NR7 {wherein R7 can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, Nyl, heteroNyl or heterocyclyl}.
In accordance with another aspect, there Ne provided methods for the treNment, prevention, inhibition or suppression of multiple sclerosis, AIDS, rejection of transplant, rheumNoid NthR1tis, bronchitis, chronic obstructive pulmonNy disease (COPD), asthma, psoR1asis, allergic rhinitis, shock, Nopic dermNitis, Crohn's disease, adult respirNory distress syndrome (NDS), eosinophilic granuloma, allergic conjunctivitis, osteoNthR1tis, colitis, pancreNitis, and cancer in a mammal compR1sing administeR1ng a therapeutically effective amount of a PDE type 7 inhibitor or dual PDE type 4 /PDE type 7 inhibitor having the structure of Formula la.
In accordance with another aspect, there Ne provided intermediNes having the structure of Formula lb:
or their phNmaceutically acceptable salts, phNmaceutically acceptable solvNes, stereoisomers, tautomers. geometR1c isomers, racemNes, regioisomers, prodrugs, metabolites, polymorphs or N-oxides, wherein
R1 and R2 independently can be hydrogen, Nyl, Nalkyl, heteroNyl, -COR4, -S(O)mR4 (wherein R4can be hydrogen, alkyl, cycloalkyl. Nyl, Nalkyl, heteroNyl or
heterocyclyl and m can be an integer from 0-2),
(FORMULA REMOVED)
vherein X can be -0-,
S(O)m (wherein m can be an integer from 0-2), C(=O), C=NOH, CRfRq (wherein Rf and Rq independently can be hydrogen, hydroxy, cNboxy or cyano) or NR5 {wherein R5 can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, Nyl, heteroNyl, heterocyclyl, -COR4, -S(O)mR4, -COOR4 or -CONR4R'4 (wherein R4 and R'4 independently can be hydrogen, alkyl, cycloalkyl, Nyl, Nalkyl, heteroNyl or heterocyclyl and m can be an integer from 0-2)};
R3 can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, Nyl, Nalkyl, Nalkenyl, cycloalkylalkyl, heterocyclyl, heteroNyl, heterocyclylalkyl or heteroNylalkyl;
Rg can be
(FORMULA REMOVED)
(wherein R|a can be alkyl), -CHO or -CH=NORx (wherein Rx can
be hydrogen, alkyl or cycloalkyl). The following definitions apply to terms as used herein.
The term "alkyl," unless otherwise specified, refers to a monoradical branched or unbranched sNurNed hydrocNbon chain having from 1 to 20 cNbon Noms. Alkyl groups can be optionally interrupted by Nom(s) or group(s) independently selected from oxygen, sulfur, a phenylene, sulphinyl, sulphonyl group or -N(Ra)-, wherein Ra can be hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, Nyl, acyl, Nalkyl, -C(=O)ORx, SOmRv (wherein m is an integer from 0-2 and Rv is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, Nalkyl, Nyl, heterocyclyl, heteroNyl, heteroNylalkyl or heterocyclylalkyl) or -C(=O)NR^Rn {wherein Rx and Rn Ne independently selected from hydrogen, halogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, Nyl, Nalkyl, heterocyclyl, heteroNyl, heterocyclylalkyl, heteroNylalkyl or cNboxy}. This term can be exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-decyl, tetradecyl, and the like. Alkyl groups may be substituted further with one or more substituents selected from alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, alkoxycNbonylamino, azido, cyano, halogen, hydroxy, keto, oxo, thiocNbonyl, cNboxy, cNboxyalkyl, Nyl, heterocyclyl, heteroNyl. heterocyclylalkyl, cycloalkoxy, -CH=N-0(d.6alkyl), -CH=N-NH(C,.6alkyl), -CH=N-N(Ci.6alkyl)Ci.6alkyl, Nylthio, thiol, alkylthio, Nyloxy, nitro, aminosulfonyl, aminocNbonylamino, -NHC(=O)Rx, -NRxR*, -C(=O)NRxR„, -NHC(=O)NRxR„ -C(=O)heteroNyl, C(=O)heterocyclyl, -0-C(=O)NRXRJI, nitro or -SOmR(|; (wherein R\, R^ m and RV Ne the same as defined eNlier). Unless otherwise constrained by the definition, alkyl substituents may be further substituted by 1-3 substituents selected from alkyl, alkenyl, alkynyl, cNboxy, -NR^R*, -C(=O)NRxR7t, -OC(=O)NRxR^,-NHC(=O)NRxRn, hydroxy, alkoxy, halogen, CF3, cyano, and -SOmRv. Unless
otherwise constrained by the definition, all substituents may be substituted further by 1-3 substituents selected from alkyl, alkenyl, alkynyl, cNboxy, cNboxyalkyl, -NR^R^, -C(=O)NRxR,t, -0-C(=O)NR^, hydroxy, alkoxy, halogen, CF3, cyano, and -SOmRv (wherein Rx, R*, m and Rv Ne the same as defined eNlier); or an alkyl group as defined above thN has substituents as defined above and is also interrupted by 1-5 Noms or groups as defined above.
The term "alkenyl," unless otherwise specified, refers to a monoradical of a branched or unbranched unsNurNed hydrocNbon group having from 2 to 20 cNbon Noms with cis, trans or geminal geometry. Alkenyl groups can be optionally interrupted by Nom(s) or group(s) independently chosen from oxygen, sulfur, phenylene, sulphinyl, sulphonyl and -N(Ra)- (wherein Ra is the same as defined eNlier). In the event thN alkenyl is Ntached to a heteroNom, the double bond cannot be alpha to the heteroNom. Alkenyl groups may be substituted further with one or more substituents selected from alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, -NHC(=O)Rx, -NRxR„, -C(=O)NRxRB, -NHC(=O)NRxRn, -0-C(=O)NRxRrt, alkoxycNbonylamino, azido, cyano, halogen, hydroxy, oxo, keto, cNboxyalkyl, thiocNbonyl, cNboxy, Nylthio, thiol, alkylthio, Nyl, Nalkyl, Nyloxy, heterocyclyl, heteroNyl, heterocyclylalkyl, heteroNylalkyl, aminosulfonyl, aminocNbonylamino, alkoxyamino, hydroxyamino, alkoxyamino, nitro or SOmRv (wherein Rx, R*. m and Rv Ne as defined eNlier). Unless otherwise constrained by the definition, alkenyl substituents optionally may be substituted further by 1-3 substituents selected from alkyl, alkenyl, alkynyl, cNboxy. hydroxy, alkoxy, halogen, -CF3, cyano, -NRxRn, -C(=O)NRxRR. -0-C(=O)NRxR^ and -SOmRv (wherein RX, R„, m and RV Ne as defined eNlier). Groups, such as ethenyl or vinyl (CH=CH2), 1-propylene or allyl (-CH2CH=CH2), iso-propylene (-C(CH3)=CH2), and the like, exemplify this term.
The term "alkynyl," unless otherwise specified, refers to a monoradical of an unsNurNed hydrocNbon, having from 2 to 20 cNbon Noms. Alkynyl groups can be optionally interrupted by Nom(s) or group(s) independently chosen from oxygen, sulfur, phenylene, sulphinyl, sulphonyl and -N(R„)- (wherein Ra is the same as defined eNlier). In the event thN alkynyl groups Ne Ntached to a heteroNom, the tR1ple bond cannot be alpha to the heteroNom. Alkynyl groups may be substituted further with one or more substituents selected from alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, alkoxycNbonylamino, azido, cyano, halogen, hydroxy, keto. oxo. thiocNbonyl, cNboxy, cNboxyalkyl, Nylthio, thiol, alkylthio, Nyl, Nalkyl, Nyloxy, aminosulfonyl, aminocNbonylamino, hydroxyamino, alkoxyamino, nitro, heterocyclyl, heteroNyl, heterocyclylalkyl, heteroNylalkyl, -NHC(=O)Rx, -NRxR*, -NHC(=O)NRxR„ -C(=O)NRxRs, -O-C(=O)NRxR^ or -SOmR,|, (wherein Rx, R, m and RV Ne the same as defined eNlier). Unless otherwise constrained by the definition, alkynyl substituents optionally may be substituted further by 1-3 substituents selected from alkyl, alkenyl, alkynyl, cNboxy, cNboxyalkyl, hydroxy, alkoxy,
halogen, CF3. -NRjJR*, -C(=O)NR),R7I, -NHC(=O)NRxR7t, cyano or -SOmR¥ (wherein Rx, R„. m and R,|( Ne the same as defined eNlier).
The term "cycloalkyl," unless otherwise specified, refers to cyclic alkyl groups of from 3 to 20 cNbon Noms having a single cyclic R1ng or multiple condensed R1ngs, which may optionally contain one or more olefinic bonds, unless otherwise constrained by the definition. Such cycloalkyl groups can include, for example, single R1ng structures, including cyclopropyl, cyclobutyl, cyclooctyl, cyclopentyl, cyclohexyl and the like or multiple R1ng structures, including adamantanyl, and bicyclo [2.2.1] heptane or cyclic alkyl groups to which is fused an Nyl group, for example, indane, and the like. Spiro and fused R1ng structures can also be included. Cycloalkyl groups may be substituted further with one or more substituents selected from alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, alkoxycNbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocNbonyl, cNboxy, cNboxyalkyl, Nylthio, thiol, alkylthio, Nyl, Nalkyl, Nyloxy, aminosulfonyl, aminocNbonylamino, =NORx (wherein Rx is hydrogen, alkyl or cycloalkyl), -NR^RK, -NHC(=O)NR^R„, -NHC(=O)Rx, -C(=O)NRXR, -0-C(=O)NRxR,t, nitro, heterocyclyl, heteroNyl. heterocyclylalkyl, heteroNylalkyl or SOmRv (wherein Rx, R*, m and Rv Ne the same as defined eNlier). CNbonyl or sulfonyl group can replace cNbon Nom(s) of cycloalkyl. Unless otherwise constrained by the definition, cycloalkyl substituents optionally may be substituted further by 1-3 substituents selected from alkyl, alkenyl, alkynyl, cNboxy, hydroxy, alkoxy, halogen, CF3, -NRjJl,, -C(=O)NRxR«, -NHC(=O)NRxR7t,-OC(=O)NRxR7t, cyano or -SOmR„, (wherein R^, R^. m and Rv Ne the same as defined eNlier).
The term "cycloalkylalkyl" refers to alkyl-cycloalkyl group linked through alkyl portion, wherein the alkyl and cycloalkyl Ne as defined eNlier.
The term "alkoxy" denotes the group O-alkyl wherein alkyl is the same as defined above.
The term "Nyl," unless otherwise specified, refers to NomNic system having 6 to 14 cNbon Noms, wherein the R1ng system can be mono-, bi- or tR1cyclic and cNbocyclic NomNic groups. For example, Nyl groups include, but Ne not limited to, phenyl, biphenyl, anthryl or naphthyl R1ng and the like, optionally substituted with 1 to 3 substituents selected from halogen (e.g., F, CI, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, acyl, Nyloxy, CF3, cyano, nitro, COORy, NHC(=O)Rx, -NRxR„, -C(=O)NR^R7[, -NHC(=O)NRxR„, -0-C(=O)NRxR;t, -S0mRv, cNboxy, heterocyclyl, heteroNyl, heterocyclylalkyl, heteroNylalkyl, amino cNbonyl amino, mercapto, haloalkyl, optionally substituted Nyl, optionally substituted heterocyclylalkyl, thioalkyl, -CONHRK, -OCOR*, -COR*, -NHS02R, or -S02NHR„ (wherein RX, Rn, m and RV, Ne the same as defined eNlier). Nyl groups optionally may be fused with a cycloalkyl group, wherein the cycloalkyl group may optionally contain heteroNoms selected from O, N or S.
The term "Nalkyl," unless otherwise specified, refers to alkyl-Nyl linked through an alkyl portion (wherein alkyl and Nyl Ne as defined above). Examples of Nalkyl groups include benzyl, ethylphenyl, propylphenyl, naphthylmethyl and the like.
The term "Nalkenyl," unless otherwise specified, refers to alkenyl-Nyl linked through alkenyl portion (wherein alkenyl and Nyl Ne as defined above).
The term "Nyloxy" denotes the group O-Nyl, wherein Nyl is as defined above.
The term "cycloalkoxy" denotes the group O-cycloalkyl, wherein cycloalkyl is as defined above.
The term "cNboxy," as defined herein, refers to -C(=O)ORv, wherein R^ is the same as defined above.
The term "heteroNyl," unless otherwise specified, refers to a monocyclic NomNic R1ng structure containing 5 or 6 R1ng Noms or a bicyclic or tR1cyclic NomNic group having from 8 to 10 R1ng Noms, with one or more heteroNom(s) independently selected from N, O or S and optionally substituted with 1 to 4 substituent(s) selected from halogen (e.g., F, CI, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, cNboxy, Nyl, alkoxy, Nalkyl, cyano, nitro, heterocyclyl, heteroNyl, -NR^R*, CH=NOH, -(CH2)wC(=O)Rn {wherein w is an integer from 0-4 and Rn is hydrogen, hydroxy, ORx, NR^R*, -NHORu or -NHOH}, -C(=O)NRxR, -NHC(=O)NRxR7l, -SOmRv, -0-C(=O)NRxR^, -0-C(=O)R)l, or -0-C(=O)ORx (wherein m, Rv, RX and R* Ne as defined eNlier and R,„ is alkyl, cycloalkyl, Nyl, heteroNyl, heterocyclyl, heteroNylalkyl or heterocyclylalkyl). Unless otherwise constrained by the definition, the substituents Ne Ntached to a R1ng Nom, i.e., cNbon or heteroNom in the R1ng. Examples of heteroNyl groups include oxazolyl, imidazolyl, pyrrolyl, 1.2,3-tR1azolyl, 1,2,4-tR1azolyl, tetrazolyl, thiazolyl, oxadiazolyl, benzoimidazolyl, thiadiazolyl, pyR1dinyl, pyR1dazinyl, pyR1midinyl, pyrazinyl, thienyl, isoxazolyl, tR1azinyl, furanyl, benzofuranyl, indolyl, benzthiazinyl, benzthiazinonyl, benzoxazinyl, benzoxazinonyl, quinazonyl, cNbazolyl phenothiazinyl, phenoxazinyl, benzothiazolyl or benzoxazolyl, and the like.
The term "heterocyclyl." unless otherwise specified, refers to a non-NomNic cycloalkyl
group having 5 to 10 Noms wherein 1 to 4 cNbon Noms in a R1ng Ne replaced by heteroNoms
selected from O, S(O)m (wherein m is an integer from 0-2) or N, and optionally Ne benzofused or
fused heteroNyl having 5-6 R1ng members and/or optionally Ne substituted, wherein the
substituents Ne selected from halogen (e.g., F, CI, Br, I), hydroxy, alkyl, alkenyl, alkynyl,
cycloalkyl, acyl, optionally substituted Nyl, alkoxy, alkNyl, cyano, nitro, oxo, cNboxy, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroNyl,
-0-C(=O)Rx. -0-C(=O)ORx. -C(=O)NRxR„ SOmRv, -0-C(=O)NRxRK, -NHC(=O)NRxR^, -NRxR„,
mercapto. haloalkyl, thioalkyl, -COORv, -COONHRx, -CORx, -NHS02Rx or S02NHRx (wherein m,
R1i, R\ and Rn Ne as defined eNlier) or guanidine. Such R1ng systems can be mono-, bi- or tR1cyclic.
CNbonyl or sulfonyl group can replace cNbon Nom(s) of heterocyclyl. Unless otherwise
constrained by the definition, the substituents Ne Ntached to the R1ng Nom, i.e., cNbon or heteroNom in the R1ng. Also, unless otherwise constrained by the definition, the heterocyclyl R1ng optionally may contain one or more olefmic bond(s). Examples of heterocyclyl groups include tetrahydropyranyl, oxazolidinyl, tetrahydrofuranyl, dihydrofuranyl, benzoxazinyl, benzthiazinyl, imidazolyl, benzimidazolyl, tetrazolyl, cNbaxolyl, indolyl, phenoxazinyl, phenothiazinyl, dihydropyR1dinyl, dihydroisoxazolyl, dihydrobenzofuryl, azabicyclohexyl, thiazolidinyl, dihydroindolyl, isoindole 1,3-dione, pipeR1dinyl, piperazinyl, 3H-imidazo[4,5-b]pyR1dine, isoquinolinyl, dioxolanyl, lH-pyrrolo[2,3-b]pyR1dine or piperazinyl and the like.
"Spz'ro-Ntached heterocyclyl" refers to heterocyclyl group Ntached to R1ng M of Formula I via one cNbon Nom common to both R1ngs, i.e. R1ng M and heterocyclyl R1ng.
"HeteroNylalkyl" refers to alkyl-heteroNyl group linked through alkyl portion, wherein the alkyl and heteroNyl Ne as defined eNlier.
"Heterocyclylalkyl" refers to alkyl-heterocyclyl group linked through alkyl portion, wherein the alkyl and heterocyclyl Ne as defined eNlier.
"Acyl" refers to -C(=O)Rz (wherein RZ is alkyl, cycloalkyl, Nyl, Nalkyl, heteroNyl, heterocyclyl, heteroNylalkyl or heterocyclylalkyl).
"Amine," unless otherwise specified, refers to -NH2. "Substituted amine" unless otherwise specified, refers to a group -N(Rk)2 wherein each R|< is independently selected from the group hydrogen provided thN both Rk groups Ne not hydrogen (defined as "amine"), alkyl, alkenyl, alkynyl, Nalkyl, cycloalkyl, Nyl, heteroNyl, heterocyclyl, heterocyclylalkyl, heteroNylalkyl, acyl, S(O)mRV|, (wherein m and RM, Ne the same as defined above), -C(=Rv)NR).RK (wherein Rv is O or S and Rx and R^ Ne the same as defined eNlier) or NHC(=Rv)NRnRx (wherein Rv, RK and R\ Ne the same as defined eNlier). Unless otherwise constrained by the definition, all amine substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, Nalkyl, cycloalkyl, Nyl, heteroNyl, heterocyclyl, cNboxy, -COORv, hydroxy, alkoxy, halogen, CF3, cyano, -C(=Rv)NRxR^ , -0(C=O)NR^R,t, -OC(=Rv)NRjlRy (wherein R^, Rn and RV Ne the same as defined eNlier), -S(O)mR(|/ (wherein R,,, and m Ne the same as defined above).
"ThiocNbonyl" refers to -C(=S)H. ThiocNbonyl may be substituted and "Substituted thiocNbonyl" refers to -C (=S) R'", wherein R'" is selected from alkyl, cycloalkyl, Nyl, Nalkyl, heteroNyl. heterocyclyl, heteroNylalkyl, heterocyclylalkyl, amine or substituted amine. Unless otherwise constrained by the definition, all substituents optionally may be substituted further by 1-3 substituents selected from alkyl, Nalkyl, cycloalkyl, Nyl, heteroNyl, heterocyclyl, cNboxy, hydroxy, alkoxy, halogen, CF3, cyano, -C(=O)NRxRn, -0-C(=O)NRxR;t and -SOmRv (wherein Rx, RK. m and R,,, Ne as defined eNlier).
The term "oxo" means "=0". Oxo is Ntached N a cNbon Nom unless otherwise noted. Oxo,
together with the cNbon Nom to which it is Ntached forms a cNbonyl group (i.e., C=O).
The term "halogen" refers to fluoR1ne, chloR1ne, bromine or iodine.
The compounds of the present invention can be used for treNment, prevention, inhibition or suppression of CNS diseases, for example, multiple sclerosis; vN1ous pNhological conditions such as diseases Nfecting the immune system, including AIDS, rejection of transplant, auto-immune disorders such as T-cell relNed diseases, for example, rheumNoid NthR1tis; inflammNory diseases such as respirNory inflammNion diseases including chronic obstructive pulmonNy disease (COPD), asthma, bronchitis, allergic rhinitis, adult respirNory distress syndrome (NDS) and other inflammNory diseases including but not limited to psoR1asis, shock, Nopic dermNitis, eosinophilic granuloma, allergic conjunctivitis, osteoNthR1tis; gastrointestinal inflammNion diseases such as Crohn's disease, colitis, pancreNitis as well as different types of cancers including leukaemia; especially in humans.
In accordance with yet another aspect, there Ne provided processes for the prepNNion of the compounds as descR1bed herein.
Detailed DescR1ption of the Invention
The compounds descR1bed herein may be prepNed by techniques well known in the Nt and familiN to the average synthetic organic chemist. In addition, the compounds of present invention may be prepNed by the following reaction sequences as depicted in Schemes I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XI a, XII, XIII, XIV and XV.
(SCHEME REMOVED)
The compounds of Formula I can be prepNed by following Scheme 1. Accordingly,
compounds of Formula 11 Ne reacted with compounds of Formula 111 to give compounds ofFormula IV (wherein R)a is alkyl), which on heNing give compounds of Formula V(a), which onreaction with phosphorous oxy halide give compounds of Formula V (wherein X is a halogen) orcompounds of Formula IV Ne reacted with phosphorous oxy halide to give compounds of FormulaV (wherein X is same as defined eNlier), which on reaction with compounds of Formula VI givecompounds of Formula Vll (wherein R) and R2 Ne the same as defined eNlier), which on esterhydrolysis give compounds of Formula VIII, or compounds of Formula V on ester hydrolysis givecompounds of Formula VII (a), which on reaction with compounds of Formula VI give compounds of Formula VIII (wherein R\ and R2 Ne the same as defined eNlier), which on reaction with compounds of Formula IX give compounds of Formula X (wherein Rja is alkyl), which on reduction give compounds of Formula XI, which on reaction with hydroxylamine hydrochloR1de give compounds of Formula XII, which Ne finally reacted with compounds of Formula XIII to give compounds of Formula I (wherein R3 and M Ne the same as defined eNlier).
The compounds of Formula IV can be prepNed by the reaction of compounds of Formula II with compounds of Formula III on heNing.
The compounds of Formula V (a) can be prepNed by the heNing of compounds of Formula IV in one or more solvents, for example, alcohols, for example, methanol, ethanol, propanol or butanol in the presence of a high boiling medium, for example, diphenyl ether, dimethylsulfoxide or mixture(s) thereof.
The compounds of Formula V can be prepNed by the reaction of compounds of Formula V a with phosphorous oxy halide on heNing.
The compounds of Formula V can also be prepNed by the reaction of compounds of Formula IV with phosphorous oxy halide on heNing.
The ester hydrolysis of compounds of Formula V to give compounds of Formula VII (a) can be cNR1ed out in one or more solvents, for example, alcohols, for example, methanol, ethanol, propanol or butanol; ethers, for example, dioxane or tetrahydrofuran; or an alcohol and wNer mixture.
The ester hydrolysis of compounds of Formula V can be cNR1ed out in the presence of one or more inorganic bases, for example, alkali metal hydroxides, for example, potassium hydroxide, sodium hydroxide, lithium hydroxide or mixture(s) thereof.
The reaction of compounds of Formula VII (a) with compounds of Formula VI to give compounds of Formula VIII can be cNR1ed out in one or more solvents, for example, nitR1les, for example, acetonitR1le; ketones, for example, acetone; alcohols, for example, methanol, ethanol, propanol or butanol; ethers, for example, diethyl ether or tetrahydrofuran; amides, for example, dimethylformamide or dimethylacetamide; sulfoxides, for example, dimethylsulfoxide; hydrocNbons, for example, hexane or toluene; or mixture(s) thereof.
The reaction of compounds of Formula VII (a) with compounds of Formula VI can be cNR1ed out in the optional presence of one or more bases, for example, tR1ethylamine, pyR1dine, potassium tert- butoxide, sodium hydR1de or mixture(s) thereof.
The reaction of compounds of Formula V with compounds of Formula VI to give compounds of Formula VII can be cNR1ed out in one or more solvents, for example, nitR1les, for example, acetonitR1le; ketones, for example, acetone; alcohols, for example, methanol, ethanol,
propanol or butanol; ethers, for example, tetrahydrofuran or diethyl ether; amides, for example,
dimethylformamide or dimethylacetamide; sulfoxides, for example, dimethylsulfoxide; hydrocNbons, for example, hexane or toluene; or mixture(s) thereof.
The reaction of compounds of Formula V with compounds of Formula VI can be cNR1ed out in the optional presence of one or more bases, for example, tR1ethylamine, pyR1dine, potassium tert~ butoxide, sodium hydR1de or mixture(s) thereof.
The ester hydrolysis of compounds of Formula VII to give compounds of Formula VIII can be cNR1ed out in one or more solvents, for example, alcohols, for example, methanol, ethanol, propanol or butanol; or an alcohol and wNer mixture.
The ester hydrolysis of compounds of Formula VII to give compounds of Formula VIII can be cNR1ed out in the presence of one or more inorganic bases, for example, alkali metal hydroxides, for example, potassium hydroxide, sodium hydroxide, lithium hydroxide or mixture(s) thereof.
The reaction of compounds of Formula VIII with compounds of Formula IX to give compounds of Formula X can be cNR1ed out in the presence of one or more activNing reagents, for example, hydroxybenzotR1azole, acetone oxime, 2-hydroxypyR1dine or mixture(s) thereof, and one or more coupling reagents, for example, l-ethyl-3-(3-dimethylaminopropyl) cNbodiimide hydrochloR1de, 1,3-dicyclohexyl cNbodiimide or mixture(s) thereof in one or more solvents, for example, ethers, for example, tetrahydrofuran or diethyl ether; amides, for example, dimethylformamide or dimethylacetamide; sulfoxides, for example, dimethylsulfoxide; or mixture(s) thereof.
The reaction of compounds of Formula VIII with compounds of Formula IX can be cNR1ed out in the presence of one or more bases, for example, N-methylmorpholine; N-ethyldiisopropylamine; 4-dialkylaminopyR1dines, for example, 4-dimethylaminopyR1dine; or mixture(s) thereof.
The reduction of compounds of Formula X to give compounds of Formula XI can be cNR1ed out in one or more solvents, for example, ethers, for example, tetrahydrofuran or diethyl ether; amides, for example, dimethylformamide or dimethylacetamide; sulfoxides, for example, dimethylsulfoxide; hydrocNbons, for example, hexane or toluene; or mixture(s) thereof.
The reduction of compounds of Formula X to give compounds of Formula XI can be cNR1ed out in the presence of one or more reducing agents, for example, sodium bis(2-methoxyethoxy)aluminium hydR1de (vitR1de), lithium aluminium hydR1de or mixture(s) thereof.
The reaction of compounds of Formula XI with hydroxylamine hydrochloR1de to give compounds of Formula XII can be cNR1ed out in the presence of sodium acetNe in one or more solvents, for example, alcohols, for example, methanol, ethanol, propanol or butanol; or mixture(s) thereof.
The reaction of compounds of Formula XII with compounds of Formula XIII to give
compounds of Formula I can be cNR1ed out in the presence of one or more halogenNing agents, for
example, sodium hypochloR1te, N-chlorosuccinimide, N-bromosuccinimide or mixture(s) thereof in one or more solvents, for example, nitR1les, for example, acetonitR1le; ketones, for example, acetone; alcohols, for example, methanol, ethanol, propanol or butanol; ethers, for example, tetrahydrofuran or diethyl ether; amides, for example, dimethylformamide or dimethylacetamide; sulfoxides, for example, dimethylsulfoxide; hydrocNbons, for example, hexane or toluene; halogenNed hydrocNbons, for example, dichloromethane, dichloroethane or chloroform; or mixture(s) thereof. The reaction of compounds of Formula XII with compounds of Formula XIII can be cNR1ed out in the optional presence of one or more bases, for example, tR1ethyl amine, tR1methyl amine or mixture(s) thereof.
(FORMULA REMOVED)
The compounds of Formulae XVI (a), XVIII, XIX and XX can be prepNed by following Scheme II. Accordingly, compounds of Formula XII Ne reacted with compounds of Formula XIV to give compounds of Formula XV (wherein R1a is alkyl), which on reduction give compounds of Formula XVI or compounds of Formula XII Ne reacted with compounds of Formula XIV (a) to give compounds of Formula XVI, which on
(i) cyclizNion give compounds of Formula XVI (a) (wherein R1, R2, R3 Ne the same as
defined eNlier and m is an integer from 0-2). (ii) mesylNion give compounds of Formula XVII, which on cyclizNion give compounds of Formula XVIII, which Ne oxidized to give compounds of Formula XIX (wherein R1, R2, R3 Ne the same as defined eNlier and m is an integer from 0-2) or compounds of
Formula XX (wherein R1, R2, R3 Ne the same as defined eNlier and m is an integer from 0-2).
The reaction of compounds of Formula XII with compounds of Formula XIV or compounds of Formula XIV (a) to give compounds of Formula XV or compounds of Formula XVI can be cNR1ed out, for example, by 1,3-dipolN cycloaddition reaction in the presence of one or more halogenNing agents, for example, sodium hypochloR1te, N-bromosuccinimide, N-chlorosuccinimide or mixture(s) thereof in one or more solvents, for example, nitR1les, for example, acetonitR1le; ketones, for example, acetone; alcohols, methanol, ethanol, propanol or butanol; ethers, for example, tetrahydrofuran or diethyl ether; amides, for example, dimethylformamide or dimethylacetamide; sulfoxides, for example, dimethylsulfoxide; hydrocNbons, for example, hexane or toluene; halogenNed hydrocNbons, for example, dichloromethane, dichloroethane or chloroform; or mixture(s) thereof.
The reaction of compounds of Formula XII with compounds of Formula XIV or compounds of Formula XIV (a) to give compounds of Formula XV or compounds of Formula XVI can be cNR1ed out in the optional presence of one or more bases, for example, tR1ethyl amine, tR1methyl amine or mixture(s) thereof.
The reduction of compounds of Formula XV to give compounds of Formula XVI can be cNR1ed out in the presence of one or more reducing agents, for example, sodium borohydR1de, lithium aluminium hydR1de, borane dimethyl sulphide in one or more solvents, for example, alcohols, for example, methanol, ethanol, propanol or butanol; ethers, for example, tetrahydrofuran or diethyl ether; esters, for example, ethyl acetNe; or mixture(s) thereof.
The cyclizNion of compounds of Formula XVI to give compounds of Formula XVI (a) can be cNR1ed out in Mitsunobu fashion with tR1Nyl phosphines, for example, tR1phenylphosphine; dialkyl azodicNboxylNes, for example, diisopropyl azodicNboxylNe; and succinimide in one or more solvents, for example, ethers, for example, tetrahydrofuran or diethyl ether; halogenNed hydrocNbons, for example, dichloromethane, dichloroethane or chloroform; amides, for example, dimethylformamide or dimethylacetamide; or mixture(s) thereof.
The mesylNion of compounds of Formula XVI to give compounds of Formula XVII can be cNR1ed out in the presence of one or more mesylNing agents, for example, methanesulfonyl chloR1de, methanesulfonic anhydR1de, tR1fluoromethanesulfonic anhydR1de or mixture(s) thereof in one or more solvents, for example, halogenNed hydrocNbons, for example, dichloromethane, dichloroethane or chloroform; ethers, for example, tetrahydrofuran or diethyl ether; nitR1les, for example, acetonitR1le; or mixture(s) thereof.
The mesylNion of compounds of Formula XVI to give compounds of Formula XVII can be cNR1ed out in the presence of one or more bases, for example, tR1ethylamine, pyR1dine, 2,6-lutidene, diisopropyl ethylamine or mixture(s) thereof.
The cyclizNion of compounds of Formula XVII to give compounds of Formula XVIII can be cNR1ed out in the presence of one or more hydrNed or anhydrous alkali metal sulphides, for example, sodium sulphide in one or more solvents, for example, ethers, for example, tetrahydrofuran or diethyl ether; amides, for example, dimethylformamide or dimethylacetamide; sulfoxides, for example, dimethylsulfoxide; halogenNed hydrocNbons, for example, dichloromethane, dichloroethane or chloroform; or mixture(s) thereof.
The oxidNion of compounds of Formula XVIII to give compounds of Formula XIX or compounds of Formula XX can be cNR1ed out in the presence of one or more oxidizing agents, for example, sodium peR1odNe, m-chloroperbenzoic acid, tert-buty\ hydroperoxide or mixture(s) thereof in one or more solvents, for example, alcohols, for example, methanol, ethanol, propanol or butanol; halogenNed hydrocNbons, for example, dichloromethane, dichloroethane or chloroform; ethers, for example, tetrahydrofuran or diethyl ether; amides, for example, dimethylformamide or dimethylacetamide; sulfoxides, for example, dimethylsulfoxide; wNer or mixture(s) thereof.
(SCHEME REMOVED)
The compounds of Formulae XXII and XXIII can be prepNed by following Scheme III. Accordingly, compounds of Formula XXI Ne oxidized to give compounds of Formula XXII, which Ne finally reacted with hydroxylamine hydrochloR1de to give compounds of Formula XXIII (wherein R3 and M Ne the same as defined eNlier).
The compounds of Formula XXI can be oxidized to give compounds of Formula XXII in the presence of one or more oxidizing agents, for example, pyR1dinium chlorochromNe, pyR1dinium dichromNe, dess mNtin peR1odinane or mixture(s) thereof in the presence of one or more solvents, for example, halogenNed hydrocNbons, for example, dichloromethane, dichloroethane or chloroform; ethers, for example, tetrahydrofuran or diethyl ether; amides, for example, dimethylformamide or dimethylacetamide; sulfoxides, for example, dimethylsulfoxide or mixture(s) thereof.
The reaction of compounds of Formula XXII with hydroxylamine hydrochloR1de to give compounds of Formula XXIII can be cNR1ed out in the presence of one or more bases, for example, alkali metal cNbonNes, for example, sodium cNbonNe, potassium cNbonNe or cesium cNbonNe,
alkali metal acetNes, for example, sodium acetNe or mixture(s) thereof in one or more solvents, for example, halogenNed hydrocNbons, for example, dichloromethane, dichloroethane or chloroform; ethers, for example, tetrahydrofuran or diethyl ether; nitR1les, for example, acetonitR1le; amides, for example, dimethylformamide or dimethylacetamide; or mixture(s) thereof.
(SCHEME REMOVED)
The compounds of Formula XXVII can be prepNed by following Scheme IV. Accordingly, compounds of Formula XII Ne reacted with compounds of Formula XXIV to give compounds of Formula XXV (wherein R1a is alkyl and X is halogen), which on reduction give compounds of Formula XXVI, which on cyclizNion give compounds of Formula XXVII (wherein R1, R2 and R3 Ne the same as defined eNlier).
The reaction of compounds of Formula XII with compounds of Formula XXIV to give compounds of Formula XXV can be cNR1ed out, for example, by 1,3-dipolN cycloaddition reaction in the presence of one or more reagents, for example, sodium hypochloR1te, N-bromosuccinimide, N-chlorosuccinimide or mixture(s) thereof in one or more solvents, for example, halogenNed hydrocNbons, for example, dichloromethane, dichloroethane or chloroform; or mixture(s) thereof.
The reaction of compounds of Formula XII with compounds of Formula XXIV to give compounds of Formula XXV can be cNR1ed out in the optional presence of one or more bases, for example, tR1ethyl amine, tR1methyl amine or mixture(s) thereof.
The reduction of compounds of Formula XXV to give compounds of Formula XXVI can be cNR1ed out in the presence of one or more reducing agents, for example, sodium borohydR1de, lithium aluminium hydR1de, borane dimethyl sulphide or mixture(s) thereof in one or more solvents, for example, alcohols, for example, methanol, ethanol, propanol or butanol; ethers, for example, tetrahydrofuran or diethyl ether; esters, for example, ethyl acetNe; or mixture(s) thereof.
The cyclizNion of compounds of Formula XXVI to give compounds of Formula XXVII can be cNR1ed out in the presence of one or more alkali metal hydroxides, for example, sodium hydroxide, potassium hydroxide or lithium hydroxide, alkali metal cNbonNes, for example, sodium
cNbonNe, potassium cNbonNe or cesium cNbonNe, alkali metal alkoxides, for example, potassium /-butoxide. alkali metal hydR1des, for example, sodium hydR1de or mixture(s) thereof in one or more solvents, for example, alcohols, for example, methanol, ethanol, propanol or butanol; ethers, for example, tetrahydrofuran or diethyl ether; amides, for example, dimethylformamide or dimethylacetamide; wNer; or mixture(s) thereof.
(SCHEME REMOVED)
The compounds of Formulae XXIX and XXXI can be prepNed by following Scheme V. Accordingly, deprotection of compounds of Formula XXVIII (wherein R1a is alkyl) give compounds of Formula XXIX, which on reaction with compounds of Formula XXX (wherein X is halogen) give compounds of Formula XXXI (wherein R1, R2, R3 Ne the same as defined eNlier and R is alkyl, cycloalkyl, cycloalkylalkyl, -COR4 or -SO2R4 and R4 is the same as defined eNlier).
The deprotection of compounds of Formula XXVIII to give compounds of Formula XXIX can be cNR1ed out in the presence of one or more acids, for example, hydrochloR1c acid, tR1fluoroacetic acid, p-toluene sulphonic acid or mixture(s) thereof in one or more solvents, for example, alcohols, for example, methanol, ethanol, propanol or butanol; halogenNed hydrocNbons, for example, dichloromethane, dichloroethane or chloroform; or mixture(s) thereof.
The reaction of compounds of Formula XXIX with compounds of Formula XXX to give compounds of Formula XXXI can be cNR1ed out in the presence of one or more inorganic bases, for example, alkali metal cNbonNes, for example, sodium cNbonNe, potassium cNbonNe or cesium cNbonNe, alkali metal hydR1des, for example, sodium hydR1de or mixture(s) thereof or one or more organic bases, for example, tR1ethyl amine, N-ethyldiisopropyl amine or mixture(s) thereof in one or more solvents, for example, halogenNed hydrocNbons, for example, dichloromethane, dichloroethane or chloroform; amides, for example, dimethylformamide or dimethylacetamide; or mixture(s) thereof.
(SCHEME REMOVED)
The compounds of Formulae XXXIII, XXXIII (a), and XXXIII (c) can be prepNed by following Scheme VI. Accordingly, hydrolysis of compounds of Formula XXXII give compounds of Formula XXXIII, which on
(a) reduction give compounds of Formula XXXIII (a) (wherein R1, R2 and R3 Ne the same
as defined eNlier and A is a 3-7 membered sNurNed, pNtially sNurNed or unsNurNed
R1ng containing cNbon Noms).
(b) reaction with chloroacetonitR1le give compounds of XXXIII (b), which Ne hydrolysed to
give compounds of Formula XXXIII (c) (wherein R1, R2 and R3 Ne the same as defined
eNlier and A is a 3-7 membered sNurNed, pNtially sNurNed or unsNurNed R1ng
containing cNbon Noms).
The hydrolysis of compounds of Formula XXXII to give compounds of Formula XXXIII can be cNR1ed out in the presence of one or more acids, for example tR1fluoroacetic acid, p-toluene sulphonic acid or mixture(s) thereof in one or more solvents, for example, halogenNed hydrocNbons, for example, dichloromethane, dichloroethane or chloroform; wNer or mixture(s) thereof.
The reduction of compounds of Formula XXXIII to give compounds of Formula XXXIII (a) can be cNR1ed out in the presence of reducing reagents, for example, sodium borohyR1de in combinNion with one or more lewis acid cNalysts, for example ceR1um chloR1de, sodium tR1acetoxy borohydR1de or sodium cyanoborohydR1de or mixture(s) thereof in one or more solvents, for example, alcohols, for example, methanol, ethanol, propanol or butanol; halogenNed hydrocNbons, for example, dichloromethane, dichloroethane or chloroform; or mixture(s) thereof.
The reaction of compounds of Formula XXXIII with chloroacetonitR1le to give compounds of Formula XXXIII (b) can be cNR1ed out in the presence of one or more phase transfer cNalysts, for example, benzyltR1ethyl ammonium chloR1de, benzyltR1ethyl ammonium iodide or 18-crown-6 in
one or more solvents, for example, ethers, for example, tetrahydrofuran or diethyl ether; nitR1les, for example, acetonitR1le; or mixture(s) thereof.
The reaction of compounds of Formula XXXIII with chloroacetonitR1le can be cNR1ed out in the presence of one or more bases, for example, alkali metal hydroxides, for example, potassium hydroxide, sodium hydroxide, lithium hydroxide, or mixture(s) thereof.
The hydrolysis of compounds of Formula XXXIII (b) to give compounds of Formula
XXXIII (c) can be cNR1ed out in the presence of lewis acid reagents, for example, lithum bromide,
magnesium bromide or mixture(s) thereof in one or more solvents, for example, wNer; nitR1les, for
example, acetonitR1le; amides, for example, dimethylformamide or dimethylacetamide; or
mixture(s) thereof.
(SCHEME REMOVED)
The compounds of Formulae XXXIV and XXXVI can be prepNed by following Scheme VII. Accordingly, compounds of Formula XXXIV (a) (wherein Pr is a protecting group, for example, p-methoxy benzyl, benzyl or 2-furanylmethyl) Ne deprotected to give compounds of Formula XXXIV, which Ne reacted with compounds of Formula XXXV (wherein X is halogen) to give compounds of Formula XXXVI (wherein R' is alkyl, cycloalkyl or cycloalkylalkyl and R\, R2, R3 and M Ne the same as defined eNlier).
The deprotection of compounds of Formula XXXIV (a) to give compounds of Formula
XXXIV can be cNR1ed out in the presence of eeR1e ammonium nitrNe; or one or more oxidizing
agents, for example, selenium dioxide; or one or more organic acids, for example, tR1fluoroacetic
acid; or under hydrogenNion conditions using hydrogen over palladium/ cNbon; in the optional
presence of one or more solvents, for example, halogenNed hydrocNbons, for example,
dichloromethane, dichloroethane or chloroform; alcohols, for example, methanol, ethanol, propanol
or butanol; esters, for example, ethyl acetNe; or mixture(s) thereof.
The reaction of compounds of Formula XXXIV with compounds of Formula XXXV to give compounds of Formula XXXVI can be cNR1ed out in the presence of one or more inorganic bases, for example, alkali metal cNbonNes, for example, sodium cNbonNe, potassium cNbonNe or cesium cNbonNe, alkali metal hydR1des, for example, sodium hydR1de or mixture(s) thereof or one or more organic bases, for example, tR1ethyl amine, N-ethyldiisopropyl amine or mixture(s) thereof
in one or more solvents, for example, halogenNed hydrocNbons, for example, dichloromethane,
dichloroethane or chloroform; amides, for example, dimethylformamide or dimethylacetamide; or mixture(s) thereof.
(SCHEME REMOVED)
The compounds of Formulae XXXVIII and XXXIX can be prepNed by following Scheme VIII. Accordingly, compounds of Formula XXXVII (wherein R1a is alkyl) Ne deprotected to give compounds of Formula XXXVIII, which Ne reacted with compounds of Formula XXX (wherein X is halogen) to give compounds of Formula XXXIX (wherein R is alkyl, cycloalkyl, cycloalkylalkyl, -COR4 or -SO2R4 and R4 is the same as defined eNlier and R3 and M Ne the same as defined eNlier).
The deprotection of compounds of Formula XXXVII to give compounds of Formula XXXV1I1 can be cNR1ed out in the presence of one or more acids, for example, hydrochloR1c acid, tR1fluoroacetic acid,/?-toluene sulphonic acid or mixture(s) thereof in one or more solvents, for example, alcohols, for example, methanol, ethanol, propanol or butanol; halogenNed hydrocNbons, for example, dichloromethane, dichloroethane or chloroform; or mixture(s) thereof.
The reaction of compounds of Formula XXXVIII with compounds of Formula XXX to give compounds of Formula XXXIX can be cNR1ed out in the presence of one or more inorganic bases, for example, alkali metal cNbonNes, for example, sodium cNbonNe, potassium cNbonNe or cesium cNbonNe, alkali metal hydR1des, for example, sodium hydR1de or mixture(s) thereof or one or more organic bases, for example, tR1ethyl amine, N-ethyldiisopropyl amine or mixture(s) thereof in one or more solvents, for example, nitR1les, for example, acetonitR1le; halogenNed hydrocNbons, for example, dichloromethane, dichloroethane or chloroform; amides, for example, dimethylformamide or dimethylacetamide; or mixture(s) thereof.
(SCHEME REMOVED)
The compounds of Formulae XLI, XLII and XLIIII can be prepNed by following Scheme IX. Accordingly, compounds of Formula XL (wherein Pr is a protecting group, for example, p-methoxy benzyl, benzyl or 2-furanylmethyl) Ne deprotected to give compounds of Formula XLI, which Ne reacted with compounds of Formula XXXV (wherein X is as defined eNlier) to give compounds of Formula XLII, which Ne finally debenzylNed to give compounds of Formula XLIII (wherein R' is alkyl, cycloalkyl or cycloalkylalkyl and R1, R2, R3, M and m Ne the same as defined eNlier).
The deprotection of compounds of Formula XL to give compounds of Formula XLI can be cNR1ed out in the presence of eeR1e ammonium nitrNe; or one or more oxidizing agents, for example, selenium dioxide; or one or more organic acids, for example, tR1fluoroacetic acid; or under hydrogenNion conditions using hydrogen over palladium/ cNbon; in the optional presence of one or more solvents, for example, halogenNed hydrocNbons, for example, dichloromethane, dichloroethane or chloroform; alcohols, for example, for example, methanol, ethanol, propanol or butanol; esters, for example, esters, for example, ethyl acetNe; or mixture(s) thereof.
The reaction of compounds of Formula XLI with compounds of Formula XXXV to give compounds of Formula XLII can be cNR1ed out in the presence of one or more inorganic bases, for example, alkali metal cNbonNes, for example, sodium cNbonNe, potassium cNbonNe or cesium cNbonNe, alkali metal hydR1des, for example, sodium hydR1de or mixture(s) thereof or one or more organic bases, for example, tR1ethyl amine, N-ethyldiisopropyl amine or mixture(s) thereof in one or more solvents, for example, halogenNed hydrocNbons, for example, dichloromethane, dichloroethane or chloroform; amides, for example, dimethylformamide or dimethylacetamide; or mixture(s) thereof.
The debenzylNion of a compounds of Formula XLII to give compounds of Formula XLIII can be cNR1ed out in the presence of one or more debenzylNing agents, for example, palladium on cNbon/hydrogen, palladium on cNbon with ammonium formNe, palladium hydroxide or mixture(s) thereof, in one or more solvents, for example, alcohols, for example, methanol, ethanol, propanol or butanol; or mixture(s) thereof.
(SCHEME REMOVED)
The compounds of Formula L can be prepNed by following Scheme X. Accordingly, compounds of Formula V (wherein X is halogen and R1a is alkyl) Ne reacted with compounds of Formula VI (a) to give compounds of Formula XLIV, which on oxidNion give compounds of Formula XLV, which on ester hydrolysis give compounds of Formula XLVI, which on reaction with compounds of Formula IX (wherein R)a is alkyl) give compounds of Formula XLVII, which on reduction give compounds of Formula XLVIII, which on reaction with hydroxylamine
hydrochloR1de give compounds of Formula XLIX, which Ne reacted with compounds of Formula XIII to give compounds of Formula L (wherein R3 and M Ne the same as defined eNlier).
The reaction of compounds of Formula V with compounds of Formula VI (a) to give compounds of Formula XLIV can be cNR1ed out in one or more solvents, for example, nitR1les, for example, acetonitR1le; ketones, for example, acetone; alcohols, for example, methanol, ethanol, propanol or butanol; ethers, for example, diethyl ether or tetrahydrofuran; amides, for example, dimethylformamide or dimethylacetamide; sulfoxides, for example, dimethylsulfoxide; hydrocNbons, for example, hexane or toluene; or mixture(s) thereof.
The reaction of compounds of Formula V with compounds of Formula VI (a) can be cNR1ed out in the optional presence of one or more bases, for example, tR1 ethyl amine, pyR1dine, potassium tert- butoxide, sodium hydR1de or mixture(s) thereof.
The oxidNion of compounds of Formula XLIV to give compounds of Formula XLV can be cNR1ed out in the presence of one or more oxidizing agents, for example, m-chloroperbenzoic acid, oxone or hydrogen peroxide in one or more solvents, for example, halogenNed hydrocNbons, for example, dichloromethane, dichloroethane or chloroform; or mixture(s) thereof.
The ester hydrolysis of compounds of Formula XLV to give compounds of Formula XLVI can be cNR1ed out in one or more solvents, for example, alcohols, for example, methanol, ethanol, propanol or butanol; or an alcohol and wNer mixture.
The ester hydrolysis of compounds of Formula XLV can be cNR1ed out in the presence of one or more inorganic bases, for example, alkali metal hydroxides, for example, potassium hydroxide, sodium hydroxide, lithium hydroxide or mixture(s) thereof.
The reaction of compounds of Formula XLVI with compounds of Formula IX to give compounds of Formula XLVII can be cNR1ed out in the presence of one or more activNing reagents, for example, hydroxybenzotR1azole, acetone oxime, 2-hydroxypyR1dine or mixture(s) thereof, and one or more coupling reagents, for example, l-ethyl-3-(3-dimethylaminopropyl) cNbodiimide hydrochloR1de, 1,3-dicyclohexyl cNbodiimide or mixture(s) thereof in one or more solvents, for example, ethers, for example, diethyl ether or tetrahydrofuran; amides, for example, dimethylformamide or dimethylacetamide; sulfoxides, for example, dimethylsulfoxide; or mixture(s) thereof.
The reaction of compounds of Formula XLVI with compounds of Formula IX can be cNR1ed out in the presence of one or more bases, for example, N-methylmorpholine; N-ethyldiisopropylamine; 4-dialkylaminopyR1dines, for example, 4-dimethylaminopyR1dine; or mixture(s) thereof.
The reduction of compounds of Formula XLVII to give compounds of Formula XLVIII can be cNR1ed out in one or more solvents, for example, ethers, for example, diethyl ether or
tetrahydrofuran; amides, for example, dimethylformamide or dimethylacetamide; sulfoxides, for example, dimethylsulfoxide; hydrocNbons, for example, hexane or toluene; or mixture(s) thereof.
The reduction of compounds of Formula XLVII can be cNR1ed out in the presence of one or more reducing agents, for example, sodium bis (2-methoxyethoxy)aluminum hydR1de (vitR1de), lithium aluminium hydR1de or mixture(s) thereof.
The reaction of compounds of Formula XLVIII with hydroxylamine hydrochloR1de to give compounds of Formula XLIX can be cNR1ed out in the presence of sodium acetNe in one or more solvents, for example, alcohols, for example, methanol, ethanol, propanol, butanol or mixture(s) thereof.
The reaction of compounds of Formula XLIX with compounds of Formula XIII to give compounds of Formula L can be cNR1ed out in the presence of one or more halogenNing agents, for example, sodium hypochloR1te, N-chlorosuccinimide, N-bromosuccinimide or mixture(s) thereof, in one or more solvents, for example, nitR1les, for example, acetonitR1le; ketones, for example, acetone; alcohols, for example, methanol, ethanol, propanol or butanol; ethers, for example, diethyl ether or tetrahydrofuran; amides, for example, dimethylformamide or dimethylacetamide; sulfoxides, for example, dimethylsulfoxide; hydrocNbons, for example, hexane or toluene; halogenNed hydrocNbons, for example, dichloromethane, dichloroethane or chloroform; or mixture(s) thereof.
The reaction of compounds of Formula XLIX with compounds of Formula XIII can be cNR1ed out in the optional presence of one or more bases, for example, tR1ethyl amine, tR1methyl amine or mixture(s) thereof.
(SCHEME REMOVED)
The compounds of Formula LXVI can be prepNed by following Scheme XI. Accordingly, compounds of Formula LI (wherein R1a is alkyl and Pr is a protecting group, for example, p-methoxy benzyl, benzyl or 2-furanylmethyl) on heNing give compounds of Formula LII, which on reaction with phosphorous oxy halide give compounds of Formula LIII (wherein X is a halogen), which on reaction with compounds of Formula LIV give compounds of Formula LV, which on ester hydrolysis give compounds of Formula LVI, which on reaction with compounds of Formula IX (wherein R|a is the same as defined eNlier) give compounds of Formula LVII, which on deprotection give compounds of Formula LVIII, which on reaction with compounds of Formula LIX (wherein X is halogen) give compounds of Formula LX, which on reduction give compounds of Formula LXI, which on reaction with hydroxylamine hydrochloR1de give compounds of Formula LXII. which on reaction with compounds of Formula XIII give compounds of Formula LXIII, which on deprotection give compounds of Formula LXIV, which Ne finally reacted with compounds of Formula LXV (wherein X is halogen) to give compounds of Formula LXVI (wherein R3b is alkyl or cycloalkyl, R3c is Nyl or heteroNyl and R3 and M Ne the same as defined eNlier).
The compounds of Formula LXIII (a) can be prepNed by following Scheme XI a. Accordingly, compounds of Formula LIII (wherein X is halogen, R]a is alkyl and Pr is a protecting group, for example, p-methoxy benzyl, benzyl or 2-furanylmethyl) on reaction with compounds of Formula VI give compounds of Formula LV (a), which on ester hydrolysis give compounds of Formula LVI (a), which on reaction with compounds of Formula IX (wherein R1a is the same as defined eNlier) give compounds of Formula LVII (a), which on deprotection give compounds of Formula LVIII (a), which on reaction with compounds of Formula LIX (wherein X is halogen) give compounds of Formula LX (a), which on reduction give compounds of Formula LXI (a), which on reaction with hydroxylamine hydrochloR1de give compounds of Formula LXII (a), which Ne finally reacted with compounds of Formula XIII to give compounds of Formula LXIII (a) (wherein R.3b is alkyl or cycloalkyl and R1, R2, R3 and M Ne the same as defined eNlier).
The compounds of Formula LII can be prepNed by heNing of compounds of Formula Formula LI in one or more solvents, for example, alcohols, for example, methanol, ethanol, propanol or butanol in the presence of a high boiling medium, for example, diphenyl ether, dimethylsulfoxide or mixture(s) thereof.
The compounds of Formula LIII can be prepNed by the reaction of compounds of LII with phosphorous oxy halide on heNing.
The reaction of compounds of Formula LIII with compounds of Formula LIV or compounds of Formula VI to give compounds of Formula LV or compounds of Formula LV (a), respectively can be cNR1ed out in one or more solvents, for example, nitR1les, for example, acetonitR1le; ketones, for example, acetone; alcohols, for example, methanol, ethanol, propanol or butanol; ethers, for example, diethyl ether or tetrahydrofuran; amides, for example, dimethylformamide or dimethylacetamide; sulfoxides, for example, dimethylsulfoxide; hydrocNbons, for example, hexane or toluene; or mixture(s) thereof.
The reaction of compounds of Formula LIII with compounds of Formula LIV or compounds of Formula VI can be cNR1ed out in the optional presence of one or more bases, for example, tR1ethylamine, pyR1dine, potassium tert- butoxide, sodium hydR1de or mixture(s) thereof.
The ester hydrolysis of compounds of Formula LV or compounds of Formula LV (a) to give compounds of Formula LVI or compounds of Formula LVI (a), respectively can be cNR1ed out in one or more solvents, for example, alcohols, for example, methanol, ethanol, propanol or butanol; or an alcohol and wNer mixture.
The ester hydrolysis of compounds of Formula LV or compounds of Formula LV (a) can be cNR1ed out in the presence of one or more inorganic bases, for example, alkali metal hydroxides, for example, potassium hydroxide, sodium hydroxide, lithium hydroxide or mixture(s) thereof.
The reaction of compounds of Formula LVI or compounds of Formula LVI (a) with
compounds of Formula IX to give compounds of Formula LVII or compounds of Formula LVII (a),
respectively can be cNR1ed out in the presence of one or more activNing reagents, for example, hydroxybenzotR1azole, acetone.oxime, 2-hydroxypyR1dine or mixture(s) thereof, and one or more coupling reagents, for example, l-ethyl-3-(3-dimethylaminopropyl) cNbodiimide hydrochloR1de, 1,3-dicyclohexyl cNbodiimide or mixture(s) thereof in one or more solvents, for example, ethers, for example, diethyl ether or tetrahydrofuran; amides, for example, dimethylformamide or dimethylacetamide; sulfoxides, for example, dimethylsulfoxide; or mixture(s) thereof.
The reaction of compounds of Formula LVI or compounds of Formula LVI (a) with compounds of Formula IX can be cNR1ed out in the presence of one or more bases, for example, N-methylmorpholine; N-ethyldiisopropylamine; 4-dialkylaminopyR1dines, for example, 4-dimethylaminopyR1dine; or mixture(s) thereof.
The deprotection of compounds of Formula LVII or compounds of Formula LVII (a) to give compounds of Formula LVIII or compounds of Formula LVIII (a), respectively can be cNR1ed out in the presence of one or more acids, for example, hydrochloR1c acid, tR1fluoroacetic acid,/7-toluene sulphonic acid or mixture(s) thereof in one or more solvents, for example, alcohols, for example, methanol, ethanol, propanol or butanol; halogenNed hydrocNbons, for example, dichloromethane, dichloroethane or chloroform; or mixture(s) thereof.
The reaction of compounds of Formula LVIII or compounds of Formula LVIII (a) with compounds of Formula LIX to give compounds of Formula LX or compounds of Formula LX (a), respectively can be cNR1ed out in the presence of one or more inorganic bases, for example, alkali metal cNbonNes, for example, sodium cNbonNe or potassium cNbonNe, alkali metal hydR1des, for example, sodium hydR1de or mixture(s) thereof or one or more organic bases, for example, tR1ethyl amine, N-ethyldiisopropyl amine or mixture(s) thereof in one or more solvents, for example, nitR1les, for example, acetonitR1le; halogenNed hydrocNbons, for example, dichloromethane, dichloroethane or chloroform; amides, for example, dimethylformamide or dimethylacetamide; or mixture(s) thereof.
The reduction of compounds of Formula LX or compounds of Formula LX (a) to give compounds of Formula LXI or compounds of Formula LXI (a), respectively can be cNR1ed out in one or more solvents, for example, ethers, for example, diethyl ether or tetrahydrofuran; amides, for example, dimethylformamide or dimethylacetamide; sulfoxides, for example, dimethylsulfoxide; hydrocNbons, for example, hexane or toluene; or mixture(s) thereof.
The reduction of compounds of Formula LX or compounds of Formula LX (a) can be cNR1ed out in the presence of one or more reducing agents, for example, sodium bis (2-methoxyethoxy)aluminum hydR1de (vitR1de), lithium aluminium hydR1de or mixture(s) thereof.
The reaction of compounds of Formula LXI or compounds of Formula LXI (a) with hydroxylamine hydrochloR1de to give compounds of Formula LXII or compounds of Formula LXII
a. respectively can be cNR1ed out in the presence of sodium acetNe in one or more solvents, for example, alcohols, for example, methanol, ethanol, propanol, butanol or mixture(s) thereof.
The reaction of compounds of Formula LXII or compounds of Formula LXII (a) with compounds of Formula XIII to give compounds of Formula LXIII or compounds of Formula LXIII (a), respectively can be cNR1ed out in the presence of one or more halogenNing agents, for example, sodium hypochloR1te, N-chlorosuccinimide, N-bromosuccinimide or mixture(s) thereof, in one or more solvents, for example, nitR1les, for example, acetonitR1le; ketones, for example, acetone; alcohols, for example, methanol, ethanol, propanol or butanol; ethers, for example, diethyl ether or tetrahydrofuran; amides, for example, dimethylformamide or dimethylacetamide; sulfoxides, for example, dimethylsulfoxide; hydrocNbons, for example, hexane or toluene; halogenNed hydrocNbons, for example, dichloromethane, dichloroethane or chloroform; or mixture(s) thereof.
The reaction of compounds of Formula LXII or compounds of Formula LXII (a) with compounds of Formula XIII can be cNR1ed out in the optional presence of one or more bases, for example, tR1ethyl amine, tR1methyl amine or mixture(s) thereof.
The deprotection of compounds of Formula LXIII to give compounds of Formula LXIV can be cNR1ed out in the presence of palladium on cNbon/hydrogen, palladium hydroxide/cNbon with hydrogen, ammonium formNe/palladium on cNbon, in one or more solvents, for example, alcohols, for example, methanol, ethanol, propanol or butanol; halogenNed hydrocNbons, for example, dichloromethane, dichloroethane or chloroform; or mixture(s) thereof.
The reaction of compounds of Formula LXIV with compounds of Formula LXV to give compounds of Formula LXVI can be cNR1ed out in the presence of one or more transition metal cNalysts, for example, tR1s(dibenzylidineacetone)dipalladium(O), palladium(II) acetNe, tetrakis(tR1phenylphosphine)palladium(O), tetrakis(methyldiphenylphosphine) palladium(O), trans-dichlorobis(methyldiphenylphosphine)palladium(II), dichlorobis
(tR1phenylphosphine)palladium(II), bis[l ,2-bis(diphenylphosphino)ethane]palladium(O), copper (I) iodide, cuprous oxide, cuprous bromide, cuprous chloR1de or mixture(s) thereof.
The reaction of compounds of Formula LXIV with compounds of Formula LXV can be cNR1ed out in the presence of one or more phosphine ligands, for example, xantphos, 1,1 '-bis(di-tert-butylphosphino)ferrocene, 2,2'-bis(diphenylphosphino)diphenyl ether (DPEphos), bis(tR1ethylphosphine)nickel (II) chloR1de, (R,S)-2,2'-bis(diphenylphosphino)-l,l'-binaphthyl, (S)-2.2'-bis(diphenylphosphino)-1,1 '-binaphthyl, (R)-2,2'-bis(diphenylphosphino)-1,1 '-binaphthyl or mixture(s) thereof.
The reaction of compounds of Formula LXIV with compounds of Formula LXV can be cNR1ed out in the presence of one or more bases, for example, amines, for example, N-ethyldiisopropylamine, tR1ethyl amine or dimethylamino pyR1dine, alkali metal alkoxides, for
example, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, lithium methoxide,
potassium methoxide or cesium methoxide, alkali metal hydroxides, for example, sodium
hydroxide, lithium hydroxide, potassium hydroxide or cesium hydroxide, alkali metal halides, for
example, potassium fluoR1de, alkali metal cNbonNes, for example, sodium cNbonNe, potassium
cNbonNe or cesium cNbonNe or mixture(s) thereof.
The reaction of compounds of Formula LXIV with compounds of Formula LXV can be
cNR1ed out in one or more solvents, for example, ethers, for example, dioxane or tetrahydrofuran,
amides, for example, dimethylformamide or dimethylacetamide; sulfoxides, for example,
dimethylsulfoxide; hydrocNbons, for example, hexane or toluene; or mixture(s) thereof.
(SCHEME REMOVED)
The compounds of Formula LXVII can be prepNed by following Scheme XII. Accordingly, ester hydrolysis of compounds of Formula LXVII (a) (wherein R1ais alkyl) gives compounds of Formula LXVII (wherein R3 and M Ne the same as defined eNlier and R1ng D is cyclobutyl or cyclohexyl R1ng).
The ester hydrolysis of compounds of Formula LXVII (a) to give compounds of Formula LXVII can be cNR1ed out in the presence of one or more acids, for example, hydrochloR1c acid, tR1fluoroacetic acid,/?-toluene sulphonic acid or mixture(s) thereof in one or more solvents, for example, halogenNed hydrocNbons, for example, dichloromethane, dichloroethane or chloroform; or mixture(s) thereof.
(SCHEME REMOVED)
The compounds of Formulae LXX, LXXI, LXXII and LXXIV can be prepNed by following Scheme XIII. Accordingly, compounds of Formula LXVIII Ne
(a) protected to give compounds of Formula LXIX (wherein PR1 is a protecting group,
for example, tosylNe, mesylNe or tR1flNe) which on reaction with sodium cyanide
give compounds of Formula LXX, which on
(i) hydrolysis give compounds of Formula LXXI (wherein R|, R2, R3, m and M Ne the same as defined eNlier).
(ii) cyclizNion give compounds of Formula LXXII (wherein R1, R2, R3, m and M Ne the same as defined eNlier).
(b) reacted with compounds of Formula LXXIII (wherein X is halogen) to give
compounds of Formula LXXIV (wherein wherein R1, R2, R3, R», m and M Ne the
same as defined eNlier).
The protection of compounds of Formula LXVIII to give compounds of Formula LXIX can be cNR1ed out with one or more protecting reagents, for example, p-toluene sulphonyl chloR1de, methyl sulphonyl chloR1de or tR1fluoromethanesulfonyl chloR1de in one or more solvents, for example, ethers, for example, dioxane, tetrahydrofuran or diethyl ether; halogenNed hydrocNbons, for example, dichloromethane, dichloroethane or chloroform; amides, for example, dimethylformamide or dimethylacetamide; or mixture(s) thereof.
The protection of compounds of Formula LXVIII to give compounds of Formula LXIX can be cNR1ed out in the presence of one or more bases, for example, tR1ethyl amine, tR1methyl amine or mixture(s) thereof.
The reaction of compounds of Formula LXIX with sodium cyanide to give compounds of Formula LXX can be cNR1ed out in the presence of one or more solvents, for example, amides, for example, dimethylformamide, dimethylacetamide or mixture(s) thereof.
The hydrolysis of compounds of Formula LXX to give compounds of Formula LXXI can be cNR1ed out in one or more solvents, for example, alcohols, for example, methanol, ethanol, propanol or butanol; or an alcohol and wNer mixture.
The hydrolysis of compounds of Formula LXX can be cNR1ed out in the presence of one or more inorganic bases, for example, alkali metal hydroxides, for example, potassium hydroxide, sodium hydroxide, lithium hydroxide or mixture(s) thereof.
The cyclizNion of compounds of Formula LXX to give compounds of Formula LXXII can be cNR1ed out in the presence of sodium azide and tR1ethyl amine hydrochloR1de in one or more solvents, for example, amides, for example, dimethylformamide or dimethylacetamide; sulfoxides, for example, dimethylsulfoxide; hydrocNbons, for example, hexane or toluene; or mixture(s) thereof.
The reaction of compounds of Formula LXVIII with compounds of Formula LXXIII to give compounds of Formula LXXIV can be cNR1ed out in the presence of one or more alkali metal hydroxides, for example, sodium hydroxide, potassium hydroxide or lithium hydroxide, alkali metal cNbonNes, for example, sodium cNbonNe, potassium cNbonNe or cesium cNbonNe, alkali metal alkoxides, for example, potassium /-butoxide, alkali metal hydR1des, for example, sodium hydR1de or mixture(s) thereof in one or more solvents, for example, alcohols, for example, methanol, ethanol, propanol or butanol; ethers, for example, tetrahydrofuran or diethyl ether; amides, for example, dimethylformamide or dimethylacetamide; wNer; or mixture(s) thereof.
(SCHEME REMOVED)
The compounds of Formulae LXXI, LXXV (a) and LXXV (b) can be prepNed by following Scheme XIV. Accordingly, compounds of Formula LXXVI (wherein R1a is alkyl) on ester hydrolysis give compounds of Formula LXXI, which Ne reacted with ammonium cNbonNe or compounds of Formula LXXV to give compounds of Formula LXXV (a) (wherein R1, R2, R3, m and M Ne the same as defined eNlier) or compounds of Formula LXXV (b) (wherein R1, R2, R3, R4, R'4. m and M Ne the same as defined eNlier) respectively.
The ester hydrolysis of compounds of Formula LXXVI to give compounds of Formula LXXI can be cNR1ed out in one or more solvents, for example, wNer; ethers, for example, diethyl ether or tetrahydrofuran; alcohols, for example, methanol, ethanol, propanol or butanol; or mixtre(s) thereof.
The ester hydrolysis of compounds of Formula LXXVI can be cNR1ed out in the presence of one or more inorganic bases, for example, alkali metal hydroxides, for example, potassium hydroxide, sodium hydroxide, lithium hydroxide or mixture(s) thereof.
The reaction of compounds of Formula LXXI with ammonium cNbonNe or compounds of Formula LXXV to give compounds of Formula LXXV (a) or compounds of Formula LXXV (b), respectively can be cNR1ed out in the presence of one or more activNing reagents, for example, hydroxybenzotR1azole, acetone oxime, 2-hydroxypyR1dine or mixture(s) thereof, and one or more coupling reagents, for example, l-ethyl-3-(3-dimethylaminopropyl) cNbodiimide hydrochloR1de, 1,3-dicyclohexyl cNbodiimide or mixture(s) thereof in one or more solvents, for example, ethers, for example, diethyl ether or tetrahydrofuran; amides, for example, dimethylformamide or dimethylacetamide; sulfoxides, for example, dimethylsulfoxide or mixture(s) thereof.
The reaction of compounds of Formula LXXI with ammonium cNbonNe or compounds of Formula LXXV can be cNR1ed out in the presence of one or more bases, for example,
N-methylmorpholine; N-ethyldiisopropylamine; 4-dialkylaminopyR1dines, for example, 4-dimethylaminopyR1dine; or mixture(s) thereof.
(SCHEME REMOVED)
The compounds of Formulae LXXVIII, LXXX and LXXXI can be prepNed by following Scheme XV. Accordingly, compounds of Formula LXIX (wherein PR1 is a protecting group, for example, tosylNe, mesylNe or tR1flNe) on reaction with sodium azide give compounds of Formula LXXVII, which on reduction give compounds of Formula LXXVIII, which on reaction with
(a) compounds of Formula LXXIX (wherein X is halogen) give compounds of Formula LXXX (wherein R1, R2, R3, R4, m and M Ne the same as defined eNlier).
(b) compounds of Formula LXXIII (wherein X is halogen) give compounds of Formula LXXXI (wherein R\, R2, R3, R4, m and M Ne the same as defined eNlier).
The reaction of compounds of Formula LXIX with sodium azide to give compounds of Formula LXXVII can be cNR1ed out in the one or more solvents, for example, amides, for example, dimethylformamide or dimethylacetamide; sulfoxides, for example, dimethylsulfoxide or mixture(s) thereof.
The reduction of compounds of Formula LXXVII to give compounds of Formula LXXVIII can be cNR1ed out in the presence of one or more reducing agents, for example, sodium
borohydR1de, lithium boro hydR1de, lithium aluminium hydR1de or hydrogen in the presence of
palladium/cNbon in one or more solvents, for example, ethers, for example, diethyl ether, dioxane or tetrahydrofuran; alcohols, for example, methanol, ethanol, propanol or butanol; or mixtre(s) thereof.
The reaction of compounds of Formula LXXVIII with compounds of Formula LXXIX or Formula LXXIII to give compounds of Formula LXXX or compounds of Formula LXXXI, respectively can be cNR1ed out in the presence of one or more inorganic bases, for example, alkali metal cNbonNes, for example, sodium cNbonNe, potassium cNbonNe or cesium cNbonNe, alkali metal hydR1des, for example, sodium hydR1de or mixture(s) thereof or one or more organic bases, for example, tR1ethyl amine, N-ethyldiisopropyl amine or mixture(s) thereof in one or more solvents, for example, halogenNed hydrocNbons, for example, dichloromethane, dichloroethane or chloroform; amides, for example, dimethylformamide or dimethylacetamide; or mixture(s) thereof.
The compounds of Formula la can be prepNed by following the methods disclosed in WO 2007/031977.
In the above schemes, where the specific solvents, bases, acids, reducing agents, oxidizing agents, activNing reagents, coupling reagents, halogenNing agents, transition metal cNalysts, phosphine ligands, mesylNing agents, lewis acid cNalysts, debenzylNing agents, protecting reagents etc., Ne mentioned, it is to be understood thN other solvents, bases, acids, reducing agents, oxidizing agents, activNing reagents, coupling reagents, halogenNing agents, transition metal cNalysts, phosphine ligands, mesylNing agents, lewis acid cNalysts, debenzylNing agents, protecting reagents etc., known to those skilled in the Nt may be used. SimilNly, the reaction temperNure and durNion may be adjusted according to the desired needs.
An illustrNive list of intermediNes includes these listed below:
4-(Cyclohexylamino)-l-ethyl-N-methoxy-N-methyl-1H-pyrazolo[3,4-b]pyR1dine-5-cNboxamide (IntermediNe No. 1),
l-Ethyl-N-methoxy-N-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1dine-5-cNboxamide (IntermediNe No. 2),
l-Ethyl-4-[(4-hydroxycyclohexyl)amino]-N-methoxy-N-methyl-1H-pyrazolo[3,4-A]pyR1dine-5-cNboxamide (IntermediNe No. 3),
4-(Cyclopropylamino)-l-ethyl-N-methoxy-N-methyl-lH-pyrazolo[3,4-b]pyR1dine-5-
cNboxamide (IntermediNe No. 4),
4-(Cyclopropylamino)-N-methoxy-N-l, 3-tR1methyl-lH-pyrazolo [3,4-b] pyR1dine-5-
cNboxamide (IntermediNe No. 5),
4-(Cyclopentylamino)-l-ethyl-N-methoxy-N-methyl-lH-pyrazolo [3,4-b] pyR1dine-5-
cNboxamide (IntermediNe No. 6),
4-(Cyclopentylamino)-N-methoxy-N-l, 3-tR1methyl-lH-pyrazolo [3,4-b] pyR1dine-5-
cNboxamide (IntermediNe No. 7),
4-(Cyclohexylamino)-l-ethyl-1H-pyrazo!o[3,4-b]pyR1dine-5-cNbaldehyde (IntermediNe
No. 8),
l-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1dine-5-cNbaldehyde
(IntermediNe No. 9),
l-Ethyl-4-[(4-hydroxycyclohexyl)amino]-1H-pyrazolo[3,4-b]pyR1dine-5-cNbaldehyde (IntermediNe No. 1O),
4-Cyclopropylamino-l -ethyl-lH-pyrazolo[3,4-b]pyR1dine-5-cNbaldehyde (IntermediNe No. 11).
4-Cyclopropylamino)-l,3-dimethyl-lH-pyrazolo[3,4-b]pyR1dine-5-cNbaldehyde (IntermediNe No. 12),
4-(Cyclopentylamino)-l-ethyl-lH-pyrazolo[3,4-b]pyR1dine-5-cNbaldehyde (IntermediNe No. 13),
4-(Cyclopentylamino)-l,3-dimethyl-lH-pyrazolo [3,4-b] pyR1dine-5-cNbaldehyde (IntermediNe No. 14),
4-(Cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-b]pyR1dine-5-cNbaldehyde oxime (IntermediNe No. 15),
l-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1dine-5-cNbaldehyde oxime (IntermediNe No. 16),
1 -Ethyl-4-[(4-hydroxycyclohexyl)amino]-1H-pyrazolo[3,4-fe]pyR1dine-5-cNbaldehyde oxime (IntermediNe No. 17),
4-Cyclopropylamino-l -ethyl-lH-pyrazolo [3,4-b] pyR1dine-5-cNbaldehyde oxime (IntermediNe No. 18),
4-(Cyclopropylamino)-1,3-dimethyl-lH-pyrazolo [3,4-b] pyR1dine-5-cNbaldehyde oxime (IntermediNe No. 19),
4-(Cyclopentylamino)-l -ethyl- lH-pyrazolo [3,4-b] pyR1dine-5-cNbaldehyde oxime (IntermediNe No. 2O),
4-(Cyclopentylamino)-l,3-dimethyl-lH-pyrazolo [3,4-b] pyR1dine-5-cNbaIdehyde oxime (IntermediNe No. 21),
tert-Butyl 4-({ l-ethyl-5-[methoxy(methyl)cNbamoyl]-1H-pyrazolo[3,4-b]pyR1din-4-yl}amino)pipeR1dine-l-cNboxylNe ((IntermediNe No. 22), l-Ethyl-N-methoxy-4-[(3-methoxyphenyl)amino]-N-methyl-1H-pyrazolo[3,4-b]pyR1dine-5-cNboxamide (IntermediNe No. 23),
4-[( 1,1 -Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-1 -ethyl-N-methoxy-yV-methyl-1H-pyrazolo[3,4-b]pyR1dine-5-cNboxamide (IntermediNe No. 24), 4-(Benzylamino)-l-ethyl-N-Methoxy-N-methyl-1H-pyrazolo[3,4-A]pyR1dine-5-cNboxamide (IntermediNe No. 25),
l-Ethyl-4-[(3-methoxyphenyl)amino]-1H-pyrazolo[3,4-b]pyR1dine-5-cNbaldehyde (IntermediNe No. 26),
tert-ButyI 4-[(l-ethyl-5-formyl-1H-pyrazolo[3,4-b]pyR1din-4-yl)amino]pipeR1dine-l-cNboxylNe (IntermediNe No. 27),
4-[( 1,1 -Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-1 -ethyl-1H-pyrazoIo[3,4-b]pyR1dine-5-cNbaldehyde (IntermediNe No. 28),
4-(Benzylamino)-l -ethyl- 1H-pyrazolo[3,4-b]pyR1dine-5-cNbaldehyde (IntermediNe No. 29),
1 -Ethyl-4-[(3-methoxyphenyl)amino]-l //-pyrazolo[3,4-b]pyR1dine-5-cNbaldehyde oxime (IntermediNe No. 3O),
4-(Benzylamino)-l -ethyl- 1H-pyrazolo[3,4-£]pyR1dine-5-cNbaldehyden oxime (IntermediNe No. 31),
tert-Butyl 4-[(l-ethyl-5-[(£)-(hydroxyimino)methyI -1H-pyrazolo[3,4-b]pyR1din-4-yl)amino]pipeR1dine-l-cNboxylNe (IntermediNe No. 32), 4-[( 1,1 -Dioxidotetrahydro-2f/-thiopyran-4-yl)amino] -1 -ethyl-1 JY-pyrazolo[3,4-b]pyR1dine-5-cNbaldehyde oxime (IntermediNe No. 33), An illustrNive list of compounds includes these listed below:
N-cyclohexyl-l-ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 1),
/v'-cyclohexyl-l-ethyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 2),
N-cyclohexyl-l-ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-
pyR1din-4-amine (Compound No. 3),
N-cyclohexyl-l-ethyl-5-(l-oxa-7-thia-2-azaspiro[4.4]non-2-en-3-yl)-1H-pyrazolo[3,4-
b]pyR1din-4-amine (Compound No. 4),
N-cyclohexyl-1 -ethyl-5-(7-oxido-1 -oxa-7-thia-2-azaspiro[4.4]non-2-en-3-yl)-1H-
pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 5),
yV-cyclohexyl-l-ethyl-5-(5-oxa-2-thia-6-azaspiro[3.4]oct-6-en-7-yl)-1H-pyrazolo[3,4-
b]pyR1din-4-amine (Compound No. 6),
l-Ethyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-
pyrazolo[3,4-£]pyR1din-4-amine (Compound No. 7),
l-Ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-
pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 8),
l-Ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-
pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 9),
4-{[l-Ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-1H-pyrazoIo[3,4-£]pyR1din-4-
yl]amino}cyclohexanol (Compound No. 1O),
4- {[ 1 -Ethyl-5-( 1 -oxa-2-azaspiro[4.5]dec-2-en-3-yl)-17/-pyrazolo[3,4-b]pyR1din-4-
yl]amino}cyclohexanol (Compound No. 11),
N-cyclohexyl-5-(l,7-dioxa-2-azaspiro[4.4]non-2-en-3-yl)-l-ethyl-1H-pyrazolo[3,4-
b]pyR1din-4-amine (Compound No. 12),
4-{[l-Ethyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-1H-pyrazolo[3,4-b]pyR1din-4-
yl]amino}cyclohexanol (Compound No. 13),
/V-cyclohexyl-5-(2,2-dioxido-5-oxa-2-thia-6-azaspiro[3.4]oct-6-en-7-yl)-l -ethyl- \H-
pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 14),
tert-Bw\y\ 3-[4-(cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-1 -oxa-2,8-
diazaspiro[4.5]dec-2-ene-8-cNboxylNe (Compound No. 15),
4- {[ 1 -Ethyl-5-( 1 -oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-H]pyR1din-4-
yl]amino}cyclohexanone (Compound No. 16),
4- {[ 1 -Ethyl-5-( 1 -oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-
yl]amino}cyclohexanone oxime (Compound No. 17),
yV-cyclohexyl-l-ethyl-5-(l-oxa-2,8-diazaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-
b]pyR1din-4-amine hydrochloR1de salt (Compound No. 18),
4-{[l-Ethyl-5-(l,9,12-tR1oxa-2-azadispiro[4.2.4.2]tetradec-2-en-3-yl)-1H-pyrazolo[3,4-
b]pyR1din-4-yl]amino}cyclohexanol (Compound No. 19),
4-{[l-Ethyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-1H-pyrazolo[3,4-fe]pyR1din-4-
yl]amino}cyclohexanone (Compound No. 2O),
4- {[ 1 -Ethyl-5-( 1 -oxa-2-azaspiro[4.4]non-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-
yl]amino}cyclohexanone (Compound No. 21),
3-{l-Ethyl-4-[(4-hydroxycyclohexyl)amino]-1H-pyrazolo[3,4-b]pyR1din-5-yl}-l-oxa-2-
azaspiro[4.5]dec-2-en-8-one (Compound No. 22),
7V-cyclohexyl-5-[8-(2,2-dimethylpropanoyl)-l-oxa-2,8-diazaspiro[4.5]dec-2-en-3-yl]-l-
ethyl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 23),
N-cyclohexyl-l-ethyl-5-{8-[(tR1fluoromethyl)sulfonyl]-l-oxa-2,8-diazaspiro[4.5]dec-2-
en-3-yl}-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 24),
N-cyclohexyl-1 -ethyl-5-[8-(ethylsulfonyl)-1 -oxa-2,8-diazaspiro[4.5]dec-2-en-3-yl]-1H-
pyrazolo[3,4-A]pyR1din-4-amine (Compound No. 25),
N-cyclohexyl-5-[8-(cyclopropylmethyl)-l-oxa-2,8-diazaspiro[4.5]dec-2-en-3-yl]-l-
ethyl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 26),
5-(8-Acetyl-l-oxa-2,8-diazaspiro[4.5]dec-2-en-3-yl)-N-cyclohexyl-l-ethyl-1H-
pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 27),
N-cyclohexyl-5-(2,5-dioxa-6-azaspiro[3.4]oct-6-en-7-yl)-l-ethyl-1H-pyrazolo[3,4-
b]pyR1din-4-amine (Compound No. 28),
N-cycIopropyl-l-ethyl-5- (l-oxa-2-azaspiro [4.5] dec-2-en-3-yl)-lH-pyrazolo[3,4-b]
pyR1din-4-amine (Compound No. 29),
N-cyclopropyl-l-ethyl-5- (l-oxa-2-azaspiro [4.4] non-2-en-3-yl)-lH-pyrazolo[3,4-b]
pyR1din-4-amine (Compound No. 3O), N-cyclopropyl-l-ethyl-5- (5-oxa-6-azaspiro [3.4] oct-6-en-7-yl)-lH-pyrazolo[3,4-b] pyR1din-4-amine (Compound No. 31),
N-cyclopentyl-1, 3-dimethyl-5- (5-oxa-6-azaspiro [3.4] oct-6-en-7-yl)-lH-pyrazolo[3,4-b] pyR1din-4-amine (Compound No. 32),
N-cyclopentyl-l, 3-dimethyl-5- (l-oxa-2-azaspiro [4.4] non-2-en-3-yl)-lH-pyrazolo[3,4-b] pyR1din-4-amine (Compound No. 33),
N-cyclopentyl-1, 3-dimethyl-5- (l-oxa-2-azaspiro [4.5] dec-2-en-3-yl)-lH-pyrazolo[3,4-b] pyR1din-4-amine (Compound No. 34),
N-cyclopropyl-1, 3-dimethyl-5- (1 -oxa-2-azaspiro [4.4] non-2-en-3-yl)-lH-pyrazolo[3,4- b] pyR1din-4-amine (Compound No. 35),
N-cyclopropyl-1, 3-dimethyl-5- (5-oxa-6-azaspiro [3.4] oct-6-en-7-yl)-lH-pyrazolo[3,4-b] pyR1din-4-amine (Compound No. 36),
N-cyclopropyl-1, 3-dimethyl-5- (1 -oxa-2-azaspiro [4.5] dec-2-en-3-yl)-lH-pyrazolo[3,4-b] pyR1din-4-amine (Compound No. 37),
N-cyclopentyl-1-ethyl-5- (5-oxa-6-azaspiro [3.4] oct-6-en-7-yl)-lH-pyrazolo[3,4-b] pyR1din-4-amine (Compound No. 38),
N-cyclopentyl-1-ethyl-5- (1 -oxa-2-azaspiro [4.4] non-2-en-3-yl)-lH-pyrazolo[3,4-b] pyR1din-4-amine (Compound No. 39),
N-cyclopentyl-5- (l,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl)-l,3-dimethyl-lH-pyrazolo [3,4-b] pyR1din-4-amine (Compound No. 4O),
l-(4-Methoxybenzyl)-N-(3-methoxyphenyl)-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 41),
(cis or trans) 3-[4-(Cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-en-8-ol (Compound No. 42),
(trans or cis) 3-[4-(Cyclohexylamino)-l-ethyl-lpyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-en-8-ol (Compound No. 43),
5-[2-(Benzyloxy)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-l-ethyl-vV-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 44),
(cis or trans) 3-[l-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-/j]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-en-8-ol (Compound No. 45),
3-[ 1 -Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-1 -oxa-2-azaspiro[4.5]dec-2-en-8-one (Compound No. 46),
7-[l-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNbonitR1le (Compound No. 47),
7-[4-(Cyclohexylamino)-1 -ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNbonitR1le (Compound No. 48),
5-(5-Oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-A]pyR1din-4-amine (Compound No. 49),
l-Methyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 5O),
5-(l-Oxa-2-azaspiro[4.4]non-2-en-3-yl)-N-(tetrahydro-2H-pyran-4-yl)-l-(2,2,2-
tR1fluoroethyl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 51),
l-Ethyl-N-[l-(methylsulfonyl)pipeR1din-4-yl]-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-
1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 52),
N-( 1 -acetylpipeR1din-4-yl)-l -ethyl-5-(l -oxa-2-azaspiro[4.5]dec-2-en-3-yl)-l H-
pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 53),
N-( 1 -acetylpipeR1din-4-yl)-1 -ethyl-5-( 1 -oxa-2-azaspiro[4.4]non-2-en-3-yl)-1H-
pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 54),
1 -(4-Methoxybenzyl)-N-(tetrahydro-2H-pyran-4-yl)-5-( 1,9,12-tR1oxa-2-
azadispiro[4.2.4.2]tetradec-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound
No. 55),
5-(5-Oxa-6-azaspiro[3.4]oct-6-en-7-yl)-//-(tetrahydro-2H-pyran-4-yl)-l-(2,2,2-
tR1fluoroethyl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 56),
7-[l-(4-Methoxybenzyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-
b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNbonitR1le (Compound No. 57),
l-(Cyclopropylmethyl)-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-(tetrahydro-2H-pyran-
4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 58),
l-Butyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-
pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 59),
l-(l-Methylethyl)-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-#-(tetrahydro-2H-pyran-4-
yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 6O),
5-(5-Oxa-6-azaspiro[3.4]oct-6-en-7-yl)-l-propyl-N-(tetrahydro-2H-pyran-4-yl)-1H-
pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 61),
5-(l-Oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-(tetrahydro-2H-pyran-4-yl)-l-(2,2,2-
tR1fluoroethyl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 62),
N-(l-CyclopentylpipeR1din-4-yl)-l-ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-1H-
pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 63),
N-( 1 -butylpipeR1din-4-yl)-1 -ethyl-5-(l -oxa-2-azaspiro[4.4]non-2-en-3-yI)-1H-
pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 64),
2-(4-{[l-Ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-
yl]amino}pipeR1din-l-yl)ethanoI (Compound No. 65),
N-[\ -(cyclopropylmethyl)pipeR1din-4-yl]-1 -ethyl-5-( 1 -oxa-2-azaspiro[4.4]non-2-en-3-
yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 66),
1 -Ethyl-N-[ 1 -(1 -methylethyl)pipeR1din-4-yl]-5-( 1 -oxa-2-azaspiro[4.4]non-2-en-3-yl)-
1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 67),
l-Ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-N-(l-propylpipeR1din-4-yl)-1H-
pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 68),
N-(l-cyclopentylpipeR1din-4-yl)-l-ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-
pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 69),
l-Ethyl-N-[l-(l-methylethyl)pipeR1din-4-yl]-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-
pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 7O),
l-Cyclopentyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-(tetrahydro-2H-pyran-4-yl)-
1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 71),
l-(Cyclopropylmethyl)-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-(tetrahydro-2H-pyran-
4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 72),
l-(l-Methylethyl)-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-(tetrahydro-2H-pyran-4-
yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 73),
5-(l-Oxa-2-azaspiro[4.5]dec-2-en-3-yl)-l-propyl-N-(tetrahydro-2H-pyran-4-yl)-1H-
pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 74),
l-Cyclopentyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-N-(tetrahydro-2H-pyran-4-yl)-
1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 75),
l-(Cyclopropylmethyl)-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-N-(tetrahydro-2H-
pyran-4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 76),
l-(l-Methylethyl)-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-N-(tetrahydro-2H-pyran-4-
yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 77),
5-( 1 -Oxa-2-azaspiro[4.4]non-2-en-3-yl)-1 -propyl -N-(tetrahydro-2H-pyran-4-yl)-1H-
pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 78),
l-Methyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-
pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 79),
A-Cyclohexyl-1 -ethyl-5-( 1,9,12-tR1oxa-2-azadispiro[4.2.4.2]tetradec-2-en-3-yl)-1H-
pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 8O),
3-[4-(Cyclohexylamino)-1 -ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-1 -oxa-2-
azaspiro[4.5]dec-2-en-8-one (Compound No. 81),
l-Ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-N-pipeR1din-4-yl-1H-pyrazolo[3,4-
b]pyR1din-4-amine (Compound No. 82),
rer/-butyl4-{[l-ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-1H-pyrazolo[3,4-
b]pyR1din-4-yl]amino}pipeR1dine-l-cNboxylNe (Compound No. 83),
l-Ethyl-N-(l-ethylpipeR1din-4-yl)-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-
pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 84),
1 -Ethyl-N-( 1 -methylpipeR1din-4-yl)-5-( 1 -oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-
pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 85),
l-Ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-pipeR1din-4-yl-1H-pyrazolo[3,4-
b]pyR1din-4-amine (Compound No. 86),
Tert-b\x\y\ 4-{[l-ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-
b]pyR1din-4-yl]amino}pipeR1dine-l-cNboxylNe (Compound No. 87),
l-EthyI-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-(l-propylpipeR1din-4-yl)-1H-
pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 88),
N-[l-(cyclopropylmethyl)pipeR1din-4-yl]-l-ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-
yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 89),
2-(4- {[ 1 -Ethyl-5-(l -oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-
yl]amino}pipeR1din-l-yl)ethanol (Compound No. 9O), N-cyclohexyl-1 -(4-methoxybenzyl)-5-( 1 -oxa-2-azaspiro[4.4]non-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 91),
3-[l-(4-Methoxybenzyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-en-8-one (Compound No" 92),
7-[l-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-en-2-ol (Compound No. 93),
l-Ethyl-N-(3-methoxyphenyl)-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-1H-pyrazolo[3,4-&]pyR1din-4-amine (Compound No. 94),
(cis or trans) 3-[4-(Cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxylic acid (Compound No. 95),
(trans or cis) 3-[4-(Cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxylic acid (Compound No. 96),
5-{2-[(Benzyloxy)methyl]-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl}-l-(4-methoxybenzyl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 97), (trans or cis) 3-[l-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-en-8-ol (Compound No. 98),
7-[l-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxylic acid (Compound No. 99),
l-(4-Methoxybenzyl)-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 10O),
5-(l-Oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 101),
l-(4-Methoxybenzyl)-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 102),
5-{2-[(Benzyloxy)methyl]-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl}-l-ethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-£]pyR1din-4-amine (Compound No. 103), (7-[l-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-en-2-yl) methanol (Compound No. 104),
7-[4-(Cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-ft]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxylic acid (Compound No. 105),
cis or trans 7-[4-(CycIohexylamino)-l-ethyl-1H-pyrazolo[3,4-£]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxamide (Compound No. 106),
(trans or cis) 7-[4-(Cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxamide (Compound No. 107),
(cis or trans) 3-[4-(Cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxamide (Compound No. 108),
(trans or cis) 3-[4-(Cyclohexylamino)-l -ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yI]-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxamide (Compound No. 109),
l-(4-Methoxybenzyl)-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 11O),
5-[2-(Benzyloxy)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-l-(4-methoxybenzyl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (CompoundNo. Ill), Ethyl (cis or trans) 3-[4-(cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxylNe (Compound No. 112),
Ethyl (trans or cis) 3-[4-(cyclohexylamino)-l -ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]- 1-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxylNe (Compound No. 113),
N-( 1,1 -dioxidotetrahydro-2H-thiopyran-4-yl)-l -ethyl-5-(l -oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine ((Compound No. 114), 3-{[l-Ethyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclobutanecNboxylic acid (Compound No. 115), 3-{[l-Ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-1H-pyrazolo[3,4-H]pyR1din-4-yl]amino}cyclobutanecNboxylic acid (Compound No. 116), 3-{[l-Ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclobutanecNboxylic acid (Compound No. 117),
3-[4-(Cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNbonitR1le (Compound No. 118),
3-[l-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxylic acid (Compound No. 119),
3-[l-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNbonitR1le (Compound No. 12O),
7-[4-(Cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-en-2-ol (Compound No. 121),
7-[l-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-en-2-ol (Compound No. 122),
7-[l-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxamide (Compound No. 123), 7-[4-(Cyclohexylamino)-1 -ethyl-1 ff-pyrazolo[3,4-b]pyR1din-5-yl]-N-methyl-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxamide (Compound No. 124),
7-[l-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-N-methyl-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxamide (Compound No. 125), 7-[4-(Cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-N-ethyl-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxamide (Compound No. 126),
N-Ethyl-7-[l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxamide (Compound No. 127),
5-(2-Amino-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-l-ethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 128),
5-(2-Amino-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-cyclohexyl-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 129),
N-{7-[4-(cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-en-2-yl}acetamide (Compound No. 13O),
.V-{7-[l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-en-2-yl}acetamide (Compound No. 131), 4- {[ 1 -Ethyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclohexanecNboxylic acid (Compound No. 132),
4- {[ 1 -Ethyl-5-( 1 -oxa-2-azaspiro[4.4]non-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-
yl]amino}cyclohexanecNboxylic acid (Compound No. 133),
4-{[l-Ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-
yl]amino}cyclohexanecNboxylic acid (Compound No. 134),
4-{[5-(2-Cyano-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-l-ethyl-l^/-pyrazolo[3,4-fe]pyR1din-4-
yl]amino}cyclohexanecNboxylic acid (Compound No. 135),
l-Ethyl-3-methyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-
pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 136),
l-Ethyl-3-methyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-N-(tetrahydro-2H-pyran-4-yl)-
1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 137),
1 -Ethyl-3-methyl-5-(l -oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-
pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 138),
7-[l-Ethyl-3-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-
5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNbonitR1le (Compound No. 139),
/V-Cyclohexyl-1 -ethyl-3-methyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-1H-pyrazolo[3,4-
b]pyR1din-4-amine (Compound No. 14O),
7-[4-(Cyclohexylamino)-l-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-
azaspiro[3.4]oct-6-ene-2-cNbonitR1le (Compound No. 141),
3-[4-(Cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-N-methyl-l-oxa-2-
azaspiro[4.5]dec-2-en-8-amine (Compound No. 142),
4-{[5-(2-Cyano-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-l-ethyl-3-methyl-1H-pyrazolo[3,4-
Z>]pyR1din-4-yl]amino}cyclohexanecNboxylic acid (Compound No. 143),
4-{[l-Ethyl-5-(2-hydroxy-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-3-methyl-1H-pyrazolo[3,4-
b]pyR1din-4-yl]amino}cyclohexanecNboxylic acid (Compound No. 144),
4-{[l-Ethyl-3-methyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-
yl]amino}cyclohexanecNboxylic acid (Compound No. 145),
4-{[l-Ethyl-3-methyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-
yl]amino}cyclohexanecNboxylic acid (Compound No. 146),
4- {[ 1 -Ethyl-5-(8-hydroxy-1 -oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-
4-yl]amino}cyclohexanecNboxylic acid (Compound No. 147),
3-{4-[(l, 1-Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-l-ethyl-1H-pyrazolo[3,4-
b]pyR1din-5-yl}-l-oxa-2-azaspiro[4.5]dec-2-en-8-ol (Compound No. 148),
3-[l-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-fe]pyR1din-5-yl]-l-oxa-2-
azaspiro[4.5]dec-2-ene-8-cNboxamide (Compound No. 149),
4-{[5-(8-CNbamoyl-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-l-ethyl-1H-pyrazolo[3,4-
&]pyR1din-4-yl]amino}cyclohexanecNboxylic acid (Compound No. 15O),
3-{[5-(8-CNbamoyl-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-l-ethyl-1H-pyrazolo[3,4-
b]pyR1din-4-yl]amino}cyclobutanecNboxylic acid (Compound No. 151),
3-{l-Ethyl-4-[(3-hydroxycyclobutyl)amino]-1H-pyrazolo[3,4-b]pyR1din-5-yl}-N-methyl-l-
oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxamide (Compound No. 152),
3-[4-(Cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-N-methyl-l-oxa-2-
azaspiro[4.5]dec-2-ene-8-cNboxamide (Compound No. 153),
3-[l-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-N-methyl-
l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxamide (Compound No. 154),
3-{4-[(l,l-Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-l-ethyl-1H-pyrazolo[3,4-
b]pyR1din-5-yl} -N-methyl-1 -oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxamide (Compound No.
155),
3- {4-[( 1,1 -Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-1 -ethyl-3-methyl-1H-
pyrazolo[3,4-b]pyR1din-5-yl}-N-methyl-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxamide
(Compound No. 156),
N-(l,l-dioxidotetrahydro-2H-thiopyran-4-yl)-l-ethyl-3-methyl-5-(5-oxa-6-azaspiro[3.4]oct-
6-en-7-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 157),
N-( 1,1 -dioxidotetrahydro-2H-thiopyran-4-yl)-1 -ethyl-3-methyl-5 -(1 -oxa-2-azaspiro[4.4]non-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 158), N-( 1,1 -dioxidotetrahydro-2H-thiopyran-4-yl)-1 -ethyl-3-methyl-5-( 1 -oxa-2-azaspiro[4.5]dec-2-en-3-yl)-l#-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 159), 3-{4-[(l ,1 -Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-l -ethyl-3-methyl-l H-pyrazolo[3,4-b]pyR1din-5-yI}-l-oxa-2-azaspiro[4.5]dec-2-en-8-ol (Compound No. 16O), 3-{4-[(l,l-Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl}-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxylic acid (Compound No. 161), 3- {4-[( 1,1 -Dioxidotetrahydro-2H-thiopyran-4-yl)amino] -1 -ethyl-3 -methyl-1H-pyrazolo[3,4-b]pyR1din-5-yl}-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxylic acid (Compound No. 162),
3-{4-[(l,l-Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-l-ethyl-1H-pyrazolo[3,4-A]pyR1din-5-yl}-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxamide (Compound No. 163), 3 - {4-[( 1,1 -Dioxidotetrahy dro-2#-thiopyran-4-y l)amino] -1 -ethyl-3 -methyl-1H-pyrazolo[3,4-b]pyR1din-5-yl}-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxamide (Compound No. 164),
3-[l-Ethyl-3-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-en-8-ol (Compound No. 165),
3-[l-Ethyl-3-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxylic acid (Compound No. 166), 3-[l-Ethyl-3-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-A]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNbonitR1le (Compound No. 167), 7-[l-Ethyl-3-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxylic acid (Compound No. 168), 7-[l-Ethyl-3-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-en-2-ol (Compound No. 169),
7-[l-Ethyl-3-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxamide (Compound No. 17O), 5-(2-Amino-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-1 -ethyl-3-methyl-N-(tetrahydro-2/f-pyran-4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 171), 3-[4-(Cyclohexylamino)-1 -ethyl-3-methyl-1H-pyrazolo[3,4-A]pyR1din-5-yl]-1 -oxa-2-azaspiro[4.5]dec-2-en-8-ol (Compound No. 172),
3-[4-(Cyclohexylamino)-l-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNbonitR1le (Compound No. 173), 3-[4-(Cyclohexylamino)-l-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxylic acid (Compound No. 174), 7-[4-(Cyclohexylamino)-l-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxylic acid (Compound No. 175), 7-[4-(Cyclohexylamino)-l-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-en-2-ol (Compound No. 176),
7-[4-(Cyclohexylamino)-l-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-N-methyl-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxamide (Compound No. 177), 5-(2-Amino-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-cyclohexyl-l-ethyl-3-methyl-1H-pyrazolo[3,4-£]pyR1din-4-amine (Compound No. 178),
4-{[l-Ethyl-3-methyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclohexanecNboxylic acid (Compound No. 179),
4-{[l-Ethyl-5-(8-hydroxy-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-3-methyl-1H-pyrazolo[3,4-A]pyR1din-4-yl]amino}cyclohexanecNboxylic acid (Compound No. 18O), 3-{[l-Ethyl-3-methyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclobutanecNboxylic acid (Compound No. 181),
3-{[l-Ethyl-3-methyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclobutanecNboxylic acid (Compound No. 182),
3-{[l-Ethyl-3-methyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclobutanecNboxylic acid (Compound No. 183),
3-{[5-(2-Cyano-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-l-ethyl-1H-pyrazolo[3,4-ft]pyR1din-4-yl]amino}cyclobutanecNboxylic acid (Compound No. 184),
3-{[5-(2-Cyano-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-l-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclobutanecNboxylic acid (Compound No. 185), 3-{[l-Ethyl-5-(8-hydroxy-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-3-methyl-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclobutanecNboxylic acid (Compound No. 186), 3-{[l-Ethyl-5-(8-hydroxy-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclobutanecNboxylic acid (Compound No. 187),
3-{[l-Ethyl-5-(2-hydroxy-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclobutanecNboxylic acid (Compound No. 188),
3-{[l-Ethyl-5-(2-hydroxy-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-3-methyl-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclobutanecNboxylic acid (Compound No. 189), 5-(2-Amino-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-(l,l-dioxidotetrahydro-2H-thiopyran-4-yl)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 19O), 5-(2-Amino-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-(l,l-dioxidotetrahydro-2H-thiopyran-4-yl)-l-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 191), N-(7-{4-[(l,l-dioxidotetrahydro-2H-thiopyran-4-yl)amino]-l-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-5-yl}-5-oxa-6-azaspiro[3.4]oct-6-en-2-yl)acetamide (Compound No. 192),
N-(7- {4-[( 1,1 -dioxidotetrahydro-2H-thiopyran-4-yl)amino]-1 -ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl}-5-oxa-6-azaspiro[3.4]oct-6-en-2-yl)acetamide (Compound No. 193), N-( 7- {4- [(1,1 -dioxidotetrahydro-2H-thiopyran-4-yl)amino] -1 -ethyl-1H-pyrazolo[3,4-/)]pyR1din-5-yl}-5-oxa-6-azaspiro[3.4]oct-6-en-2-yl)propanamide (Compound No. 194), N-(7-{4-[(l,l-dioxidotetrahydro-2H-thiopyran-4-yl)amino]-l-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-5-yl}-5-oxa-6-azaspiro[3.4]oct-6-en-2-yl)propanamide (Compound No. 195),
3-{[5-(2-Amino-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-l -ethyl-17/-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclobutanecNboxylic acid (Compound No. 196),
3-{[5-(2-Amino-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-l-ethyl-3-methyl-1H-pyrazolo[3,4-/)]pyR1din-4-yl]amino}cyclobutanecNboxylic acid (Compound No. 197), 3-({5-[2-(Acetylamino)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-l-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-4-yl}amino)cyclobutanecNboxylic acid (Compound No. 198), 3-({5-[2-(Acetylamino)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-4-yl}amino)cyclobutanecNboxylic acid (Compound No. 199), 3-({l-Ethyl-5-[2-(propanoylamino)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-1H-pyrazolo[3,4-b]pyR1din-4-yl}amino)cyclobutanecNboxylic acid (Compound No. 20O), 3-({l-Ethyl-3-methyl-5-[2-(propanoylamino)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-1H-pyrazolo[3,4-b]pyR1din-4-yl}amino)cyclobutanecNboxylic acid (Compound No. 201), N-ethyl-7-[l-ethyl-3-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxamide (Compound No. 202), N-{7-[4-(cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-en-2-yl}propanamide (Compound No. 203),
N-{7-[l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-en-2-yl}propanamide (Compound No. 204),
.V-{7-[l-ethyl-3-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b7]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-en-2-yl}propanamide (Compound No. 205), 4-{[5-(8-Amino-l-oxa-2-azaspko[4.5]dec-2-en-3-yl)-l-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclohexanecNboxylic acid (Compound No. 206), 4-{[5-(8-Amino-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclohexanecNboxylic acid (Compound No. 207),
4-({5-[8-(Acetylamino)-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl]-l-ethyl-1H-pyrazolo[3,4-
b]pyR1din-4-yl}amino)cyclohexanecNboxylic acid (Compound No. 208),
4-( {5-[8-(Acetylamino)-1 -oxa-2-azaspiro[4.5]dec-2-en-3-yl]-1 -ethyl-3-methyl-1H-
pyrazolo[3,4-b]pyR1din-4-yl}amino)cyclohexanecNboxylic acid (Compound No. 209),
4-({l-Ethyl-3-methyI-5-[8-(propanoylamino)-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl]-1H-
pyrazolo[3,4-b]pyR1din-4-yl}amino)cyclohexanecNboxylic acid (Compound No. 21O),
4-({l-Ethyl-5-[8-(propanoylamino)-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl]-1H-pyrazolo[3,4-
b]pyR1din-4-yl}amino)cyclohexanecNboxylic acid (Compound No. 211),
7-{4-[(4-CNboxycyclohexyl)amino]-l-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-5-yl}-5-
oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxylic acid (Compound No. 212),
7-{4-[(4-CNboxycyclohexyl)amino]-l-ethyl-1H-pyrazolo[3,4-bj]pyR1din-5-yl}-5-oxa-6-
azaspiro[3.4]oct-6-ene-2-cNboxylic acid (Compound No. 213),
4-{[5-(2-CNbamoyl-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-l-ethyl-1H-pyrazolo[3,4-
fr]pyR1din-4-yl]amino}cyclohexanecNboxylic acid (Compound No. 214),
4-{[5-(2-CNbamoyl-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-l-ethyl-3-methyl-1H-
pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclohexanecNboxylic acid (Compound No. 215),
4-({l-Ethyl-3-methyl-5-[2-(methylcNbamoyl)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-1H-
pyrazolo[3,4-b]pyR1din-4-yl}amino)cyclohexanecNboxylic acid (Compound No. 216),
4-({l-Ethyl-5-[2-(methylcNbamoyl)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-1H-pyrazolo[3,4-
b]pyR1din-4-yl}amino)cyclohexanecNboxylic acid (Compound No. 217),
4-({l-Ethyl-5-[2-(ethylcNbamoyl)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-1H-pyrazolo[3,4-
b]pyR1din-4-yl}amino)cyclohexanecNboxylic acid (Compound No. 218),
4-({l-Ethyl-5-[2-(ethylcNbamoyl)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-3-methyl-1H-
pyrazolo[3,4-b]pyR1din-4-yl}amino)cyclohexanecNboxylic acid (Compound No. 219),
3-{4-[(4-CNboxycyclohexyl)amino]-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl}-l-oxa-2-
azaspiro[4.5]dec-2-ene-8-cNboxylic acid (Compound No. 22O),
3-{4-[(4-CNboxycyclohexyl)amino]-l-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-5-yl}-l-
oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxylic acid (Compound No. 221),
4- {[5-(8-CNbamoy 1-1 -oxa-2-azaspiro [4.5 ]dec-2-en-3-yl)-1 -ethyl-3 -methyl-1H-
pyrazoIo[3,4-b]pyR1din-4-yl]amino}cyclohexanecNboxylic acid (Compound No. 222),
4-({l-Ethyl-5-[8-(methylcNbamoyl)-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl]-1H-pyrazolo[3,4-
b]pyR1din-4-yl}amino)cyclohexanecNboxylic acid (Compound No. 223),
4-({l-Ethyl-3-methyl-5-[8-(methylcNbamoyl)-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl]-1H-
pyrazolo[3,4-b]pyR1din-4-yl}amino)cyclohexanecNboxylic acid (Compound No. 224),
4-({l-Ethyl-5-[8-(ethylcNbamoyl)-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl]-3-methyl-1H-
pyrazolo[3,4-b]pyR1din-4-yl}amino)cyclohexanecNboxylic acid (Compound No. 225),
4-({l-Ethyl-5-[8-(ethylcNbamoyl)-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl]-1H-pyrazolo[3,4-
b]pyR1din-4-yl}amino)cyclohexanecNboxylic acid (Compound No. 226),
4- {[ 1 -Ethyl-5-(8-methoxy-1 -oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1 7/-pyrazolo[3,4-£]pyR1din-
4-yl]amino}cyclohexanecNboxylic acid (Compound No. 227),
4-{[5-(8-Ethoxy-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-4-
yl]amino}cyclohexanecNboxylic acid (Compound No. 228),
4-({l-Ethyl-5-[8-(2-hydroxyethoxy)-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl]-1H-pyrazolo[3,4-
b]pyR1din-4-yl}amino)cyclohexanecNboxylic acid (Compound No. 229),
l-Ethyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-pyR1din-4-yl-1H-pyrazolo[3,4-b]pyR1din-
4-amine (Compound No. 23O),
l-Ethyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-pyR1din-3-yl-1H-pyrazolo[3,4-b]pyR1din-
4-amine (Compound No. 231),
l-Ethyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-pyR1din-2-yl-1H-pyrazolo[3,4-b]pyR1din-
4-amine (Compound No. 232),
l-Ethyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-pyrazin-2-yl-1H-pyrazolo[3,4-b]pyR1din-
4-amine (Compound No. 233),
l-Ethyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-pyR1midin-2-yI-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 234), l-Ethyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-l,2,4-tR1azin-5-yl-1H-pyrazolo[3,4-
b]pyR1din-4-amine(Compound No. 235), l-Ethyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-l,3-thiazol-2-yl-1H-pyrazolo[3,4-
A]pyR1din-4-amine (Compound No. 236), l-Ethyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-4//-l,2,4-tR1azol-4-yl-1H-pyrazoIo[3,4-
b]pyR1din-4-amine (Compound No. 237),
l-Ethyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-2H-tetrazol-5-yl-1H-pyrazolo[3,4-
b]pyR1din-4-amine (Compound No. 238),
l-Ethyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-1H-tetrazol-5-yl-1H-pyrazolo[3,4-
b]pyR1din-4-amine (Compound No. 239),
l-Ethyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-pyR1midin-5-yl-1H-pyrazolo[3,4-
b]pyR1din-4-amine (Compound No. 24O),
l-Ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-pyR1din-4-yl-1H-pyrazolo[3,4-fc]pyR1din-
4-amine (Compound No. 241),
l-Ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-N-pyR1din-4-yl-1H-pyrazolo[3,4-b]pyR1din-
4-amine (Compound No. 242),
l-Ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-pyR1din-3-yl-1H-pyrazolo[3,4-*]pyR1din-
4-amine (Compound No. 243),
l-Ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-pyR1din-2-yl-1H-pyrazolo[3,4-b]pyR1din-
4-amine (Compound No. 244),
l-Ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-pyR1midin-2-yl-1H-pyrazolo[3,4-
b]pyR1din-4-amine (Compound No. 245),
l-Ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-pyR1midin-5-yl-1H-pyrazolo[3,4-
b]pyR1din-4-amine (Compound No. 246),
l-Ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-l,2,4-tR1azin-5-yl-1H-pyrazolo[3,4-
fr]pyR1din-4-amine (Compound No. 247),
l-Ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-l,3-thiazol-2-yl-1H-pyrazolo[3,4-
b]pyR1din-4-amine (Compound No. 248),
l-Ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yI)-N-4//-l,2,4-tR1azol-4-yl-1H-pyrazolo[3,4-
b]pyR1din-4-amine (Compound No. 249),
l-Ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-2H-tetrazol-5-yl-1H-pyrazolo[3,4-
fr]pyR1din-4-amine (Compound No. 25O),
l-Ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-1H-tetrazol-5-yl-1H-pyrazolo[3,4-
b]pyR1din-4-amine (Compound No. 251),
l-Ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-A''-pyR1din-3-yl-1H-pyrazo!o[3,4-b]pyR1din-
4-amine (Compound No. 252),
l-Ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-yV-pyR1din-2-yl-1H-pyrazolo[3,4-b]pyR1din-
4-amine (Compound No. 253),
l-Ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-N-pyR1midin-2-yl-1H-pyrazolo[3,4-
b]pyR1din-4-amine (Compound No. 254),
l-Ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-N-pyR1midin-5-yl-1H-pyrazolo[3,4-
A]pyR1din-4-amine (Compound No. 255),
l-Ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-N-l,2,4-tR1azin-5-yl-1H-pyrazolo[3,4-
b]pyR1din-4-amine (Compound No. 256),
l-Ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-N-1H-tetrazol-5-yl-1H-pyrazolo[3,4-
/7]pyR1din-4-amine (Compound No. 257),
l-Ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-N-2H-tetrazol-5-yl-1H-pyrazolo[3,4-
b]pyR1din-4-amine (Compound No. 258),
1 -Ethy l-5-( 1 -oxa-2-azaspiro[4.4]non-2-en-3-yl)-N-4H-1,2,4-tR1azol-4-yl-1H-pyrazolo[3,4-
b]pyR1din-4-amine (Compound No. 259),
1 -Ethyl-5-( 1 -oxa-2-azaspiro[4.4]non-2-en-3-yl)-N-l ,3-thiazol-2-yl-1H-pyrazolo[3,4-
A]pyR1din-4-amine (Compound No. 26O),
l-Ethyl-N-furan-3-yl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-
amine (Compound No. 261),
1 -Ethyl-N-furan-3-yl-5-( 1 -oxa-2-azaspiro[4.4]non-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-
amine (Compound No. 262),
1 -Ethyl-N-furan-3-yl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yI)-1H-pyrazolo[3,4-b]pyR1din-4-
amine (Compound No. 263),
l-EthyI-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-y!)-N-pyrazin-2-yl-1H-pyrazolo[3,4-b]pyR1din-
4-amine (Compound No. 264),
l-Ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-pyrazin-2-yl-1H-pyrazolo[3,4-b]pyR1din-
4-amine (Compound No. 265),
7-{4-[(l,l-Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-l-ethyl-1H-pyrazolo[3,4-
b]pyR1din-5-yl}-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNbonitR1le (Compound No. 266),
7-{4-[(l,l-Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-l-ethyl-1H-pyrazolo[3,4-
A]pyR1din-5-yl}-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxylic acid (Compound No. 267),
Methyl 7-{4-[(l,l-dioxidotetrahydro-2H-thiopyran-4-yl)amino]-l-ethyl-1H-pyrazolo[3,4-
b]pyR1din-5-yl}-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxylNe (Compound No. 268),
Ethyl 7-{4-[( 1,1 -dioxidotetrahydro-2H-thiopyran-4-yl)amino]-1 -ethyl-1H-pyrazolo[3,4-
b]pyR1din-5-yl}-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxylNe (Compound No. 269),
tert-Buty] 7-{4-[( 1,1 -dioxidotetrahydro-2H-thiopyran-4-yl)amino]-1 -ethyl-1H-
pyrazolo[3,4-b]pyR1din-5-yl}-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxylNe (Compound No.
27O),
7- {4-[( 1,1 -Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-1 -ethyl-1H-pyrazolo[3,4-
b]pyR1din-5-yl}-#-methyl-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxamide (Compound No.
271),
7-{4-[(l,l-Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-l-ethyl-1H-pyrazolo[3,4-
^]pyR1din-5-yl}-N-ethyl-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxamide (Compound No.
272),
N-cyclopropyl-7-{4-[( 1,1 -dioxidotetrahydro-2H-thiopyran-4-yl)amino]-1 -ethyl-1H-
pyrazolo[3,4-£]pyR1din-5-yl}-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxamide (Compound
No. 273),
7-{4-[(l,l-Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-l-ethyl-1H-pyrazolo[3,4-
b]pyR1din-5-yl}-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxamide (Compound No. 274),
7-[4-(Cyclohexylamino)-l-ethyl-l/Z-pyrazolotSjpyR1din-S-ycyclopropyl-S-oxN-
azaspiro[3.4]oct-6-ene-2-cNboxamide (Compound No. 275),
yV-cyclopropyl-7-[l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-A]pyR1din-5-
yl]-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxamide (Compound No. 276),
l-Ethyl-5-(8-methoxy-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-(tetrahydro-2H-pyran-4-yl)-
1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 277),
5-(8-Ethoxy-1 -oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1 -ethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-
pyrazoIo[3,4-b]pyR1din-4-amine (Compound No. 278),
yV-cyclohexyl-5-(8-ethoxy-1 -oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1 -ethyl-1H-pyrazolo[3,4-
b]pyR1din-4-amine (Compound No. 279),
.V-cyclohexyl-l-ethyl-5-(8-methoxy-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-
b]pyR1din-4-amine (Compound No. 28O),
3-{4-[(l,l-Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-l-ethyl-1H-pyrazolo[3,4-
b]pyR1din-5-yl}-N-ethyl-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxamide (Compound No.
281),
N-cyclopropyl-3-{4-[(l,l-dioxidotetrahydro-2H-thiopyran-4-yl)amino]-l-ethyl-1H-pyrazolo[3.4-A]pyR1din-5-yl}-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxamide (Compound No. 282),
3-[4-(Cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-yV-cyclopropyl-l-oxa-2-
azaspiro[4.5]dec-2-ene-8-cNboxamide (Compound No. 283),
N-cyclopropyl-3-[l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-fe]pyR1din-5-
yl]-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxamide (Compound No. 284),
N-ethyl-3 -[ 1 -ethyl-4-(tetrahydro-2#-pyran-4-ylamino)-1H-pyrazolo [3,4-b]pyR1din-5 -yl]-1 -
oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxamide (Compound No. 285),
3-[4-(Cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-fe]pyR1din-5-yl]-N-ethyl-l-oxa-2-
azaspiro[4.5]dec-2-ene-8-cNboxamide (Compound No. 286),
Ethyl 3-{4-[(l,l-dioxidotetrahydro-2H-thiopyran-4-yl)amino]-l-ethyl-1H-pyrazolo[3,4-
b]pyR1din-5-yl}-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxylNe (Compound No. 287),
Methyl 3-{4-[( 1,1 -dioxidotetrahydro-2H-thiopyran-4-yl)amino]-1 -ethyl-1H-pyrazolo[3,4-
b]pyR1din-5-yl}-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxylNe (Compound No. 288),
tert-Bu\y\ 3- {4-[( 1,1 -dioxidotetrahydro-2H-thiopyran-4-yl)amino]-1 -ethyl-1H-
pyrazolo[3,4-b]pyR1din-5-yl}-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxylNe (Compound
No. 289),
N-( 1,1 -dioxidotetrahydro-2H-thiopyran-4-yl)-1 -ethyl-5-(8-methoxy-1 -oxa-2-
azaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 29O),
N-(l ,1 -dioxidotetrahydro-2H-thiopyran-4-yl)-5-(8-ethoxy-l -oxa-2-azaspiro[4.5]dec-2-en-3-
yl)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 291),
l-Ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-N-l,2,4-tR1azin-3-yl-1H-pyrazolo[3,4-
b]pyR1din-4-amine (Compound No. 292),
l-Ethyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-l,2,4-tR1azin-3-yl-1H-pyrazolo[3,4-
b]pyR1din-4-amine (Compound No. 293),
l-Ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-l,2,4-tR1azin-3-yl-1H-pyrazolo[3,4-
fr]pyR1din-4-amine (Compound No. 294),
l-Ethyl-5-(2-methoxy-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-(tetrahydro-2H-pyran-4-yl)-
1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 295),
N-cyclohexyl-l-ethyl-5-(2-methoxy-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-1H-pyrazolo[3,4-
b]pyR1din-4-amine (Compound No. 296),
N-( 1,1 -dioxidotetrahydro-2H-thiopyran-4-yl)-1 -ethyl-5-(2-methoxy-5-oxa-6-
azaspiro[3.4]oct-6-en-7-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 297),
N-(l,l-dioxidotetrahydro-2H-thiopyran-4-yl)-5-(2-ethoxy-5-oxa-6-azaspiro[3.4]oct-6-en-7-
yl)-l-ethyl-1H-pyrazolo[3,4-ft]pyR1din-4-amine (Compound No. 298),
N-cyclohexyl-5-(2-ethoxy-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-l-ethyl-1H-pyrazolo[3,4-
b]pyR1din-4-amine (Compound No. 299),
5-(2-Ethoxy-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-l-ethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-
pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 30O),
{7-[4-(Cyclohexylamino)-l -ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-
azaspiro[3.4]oct-6-en-2-yl}methanol (Compound No. 301),
(7- {4-[( 1,1 -Dioxidotetrahydro-2H-thiopyran-4-yl)amino] -1 -ethyl-17/-pyrazolo[3,4-
b]pyR1din-5-yl}-5-oxa-6-azaspiro[3.4]oct-6-en-2-yl)methanol (Compound No. 302),
yV-(l,l-dioxidotetrahydro-2H-thiopyran-4-yl)-l-ethyl-5-[2-(methoxymethyl)-5-oxa-6-
azaspiro[3.4]oct-6-en-7-yl]-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 303),
N-( 1,1 -dioxidotetrahydro-2H-thiopyran-4-yl)-5-[2-(ethoxymethyl)-5-oxa-6-
azaspiro[3.4]oct-6-en-7-yl]-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No.
304).
N-cyclohexyl-5-[2-(ethoxymethyl)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-l -ethyl- \H-
pyrazolo[3,4-/)]pyR1din-4-amine (Compound No. 305),
5-[2-(Ethoxymethyl)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-l-ethyl-N-(tetrahydro-2H-pyran-
4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 306),
l-Ethyl-5-[2-(methoxymethyl)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-N-(tetrahydro-2H-
pyran-4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 307),
N-cyclohexyl-l-ethyl-5-[2-(methoxymethyl)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-1H-
pyrazolo[3,4-H]pyR1din-4-amine (Compound No. 308),
5-[2-(Aminomethyl)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-N-cyclohexyl-l -ethyl- \H-
pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 309),
5-[2-(Aminomethyl)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-l-ethyl-N-(tetrahydro-2H-pyran-
4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 31O),
5-[2-(Aminomethyl)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-N-(l,l-dioxidotetrahydro-2H-
thiopyran-4-yl)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 311),
N-[(7-{4-[(l,l-dioxidotetrahydro-2H-thiopyran-4-yl)amino]-l-ethyl-17/-pyrazolo[3,4-
b]pyR1din-5-yl}-5-oxa-6-azaspiro[3.4]oct-6-en-2-yl)methyl]acetamide (Compound No.
312),
A-[(7- {4-[( 1,1 -dioxidotetrahydro-2H-thiopyran-4-yl)amino]-1 -ethyl-1H-pyrazolo[3,4-
b]pyR1din-5-yl}-5-oxa-6-azaspiro[3.4]oct-6-en-2-yl)methyl]propanamide (Compound No.
313),
N-({7-[l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-
6-azaspiro[3.4]oct-6-en-2-yl}methyl)propanamide (Compound No. 314),
N-({7-[4-(cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-
azaspiro[3.4]oct-6-en-2-yl}methyl)propanamide (Compound No. 315),
N-( {7-[4-(cyclohexylamino)-1 -ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-
azaspiro[3.4]oct-6-en-2-yl}methyl)acetamide (Compound No. 316),
/V-({7-[l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-
6-azaspiro[3.4]oct-6-en-2-yl}methyl)acetamide (Compound No. 317),
l-Ethyl-N-(tetrahydro-2H-pyran-4-yl)-5-[2-(1H-tetrazol-5-yl)-5-oxa-6-azaspiro[3.4]oct-6-
en-7-yl]-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 318),
N-cyclohexyl-l-ethyl-5-[2-(1H-tetrazol-5-yl)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-1H-
pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 319),
N-(l,l-dioxidotetrahydro-2H-thiopyran-4-yl)-l-ethyl-5-[2-(1H-tetrazol-5-yl)-5-oxa-6-
azaspiro[3.4]oct-6-en-7-yl]-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 32O),
l-Ethyl-A7-(tetrahydro-2H-pyran-4-yl)-5-[8-(1H-tetrazol-5-yl)-l-oxa-2-azaspiro[4.5]dec-2-
en-3-yl]-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 321),
N-cyclohexyl-l-ethyl-5-[8-(1H-tetrazol-5-yl)-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl]-1H-
pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 322),
N-( 1,1 -dioxidotetrahydro-2H-thiopyran-4-yl)-1 -ethyl-5-[8-( 1H-tetrazol-5-yl)-1 -oxa-2-
azaspiro[4.5]dec-2-en-3-yl]-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 323),
N-( 1,1 -dioxidotetrahydro-2J7-thiopyran-4-yl)-1 -ethyl-5-[8-(2H-tetrazol-5-yl)-1 -oxa-2-
azaspiro[4.5]dec-2-en-3-yl]-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 324),
N-cyclohexyl-1 -ethyl-5-[8-(2H-tetrazol-5-yl)-1 -oxa-2-azaspiro[4.5]dec-2-en-3-yl]-1H-
pyrazolo[3,4-H]pyR1din-4-amine (Compound No. 325),
l-Ethyl-N-(tetrahydro-2H-pyran-4-yl)-5-[8-(2H-tetrazol-5-yl)-l-oxa-2-azaspiro[4.5]dec-2-
en-3-yl]-1H-pyrazoIo[3,4-b]pyR1din-4-amine (Compound No. 326),
l-Ethyl-N-(tetrahydro-2H-pyran-4-yl)-5-[2-(2H-tetrazol-5-yl)-5-oxa-6-azaspiro[3.4]oct-6-
en-7-yl]-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 327),
yV-cyclohexyl-l-ethyl-5-[2-(2H-tetrazol-5-yl)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-1H-
pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 328),
N-( 1,1 -dioxidotetrahydro-2H-thiopyran-4-yl)-1 -ethyl-5-[2-(2#-tetrazol-5-yl)-5-oxa-6-
azaspiro[3.4]oct-6-en-7-yl]-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 329),
Ethyl 3-[ 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-17/-pyrazolo[3,4-b]pyR1din-5-yl]-1 -
oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxylNe (Compound No. 33O),
Ethyl 3-[4-(cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-
azaspiro[4.5]dec-2-ene-8-cNboxylNe (Compound No. 331),
Methyl 3-[4-(cyclohexylamino)-1 -ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-1 -oxa-2-
azaspiro[4.5]dec-2-ene-8-cNboxylNe (Compound No. 332),
Methyl 3-[l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxylNe (Compound No. 333), tert-Buty\ 3-[l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxylNe (Compound No. 334), tert-Buiy\ 3-[4-(cyclohexylammo)-l-ethyl-1H-pyrazolo[3,4-H]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxylNe (Compound No. 335),
A-( 1,1 -dioxidotetrahydro-2H-thiopyran-4-yl)-l -ethyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 336),
7V-(l,l-dioxidotetrahydro-2H-thiopyran-4-yl)-l-ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 337),
3-[4-(Cyclohexylamino)-1 -ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-1 -oxa-2-azaspiro[4.5]dec-2-en-8-amine (Compound No. 338), or their phNmaceutically acceptable salts, phNmaceutically acceptable solvNes, stereoisomers,
tautomers, geometR1c isomers, racemNes, regioisomers, prodrugs, metabolites, polymorphs or N-
oxides. thereof.
The term "phNmaceutically acceptable" means approved by regulNory agency of the federal or a stNe government or listed in the U.S. PhNmacopoeia or other generally recognized phNmacopoeia for use in mammals, and more pNticulNly in humans.
The term "phNmaceutically acceptable salts" refers to deR1vNives of compounds thN can be modified by forming their corresponding acid or base salts. Examples of phNmaceutically acceptable salts include, but Ne not limited to, mineral or organic acids salts of basic residues (such as amines), or alkali or organic salts of acidic residues (such as cNboxylic acids), and the like.
The term "phNmaceutically acceptable solvNes" refers to solvNes with wNer such as hydrNes, hemihydrNe or sesquihydrNe or phNmaceutically acceptable solvents, for example solvNes with common organic solvents as ethanol and the like. Such solvNes Ne also encompassed within the scope of the disclosure.
The present invention also includes within its scope prodrugs of these agents. In general, such prodrugs will be functional deR1vNives of these compounds, which Ne readily convertible in vivo into the required compound. Conventional procedures for the selection and prepNNion of prodrugs Ne known.
The disclosed compounds may get metabolized in vivo and these metabolites Ne also encompassed within the scope of this invention.
The term "polymorphs" includes all crystalline form as well as amorphous form for compounds descR1bed herein and as such Ne intended to be included in the present invention.
All stereoisomers of the compounds of the invention Ne contemplNed, either in admixture or in pure or substantially pure form. The compounds of the present invention can have asymmetR1c centers N any of the cNbon Noms including all the substituents. Consequently, compounds of present invention can exist in enantiomeR1c or diastereomeR1c forms or in mixture thereof. The processes for the prepNNion can utilize racemNes, enantiomers, or diastereomers as stNting
mNeR1als. When diastereomeR1c or enantiomeR1c products Ne prepNed, they can be sepNNed by conventional methods, for example, chromNographic or fractional crystallizNion.
The term "tautomer" includes one of two or more structural isomers thN exist in equilibR1um and Ne readily converted from one isomeR1c form to another. Certain compounds of the general Formula (I) may furthermore be present in tautomeR1c forms.
The term, "geometR1c isomers", refres to compounds, having the same moleculN formula as another but a different geometR1c configurNion, as when Noms or groups of Noms Ne Ntached in different spNial Nrangements on either side of a double bond or other R1gid bond.
The term "regioisomers" refers to compounds, which have the same moleculN formula but differ in the connectivity of the Noms.
The term "racemNe" includes a mixture of equal amounts of left- and R1ght-handed stereoisomers of chiral molecules.
When a bond to a substituent is shown to cross a bond connecting two Noms in a R1ng, then such substituent may be bonded to any Nom on the R1ng.
In another aspect, the present invention includes phNmaceutical compositions compR1sing, as an active ingredient, N least one of the disclosed compound or a phNmaceutically acceptable salt, a phNmaceutically acceptable solvNe, stereoisomer, tautomer, geometR1c isomer, racemNe, regioisomer, prodrug, metabolite, polymorph or N-oxide, together with a phNmaceutically acceptable cNR1er, excipient or diluent. Compounds disclosed herein may be administered to mammal for treNment by any route, which effectively transports the active compound to the appropR1Ne or desired site of action such as oral, nasal, pulmonNy, transdermal or pNenteral (rectal, subcutaneous, intravenous, intraurethral, intramusculN, intranasal). The phNmaceutical composition of the present invention compR1ses a phNmaceutically effective amount of a compound of the present invention formulNed together with one or more phNmaceutically acceptable cNR1ers, excipients or diluents. The choice of phNmaceutical cNR1er, excipient or diluent can be made with regNd to the intended route of administrNion and standNd phNmaceutical practice.
Where desired, the compounds of the invention and/ or their phNmaceutically acceptable salts, phNmaceutically acceptable solvNes, stereoisomers, tautomers, geometR1c isomers, racemNes. regioisomers, prodrugs, metabolites, polymorphs or N-oxides may be advantageously used in combinNion with one or more other compounds. Examples of other compounds,, which may be used in combinNion with compounds of this invention and/ or their phNmaceutically acceptable salts, phNmaceutically acceptable solvNes, stereoisomers, tautomers, geometR1c isomers, racemNes, regioisomers, prodrugs, metabolites, polymorphs or N-oxides include 82-agonists, corticosteroids, leukotR1ene antagonists, 5-lipoxygenase inhibitors, chemokine inhibitors,
p38 kinase inhibitors, anticholinergics, antiallergics, PN (plNelet activNing factor) antagonists,
EGFR (epidermal growth factor receptor) kinase inhibitors, muscN1nic receptor antagonists or combinNions thereof.
The one or more B2- agonist as descR1bed herein may be chosen from those descR1bed in the Nt. The B2-agonists may include one or more compounds descR1bed in U.S. PNent Nos. 3,705,233; 3,644,353; 3,642,896; 3,700,681; 4,579,985; 3,994,974; 3,937,838; 4,419,364; 5,126,375; 5,243.076; 4,992,474; and 4,011,258.
B2-agonists include, for example, one or more of albuterol, salbutamol, biltolterol, pirbuterol, levosalbutamol, tulobuterol, terbutaline, bambuterol, metaproterenol, fenoterol, salmeterol, cNmoterol, Nformoterol, formoterol, and their phNmaceutically acceptable salts or solvNes thereof.
Corticosteroids as descR1bed herein may be chosen from those descR1bed in the Nt. Corticosteroids may include one or more compounds descR1bed in U.S. PNent Nos 3,312,590; 3.983,233; 3,929.768; 3,721,687; 3,436,389; 3,506,694; 3,639,434; 3,992,534; 3.928,326; 3.980.778; 3,780,177; 3.652,554; 3,947,478; 4,076,708; 4,124,707; 4,158,055; 4,298,604; 4,335,121; 4,081,541; 4,226,862; 4,290,962; 4,587,236; 4,472,392; 4,472,393; 4,242,334; 4,014,909; 4,098,803; 4,619,921; 5,482,934; 5,837,699; 5,889,015; 5,278,156; 5,015,746; 5,976,573; 6,337,324; 6,057,307; 6,723,713; 6,127,353; and 6,180,781.
Corticosteroids may include, for example, one or more of alclometasone, amcinonide, amelometasone, beclometasone, betamethasone, budesonide, ciclesonide, clobetasol, cloticasone, cyclomethasone, deflazacort, deprodone, dexbudesonide, diflorasone, difluprednNe, fluticasone, flunisolide, halometasone. halopredone, hydrocortisone, hydrocortisone, methylprednisolone, mometasone, prednicNbNe, prednisolone, R1mexolone, tixocortol, tR1amcinolone, ulobetasol, rofleponide, GW 215864, KSR 592, ST-126, dexamethasone and phNmaceutically acceptable salts, solvNes thereof. Preferred corticosteroids include, for example, flunisolide, beclomethasone, tR1amcinolone, budesonide, fluticasone, mometasone, ciclesonide, and dexamethasone. Examples of possible salts or deR1vNives include: sodium salts, sulfobenzoNes, phosphNes, isonicotinNes, acetNes, propionNes, dihydrogen phosphNes, palmitNes, pivalNes, or furoNes. In some cases, the corticosteroids may also occur in the form of their hydrNes.
The leukotR1ene antagonist can be selected from compounds, for example, those descR1bed in U.S. PNent Nos. 5,565,473, US 5,583,152, US 4,859,692 or US 4,780,469.
Examples of leukotR1ene antagonist include, but Ne not limited to, montelukast, zNirlukast, pranlukast and phNmaceutically acceptable salts thereof.
5-Lipoxygenase inhibitors can be selected from for example, compounds in U.S. PNent Nos. 4,826,868, or 4,873,259, or European PNent Nos. EP 419049, EP 542356 or EP 542355. Examples may include, but Ne not limited to, Nreleuton, zyflo (zileuton), ABT-761, fenleuton or tepoxalin.
Examples of the chemokine inhibitors include, but Ne not limited to, endogenous ligands of chemokine receptors or deR1vNives thereof, and non-peptidic low moleculN compounds or antibodies for chemokine receptors.
Examples of the endogenous ligands of chemokine receptors include, but Ne not limited to, MlP-la, MIP-lp, Rantes, SDF-la, SDF-ip, MCP-1, MCP-2, MCP4, Eotaxin, MDC. Examples of the deR1vNives of endogenous ligands include, but Ne not limited to, AOP-RANTES, Met-SDF-la. Met-SDF-ip.
Examples of the antibodies for chemokine receptors include, but Ne not limited to, Pro-140.
Examples of the non-peptidic low moleculN compounds include, but Ne not limited to, antagonists and agonists for CCR1, CCR2, CCR3, CCR4, CCR5, CXCR1, CXCR2, CXCR3 and CXCR4 receptors.
p38 kinase inhibitors include compounds disclosed in WO06021848, WO06016237, WO06056863, WO06117657 and WO06082492. Any reference to the above mentioned p38 kinase inhibitors also includes any phNmacologically acceptable salts thereof which may exist.
Anticholinergics include, for example, tiotropium salts, iprNropium salts, oxitropium salts, salts of the compounds known from WO 02/32899: tropenol N-methyl-2,2-diphenylpropionNe, scopine N-methyl-2,2-diphenylpropionNe, scopine N-methyl-2-fluoro-2,2-diphenylacetNe and tropenol N-methyl-2-fluoro-2,2-diphenylacetNe; as well as salts of the compounds known from WO 02/32898: tropenol N-methyl-3,3',4,4'-tetrNluorobenzilNe, scopine N-methyl-3,3',4,4'-tetrNluorobenzilNe, scopine N-methyl-4,4'-dichlorobenzilNe, scopine N-methyl-4,4'-difluorobenzilNe, tropenol N-methyl-3,3'-difluorobenzilNe, scopine N-methyl-3,3'-difluorobenzilNe, and tropenol N-ethyl-4,4'-difluorobenzilNe, optionally in the form of their hydrNes and solvNes. By salts Ne meant those compounds which contain, in addition to the above mentioned cNions, as counter-ion, an anion with a single negNive chNge selected from among the chloR1de, bromide, and methanesulfonNe.
Preferred anticholinergics include, for example, tiotropium bromide, iprNropium bromide, oxitropium bromide, tropenol 2,2-diphenylpropionNe methobromide, scopine 2,2-diphenylpropionNe methobromide, scopine 2-fluoro-2,2-diphenylacetNe methobromide, tropenol 2-fluoro-2.2-diphenylacetNe methobromide, tropenol 3,3',4,4'-tetrNluorobenzilNe methobromide, scopine 3,3',4,4'-tetrNluorobenzilNe methobromide, scopine 4,4'-dichlorobenzilNe methobromide, scopine 4,4'-difluorobenzilNe methobromide, tropenol 3,3'-difluorobenzilNe methobromide, scopine 3,3'-difluorobenzilNe methobromide, and tropenol 4,4'-difluorobenzilNe ethylbromide.
Antiallergics include, for example, epinastine, cetiR1zine, azelastine, fexofenadine,
levocabastine. lorNadine, mizolastine, ketotifene, emedastine, dimetindene, clemastine, bamipine,
hexachloropheniramine, pheniramine, doxylamine, chlorophenoxamine, dimenhydR1nNe,
diphenhydramine, promethazine, ebastine, deslorNadine, and meclizine. Preferred antiallergic agents include, for example, epinastine, cetiR1zine, azelastine, fexofenadine, levocabastine, lorNadine, ebastine, deslorNadine, and mizolastine. Any reference to the above-mentioned antiallergic agents also includes any phNmacologically acceptable salts thereof, which may exist.
PN antagonists include, for example, 4-(2-chlorophenyl)-9-methyl-2-[3-(4-morphoiinyl)-3-propanon-l-yl]-6H-thieno[3,2-f][l,2,4]tR1azolo[4,3-a][l,4]diazepine and 6-(2-chlorophenyl)-8,9-dihydro-l-methyl-8-[(4-morpholinyl)cNbonyl]-4H,7H-cyclopenta[4.5]thieno[3,2-fj [ 1,2,4]tR1azolo[4,3-a] [ 1,4]diazepine.
EGFR kinase inhibitors include, for example, 4-[(3-chloro-4-fluorophenyl)amino]-7-(2-{4-[(S)-(2-oxotetrahydrofuran-5-yl)cNbonyl]piperazin-l-yl}-ethoxy)-6-
[(vinylcNbonyl)amino]quinazoline, 4-[(3-chloro4-fluorophenyl)amino]-7-[4-((S)-6-methyl-2-
oxomorpholin-4-yl)butyloxy]-6-[(vinylcNbonyl)amino]quinazoline, 4-[(3-chloro4-
fluorophenyl)amino]-7-[4-((R)-6-methyl-2-oxomorpholin-4-yl)butyloxy]-6-
[(vinylcNbonyl)amino]quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-7-[2-((S)-6-methyl-2-
oxomorpholin-4-yl)ethoxy]-6-[(vinylcNbonyl)amino]quinazoline, 4-[(3-chloro-4-
fluorophenyl)amino]-6-[(4-{N-[2-(ethoxycNbonyl)ethyl]-N-[(ethoxycNbonyl)methyl]-amino}-l-oxo-2-buten-l-yl)amino]-7-cyclopropylmethoxyquinazoline, 4-[(R)-(l-phenylethyl)amino]-6-{[4-(morpholin-4-yl)-l-oxo-2-buten-l-yl]amino}-7-cyclopropyl-methoxyquinazoline, and 4-[(3-chloro-4-fluorophenyl)amino]-6-[3-(morpholin-4-yl)propyloxy]-7-methoxyquinazoline. Any reference to the above-mentioned EGFR kinase inhibitors also includes any phNmacologically acceptable salts thereof which may exist.
MuscN1nic receptor antagonists include substances thN directly or indirectly block activNion of muscN1nic cholinergic receptors. Examples include, but Ne not limited to, quNernNy amines (e.g., methantheline, iprNropium, propantheline), tertiNy amines (e.g., dicyclomine, scopolamine) and tR1cyclic amines (e.g., telenzepine). Other muscN1nic receptor antagonists include benztropine, hexahydro-sila-difenidol hydrochloR1de (HHSID hydrochloR1de), (+/-)-3-quinuclidinyl xanthene-9-cNboxylNe hemioxalNe (QNX-hemioxalNe), telenzepine dihydrochloR1de and tolterodine, oxybutynin, and Nropine.
Examples set forth below demonstrNe the synthetic procedures for the prepNNion of the representNive compounds. The examples Ne provided to illustrNe pNticulN aspect of the disclosure and do not constrain the scope of the present invention as defined by the claims.
ExpeR1mental details
Example la: PrepNNion of l-(4-methoxybenzyl)-1H-pvrazol-5-amine
This compound was synthesized according to procedure reported in Bioorganic and medicinal chemistry letters, EL 1133-1136 (2003).
Example lb: PrepNNion of l-ethyl-3-methvl-lff-pyrazol-5-amine
This compound was synthesized according to procedure reported in Chem. PhNm. Bull. 52(9), 1098-1104 (2004).
Example 1c: PrepNNion of tetrahydro-2H-pyran-4-amine hydrochloR1de
This compound was synthesized according to the procedure reported in Tetrahedron letters, 42.4257-4259,(2001).
Example Id: PrepNNion of tetrahydro-2H-thiopyran-4-amine
Step a: Tetrahydro-4//-thiopyran-4-one (15 gm, 0.129 mole), hydroxylamine hydrochloR1de (15.27 gm, 0.219 mole) and sodium acetNe tR1hydrNe (30 gm, 0.219 mole) were taken together in a mixture of wNer (150 ml) and ethanol (60 ml). The reaction mixture was refluxed for about 4 hours. The solvent was evaporNed under reduced pressure. Solid compound, which sepNNed out, was filtered and dR1ed under vacuum.
Yield: 15gm(99%)
Step b: Lithium aluminum hydR1de (6.96 gm, 0.183 mole) was taken in tetrahydrofuran (80 ml) and solution of tetrahydro-4//-thiopyran-4-one oxime (8 gm, 0.0610 mole) (step a) in tetrahydrofuran (20 ml) was added to it drop wise N 0°C. The reaction mixture was refluxed for about 4 hours and quenched with sNurNed ammonium chloR1de solution. Extraction was done using ethyl acetNe, organic layer was dR1ed over anhydrous sodium sulphNe and concentrNed under reduced pressure to get the title compound.
Yield: 8 gm (crude) (100%)
Example 2: PrepNNion of diethyl {[(1 -ethyl- 1H-pyrazol-5-yamino]methylidene| propanedioNe
A mixture of 5-amino-l-ethylpyrazole (5 gm, 0.0448 mole) and diethylethoxy methylenemalonNe (10.35 ml, 0.0448 mole) was stirred N 120°C for about 1 hour. The reaction mixture was poured into wNer and extraction was done with ethyl acetNe. The organic layer was dR1ed over anhydrous sodium sulphNe and concentrNed under reduced pressure to give viscous oil.
Yield: 15 gm (crude) (124%)
The following compounds were prepNed similNly
- Diethyl {[(l,3-dimethyl-1H-pyrazol-5-yl)amino]methylidene}propanedioNe
- Diethyl ({[l-(4-methoxybenzyl)-1H-pyrazol-5-yl]amino}methylidene)propanedioNe The following compound can be prepNed similNly
Diethyl {[(1 -ethyl-3-methyl-1H-pyrazol-5-yl)amino]methylidene}propanedioNe
Example: 2a: PrepNNion of ethyl 4-hydroxy-l-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyR1dine-5-cNboxylNe
Diphenyl ether (180 ml) was heNed to about 230°C (Internal temperNure 200-210°C) under inert Nmosphere in a round bottom flask fitted with distillNion set and a solution of diethyl ({[l-(4-methoxybenzyl)-1H-pyrazol-5-yl]amino}methylidene) propanedioNe (85 gm, 0.227 mol) (example 2) in absolute ethanol (130 ml) was added dropwise. The reaction mixture was heNed for about 2 hours. VolNile solubles were distilled out. The mixture was cooled to 45°C and methanol (150 ml) was added dropwise. Solid, which precipitNed out was filtered and washed with methanol and hexane and dR1ed under vacuum.
Yield: 33 gm (crude) (45%)
m/z: (M++l) 328.10
Example 3: PrepNNion of ethyl 4-chloro-l -ethyl- lH-pyrazolo [3,4-b] pyR1dine-5-cNboxylNe
A mixture of diethyl {[(l-ethyl-1H-pyrazol-5-yl)amino]methylidene} propanedioNe (15 gm, 0.0533 mole) (example 2) and phosphorous oxy chloR1de (76.64 ml, 0.7998 mole) was heNed N 110-120°C under stirR1ng for about 4 hours under Ngon Nmosphere. The reaction mixture was cooled and then poured drop wise into ice wNer. A pale yellow solid sepNNed which was filtered. The solid was first washed twice with ice cold wNer and then finally with hexane and dR1ed over vacuum.
Yield: 10gm(70%) m/z: (M++l) 254.2
The following compound was prepNed similNly
Ethyl 4-chloro-l, 3-dimethyl-lH-pyrazolo [3,4-b] pyR1dine-5-cNboxylNe
The following compound can be prepNed similNly
Ethyl 4-chloro-l-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1dine-5-cNboxylNe
Example 3a: PrepNNion of ethyl 4-chloro-l-(4-methoxvbenzyl)-1H-pyrazolo[3,4-H1pyR1dine-5-cNboxylNe
The title compound was prepNed by following the procedure of example 3 using ethyl 4-hydroxy-l-(4-methoxybenzyl)-l#-pyrazolo[3,4-b]pyR1dine-5-cNboxylNe (example 2a).
m/z: (M++l) 346.09
Example 4: PrepNNion of ethyl 4-(cyclohexyIamino)-l-ethyl-17/-pyrazolof3,4-b1pyR1dine-5-cNboxylNe
Cyclohexyl amine (9.07 ml, 0.7905 mole) was added to a mixture of ethyl 4-chloro-l-ethyl-lH-pyrazolo[3,4-b]pyR1dine-5-cNboxylNe (10 gm, 0.0395 mole) (example 3) in acetonitR1le. Nter stirR1ng for about 2 h N 110° C, acetonitR1le was removed under reduced pressure. WNer was added and the reaction mixture was extracted with ethyl acetNe. The organic layer was washed with bR1ne, dR1ed over anhydrous sodium sulphNe and concentrNed in vacuo to give brownish solid.
Yield: 9.6 gm (78%)
m/z: (M++l) 317.22
The following compounds were prepNed similNly
Ethyl l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1dine-5-cNboxylNe m/z: (M++l) 319.26
Ethyl l-ethyl-4-[(4-hydroxycyclohexyl)amino]-1H-pyrazolo[3,4-b]pyR1dine-5-cNboxylNe m/z: (M++1)333.06
Ethyl 4-cyclopropylamino-l -ethyl- lH-pyrazolo [3,4-b] pyR1dine-5-cNboxylNe m/z: (M++l) 275.0
Ethyl 4-(cyclopropylamino)-l,3-dimethyl-lH-pyrazolo [3,4-b] pyR1dine-5-cNboxylNe Ethyl 4-(cyclopentylamino)-l-ethyl-lH-pyrazolo [3,4-b] pyR1dine-5-cNboxylNe Ethyl 4-(cyclopentylamino)-l,3-dimethyl-lH-pyrazolo [3,4-b] pyR1dine-5-cNboxylNe Ethyl l-(4-methoxybenzyl)-4-(tetrahydro-2H-thiopyran-4-ylamino)-1H-pyrazolo[3,4-fr]pyR1dine-5-cNboxylNe m/z: (M++l) 427.14
Ethyl 4-(cyclohexylamino)-l-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyR1dine-5-cNboxylNe m/z: (M++1)409.22
Ethyl 4-{[ 1 -(ter?-butoxycNbonyl)pipeR1din-4-yl]amino}-1 -ethyl-1H-pyrazolo[3,4-b]pyR1dine-5-cNboxylNe m/z: (M++l) 418.39
Ethyl l-(4-methoxybenzyl)-4-[(3-methoxyphenyl)amino]-1H-pyrazolo[3,4-b]pyR1dine-5-cNboxylNe m/z: (M++1)433.63
Ethyl 1 -(4-methoxybenzyl)-4-(tetrahydro-2H-pyran-4-ylamino)-l //-pyrazolo[3.4-fr]pyR1dine-5-cNboxylNe m/z: (M++l)411.14
Ethyl 4-(benzylamino)-l-(4-methoxybenzyl)-1H-pyrazolo[3,4-H]pyR1dine-5-cNboxylNe m/z: (M++l) 417.14
Ethyl l-ethyl-4-(tetrahydro-2H-thiopyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1dine-5-cNboxylNe Example 4a: PrepNNion of 4-chloro-l-ethyl-1H-pyrazolo[3,4-b]pvR1dine-5-cNboxylic acid
A solution of ethyl 4-chloro-l-ethyl-1H-pyrazolo[3,4-b]pyR1dine-5-cNboxylNe (0.013 mol)
(example 3) in dioxane is treNed with potassium hydroxide (0.13 mol in 30 ml wNer) solution. The
reaction mixture is stirred for about 3-4 hrs and concentrNed under reduced pressure. It is acidified
with hydrochloR1c acid to pH of about 3-4, extracted with ethyl acetNe, washed with bR1ne and dR1ed
under vacuo
Example 4b: PrepNNion of 4-{[4-(ferr-butoxvcNbonvl)cyclohexyl]amino|-l-ethvl-1H-pyrazolo[3,4-b]pyR1dine-5-cNboxylic acid
A solution of 4-chloro-l-ethyl-1H-pyrazolo[3,4-b]pyR1dine-5-cNboxylic acid (0.0088 mol) (example 4a) in acetonitR1le is treNed with tert-butyl 4-aminocyclohexanecNboxylNe (0.026 mol). The reaction mixture is refluxed for about 3-4 hrs. Solvent is evaporNed off and wNer is added and extraction is done with ethyl acetNe. The organic layer is washed with bR1ne, dR1ed and concentrNed under reduced pressure to give crude compound, which is puR1fied by column chromNography.
The following compound can be prepNed similNly
4-{[3-(tert-ButoxycNbonyl)cyclobutyl]amino}-l-ethyl-1H-pyrazolo[3,4-b]pyR1dine-5-cNboxylic acid
Example 4c: PrepNNion of ethyl 4-f(l,l-dioxidotetrahvdro-2H-thiopyran-4-yl)aminol-l-(4-
methoxybenzyl)-1H-pyrazolof3,4-H]pyR1dine-5-cNboxylNe
Ethyl 1 -(4-methoxybenzyl)-4-(tetrahydro-2H-thiopyran-4-ylamino)-17/-pyrazolo[3,4-b]pyR1dine-5-cNboxylNe (500 mg, 0.00117 mole) (example 4) was taken in dichloromethane (5 ml). N 0°C, m- chloroperbenzoic acid (600 mg, 0.00352 mole) was added and the mixture was stirred overnight. WNer was added and extraction was done using dichloromethane. The organic layer was washed with sNurNed ammonium bicNbonNe and then with bR1ne, dR1ed over anhydrous sodium sulphNe and concentrNed under reduced pressure to get the title compound.
Yield: 500 mg (93 %) m/z: (M++l) 495.16 The following compound can be prepNed similNly
Ethyl 4-[( 1,1 -dioxidotetrahydro-2H-thiopyran-4-yl)amino]-1 -ethyl-1H-pyrazolo[3,4-b]pyR1dine-5-cNboxylNe
Example 5: PrepNNion of 4-cyclohexylamino-l-ethyl-lH-pyrazolo [3,4-b] pyR1dine-5-cNboxylic acid
Sodium hydroxide solution (4.09 gm in 20 ml wNer) was added to a solution of ethyl 4-(cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-b]pyR1dine-5-cNboxylNe (9.32 gm, 0.0294 mole) (example 4) in ethanol. The reaction mixture was stirred for about 14 h N room temperNue and then wNmed for about 1 h N 60°C . WNer was added and the reaction mixture was extracted with ethyl acetNe. Aqueous layer was acidified by using hydrochloR1c acid (2N) to pH of about 4-5. White solid, which was obtained, was filtered and dR1ed in vacuo.
Yield: 9 gm crude (100%)
m/z: (M++1)289.22
The following compounds were prepNed similNly
l-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1dine-5-cNboxylic acid m/z: (M++l) 291.36
l-Ethyl-4-[(4-hydroxycyclohexyl)amino]-1H-pyrazolo[3,4-b]pyR1dine-5-cNboxylic acid
m/z: (M++1)305.10
4-Cyclopropylamino-l-ethyl-lH-pyrazolo [3,4-b] pyR1dine-5-cNboxylic acid
m/z: (M++1)274.2
4-(Cyclopropylamino)-l,3-dimethyl-lH-pyrazolo [3,4-b] pyR1dine-5-cNboxylic acid
4-(Cyclopentylamino)-l-ethyl-lH-pyrazolo [3,4-b] pyR1dine-5-cNboxylic acid
4-(Cyclopentylamino)-l,3-dimethyl-lH-pyrazolo [3,4-b] pyR1dine-5-cNboxylic acid
4-[(l,l-Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-l-ethyl-1H-pyrazolo[3,4-b]pyR1dine-
5-cNboxylic acid
4-[(l ,1 -Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-l -(4-methoxybenzyl)-l H-
pyrazolo[3,4-b]pyR1dine-5-cNboxylic acid
m/z: (M++l) 383.28
4-(Benzylamino)-l -(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyR1dine-5-cNboxylic acid
m/z: (M++l) 389.08
4-(Cyclohexylamino)-l-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyR1dine-5-cNboxylic acid
4-{[l-(tert-ButoxycNbonyl)pipeR1din-4-yl]amino}-l-ethyl-1H-pyrazolo[3,4-b]pyR1dine-5-
cNboxylic acid
m/z: (M++1)390.40
l-(4-Methoxybenzyl)-4-[(3-methoxyphenyl)amino]-1H-pyrazolo[3,4-b]pyR1dine-5-
cNboxylic acid
m/z: (M++1)405.05
l-(4-Methoxybenzyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1dine-5-
cNboxylic acid
m/z: (M++l) 383.28
Example 6: PrepNNion of 4-(cvclohexvlamino)-l-ethyl-N-methoxv-N-methvl-1H-pvrazolo[3,4-folpyR1dine-5-cNboxamide (IntermediNe No. 1)
4-Cyclohexylamino-l-ethyl-lH-pyrazolo[3,4-b]pyR1dine-5-cNboxylic acid (0.200 gm, 0.0006 mole) (example 5) and N, O-dimethylhydroxylamine hydrochloR1de (0.102 gm, 0.0010 mole) were taken in dimethylformamide. N 0°C, hydroxybenzotR1azole (0.162 gm, 0.0012 mole) and N-methylmorpholine (0.30 ml, 0.0027 mole) were added and the reaction mixture was stirred for about 1 h. l-Ethyl-3-(3-dimethylaminopropyl) cNbodiimide hydrochloR1de (0.266 gm, 0.0012 mole) was added and the reaction mixture was stirred for about 14 h. WNer was added and extraction was cNR1ed out with ethyl acetNe. The organic layer was washed with bR1ne, dR1ed over anhydrous sodium sulphNe and concentrNed in vacuo. The compound was puR1fied over prepNNive thin layer chromNography.
Yield: 136mg(59%) m/z: (M++l) 332.26
The following intermediNes were prepNed similNly
l-Ethyl-N-methoxy-N-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1dine-5-cNboxamide (IntermediNe No. 2) m/z: (M++l) 334.11
l-Ethyl-4-[(4-hydroxycyclohexyl)amino]-N-methoxy-N-methyl-1H-pyrazolo[3,4-b]pyR1dine-5-cNboxamide (IntermediNe No. 3) m/z: (M++l) 348.05
4-(Cyclopropylamino)-l-ethyl-N-methoxy-N-methyl-lH-pyrazolo[3,4-b]pyR1dine-5-cNboxamide (IntermediNe No. 4) m/z: (M++l) 290.2
4-(Cyclopropylamino)-N-methoxy-N-l, 3-tR1methyl-lH-pyrazolo [3,4-b] pyR1dine-5-cNboxamide (IntermediNe No. 5)
4-(Cyclopentylamino)-l-ethyl-N-methoxy-N-methyl-lH-pyrazoIo [3,4-b] pyR1dine-5-cNboxamide (IntermediNe No. 6)
4-(Cyclopentylamino)-N-methoxy-N-l, 3-tR1methyl-lH-pyrazolo [3,4-b] pyR1dine-5-cNboxamide (IntermediNe No. 7)
4-[( 1,1 -Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-1 -ethyl-N-methoxy-N-methyl-1H-pyrazolo[3,4-b]pyR1dine-5-cNboxamide ((IntermediNe No. 24), m/z: (M++l) 382.10
4-(Benzylamino)-yV-methoxy-l-(4-methoxybenzyl)-N-methyl-1H-pyrazolo[3,4-b)]pyR1dine-5-cNboxamide m/z: (M++1)432.10
4-[( 1,1 -Dioxidotetrahydro-2H-thiopyran-4-yI)amino]-N-methoxy-1 -(4-methoxybenzyl)-N-methyl-1H-pyrazolo[3,4-b]pyR1dine-5-cNboxamide m/z: (M++1)474.06
4-(Cyclohexylamino)-N-methoxy-l-(4-methoxybenzyI)-/l/-methyl-1H-pyrazolo[3,4-b]pyR1dine-5-cNboxamide m/z: (M++l) 332.26
l-Ethyl-N-methoxy-4-[(3-methoxyphenyl)amino]-N-methyl-1H-pyrazolo[3,4-b]pyR1dine-5-cNboxamide (IntermediNe No. 23),
te/Y-Butyl 4-({ l-ethyl-5-[methoxy(methyl)cNbamoyl]-1H-pyrazolo[3,4-b]pyR1din-4-yl}amino)pipeR1dine-l-cNboxylNe (IntermediNe No. 22), m/z: (M++1)433.36
N-methoxy-l-(4-methoxybenzyl)-4-[(3-methoxyphenyl)amino]-N-methyl-1H-pyrazolo[3,4-b]pyR1dine-5-cNboxamide m/z: (M++1)448.15
TV-methoxy-1 -(4-methoxybenzyl)-N-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1dine-5-cNboxamide m/z: (M++1)426.38 The following compounds can be prepNed similNly
/ert-Butyl 3-({l-ethyl-5-[methoxy(methyl)cNbamoyl]-1H-pyrazolo[3,4-b]pyR1din-4-y 1} amino)cyclobutanecNboxylNe
fer/-Butyl 4-({ 1 -ethyl-5-[methoxy(methyl)cNbamoyl]-1H-pyrazolo[3,4-b]pyR1din-4-y 1} amino)cyclohexanecNboxylNe
Example 6a: PrepNNion of 4-(benzylamino)-N-methoxv-N-methyl-1H-pyrazolo[3,4-b]pyR1dine-5-
cNboxamide
TR1fluoroacetic acid (5.35 ml, 69.6 mmol) was added to the solution of 4-(benzylamino)-N-methoxy-l-(4-methoxybenzyl)-N-methyl-1H-pyrazolo[3,4-b]pyR1dine-5-cNboxamide (3 gm, 6.96 mmol) (example 6) in dichloroethane (20 ml) and the reaction mixture was refluxed for about 2 hours under inert Nmosphere. It was cooled, diluted with ethyl acetNe, washed with sNurNed sodium bicNbonNe, wNer and bR1ne, dR1ed over anhydrous sodium sulphNe and concentrNed under reduced pressure to get the title compound.
Yield: 2 gm (92 %)
The following compound was prepNed similNly
- 4-(Cyclohexylamino)-N-methoxy-N-methyl-1H-pyrazolo[3,4-b]pyR1dine-5-cNboxamide
m/z: (M++1)304.12 Example 6b: PrepNNion of 4-(benzvlamino)-l-ethvl-N-methoxy-N-methyl-1H-pvrazolor3,4-folpvR1dine-5-cNboxamide (IntermediNe No. 25)
Ethyl iodide (1.52 gm, 9.63 mmol) and potassium cNbonNe (2.214 gm, 16.05 mmol) were added to the solution 4-(benzylamino)-N-methoxy-N-methyl-1H-pyrazolo[3,4-b]pyR1dine-5-cNboxamide (1 gm, 3.21 mmol) (example 6a) in dimethylformamide and the reaction mixture was stirred N 60°C for about 5 hours. It was cooled, diluted with wNer and extracted with ethyl acetNe. The organic layer was washed with bR1ne, dR1ed over anhydrous sodium sulphNe and concentrNed under reduced pressure. The crude product was puR1fied over silica gel column.
Yield: 0.800 gm (73%)
m/z: (M++l) 340.22
Example 7: PrepNNion of 4-(cyclohexylamino)-l-ethyl-1H-pyrazolo|"3,4-b]pvR1dine-5-cNbaldehvde (IntermediNe No. 8)
Toluene was cooled to -30 to -35°C and vitR1de (0.12 ml, 0.0006 mole) was added. Nter about 10 min„ 4-(cyclohexylamino)-l-ethyl-N-methoxy-N-methyl-1H-pyrazolo[3,4-b]pyR1dine-5-cNboxamide (0.10 gm, 0.0003 mole) (example 6) was added and the reaction mixture was stirred for about 4 h. CitR1c acid (10%) solution was added dropwise to quench the reaction and the reaction mixture was extracted with ethyl acetNe. The organic layer was washed with bR1ne and dR1ed over anhydrous sodium sulphNe and concentrNed in vacuo. The compound was puR1fied over prepNNive thin layer chromNography.
Yield: 54 mg (65%)
m/z: 273.23
The following intermediNes were prepNed similNly
l-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1dine-5-cNbaldehyde
(IntermediNe No. 9)
m/z: (M++l) 275.06
l-Ethyl-4-[(4-hydroxycyclohexyl)amino]-1H-pyrazolo[3,4-b]pyR1dine-5-cNbaldehyde
(IntermediNe No. 1O)
m/z: (M++1)289.06
4-Cyclopropylamino-l-ethyl-lH-pyrazolo [3,4-b] pyR1dine-5-cNbaldehyde (IntermediNe
No. 11)
m/z: (M++l) 231.1
4-Cyclopropylamino)-l,3-dimethyl-lH-pyrazolo[3,4-b]pyR1dine-5-cNbaldehyde
(IntermediNe No. 12)
4-(Cyclopentylamino)-l -ethyl- lH-pyrazolo[3,4-b]pyR1dine-5-cNbaldehyde (IntermediNe No. 13)
4-(Cyclopentylamino)-l,3-dimethyl-lH-pyrazolo[3,4-b]pyR1dine-5-cNbaldehyde
(IntermediNe No. 14)
l-Ethyl-4-[(3-methoxyphenyl)amino]-1H-pyrazolo[3,4-b]pyR1dine-5-cNbaldehyde
(IntermediNe No. 26),
l-(4-Methoxybenzyl)-4-[(3-methoxyphenyl)amino]-1H-pyrazolo[3,4-b]pyR1dine-5-
cNbaldehyde
m/z: (M++1)389.08
tert-Buly\ 4-[(l-ethyl-5-formyl-1H-pyrazolo[3,4-b]pyR1din-4-yl)amino]pipeR1dine-l-
cNboxylNe (IntermediNe No. 27),
m/z: (M++l) 374.35
4-[( 1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-l-ethyl-1H-pyrazolo[3,4-b]pyR1dine-
5-cNbaldehyde (IntermediNe No. 28),
m/z: (M++1)323.19
4-(Benzylamino)-l-ethyl-1H-pyrazolo[3,4-b]pyR1dine-5-cNbaldehyde (IntermediNe No.
29),
m/z: (M++l) 281.11
4-(Cyclohexylamino)-l-(4-methoxybenzyl)-1H-pyrazolo[3,4-H]pyR1dine-5-cNbaldehyde
m/z: (M++l) 365.31
l-(4-Methoxybenzyl)-4-(tetrahydro-2H-pyran-4-yIamino)-1H-pyrazolo[3,4-b]pyR1dine-5-
cNbaldehyde
m/z: (M++1)367.10
The following compounds can be prepNed similNly
tert-Butyl 4-[(l-ethyl-5-formyl-1H-pyrazolo[3,4-b]pyR1din-4-yl)amino]cyclohexane
cNboxylNe
tert-Butyl 3-[(l-ethyl-5-formyl-1H-pyrazolo[3,4-b]pyR1din-4-yl)amino]cyclobutane
cNboxylNe
Example 8: PrepNNion of 4-(cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-b]pyR1dine-5-
cNbaldehyde oxime (IntermediNe No. 15)
Hydroxylamine hydrochloR1de (0.255 gm, 0.0036 mole) and sodium acetNe (0.301 gm, 0.0036 mole) were added to a stirred solution of 4-(cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-b]pyR1dine-5-cNbaldehyde (0.250 gm, 0.0009 mole) (example 7) in ethanol. The reaction mixture was allowed to stir N room temperNure for about 2 h. Ethanol was removed under reduced pressure and residue was poured in wNer. The title compound was then filtered and washed with wNer twice and finally with hexane.
Yield: 0.202 gm (77%)
m/z: (M++l) 288.31
The following intermediNes were prepNed similNly:
l-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1dine-5-cNbaldehyde
oxime (IntermediNe No. 16)
m/z: (M++1)290.13
l-Ethyl-4-[(4-hydroxycyclohexyl)amino]-1H-pyrazolo[3,4-b]pyR1dine-5-cNbaldehyde
oxime (IntermediNe No. 17)
m/z: (M++1)304.11
4-Cyclopropylamino-l -ethyl- lH-pyrazolo [3,4-b] pyR1dine-5-cNbaldehyde oxime
(IntermediNe No. 18)
m/z: (M++1)246.1
* - 4-(Cyclopropylamino)-l,3-dimethyl-lH-pyrazolo [3,4-b] pyR1dine-5-cNbaldehyde oxime
(IntermediNe No. 19)
4-(Cyclopentylamino)-l -ethyl- lH-pyrazolo [3,4-b] pyR1dine-5-cNbaldehyde oxime
(IntermediNe No. 2O)
4-(Cyclopentylamino)-1,3-dimethyl-lH-pyrazolo [3,4-b] pyR1dine-5-cNbaldehyde oxime
(IntermediNe No. 21)
1 -Ethyl-4-[(3-methoxyphenyl)amino]-1H-pyrazolo[3,4-b]pyR1dine-5-cNbaldehyde oxime
(intermediNe No. 3O)
tert-Butyl 4-[(l-ethyl-5-[(£)-(hydroxyimino)methyl -1H-pyrazolo[3,4-b]pyR1din-4-
yl)amino]pipeR1dine-l-cNboxylNe (intermediNe No. 32)
m/z: (M++l) 389.22
4-[(l,l-Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-l-ethyl-1H-pyrazolo[3,4-b]pyR1dine-
5-cNbaldehyde oxime (intermediNe No. 33)
m/z: (M++l) 338.22
4-(Benzylamino)-l -ethyl-1H-pyrazolo[3,4-b]pyR1dine-5-cNbaldehyde oxime (intermediNe
No. 31)
4-(Cyclohexylamino)-l-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyR1dine-5-cNbaldehyde
oxime
l-(4-Methoxybenzyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1dine-5-
cNbaldehyde oxime
m/z: (M++l) 382.21
l-(4-Methoxybenzyl)-4-[(3-methoxyphenyl)amino]-1H-pyrazolo[3,4-b)]pyR1dine-5-
cNbaldehyde oxime
m/z: (M++1)404.11 The following compounds can be prepNed similNly
tert-b\xty\ 3-({ l-emyl-5-[(Z)-(hydroxyimino)methyl]-1H-pyrazolo[3,4-b]pyR1din-4-yl} amino)cyclobutanecNboxylNe
/]pyR1din-4-amine (Compound No. 239),
l-Ethyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-pyR1midin-5-yl-1H-pyrazolo[3,4-A]pyR1din-4-amine (Compound No. 24O),
l-Ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-pyR1din-4-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 241),
l-Ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-N-pyR1din-4-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 242),
l-Ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-pyR1din-3-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 243),
l-Ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-pyR1din-2-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 244),
l-Ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-pyR1midin-2-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 245),
l-Ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-pyR1midin-5-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 246),
l-Ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-l,2,4-tR1azin-5-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 247),
l-Ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-l,3-thiazol-2-yl-1H-pyrazolo[3,4-b]pyR1din-4-amtne (Compound No. 248),
l-Ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-4H-l,2,4-tnazol-4-yl-1H-pyrazolo[3,4-&]pyR1din-4-amine (Compound No. 249),
l-Ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-2H-tetrazol-5-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 25O),
1 -Ethyl-5-( 1 -oxa-2-azaspiro[4.5]dec-2-en-3-yl)-.N-1H-tetrazol-5-yl-1H-pyrazolo[3,4-/j]pyR1din-4-amine (Compound No. 251),
l-Ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-N-pyR1din-3-yl-1H-pyrazolo[3,4-bj]pyR1din-4-amine (Compound No. 252),
l-Ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-N-pyR1din-2-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 253),
l-Ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-N-pyR1midin-2-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 254),
l-Ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-N-pyR1midin-5-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 255),
l-Ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-N-l,2,4-tR1azin-5-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 256),
l-Ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-N-1H-tetrazol-5-yl-1H-pyrazolo[3,4-A]pyR1din-4-amine (Compound No. 257),
l-Ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-//-2H-tetrazol-5-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 258),
l-Ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-N-4H-l,2,4-tR1azol-4-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 259),
l-Ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-N-l,3-thiazol-2-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 26O),
l-Ethyl-N-furan-3-yl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 261),
1 -Ethyl-N-furan-3-yl-5-( 1 -oxa-2-azaspiro[4.4]non-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 262).
l-Ethyl-N-furan-3-yl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 263),
l-Ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-N-pyrazin-2-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 264),
l-Ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-pyrazin-2-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 265),
1 -Ethyl-5-( 1 -oxa-2-azaspiro[4.4]non-2-en-3-yl)-N-1,2,4-tR1azin-3-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 292),
l-Ethyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-AM,2,4-tR1azin-3-yl-1H-pyrazolo[3,4-fr]pyR1din-4-amine (Compound No. 293),
l-Ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-l,2,4-tR1azin-3-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 294).
Example 38; PrepNNion of 3-{f l-ethyl-5-(5-oxa-6-azaspiro[3.41oct-6-en-7-yl)-lH-pyrazolof3,4-
b]pvR1din-4-vl]amino)cvclobutanecNboxylic acid (Compound No. 115)
TR1fluoroacetic acid (4 equivalent) is added to the solution of tert-butyl 3-{[l-ethyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclobutanecNboxylNe (1 equivalent) (example 9) in dichloroethane and the reaction mixture is stirred N room temperNure for about 2 hours under inert Nmosphere. It is cooled and diluted with ethyl acetNe. The organic layer is washed with sNurNed sodium bicNbonNe, wNer and bR1ne, dR1ed over anhydrous sodium sulphNe and concentrNed under reduced pressure to get the title compound.
The following compounds can be prepNed similNly
3- {[ 1 -Ethyl-5-( 1 -oxa-2-azaspiro[4.4]non-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-
yl]amino}cyclobutanecNboxylic acid (Compound No. 116),
3-{[l-Ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclobutanecNboxylic acid (Compound No. 117),
4- {[ 1 -Ethyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-1H-pyrazolo[3,4-b]pyR1din-4-
yl]amino}cyclohexanecNboxylic acid (Compound No. 132),
4- {[ 1 -Ethyl-5-( 1 -oxa-2-azaspiro[4.4]non-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclohexanecNboxylic acid (Compound No. 133),
4-{[l-Ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclohexanecNboxylic acid (Compound No. 134),
4-{[5-(2-Cyano-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclohexanecNboxylic acid (Compound No. 135),
4-{[5-(2-Cyano-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-l-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclohexanecNboxylic acid (Compound No. 143),
4-{[l-Ethyl-5-(2-hydroxy-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-3-methyl-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclohexanecNboxylic acid (Compound No. 144),
4- {[ 1 -Ethyl-3 -methyl-5-( 1 -oxa-2-azaspiro[4.4]non-2-en-3 -yl)-1 #-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclohexanecNboxylic acid (Compound No. 145),
4-{[l-Ethyl-3-methyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclohexanecNboxylic acid (Compound No. 146),
4- {[ 1 -Ethyl-5-(8-hydroxy-1 -oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclohexanecNboxylic acid (Compound No. 147),
4-{[5-(8-CNbamoyl-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclohexanecNboxylic acid (Compound No. 15O),
3- {[5-(8-CNbamoyl-1 -oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1 -ethyl-1H-pyrazolo[3,4-ft]pyR1din-4-yl]amino}cyclobutanecNboxylic acid (Compound No. 151),
4-{[l-Ethyl-3-methyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclohexanecNboxylic acid (Compound No. 179),
4- {[ 1 -Ethyl-5-(8-hydroxy-1 -oxa-2-azaspiro [4.5 ]dec-2-en-3 -yl)-3 -methyl-1H-pyrazolo [3,4-b]pyR1din-4-yl]amino}cyclohexanecNboxylic acid (Compound No. 18O),
3-{[l-Ethyl-3-methyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclobutanecNboxylic acid (Compound No. 181),
3-{[l-Ethyl-3-methyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-lW-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclobutanecNboxylic acid (Compound No. 182),
3-{[l-Ethyl-3-methyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclobutanecNboxylic acid (Compound No. 183),
3-{[5-(2-Cyano-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-l -ethyl- 1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclobutanecNboxylic acid (Compound No. 184),
3-{[5-(2-Cyano-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-l-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclobutanecNboxylic acid (Compound No. 185),
3-{[l-Ethyl-5-(8-hydroxy-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-3-methyl-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclobutanecNboxylic acid (Compound No. 186),
3-{[l-Ethyl-5-(8-hydroxy-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclobutanecNboxylic acid (Compound No. 187),
3-{[l-Ethyl-5-(2-hydroxy-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclobutanecNboxylic acid (Compound No. 188),
3-{[l-Ethyl-5-(2-hydroxy-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-3-methyl-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclobutanecNboxylic acid (Compound No. 189),
3-{[5-(2-Amino-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclobutanecNboxylic acid (Compound No. 196),
3-{[5-(2-Amino-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-l-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclobutanecNboxylic acid (Compound No. 197),
3-({5-[2-(Acetylamino)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-l-ethyl-3-methyl-1H-pyrazolo[3,4-£]pyR1din-4-yl}amino)cyclobutanecNboxylic acid (Compound No. 198),
3-({5-[2-(Acetylamino)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-4-yl}amino)cyclobutanecNboxylic acid (Compound No. 199),
3-({l-Ethyl-5-[2-(propanoylamino)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-1H-pyrazolo[3,4-A]pyR1din-4-yl}amino)cyclobutanecNboxylic acid (Compound No. 20O),
3-({l-Ethyl-3-methyl-5-[2-(propanoylamino)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-1H-pyrazolo[3,4-£]pyR1din-4-yl}amino)cyclobutanecNboxylic acid (Compound No. 201),
4- {[5-(8-Amino-1 -oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1 -ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclohexanecNboxylic acid (Compound No. 206),
4-{[5-(8-Amino-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-l -ethyl- 1H-pyrazolo[3,4-£]pyR1din-4-yl]amino}cyclohexanecNboxylic acid (Compound No. 207),
4-({5-[8-(Acetylamino)-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl]-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-4-yl}Nnino)cyclohexanecNboxylic acid (Compound No. 208),
4-({5-[8-(Acetylamino)-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl]-l-ethyl-3-methyl-1H-pyrazolo[3,4-£]pyR1din-4-yl}amino)cyclohexanecNboxylic acid (Compound No. 209),
4-({l-Ethyl-3-methyl-5-[8-(propanoylamino)-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl]-1H-pyrazolo[3,4-b]pyR1din-4-yl}amino)cyclohexanecNboxylic acid (Compound No. 21O),
4-({l-Ethyl-5-[8-(propanoylamino)-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl]-1H-pyrazolo[3,4-A]pyR1din-4-yl}amino)cyclohexanecNboxylic acid (Compound No. 211),
7- {4-[(4-CNboxycyclohexyl)aminoj-1 -ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-5-yl} -5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxylic acid (Compound No. 212),
7- {4-[(4-CNboxycyclohexyl)amino]-1 -ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl} -5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxylic acid (Compound No. 213),
4-{[5-(2-CNbamoyl-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclohexanecNboxylic acid (Compound No. 214),
4-{[5-(2-CNbamoyl-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-l-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclohexanecNboxylic acid (Compound No. 215),
4-({l-Ethyl-3-methyl-5-[2-(methylcNbamoyl)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-1H-pyrazolo[3,4-b]pyR1din-4-yl}amino)cyclohexanecNboxylic acid (Compound No. 216),
4-({l-Ethyl-5-[2-(methylcNbamoyl)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-1H-pyrazolo[3,4-b]pyR1din-4-yl}amino)cyclohexanecNboxylic acid (Compound No. 217),
4-({ 1 -Ethyl-5-[2-(ethylcNbamoyl)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-1H-pyrazolo[3,4-/)]pyR1din-4-yl}amino)cyclohexanecNboxylic acid (Compound No. 218),
4-({l-Ethyl-5-[2-(ethylcNbamoyl)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-3-methyl-1H-pyrazolo[3,4-b]pyR1din-4-yl}amino)cyclohexanecNboxylic acid (Compound No. 219),
3-{4-[(4-CNboxycyclohexyl)amino]-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl}-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxylic acid (Compound No. 22O),
3. {4-[(4-CNboxycyclohexyl)amino]-1 -ethyl-3 -methyl-1H-pyrazolo[3,4-b]pyR1din-5-yl} -1 -oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxylic acid (Compound No. 221),
4- {[5-(8-CNbamoyl-1 -oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1 -ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclohexanecNboxylic acid (Compound No. 222),
4-({l-Ethyl-5-[8-(methylcNbamoyl)-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl]-1H-pyrazolo[3,4-fr]pyR1din-4-yl}amino)cyclohexanecNboxylic acid (Compound No. 223),
4-({l-Ethyl-3-methyl-5-[8-(methylcNbamoyl)-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl]-1H-pyrazolo[3,4-b]pyR1din-4-yl}amino)cyclohexanecNboxylic acid (Compound No. 224),
4-({l-Ethyl-5-[8-(ethylcNbamoyl)-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl]-3-methyl-1H-pyrazolo[3,4-b]pyR1din-4-yl}amino)cyclohexanecNboxylic acid (Compound No. 225),
4-({l-Ethyl-5-[8-(ethylcNbamoyl)-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl]-1H-pyrazolo[3,4-b]pyR1din-4-yl}amino)cyclohexanecNboxylic acid (Compound No. 226),
4-{[l-Ethyl-5-(8-methoxy-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclohexanecNboxylic acid (Compound No. 227),
4-{[5-(8-Ethoxy-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-l -ethyl-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclohexanecNboxylic acid (Compound No. 228),
4-({l-Ethyl-5-[8-(2-hydroxyethoxy)-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl]-1H-pyrazolo[3,4-fr]pyR1din-4-yl}amino)cyclohexanecNboxylic acid (Compound No. 229).
Example: 39: PrepNNion of 3-[4-(cyclohexylamino)-1-ethyl-3-methyl-1H-pyrazolo[3,4-b1pyR1din-5-yl]-l-oxa-2-azaspiro[4.51dec-2-en-8-yl4-methvlbenzenesulfonNe
3-[4-(Cyclohexylamino)-l-ethyl-3-methyl-1H-pyrazolo[3,4-A]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-en-8-ol (0.0025 mole) (example 26) is dissolved in dichloromethane. TR1ethyl
amine (0.0050 mol) is added N 0 and p-toluene sulphonyl chloR1de (0.0050 mole) is added. The reaction mixture is stirred for about 5 hrs. WNer is added and extraction is done with dichloromethane. The organic layer is washed with bR1ne, dR1ed and concentrNed under reduced pressure to give crude product, which is puR1fied by column chromNography. The following compound can be prepNed similNly
3-[4-(Cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-en-8-yl 4-methylbenzenesulfonNe
Example 40: PrepNNion of 3-[4-(Cyclohexvlamino)-l-ethvl-3-methvl-1H-pyrazolo[3,4-b1pyR1din-
5-vl]-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNbonitR1le (Compound No. 173)
3-[4-(Cyclohexylamino)-l-ethyl-3-methyl-1H-pyrazolo[3,4-fc]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-en-8-yl 4-methylbenzenesulfonNe (0.0018 mole) (example 39) is taken in dimethylformamide. Sodium cyanide (0.0036 mole) is added and the reaction mixture is stirred N 60-65°C overnight. WNer is added and extraction is done with ethyl acetNe. The organic layer is washed with bR1ne, dR1ed and concentrNed under reduced pressure to give crude compound, which is puR1fied by column chromNography.
The following compounds can be prepNed similNly
3-[4-(Cyclohexylamino)-l -ethyl- 1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNbonitR1le (Compound No. 118),
3-[ 1 -Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-1 -oxa-2-azaspiro[4.5]dec-2-ene-8-cNbonitR1le (Compound No. 12O),
3-[l-Ethyl-3-methyl-4-(tetiahydro-2/f-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNbonitR1le (Compound No. 167).
Example 41: PrepNNion of N-cyclohexyl-l-ethyl-5-[8-(1H-tetrazol-5-vl)-l-oxa-2-azaspirof4.5]dec-2-en-3-yl1-1H-pyrazolo|"3,4-b1pvR1din-4-amine (Compound No. 322)
3-[4-(Cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNbonitR1le (0.00098 mole) (example 4O), sodium azide (0.00147 mole) and tR1ethyl amine hydrochloR1de (0.00147 mol) is taken in toluene. The reaction mixture is refluxed overnight. Toluene is removed and wNer is added. The extraction is done with ethyl acetNe. The organic layer is washed with bR1ne, dR1ed and concentrNed under reduced pressure to give crude compound, which is puR1fied by column chromNography
The following compounds can be prepNed similNly
l-Ethyl-N-(tetrahydro-2H-pyran-4-yl)-5-[2-(1H-tetrazol-5-yl)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 318),
N-cyclohexyl-l-ethyl-5-[2-(1H-tetrazol-5-yl)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 319),
N-{ 1,1 -dioxidotetrahydro-2H-thiopyran-4-yl)-l -ethyl-5-[2-( 1H-tetrazol-5-yl)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 32O),
1 -Ethyl-N-(tetrahydro-2H-pyran-4-yl)-5-[8-(1H-tetrazol-5-yl)-l -oxa-2-azaspiro[4.5]dec-2-en-3-yl]-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 321),
#-(1,1 -dioxidotetrahydro-2H-thiopyran-4-yl)-1 -ethyl-5-[8-( 1H-tetrazol-5-yl)-1 -oxa-2-azaspiro[4.5]dec-2-en-3-yl]-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 323),
N-( 1,1 -dioxidotetrahydro-2H-thiopyran-4-yl)-1 -ethyl-5-[8-(2H-tetrazol-5-yl)-1 -oxa-2-azaspiro[4.5]dec-2-en-3-yl]-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 324),
N-cyclohexyl-l-ethyl-5-[8-(2H-tetrazol-5-yl)-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl]-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 325),
1-Ethyl-N-(tetrahydro-2H-pyran-4-yl)-5-[8-(2H-tetrazol-5-yl)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl]-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 326),
l-Ethyl-N-(tetrahydro-2H-pyran-4-yl)-5-[2-(2H-tetrazol-5-yl)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 327),
N-cyclohexyl-l-ethyl-5-[2-(2H-tetrazol-5-yl)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 328),
N-( 1,1 -dioxidotetrahydro-2H-thiopyran-4-yl)-1 -ethyl-5-[2-(2H-tetrazol-5-yl)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 329).
Example 42: PrepNNion of N-(l,l-dioxidotetrahvdro-2H-thiopvran-4-yl)-l-ethyl-5-(8-methoxy-l-
oxa-2-azaspiro[4.51dec-2-en-3-yl)-1H-pvrazolo[3,4-b1pyR1din-4-amine (Compound No. 29O)
3- {4-[( 1,1 -Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-1 -ethyl-1H-pyrazolo[3,4-fr]pyR1din-5-yl}-l-oxa-2-azaspiro[4.5]dec-2-en-8-ol (0.00025 mole) (example 26) and potassium cNbonNe (0.00050 mole ) is taken in dimethylformamide and methyl iodide (0.0010 mole) is added. The reaction mixture is stirred N room temperNure overnight. WNer is added and the extraction is done with ethyl acetNe. The organic layer is washed with bR1ne, dR1ed and concentrNed under reduced pressure to give crude compound, which is puR1fied by column chromNography.
The following compounds can be prepNed similNly
l-Ethyl-5-(8-methoxy-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 277),
5-(8-Ethoxy-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-l-ethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 278)
N-cyclohexyl-5-(8-ethoxy-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 279)
N-cyclohexyl-l-ethyl-5-(8-methoxy-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 28O).
N-(l,l-dioxidotetrahydro-2H-thiopyran-4-yl)-5-(8-ethoxy-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-l-ethyl-ltf-pyrazolo[3,4-//)pyR1din-4-amine (Compound No. 291),
l-Ethyl-5-(2-methoxy-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 295),
N-cyclohexyl-l-ethyl-5-(2-methoxy-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 296),
iY-( 1.1 -dioxidotetrahydro-2H-thiopyran-4-yl)-1 -ethyl-5-(2-methoxy-5-oxa-6-azaspirotS^Joct^-en-T-yO-l/f-pyrazolotS^-ftJpyR1din^-amine (Compound No. 297),
N-( 1,1 -dioxidotetrahydro-2H-thiopyran-4-yl)-5-(2-ethoxy-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 298),
N-cyclohexyl-5-(2-ethoxy-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-1 -ethyl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 299),
5-(2-Ethoxy-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-l-ethyl-N-(tetrahydro-2H-pyran-4-yl)-lH-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 30O),
N-( 1,1 -dioxidotetrahydro-2H-thiopyran-4-yl)-1 -ethyl-5-[2-(methoxymethyl)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 303),
N-(], 1 -dioxidotetrahydro-2H-thiopyran-4-yl)-5-[2-(ethoxymethyl)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yI]-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 304),
N-cydohexyl-5-[2-(ethoxymethyl)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-l -ethyl- \H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 305),
5-[2-(Ethoxymethyl)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-l-ethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 306),
l-Ethyl-5-[2-(methoxymethyl)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 307),
N-cyclohexyl-l-ethyl-5-[2-(methoxymethyl)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 308).
Example 43: PrepNNion of 7-[4-(cyclohexvlamino)-l-ethvl-1H-pvrazolo[3,4-b1pyR1din-5-yl1-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxylicacid (Compound No. 105)
7-[4-(Cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNbonitR1le (300 mg, 0.00079 mole) (example 9) was dissolved in ethanol (10 ml). Aqueous potassium hydroxide (178 mg, 0.0031 mole) was added and reaction mixture was refluxed for about 3-4 hrs. Ethanol was evaporNed off and reaction mixture was diluted with wNer, acidifed with dilute hydrochloR1c acid to pH of about 6. It was extracted with ethyl acetNe. The organic layer was washed with bR1ne, dR1ed and concentrNed under reduced pressure to give crude compound. The title compound was puR1fied by prepNNive thin layer chromNography.
Yield: 2%
m/z:(M++l) 398.14
NMR: NMR: (S,CDC13) 9.05-9.03 (d, IH), 8.67 (s, IH), 7.9 (s, IH), 4.44-4.39 (m, 2H), 4.03 (s, 2H), 3.95 (s, IH), 3.17-3.12 (m, IH), 2.90 (m, 2H), 2.6-2.68 (m,2H), 2.15-2.11 (m, 4H), 1.70-1.57 (m. 6H). 1.52-1.35 (m,3H).
The following compound was prepNed similNly
7-[l-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-A]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxylic acid (Compound No. 99)
Yield: 50%
m/z: (M++l) 400.09
The following compounds can be prepNed similNly
7-[ 1 -Ethyl-3-methyl-4-(tetrahydro-2#-pyran-4-ylamino)-17/-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxylic acid (Compound No. 168)
7-[4-(Cyclohexylamino)-l-ethyl-3-methyl-1H-pyrazolo[3,4-/)]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxylic acid (Compound No. 175)
7- {4-[( 1,1 -Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-1 -ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl}-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxylic acid (Compound No. 267)
Example 44: PrepNNion of (cis or trans) 3-|4-(cvclohexvlamino)-l-ethyl-1H-pvrazolof3,4-
/7"|pyR1din-5-yl"j-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxylic acid (Compound No. 95)
Ethyl (cis or trans) 3-[4-(cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxylNe (130 mg, 0.000286 mole) (example 9) was taken in tetrahydrofuran (5 ml). Aqueous lithium hydroxide (48 mg, 0.00147mole) in 2 ml wNer was added to it. The reaction mixture was stirred N room temperNure overnight. The solvent was removed under reduced pressure. The mixture was acidified with 3N hydrochloR1c acid to about pH of 6. The extraction was done with ethyl acetNe. The organic layer was washed with wNer and bR1ne, dR1ed and concentrNed under reduced pressure to get crude product. The title compound was puR1fied by prepNNive thin layer chromNography. Yield: 53% m/z:(M+l) 426.20
The following compound was prepNed similNly
(trans or cis) 3-[4-(Cyclohexylamino)-l -ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxylic acid (Compound No. 96)
Yield 62%
m/z: (M+l) 426.20
The following compounds can be prepNed similNly
3-[ 1 -Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-1 -oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxylic acid (Compound No. 119),
3-{4-[(l,l-Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-l-ethyl-17/-pyrazolo[3,4-b]pyR1din-5-yl}-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxylic acid (Compound No. 161),
3- {4-[( 1,1 -Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-1 -ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-5-yl}-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxylic acid (Compound No. 162),
3-[l-Ethyl-3-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxylic acid (Compound No. 166),
3-[4-(Cyclohexylamino> 1 -ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-1 -oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxylic acid (Compound No. 174).
Example 45: PrepNNion of cis or trans 3-|"4-(cyclohexylamino)-l -ethyl- 1H-pyrazolo[3,4-H]pyR1din-5-yl1-l-oxa-2-azaspirof4.5]dec-2-ene-8-cNboxamide (Compound No. 108)
(cis or trans) 3-[4-(Cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxylic acid (70 mg, 0.00016 mole) (example 44), ammonium cNbonNe (47 mg, 0.00049 mg), hydroxybenzotR1azole (24 mg, 0.00018 mole) were taken in dimethylformamide. N-methylmorpholine (0.03 ml, 0.00032 mole) was added N 0°C. The reaction mixture was stirred for about an hour N this temperNure. l-Ethyl-3-(3-dimethylaminopropyl) cNbodiimide hydrochloR1de (34 mg, 0.00018 mole) was added and the mixture was stirred N room temperNure overnight. WNer was added and extraction was done with ethyl acetNe. The organic layer was washed with bR1ne, dR1ed and concentrNed under reduced pressure to give crude compound, which was puR1fied by column chromNography.
Yield 28.9 % m/z:M+l 425. 15
NMR: (5, CDC13) 8.82-8.80 (m 1H), 8.03 (s, 1H), 7.90 (s, 1H), 5.45( s, 2H), 4.43-4.37(m, 2H), 3.86 (s, 1H), 3.23 (s, 2H), 2.25 (s, 1H), 2.20-1.59 (m 18H)
Chiral puR1ty: 99.73%
(trans or cis) 3-[4-(Cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxamide (Compound No. 109)
Yield 43.4%
m/z:M+l 425.15
NMR: (5, CDC13) 8.79-8.77 (m 1H), 8.00 (s, 1H), 7.90 (s, 1H), 5.48 (s, 2H), 4.42-4.38 (m, 2H), 3.85 (s, 1H), 3.16 (s, 2H). 2.19- 2.17 (m, 1H), 2.08-1.40 (m, 18H)
Chiral puR1ty 97.81%
The following compounds were prepNed similNly
(cis or trans) 7-[4-(Cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxamide (Compound No. 106)
Yield: 2%
m/z:M+l 397.13
(trans or cis) 7-[4-(Cyclohexylamino)-l -ethyl-17/-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxamide (Compound No. 107)
Yield: 2%
m/z:M+l 397.13
The following compounds can be prepNed similNly
7-[l-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxamide (Compound No. 123),
7-[4-(Cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-N-methyl-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxamide (Compound No. 124),
7-[l-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-N-methyl-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxamide (Compound No. 125),
7-[4-(Cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-N-ethyl-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxamide (Compound No. 126),
N-ethyl-7-[l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-fe]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxamide (Compound No. 127),
3-[l-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxamide (Compound No. 149),
3-{l-Ethyl-4-[(3-hydroxycyclobutyl)amino]-1H-pyrazolo[3,4-b]pyR1din-5-yl}-N-methyl-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxamide (Compound No. 152),
3-[4-(Cyclohexylamino)-l-ethyl-l/f-pyrazolo[3,4-b]pyR1din-5-yl]-N-methyl-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxamide (Compound No. 153),
3-[l-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-N-methyl-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxamide (Compound No. 154),
3- {4-[( 1,1 -Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-1 -ethyl-1H-pyrazolo[3,4-A]pyR1din-5-yl}-N-methyl-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxamide (Compound No. 155),
3-{4-[(l,l-Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-l-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-5-yl}-N-methyl-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxamide (Compound No. 156),
3- {4-[( 1,1 -Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-1 -ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl}-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxamide (Compound No. 163),
3-{4-[(l,l-Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-l-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-5-yl}-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxamide (Compound No. 164),
7-[l-Ethyl-3-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxamide (Compound No. 17O),
7-[4-(Cyclohexylamino)-l-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-N-methyl-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxamide (Compound No. 177),
N-ethyl-7-[l-ethyl-3-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxamide (Compound No. 202),
7-{4-[(l,l-Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-l-ethyl-1H-pyrazolo[3,4-ft]pyR1din-5-yl}-N-methyl-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxamide (Compound No. 271).
7- {4-[( 1,1 -Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-1 -ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl}-N-ethyl-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxamide (Compound No.
272),
/V-cyclopropyl-7-{4-[( 1,1 -dioxidotetrahydro-2H-thiopyran-4-yl)amino]-l -ethyl- \H-pyrazolo[3,4-£]pyR1din-5-yl}-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxamide (Compound No. 273),
7- {4-[( 1,1 -Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-1 -ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl}-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxamide (Compound No. 274),
7-[4-(Cyclohexylamino)-l -ethyl- 1H-pyrazolo[3,4-b]pyR1din-5-yl]-./V-cyclopropyl-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxamide (Compound No. 275),
N-cyclopropyl-7-[l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxamide (Compound No. 276),
3- {4-[( 1,1 -Dioxidotetrahydro-2/f-thiopyran-4-yl)amino]-1 -ethyl-1H-pyrazolo[3,4-/)]pyR1din-5-yl}-N-ethyl-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxamide (Compound No. 281),
vV-cyclopropyl-3- {4-[( 1,1 -dioxidotetrahydro-2H-fhiopyran-4-yl)amino]-1 -ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl}-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxamide (Compound No. 282),
3-[4-(Cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-N-cyclopropyl-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxamide (Compound No. 283),
yV-cyclopropyl-3-[l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxamide (Compound No. 284),
N-ethyl-3-[l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b)]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxamide (Compound No. 285),
3-[4-(Cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-N-ethyl-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxamide (Compound No. 286).
Example 46: PrepNNion of 5-(8-azido-l-oxa-2-azaspirof4.5]dec-2-en-3-yD-N-cyclohexyl-l-ethyl-lH-pvrazolof3,4-b"|pyR1din-4-amine
3-[4-(Cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-en-8-yl 4-methylbenzenesulfonNe (0.00090 mole) (example 39) is taken in dimethylformamide. Sodium azide (0.0027 mole) is added. The reaction mixture is stirred N 60-70°C overnight. It is cooled and wNer is added and extraction is done with ethyl acetNe. The organic layer is washed with bR1ne, dR1ed and concentrNed under reduced pressure to give crude compound, which is puR1fied by column chromNography.
Example 47: PrepNNion of 3-f4-(cyclohexylamino)-l-ethyl-1H-pyrazolof3,4-fe"jpyR1din-5-yl]-l-oxa-2-azaspiro|"4.5]dec-2-en-8-amine (Compound No. 338)
Lithium aluminium hydR1de (0.0018 mole) is taken in tetrahydrofuran. 5-(8-Azido-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-cyclohexyl-l-ethyl-lH-pyrazolo[3,4-b]pyR1din-4-amine (0.00047 mole) (example 46) is added. The reaction mixture is stirred N room temperNure overnight. It is quenched with aqueous sodium sulphNe solution followed by ethyl acetNe. The filtrNion is done through celite pad and extraction is done with ethyl acetNe. The organic layer is washed with bR1ne, dR1ed and concentrNed under reduced pressure to give crude compound, which is puR1fied by column chromNography.
The following compounds can be prepNed similNly
5-(2-Amino-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-1 -ethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 128),
5-(2-Amino-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-cyclohexyl-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 129),
5-(2-Amino-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-l-ethyl-3-methyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 171),
5-(2-Amino-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-cyclohexyl-l-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 178),
5-(2-Amino-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-( 1,1 -dioxidotetrahydro-2H-thiopyran-4-yl)-t-ethyl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 19O),
5-(2-Amino-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-(l,l-dioxidotetrahydro-2H-thiopyran-4-yl)-l-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 191),
5-[2-(Aminomethyl)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-N-cyclohexyl-l -ethyl- \H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 309),
5-[2-(Aminomethyl)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-1 -ethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 31O),
5-[2-(Aminomethyl)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-N-(l,l-dioxidotetrahydro-2H-thiopyran-4-yl)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 311).
Example 48: PrepNNion of 3-[4-(cvclohexvlamino)-l-ethvl-1H-pvrazolo[3,4-b"|pvR1din-5-yll-N-
methyl-l-oxa-2-azaspiro[4.5]dec-2-en-8-amine (Compound No. 142)
The title compound is prepNed by following the procedure of example 24.
Example 49: PrepNNion of AM7-[4-(cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl1-5-oxa-6-azaspiro[3.41oct-6-en-2-yl}acetamide (Compound No. 13O)
The title compound is prepNed by following the procedure of example 23.
The following compounds can be prepNed similNly
N-{7-[l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-en-2-yl}acetamide (Compound No. 131),
N-(7-{4-[(l,l-dioxidotetrahydro-2H-thiopyran-4-yl)amino]-l-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-5-yl}-5-oxa-6-azaspiro[3.4]oct-6-en-2-yl)acetamide (Compound No. 192),
;V-(7-{4-[(l,l-dioxidotetrahydro-2H-thiopyran-4-yl)amino]-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl}-5-oxa-6-azaspiro[3.4]oct-6-en-2-yl)acetamide (Compound No. 193),
N-(7-{4-[(l,l-dioxidotetrahydro-2H-thiopyran-4-yl)amino]-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl}-5-oxa-6-azaspiro[3.4]oct-6-en-2-yl)propanamide (Compound No. 194),
N-(7-{4-[(l,l-dioxidotetrahydro-2H-thiopyran-4-yl)amino]-l-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-5-yl}-5-oxa-6-azaspiro[3.4]oct-6-en-2-yl)propanamide (Compound No. 195),
N- {7-[4-(cyclohexylamino)-l -ethyl- 1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-en-2-yl}propanamide (Compound No. 203),
.V-{7-[l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b)]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-en-2-yl}propanamide (Compound No. 204),
N-{7-[l-ethyl-3-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-en-2-yl}propanamide (Compound No. 205),
N-[(7-{4-[(l,l-dioxidotetrahydro-2H-thiopyran-4-yl)amino]-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl}-5-oxa-6-azaspiro[3.4]oct-6-en-2-yl)methyl]acetamide (Compound No. 312),
N-[(7-{4-[(l,l-dioxidotetrahydro-2/f-thiopyran-4-yl)amino]-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl}-5-oxa-6-azaspiro[3.4]oct-6-en-2-yl)methyl]propanamide (Compound No. 313),
N-({7-[l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-en-2-yl}methyl)propanamide (Compound No. 314),
AH{7-[4-(cyclohexylamino)-l -ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-en-2-yl}methyl)propanamide (Compound No. 315),
A4{7-[4-(cyclohexylamino)-l -ethyl- 1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-en-2-yl}methyl)acetamide (Compound No. 316),
N-({7-[l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-en-2-yl}methyl)acetamide (Compound No. 317).
Example 50: Efficacy of compounds
(a)(i) PDE4B Enzyme Assay
The efficacy of compounds as PDE4 inhibitors was determined by an enzyme assay using cell lysNe of HEK293 cells transfected with PDE4B2 plasmids as PDE4B source. The enzyme reaction was cNR1ed out in the presence of cAMP (1 uM) N 30 °C in the presence or absence of test compound for 45 -60 min. An aliquot of this reaction mixture was taken further for the ELISA assay and the protocol of the kit followed to determine level of cAMP in the sample. The concentrNion of the cAMP in the sample directly correlNed with the degree of PDE4 enzyme inhibition. Results were expressed as percent control and the IC50 values of test compounds were reported. IC>0 values of test compounds were found to be in the range of 3 nM to 10 uM concentrNion.
(a)(ii) PDE7 Enzyme Assay
The efficacy of compounds as PDE7 inhibitors was determined by an enzyme assay using recombinant human PDE7A enzyme (J. Med. Chem. (200O) 43, 683-689). The enzyme reaction was cNR1ed out in the presence of cAMP (1 uM) N 37°C in the presence or absence of test compound for 60 min. An aliquot of this reaction mixture was taken further for the ELISA assay and the protocol of the kit was followed to determine level of cAMP in the sample. The concentrNion of the cAMP in the sample directly correlNed with the degree of PDE7 enzyme inhibition. Results were expressed as percent control and the IC50 values of test compounds, calculNed using Graph pad pR1sm, were found to be in the range of 3 NM to 10 uM concentrNion.
(b) Cell based Assay for TNF-a release
Method of isolNion of Human PeR1pheral Blood MononucleN Cells (PBMNC 's)
Human whole blood was collected in vacutainer tubes containing hepN1n or. EDTA as an anti coagulant. The blood was diluted (1:1) in steR1le phosphNe buffered saline and 10 ml was cNefully layered over 5 ml Ficoll Hypaque gradient (density 1.077 g/ml) in a 15 ml conical centR1fuge tube. The sample was centR1fuged N 3000 rpm for 25 minutes in a swing-out rotor N room temperNure. Nter centR1fugNion, interface of cells were collected, diluted N least 1:5 with PBS (phosphNe buffered saline) and washed three times by centR1fugNion N 2500 rpm for 10 minutes N room temperNure. The cells were resuspended in serum free RPMI 1640 medium N a concentrNion of 2 million cells/ml.
LPS (lipopolysacchN1de) stimulNion of Human PBMNC 's
PBMN cells (0.1 ml; 2 million/ml) were co-incubNed with 20 ul of compound (final
DMSO concentrNion of 0.2 %) for 10 min in a flN bottom 96 well microtiter plNe. Compounds
were dissolved in DMSO initially and diluted in medium for a final concentrNion of 0.2 % DMSO.
LPS (1 ug/ml, final concentrNion) was then added N a volume of 10 ul per well. Nter 30 min, 20
ul of fetal calf serum (final concentrNion of 10 %) was added to each well. Cultures were incubNed
overnight N 37 °C in an Nmosphere of 5 % CO2 and 95 % air. SupernNant were then removed and
tested by ELISA for TNF-a release using a commercial kit (e.g. BD Biosciences). For whole blood,
the plasma samples were diluted 1:20 for ELISA. The level of TNF-a in treNed wells was
compNed with the vehicle (0.2% DMSO in RPMI medium) treNedD controls and inhibitory
potency of compound was expressed as IC50 values calculNed by using Graph pad pR1sm. IC50
values of test compounds were found to be in the range of 5 nM to 2.5 uM concentrNion.
(c) In-vitro assay to evaluNe efficacy of compounds in combinNion with p38 MAP Kinase
inhibitors
Perform the assay as descR1bed in (b) above, with individual compounds and their combinNions tested N sub-optimal doses.
(d) In-vitro assay to evaluNe efficacy of compounds in combinNion with P2- agonists
Measurement of IntracellulN cAMP ElevNion in U937 Cells
Grow U937 cells (human promonocytic cell line) in endotoxin-free RPMI 1640 + HEPES medium containing 10% (v/v) heN-inactivNed foetal bovine serum and 1 % (v/v) of an antibiotic solution (5000 IU/ml penicillin, 5000 fag/ml streptomycin). Resuspend cells (0.25 x 106/200 ul) in Krebs' buffer solution and incubNe N 37°C for 15 min in the presence of test compounds or vehicle
(0.2% DMSO in RPMI medium). InitiNe generNion of cAMP by adding 50 ul of 10 uM prostaglandin (PGE2). Stop the reaction Nter 15 min, by adding 1 N HCl (50 ul) and place on ice for 30 min. CentR1fuge the sample (45 Og, 3 min). and measure levels of cAMP in the supernNant using cAMP enzyme-linked immunosorbent assay kit (Assay Designs). CalculNe percent inhibition by the following formula and calculNe IC50 value using Graph pad pR1sm.

WE CLAIM:
1. A compound having the structure of Formula I:
(FORMULA REMOVED)
or its pharmaceutically acceptable salts, wherein
R1 and R2 independently are hydrogen, aryi, heteroaryl, -COR4, -S(O)mR4 (wherein R4 is
hydrogen, alkyl, cycloaikyl, aryl, aralkyl, heteroaryl or heterocyclyl and m is an integer
from 0-2),
(FORMULA REMOVED)
wherein X is -0-, S(O)m (wherein m is an integer from 0-2),
C(=O), C=NOH, CRfRq (wherein Rt- and Rq independently are hydrogen, hydroxy, carboxy or cyano) or NR5 {wherein R5 is hydrogen, alkyl, alkenyl, alkynyl, cycloaikyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, -COR4, -S(O)mR4, -COOR4 or-CONR4R'4 (wherein R4 and R'4 independently are hydrogen, alkyl, cycloaikyl, aryl, aralkyl, heteroaryl or heterocyclyl and m is an integer from 0-2)};
R3 is hydrogen, alkyl, alkenyl, alkynyl, cycloaikyl, aryl, aralkyl, aralkenyl, cycloalkylalkyl, heterocyclyl, heteroaryl, heterocyclylalkyl or heteroarylalkyl;
M is a 3-7 membered saturated, partially saturated or unsaturated R1ng containing carbon atoms wherein one or more carbon atoms optionally are replaced by heteroatoms selected from O, S(O)m (wherein m is an integer from 0-2} or NR6 {wherein R6 is hydrogen, alkyl, alkenyl, alkynyl, cycloaikyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, -COR4, -S(O)mR4, -COOR4 or -CONR4R'4 (wherein R4 and R'4 independently are hydrogen, alkyl, cycloaikyl, aryl, aralkyl, heteroaryl or heterocyclyl and m is an integer from 0-2)}, or one or more carbon atoms optionally are substituted with oxo, halogen, spiroo-attached heterocyclyl, hydroxy, cyano, alkyl, heteroaryl, heteroarylalkyl, -(CH2NR4R4, -(CH2)mOR4, -CH2)m CONR4R'4, -(CH2)inNR4COR4, or -(CH2)tnCOOR4 (wherein m, R4 and R'4 are the same as defined above)
2. A compound, which is selected from
N-cyclohexyl-l-ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-lH-pyrazolo[3,4-6]pyR1din-4-amine (Compound No. 1),
N-cyclohexyl-1 -ethyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-1H-pyrazolo[3,4-6]pyR1din-4-amine (Compound No. 2),
N-cyclohexyl-1 -ethyl-5 -(1 -oxa-2-azaspiro [4.5]dec-2-en-3 -yl)-1H-pyrazolo [3,4-6]pyR1din-4-amine (Compound No. 3).
N-cyclohexyl-l-ethyl-5-(l-oxa-7-thia-2-azaspiro[4.4]non-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 4).
N-cyclohexyl-l-ethyl-5-(7-oxido-l-oxa-7-thia-2-azaspiro[4.4]non-2-en-3-yl)-1H-pyrazolo[3,4-6]pyR1din-4-amine (Compound No. 5),
N-cyclohexyl-l-ethyl-5-(5-oxa-2-thia-6-azaspiro[3.4]oct-6-en-7-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 6),
l-Ethyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-6]pyR1din-4-amine (Compound No. 7),
l-Ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-6]pyR1din-4-amine (Compound No. 8),
l-Ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-6]pyR1din-4-amine (Compound No. 9),
4-{[l-Ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclohexanol (Compound No. 1O),
4-{[l-Ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclohexanol (Compound No. 11),
N-cyclohexyl-5-(l,7-dioxa-2-azaspiro[4.4]non-2-en-3-yl)-l -ethyl- 1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 12).
4-{[l-Ethyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-1H-pyrazolo[3,4-6]pyR1din-4-yl]amino}cyclohexanol (Compound No. 13),
N-cyclohexyl-5-(2,2-dioxido-5-oxa-2-thia-6-azaspiro[3.4]oct-6-en-7-yl)-1 -ethyl-1H-pyrazolo[3,4-6]pyR1din-4-amine (Compound No. 14),
tert-Butyl 3-[4-(cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-6]pyR1din-5-yl]-l-oxa-2,8-diazaspiro[4.5]dec-2-ene-8-carboxylate (Compound No. 15),
4-{[l-Ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-pyrazoIo[3,4-6]pyR1din-4-yl]amino}cyclohexanone (Compound No. 16),
4-{[l-Ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-6]pyR1din-4-yl]amino}cyclohexanone oxime (Compound No. 17),
7V-cyclohexyl-l-ethyl-5-(l-oxa-2,8-diazaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-6]pyR1din-4-amine hydrochloR1de salt (Compound No. 18),
4- {[ 1 -Ethyl-5-( 1,9,12-tR1oxa-2-azadispiro[4.2.4.2]tetradec-2-en-3-yl)-1H-pyrazolo[3,4-6]pyR1din-4-yl]amino}cyclohexanol (Compound No. 19),
4-{[l-Ethyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-1H-pyrazolo[3,4-6]pyR1din-4-yl]amino}cyclohexanone (Compound No. 2O),
4-{[l-Ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-1H-pyrazolo[3,4-6]pyR1din-4-yl]amino}cyclohexanone (Compound No. 21),
3 - {1 -Ethy 1-4- [(4-hydroxycyclohexyl)amino]-1H-pyrazolo[3,4--b]pyR1din-5-yl} -1 -oxa-2-azaspiro[4.5]dec-2-en-8-one (Compound No. 22),
N-cyclohexyl-5-[8-(2,2-dimethylpropanoyl)-l-oxa-2,8-diazaspiro[4.5]dec-2-en-3-yl]-l-ethyl-1H-pyrazolo[3,4-6]pyR1din-4-amine (Compound No. 23),
N-cyclohexyl-l-ethyl-5-{8-[(tR1fluoromethyl)sulfonyl]-l-oxa-2,8-diazaspiro[4.5]dec-2-en-3-yl}-1H-pyrazolo[3,4-6]pyR1din-4-amine (Compound No. 24),
N-cyclohexyl-l-ethyl-5-[8-(ethylsulfonyl)-l-oxa-2,8-diazaspiro[4.5]dec-2-en-3-yl]-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 25),
N-cyclohexyl-5-[8-(cyclopropylmethyl)-]-oxa-2,8-diazaspiro[4.5]dec-2-en-3-yl]-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 26),
5-(8-Acetyl-1 -oxa-2,8-diazaspiro[4.5]dec-2-en-3-yl)-Ar-cyclohexyl-1 -ethyl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 27),
N-cyclohexyl-5-(2,5-dioxa-6-azaspiro[3.4]oct-6-en-7-yl)-l-ethyl-1H-pyrazolo[3,4-6]pyR1din-4-amine (Compound No. 28),
l-(4-Methoxybenzyl)-N-(3-methoxyphenyl)-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 41),
(cis or trans) 3-[4-(Cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-en-8-ol (Compound No. 42),
(trans or cis) 3-[4-(Cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-en-8-ol (Compound No. 43),
5-[2-(Benzyloxy)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-l-ethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 44),
(cis or trans) 3-[l-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-en-8-ol (Compound No. 45),
3-[l-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-en-8-one (Compound No. 46),
7-[l-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-ene-2-carbonitR1le (Compound No. 47),
7-[4-(CycIohexylamino)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-ene-2-carbonitR1le (Compound No. 48).
5-(5-Oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-6]pyR1din-4-amine (Compound No. 49),
l-Methyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 5O),
5-(l-Oxa-2-azaspiro[4.4]non-2-en-3-yl)-N-(tetrahydro-2H-pyran-4-yl)-l-(2,2,2-tR1fluoroethyl)-1H-pyrazolo[3,4-H]pyR1din-4-amine (Compound No. 51),
l-Ethyl-N-[l-(methylsulfonyl)pipeR1din-4-yl]-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 52),
N-(l-acetylpipeR1din-4-yl)-l-ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 53),
N-( I -acetylpipeR1din-4-yl)-1 -ethyl-5-(l -oxa-2-azaspiro[4.4]non-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 54),
l-(4-Methoxybenzyl)-N-(tetrahydro-2H-pyran-4-yl)-5-(l,9,12-tR1oxa-2-azadispiro[4.2.4.2]tetradec-2-en-3-yl)-l H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No.
55),
5-(5-Oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-(tetrahydro-2H-pyr an-4-yl)-l-(2,2,2-tR1fluoroethyl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 56),
7-[l-(4-Methoxybenzyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-ene-2-carbonitR1le (Compound No. 57),
l-(Cyclopropylmethyl)-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 58),
l-Butyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 59),
l-(l-Methylethyl)-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 6O),
5-(5-Oxa-6-azaspiro[3.4]oct-6-en-7-yl)-l-propyl-N-(tetrahydro-2H-pyran-4-y])-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 61),
5-(l-Oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-(tetrahydro-2H-pyran-4-yl)-l -(2,2,2-tR1fluoroethyl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 62),
N-{ 1 -CyclopentylpipeR1din-4-yl)-1 -ethyl-5-( 1 -oxa-2-azaspiro[4.4]non-2-en-3-yl)-l H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 63),
N-( 1 -butylpipeR1din-4-yl)-1 -ethyl-5-( 1 -oxa-2-azaspiro[4.4]non-2-en-3-yl)-1H-pyrazolo[3,4-6]pyR1din-4-amine (Compound No. 64),
2-(4-{[l-Ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}pipeR1din-l-yl)ethanol (Compound No. 65),
N-[l-(cyclopropylmethyl)pipeR1din-4-yl]-l-ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 66),
1 -Ethyl-N-[ 1 -(1 -methylethyl)pipeR1din-4-yl]-5-( 1 -oxa-2-azaspiro[4.4]non-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 67),
l-Ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-N-(l-propylpipeR1din-4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 68),
N-{\ -cycIopentylpipeR1din-4-yl)-l -ethyl-5-(l -oxa-2-azaspiro[4.5]dec-2-en-3-yl)-l H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 69),
l-Ethyl-N-[l-(l-methylethyl)pipeR1din-4-yl]-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-y])-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 7O),
l-Cyclopentyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 71),
1 -(Cyclopropylmethyl)-5-( 1 -oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 72),
l-(l-Methylethyl)-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 73),
5-( 1 -Oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1 -propyl-N-(tetrahydro-2H-pyran-4-yl)-l H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 74),
l-Cyclopentyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 75),
l-(Cyclopropylmethyl)-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 76),
l-(l-Methylethyl)-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 77),
5-(l-Oxa-2-azaspiro[4.4]non-2-en-3-yl)-l-propyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 78),
l-Methyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 79),
N-Cyclohexyl-l-ethyl-5-(l,9,12-tR1oxa-2-azadispiro[4.2.4.2]tetradec-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 8O),
3-[4-(Cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-en-8-one (Compound No. 81),
l-Ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-N-pipeR1din-4-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 82),
tert-butyl 4-{[l-ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-1H-pyrazolo[3,4-A]pyR1din-4-yl]amino}pipeR1dine-l-cNboxylNe (Compound No. 83),
l-Ethy]-N-(l-ethylpipeR1din-4-yl)-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 84),
l-Ethyl-N-(l-methylpipeR1din-4-yl)-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 85),
l-Ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-pipeR1din-4-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 86),
tert-butyl 4-{[l-ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-y]]amino}pipeR1dine-l-cNboxylNe (Compound No. 87),
l-Ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-(l-propylpipeR1din-4-yl)-1H-pyrazolo[3,4-6]pyR1din-4-amine (Compound No. 88),
N-[l-(cyclopropylmethyl)pipeR1din-4-yl]-l-ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 89),
2-(4-{[l-Ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}pipeR1din-l-yl)ethanol (Compound No. 9O),
N-cyclohexyl-l-(4-methoxybenzyl)-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 91),
3-[l-(4-Methoxybenzyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-en-8-one (Compound No. 92),
7-[l-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b)]pyR1din-5-y]]-5-oxa-6-azaspiro[3.4]oct-6-en-2-ol (Compound No. 93),
l-Ethyl-N-(3-methoxypheny])-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 94),
(cis or trans) 3-[4-(Cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxylic acid (Compound No. 95),
(trans or cis) 3-[4-(Cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxylic acid (Compound No. 96),
5-{2-[(Benzyloxy)methyl]-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl}-l-(4-methoxybenzyl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 97),
(trans or cis) 3-[l-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-en-8-ol (Compound No. 98),
7-[l-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxylic acid (Compound No. 99),
1 -(4-Methoxybenzyl)-5-( 1 -oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 10O),
5-(l-Oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-6]pyR1din-4-amine (Compound No. 101).
1 -(4-Methoxybenzyl)-5-( 1 -oxaJ-2-azaspiro[4.4]non-2-en-3-yl)-Ntetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 102),
5-{2-[(Benzyloxy)methyl]-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl}-l-ethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 103),
{7-[l-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-en-2-yl}methanol (Compound No. 104),
7-[4-(Cyclohexylamino)-l -ethyl- 1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxylic acid (Compound No. 105).
cis or trans 7-[4-(Cyclohexylamino)-l -ethyl- 1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxamide (Compound No. 106),
(trans or cis) 7-[4-(Cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yI]-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxamide (Compound No. 107),
(cis or trans) 3-[4-(Cyclohexylamino)-l -ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxamide (Compound No. 108),
(trans or cis) 3-[4-(Cyclohexylamino)-l -ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxamide (Compound No. 109),
l-(4-Methoxybenzyl)-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 110),
5-[2-(Benzyloxy)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-l-(4-methoxybenzyl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (CompoundNo. Ill),
Ethyl (cis or trans) 3-[4-(cyclohexylamino)-l -ethyl- 1H-pyrazolo[3,4-b]pyR1din-5-yl]- 1-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxylNe (Compound No. 112),
Ethyl (trans or cis) 3-[4-(cyclohexylamino)-l -ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]- 1-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxylNe (Compound No. 113),
N-(l,\ -dioxidotetrahydro-2H-thiopyran-4-yl)-1 -ethyl-5-( 1 -oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine ((Compound No. 114),
3-{[l-Ethyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclobutanecNboxylic acid (Compound No. 115),
3-{[l-Ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclobutanecNboxylic acid (Compound No. 116),
3-{[l-Ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclobutanecNboxylic acid (Compound No. 117),
3-[4-(Cyclohexylamino)-l -ethyl- 1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNbonitR1le (Compound No. 118),
3-[ 1 -Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-1 -oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxylic acid (Compound No. 119),
3-[ 1 -Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-1 -oxa-2-azaspiro[4.5]dec-2-ene-8-cNbonitR1le (Compound No. 12O),
7-[4-(Cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-en-2-ol (Compound No. 121),
7-[l-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-en-2-ol (Compound No. 122),
7-[l-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxamide (Compound No. 123),
7-[4-(Cyclohexylamino)-l -ethyl- 1H-pyrazolo[3,4-A]pyR1din-5-yl]-N-methyl-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxamide (Compound No. 124),
7-[l-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b)]pyR1din-5-yl]-N-methyl-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxamide (Compound No. 125),
7-[4-(Cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-N-ethyl-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxamide (Compound No. 126),
N-Ethyl-7-[l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxamide (Compound No. 127),
5-(2-Amino-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-l-ethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 128),
5-(2-Amino-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-cyclohexyl-l-ethyl-1H-pyrazolo[3,4-6]pyR1din-4-amine (Compound No. 129).
7V-{7-[4-(cyclohexylamino)-l -ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-en-2-yl}acetamide (Compound No. 13O),
N-{7-[l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-en-2-yl} acetamide (Compound No. 131),
4-{[l-Ethyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclohexanecNboxylic acid (Compound No. 132),
4-{[l-Ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclohexanecNboxylic acid (Compound No. 133),
4-{[l-Ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclohexanecNboxylic acid (Compound No. 134),
4-{[5-(2-Cyano-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclohexanecNboxylic acid (Compound No. 135),
l-Ethyl-3-methyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 136),
l-Ethyl-3-methyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 137),
l-Ethyl-3-methyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 138),
7-[l-Ethyl-3-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNbonitR1le (Compound No. 139),
N-Cyclohexyl-l-ethyl-3-methyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 140).
7-[4-(Cyclohexylamino)-l-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNbonitR1le (Compound No. 141),
3-[4-(Cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-N-methyl-l-oxa-2-azaspiro[4.5]dec-2-en-8-amine (Compound No. 142),
4-{[5-(2-Cyano-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-l-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclohexanecNboxylic acid (Compound No. 143),
4- {[ 1 -Ethyl-5-(2-hydroxy-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-3-methyl-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclohexanecNboxylic acid (Compound No. 144),
4-{[l-Ethyl-3-methyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclohexanecNboxylic acid (Compound No. 145),
4-{[l-Ethyl-3-methyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-b)]pyR1din-4-yl]amino}cyclohexanecNboxylic acid (Compound No. 146),
4-{[l-Ethyl-5-(8-hydroxy-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclohexanecNboxylic acid (Compound No. 147),
3- {4-[( 1,1 -Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-1 -ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl}-l-oxa-2-azaspiro[4.5]dec-2-en-8-ol (Compound No. 148),
3-[ 1 -Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-1 -oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxamide (Compound No. 149),
4-{[5-(8-CNbamoyl-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-l -ethyl- 1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclohexanecNboxylic acid (Compound No. 15O),
3-{[5-(8-CNbamoyl-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclobutanecNboxylic acid (Compound No. 151),
3-{l-Ethyl-4-[(3-hydroxycyclobutyl)amino]-1H-pyrazolo[3,4-b]pyR1din-5-yl}-N-methyl-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxamide (Compound No. 152),
3-[4-(Cyclohexylamino)-1 -ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-N-methyl-1 -oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxamide (Compound No. 153),
3-[l-Ethyl-4-(tetrahydro-2f/-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-N-methyl-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxamide (Compound No. 154),
3-{4-[(l,l-Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl}-N-methyl-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxamide (Compound No. 155),
3-{4-[(l,l-Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-l-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-5-yl}-N-methyl-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxamide (Compound No. 156),
N-(\,\ -dioxidotetrahydro-2H-thiopyran-4-yl)-1 -ethyl-3-methyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 157),
N-(l, 1 -dioxidotetrahydro-2H-thiopyran-4-yl)-1 -ethyl-3-methyl-5-( 1 -oxa-2-azaspiro[4.4]non-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 158),
N-( 1,1 -dioxidotetrahydro-2H-thiopyran-4-yl)-1 -ethyl-3-methyl-5-( 1 -oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 159),
3- {4-[( 1,1 -Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-1 -ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-5-yl}-l-oxa-2-azaspiro[4.5]dec-2-en-8-ol (Compound No. 16O),
3- {4-[( 1,1 -Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-1 -ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl}-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxylic acid (Compound No. 161),
3-{4-[( 1,1 -Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-1 -ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-5-yl}-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxylic acid (Compound No. 162),
3-{4-[(l,l-Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl}-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxamide (Compound No. 163),
3- {4-[( 1,1 -Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-1 -ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-5-yl}-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxamide (Compound No. 164),
3-[l-Ethyl-3-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-en-8-ol (Compound No. 165),
3-[l-Ethyl-3-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxylic acid (Compound No. 166),
3-[l-Ethyl-3-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNbonitR1le (Compound No. 167),
7-[l-Ethyl-3-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxylic acid (Compound No. 168),
7-[l-Ethyl-3-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-en-2-ol (Compound No. 169),
7-[l-Ethyl-3-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxamide (Compound No. 17O),
5-(2-Amino-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-1 -ethyl-3-methyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 171),
3-[4-(Cyclohexylamino)-l-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-en-8-ol (Compound No. 172),
3-[4-(Cyclohexylamino)-l-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNbonitR1le (Compound No. 173),
3-[4-(Cyclohexylamino)-l-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxylic acid (Compound No. 174),
7-[4-(Cyclohexylamino)-l-ethyl-3-methyI-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxylic acid (Compound No. 175),
7-[4-(Cyclohexylamino)-1 -ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-en-2-ol (Compound No. 176),
7-f4-(Cyclohexylamino)-l-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-N-methyl-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxamide (Compound No. 177),
5-(2-Amino-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-cyclohexyl-l-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 178),
4- {[ 1 -Ethyl-3-methyl-5-(5-oxa-6-azaspiro[3,4]oct-6-en-7-yl)-1 7/-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclohexanecNboxylic acid (Compound No. 179),
4- {[ 1 -Ethyl-5-(8-hydroxy-1 -oxa-2-azaspiro[4.5]dec-2-en-3-yl)-3-methyl-1H-pyrazolo[3,4-£]pyR1din-4-yl]amino}cyclohexanecNboxylic acid (Compound No. 18O),
3-{[l-Ethyl-3-methyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclobutanecNboxylic acid (Compound No. 181),
3-{[l-Ethyl-3-methyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclobutanecNboxylic acid (Compound No. 182),
3-{[l-Ethyl-3-methyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-A]pyR1din-4-yl]amino}cyclobutanecNboxylic acid (Compound No. 183),
3-{[5-(2-Cyano-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-l-ethyl-1H-pyrazolo[3,4-A]pyR1din-4-yl]amino}cyclobutanecNboxylic acid (Compound No. 184),
3-{[5-(2-Cyano-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-l-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclobutanecNboxylic acid (Compound No. 185),
3-{[l-Ethyl-5-(8-hydroxy-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-3-methyl-1H-pyrazolo[3,4-6]pyR1din-4-yl]amino}cyclobutanecNboxylic acid (Compound No. 186),
3-{[l-Ethyl-5-(8-hydroxy-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclobutanecNboxylic acid (Compound No. 187),
3-{[l-Ethyl-5-(2-hydroxy-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclobutanecNboxylic acid (Compound No. 188),
3-{[l-Ethyl-5-(2-hydroxy-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-3-methyl-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclobutanecNboxylic acid (Compound No. 189),
5-(2-Amino-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-(l,l-dioxidotetrahydro-2H-thiopyran-4-yl)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 19O),
5-(2-Amino-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-(l,l-dioxidotetrahydro-2H-thiopyran-4-yl)-l-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 191),
N-(7-{4-[(l,l-dioxidotetrahydro-2H-thiopyran-4-yl)amino]-l-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-5-yl}-5-oxa-6-azaspiro[3.4]oct-6-en-2-yl)acetamide (Compound No.
192),
N'-(7- {4-[( 1,1 -dioxidotetrahydro-2H-thiopyran-4-y l)amino]-1 -ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl}-5-oxa-6-azaspiro[3.4]oct-6-en-2-yl)acetamide (Compound No. 193),
N-(7-{4-[(l,l-dioxidotetrahydro-2H-thiopyran-4-yl)amino]-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl}-5-oxa-6-azaspiro[3.4]oct-6-en-2-yI)propanamide (Compound No. 194),
N-(7-{4-[(l,l-dioxidotetrahydro-2H-thiopyran-4-yl)amino]-l-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-5-yl}-5-oxa-6-azaspiro[3.4]oct-6-en-2-yl)propanamide (Compound No. 195),
3-{[5-(2-Amino-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclobutanecNboxylic acid (Compound No. 196),
3-{[5-(2-Amino-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-l-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclobutanecNboxyIic acid (Compound No. 197),
3-({5-[2-(Acetylamino)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-l-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-4-yl}amino)cyclobutanecNboxylic acid (Compound No. 198),
3-({5-[2-(Acetylamino)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-4-yl}amino)cyclobutanecNboxylic acid (Compound No. 199),
3-({l-Ethyl-5-[2-(propanoylamino)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-1H-pyrazolo[3,4-b]pyR1din-4-yl}amino)cyclobutanecNboxylic acid (Compound No. 20O),
3-({l-Ethyl-3-methyl-5-[2-(propanoylamino)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-1H-pyrazolo[3,4-b]pyR1din-4-yl}amino)cyclobutanecNboxylic acid (Compound No. 201),
N-ethyl-7-[l-ethyl-3-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxamide (Compound No. 202),
N-{7-[4-(cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-en-2-yl}propanamide (Compound No. 203),
N-{7-[l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-en-2-yl}propanamide (Compound No. 204),
N-{7-[l-ethyl-3-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-en-2-yl}propanamide (Compound No. 205),
4-{[5-(8-Amino-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-l-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclohexanecNboxyIic acid (Compound No. 206),
4-{[5-(8-Amino-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclohexanecNboxylic acid (Compound No. 207),
4-({5-[8-(Acetylamino)-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl]-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-4-yl}amino)cyclohexanecNboxylic acid (Compound No. 208),
4-({5-[8-(Acetylamino)-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl]-l-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-4-yl}amino)cyclohexanecNboxylic acid (Compound No. 209),
4-({l-Ethyl-3-methyl-5-[8-(propanoylamino)-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl]-1H-pyrazolo[3,4-b]pyR1din-4-yl}amino)cyclohexanecNboxylic acid (Compound No. 21O),
4-({l-Ethyl-5-[8-(propanoylamino)-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl]-1H-pyrazolo[3,4-b]pyR1din-4-yl}amino)cyclohexanecNboxylic acid (Compound No. 211),
7-{4-[(4-CNboxycyclohexyl)amino]-l-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-5-yl}-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxylic acid (Compound No. 212),
7-{4-[(4-CNboxycyclohexyl)amino]-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl}-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxylic acid (Compound No. 213),
4-{[5-(2-CNbamoyl-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclohexanecNboxylic acid (Compound No. 214),
4-{[5-(2-CNbamoyl-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-l-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclohexanecNboxylic acid (Compound No. 215),
4-({l-Ethyl-3-methyl-5-[2-(methylcNbamoyl)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-1H-pyrazolo[3,4-b]pyR1din-4-yl}amino)cyclohexanecNboxylic acid (Compound No. 216),
4-({l-Ethyl-5-[2-(methylcNbamoyl)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-1H-pyrazolo[3,4-b]pyR1din-4-yl}amino)cyclohexanecNboxylic acid (Compound No. 217),
4-({l-Ethyl-5-[2-(ethylcNbamoyl)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-1H-pyrazolo[3,4-b]pyR1din-4-yl}amino)cyclohexanecNboxylic acid (Compound No. 218),
4-({l-Ethyl-5-[2-(ethylcNbamoyl)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-3-methyl-1H-pyrazolo[3,4-b]pyR1din-4-yl}amino)cyclohexanecNboxylic acid (Compound No. 219),
3-{4-[(4-CNboxycyclohexyl)amino]-l -ethyl-1 7/-pyrazolo[3,4-b]pyR1din-5-yl}- l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxylic acid (Compound No. 22O),
3-{4-[(4-CNboxycyclohexyl)amino]-l-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-5-yl}-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxylic acid (Compound No. 221),
4-{[5-(8-CNbamoyl-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-l-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclohexanecNboxylic acid (Compound No. 222),
4-( {1 -Ethyl-5-[8-(methylcNbamoyl)-1 -oxa-2-azaspiro[4.5]dec-2-en-3-yl]-1H-pyrazolo[3,4-b]pyR1din-4-yl}amino)cyclohexanecNboxylic acid (Compound No. 223),
4-({l-Ethyl-3-methyl-5-[8-(methylcNbamoyl)-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl]-1H-pyrazolo[3,4-b]pyR1din-4-yl}amino)cyclohexanecNboxylic acid (Compound No. 224),
4-( {1 -Ethyl-5-[8-(ethylcNbamoyl)-1 -oxa-2-azaspiro[4.5]dec-2-en-3-yl]-3-methyl-1H-pyrazolo[3,4-£]pyR1din-4-yl}amino)cyclohexanecNboxylic acid (Compound No. 225),
4-( {1 -Ethyl-5-[8-(ethylcNbamoyl)-1 -oxa-2-azaspiro[4.5]dec-2-en-3-yl]-1H-pyrazolo[3,4-b]pyR1din-4-yl}amino)cyclohexanecNboxylic acid (Compound No. 226),
4-{[l-Ethyl-5-(8-methoxy-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclohexanecNboxylic acid (Compound No. 227),
4-{[5-(8-Ethoxy-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-4-yl]amino}cyclohexanecNboxylic acid (Compound No. 228),
4-( {1 -Ethyl-5-[8-(2-hydroxyethoxy)-1 -oxa-2-azaspiro[4.5]dec-2-en-3-yl]-1H-pyrazolo[3,4-A]pyR1din-4-yl}amino)cyclohexanecNboxylic acid (Compound No. 229),
l-£thyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-pyR1din-4-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 23O),
l-Ethyl-5-(5-oxa-6-azaspiro|3.4]oct-6-en-7-yl)-N-pyR1din-3-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 231),
l-Ethyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-pyR1din-2-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 232),
l-Ethyl-5-(5-oxa-6-azaspirol3.4]oct-6-en-7-yl)-N-pyrazin-2-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 233),
1 -Ethyl-5-(5-oxa-6-azaspiro[ 3.4]oct-6-en-7-yl)-N-pyR1midin-2-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 234).
l-Ethyl-5-(5-oxa-6-azaspirof3.4]oct-6-en-7-yl)-N-l,2,4-tR1azin-5-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine(Compound No. 235),
l-Ethyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-l,3-thiazol-2-yl-1H-pyrazoIo[3,4-b]pyR1din-4-amine (Compound No. 236).
l-Ethyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-4H-l,2,4-tR1azol-4-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 237).
l-Ethyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-2H-tetrazol-5-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 238).
l-Ethyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-1H-tetrazol-5-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 239).
l-Ethyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-pyR1midin-5-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 24O).
l-Ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-pyR1din-4-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 241),
l-Ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-N-pyR1din-4-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 242),
l-Ethyl-5-(l-oxa-2-azaspirof4.5]dec-2-en-3-yl)-N-pyR1din-3-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 243),
l-Ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-pyR1din-2-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 244),
l-Ethyl-5-(l-oxa-2-azaspirof4.5]dec-2-en-3-yl)-N-pyR1midin-2-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 245).
l-Ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-pyR1midin-5-yl-1H-pyrazolo[3,4-&]pyR1din-4-amine (Compound No. 246).
l-Ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-l,2,4-tR1azin-5-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 247).
l-Ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-l,3-thiazol-2-yl-1H-pyrazolo[3,4-A]pyR1din-4-amine (Compound No. 248).
l-Ethyl-5-(l-oxa-2-azaspirof4.5]dec-2-en-3-yl)-N-4H-l,2,4-tR1azol-4-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 249).
l-Ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-2H-tetrazol-5-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 25O).
l-Ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-1H-tetrazol-5-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 251).
l-Ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-N-pyR1din-3-yl-1H-pyrazolo[3,4-A]pyR1din-4-amine (Compound No. 252).

l-Ethyl-5-(l-oxa-2-azaspiro|4.4]non-2-en-3-yl)-N-pyR1din-2-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 253),
l-Ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-N-pyR1midin-2-yl-1H-pyrazolo[3,4-&]pyR1din-4-amine (Compound No. 254),
l-Ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-N-pyR1midin-5-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 255),
l-Ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-N-l,2,4-tR1azin-5-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 256),
l-Ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-N-1H-tetrazol-5-yI-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 257).
l-Ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-N-2H-tetrazol-5-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 258),
l-Ethyl-5-(l-oxa-2-azaspirof4.4]non-2-en-3-yl)-N-4H-l,2,4-tR1azoI-4-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 259).
l-Ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-N-l,3-thiazol-2-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 26O).
1-Ethyl-TV-furan-3-yl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 261).
1 -Ethyl-TV-furan-3-yl-5-( 1 -oxa-2-azaspiro[4.4]non-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 262).
1 -Ethyl-TV-furan-3-yl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 263).
l-Ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-N-pyrazin-2-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 264),
l-Ethyl-5-(l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-pyrazin-2-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 265),
7-{4-[(l,l-Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-l-ethyl-1H-pyrazolo[3,4-A]pyR1din-5-yl}-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNbonitR1le (Compound No. 266),
7-{4-[( 1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl}-5-oxa-6-azaspiro[3.4Joct-6-ene-2-cNboxyIic acid (Compound No. 267),
Methyl 7-{4-[( 1,1 -dioxidotetrahydro-2H-thiopyran-4-yl)amino]-1 -ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl}-5-oxa-6-azaspiro[3.4|oct-6-ene-2-cNboxylNe (Compound No. 268),
Ethyl 7-{4-[( 1,1 -dioxidotetrahydro-2H-thiopyran-4-yl)amino]-1 -ethyl-1 /7-pyrazolo[3,4-A]pyR1din-5-yl}-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxylNe (Compound No. 269),
tert-Butyl 7-{4-[(l,l-dioxidotetrahydro-2/:/-thiopyran-4-yl)amino]-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl}-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxylNe (Compound No. 27O),
7- {4-[( 1,1 -Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-1 -ethyl-1H-pyrazolo[3,4-/)]pyR1din-5-yl}-N-methyl-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxamide (Compound No.
271),
7- {4-[( 1,1 -Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-1 -ethyl-1H-pyrazolo[3,4-^]pyR1din-5-yl}-N-ethyl-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxamide (Compound No.
272),
N-cyclopropyl-7- {4-[( 1,1 -dioxidotetrahydro-2H-thiopyran-4-yl)amino]-1 -ethyl-1H-pyrazolo[3,4-%yR1din-5-yl J -5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxamide (Compound
No. 273),
7- {4-[( 1,1 -Dioxidotetrahydro-2/7-thiopyran-4-y 1 )amino]-1 -ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl}-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxamide (Compound No. 274),
7-[4-(Cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-N-cyclopropyl-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxamide (Compound No. 275),
N-cyclopropyl-7-[ 1 -ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-ene-2-cNboxamide (Compound No. 276),
l-Ethyl-5-(8-methoxy-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 277),
5-(8-Ethoxy-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-l-ethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 278),
N-cyclohexyl-5-(8-ethoxy-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 279),
N-cyclohexyl-1 -ethyl-5-(8-methoxy-1 -oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 28O),
3-{4-[(l, l-Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-l-ethyl-1H-pyrazolo[3,4-A]pyR1din-5-yl}-N-ethyl-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxamide (CompoundNo. 281),
7V-cyclopropyl-3-{4-[( 1,1 -dioxidotetrahydro-2H-thiopyran-4-yl)amino]-l -ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl)-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxamide (Compound No. 282),
3-[4-(Cyclohexylamino)-l -ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-N-cyclopropyl- l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxamide (Compound No. 283),
N-cyclopropyl-3-[l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxamide (Compound No. 284),
N-ethyl-3-[l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxamide (Compound No. 285),
3-[4-(Cyclohexylamino)-1 -ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-./V-ethyl-l -oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxamide (Compound No. 286),
Ethyl 3-{4-[(l,l-dioxidotetrahydro-2H-thiopyran-4-yl)amino]-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl}-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxylNe (Compound No. 287),
Methyl 3-{4-[( 1,1 -dioxidotetrahydro-2H-thiopyran-4-yl)amino]-1 -ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl}-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxylNe (Compound No. 288),
tert-Butyl 3-{4-[(l,l-dioxidotetrahydro-2/Y-thiopyran-4-yl)amino]-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl}-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxylNe (Compound No. 289),
N-( 1,1 -dioxidotetrahydro-2H-thiopyran-4-yl)-1 -ethyl-5-(8-methoxy-1 -oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 29O),
A?-(l,l-dioxidotetrahydro-2H-thiopyran-4-yl)-5-(8-ethoxy-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 291),
l-Ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-AM,2,4-tR1azin-3-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 292),
l-Ethyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-.Y-l,2,4-tR1azin-3-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 293).
1 -Ethyl-5-(l -oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-1,2,4-tR1azin-3-yl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 294),
l-Ethyl-5-(2-methoxy-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazoIo[3,4-b]pyR1din-4-amine (Compound No. 295),
N-cyclohexyl-l-ethyl-5-(2-methoxy-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 296).
N-( 1,1 -dioxidotetrahydro-2H-thiopyran-4-yl)-1 -ethyl-5-(2-methoxy-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 297),
N-(l,l-dioxidotetrahydro-2H-thiopyran-4-yl)-5-(2-ethoxy-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-l-ethyl-1H-pyrazolo[3,4-/7]pyR1din-4-amine (Compound No. 298),
N-cyclohexyl-5-(2-ethoxy-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-l-ethyI-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 299).
5-(2-Ethoxy-5-oxa-6-azaspiro[3,4]oct-6-en-7-yl)-1 -ethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 30O),
{7-[4-(Cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-en-2-yl}methanol (Compound No. 301),
(7-{4-[(l,l-Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl}-5-oxa-6-azaspiro[3.4]oct-6-en-2-yl)methanol (Compound No. 302),
N-(\,\ -dioxidotetrahydro-2/Y-thiopyran-4-yl)-1 -ethyl-5-[2-(methoxymethyl)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-1H-pyrazolo[3,4-£]pyR1din-4-amine (Compound No. 303),
N-( 1,1 -dioxidotetrahydro-2/7-thiopyran-4-yl)-5-[2-(ethoxymethyl)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-l -ethyl- 1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 304),
/V-cyclohexyl-5-[2-(ethoxymethyl)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-l -ethyl- \H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 305),
5-[2-(Ethoxymethyl)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-l-ethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-£]pyR1din-4-amine (Compound No. 306),
l-Ethyl-5-[2-(methoxymethyl)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3.4-b]pyR1din-4-amine (Compound No. 307),
N-cyclohexyl-l-ethyl-5-[2-(methoxymethyl)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 308),
5-[2-(Aminomethyl)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-ALcyclohexyl-l -ethyl- \H-pyrazolo[3,4-£]pyR1din-4-amine (Compound No. 309),
5-[2-(Aminomethyl)-5-oxa-6-azaspiro|3.4]oct-6-en-7-yl]-l-ethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 31O),
5-[2-(Aminomethyl)-5-oxa-6-azaspiro[ 3.4]oct-6-en-7-yl]-./V-( 1,1 -dioxidotetrahydro-2H-thiopyran-4-yl)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 311),
N-[{1- {4-[( 1,1 -dioxidotetrahydro-2H-thiopyran-4-yl)amino]-1 -ethyl-1H-pyrazolo[3,4-&]pyR1din-5-yl}-5-oxa-6-azaspiro[3.4]oct-6-en-2-yl)methyl]acetamide (Compound No. 312),
N-[(7- {4-[( 1,1 -dioxidotetrah ydro-2H-thiopyran-4-yl)amino]-1 -ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl}-5-oxa-6-azaspiro[3.4]oct-6-en-2-yl)methyl]propanamide (Compound No.
313),
N-({7-[l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-en-2-yl }methyl)propanamide (Compound No. 314),
N-({7-[4-(cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-en-2-yl} methyl )propanamide (Compound No. 315),
N-({7-[4-(cyclohexylamino)-l -ethyl-1 /f-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-en-2-yl) methyl )acetamide (Compound No. 316),
N-({7-[l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-5-oxa-6-azaspiro[3.4]oct-6-en-2-yi} methyl jacetamide (CompoundNo. 317),
l-Ethyl-N-(tetrahydro-2H-pyran-4-yl)-5-[2-(1H-tetrazol-5-yl)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 318),
N-cyclohexyl-l-ethyl-5-[2-(l/7-tetrazol-5-yl)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 319),
N-{\ ,1 -dioxidotetrahydro-2H-thiopyran-4-yl)-l -ethyl-5-[2-(1H-tetrazol-5-yl)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 32O),
l-Ethyl-N(tetrahydro-2H-pyran-4-yl)-5-[8-(1H-tetrazol-5-yl)-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl]-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 321),
N-cyclohexyl-l-ethyl-5-[8-(1H-tetrazol-5-yl)-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl]-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 322),
N-(l,l-dioxidotetrahydro-2H-thiopyran-4-yl)-l-ethyl-5-[8-(1H-tetrazol-5-yl)-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl]-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 323),
N-{ 1,1 -dioxidotetrahydro-2H-thiopyran-4-yl> 1 -ethyl-5-[8-(2H-tetrazol-5-yl)-l -oxa-2-azaspiro[4.5]dec-2-en-3-yl]-1H-pyrazolo[3.4-b]pyR1din-4-amine (Compound No. 324),
N-cyclohexyl-l-ethyl-5-[8-(2H-tetrazol-5-yl)-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl]-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 325),
l-Ethyl-N-(tetrahydro-2H-pyran-4-yl)-5-[8-(2H-tetrazol-5-yl)-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl]-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 326),
l-Ethyl-N-(tetrahydro-2H-pyran-4-yl)-5-[2-(2H-tetrazol-5-yl)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 327),
A7-cyclohexyl-l-ethyl-5-[2-(2H-tetrazol-5-yl)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 328),
N-(l,l-dioxidotetrahydro-2H-thiopyran-4-yl)-l-ethyl-5-[2-(2H-tetrazol-5-yl)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 329),
Ethyl 3-[l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b']pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxylNe (Compound No. 33O),
Ethyl 3-[4-(cyclohexylamino)-l-ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxylNe (Compound No. 331),
Methyl 3-[4-(cyclohexylamino)-1 -ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxylNe (Compound No. 332),
Methyl 3-[l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-ene-8-eNboxyiNe (Compound No. 333),
tert-Butyl 3-[l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1din-5-yl]-l-oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxylNe (Compound No. 334),
tert-Butyl 3-[4-(cyclohexylamino)-1 -ethyl-1H-pyrazolo[3,4-b]pyR1din-5-yl]-1 -oxa-2-azaspiro[4.5]dec-2-ene-8-cNboxe (Compound No. 335),
N-( 1,1 -dioxidotetrahydro-2H-thiopyran-4-yl)-1 -ethyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 336),
N-(l,l-dioxidotetrahydro-2/7-thiopyran-4-yl)-l-ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-1H-pyrazolo[3,4-b]pyR1din-4-amine (Compound No. 337),
3-[4-(CycIohexylamino)-1 -ethyl-1H-pyrazolo[3.4-b]pyR1din-5-yl]-1 -oxa-2-azaspiro[4.5]dec-2-en-8-amine (Compound No. 338),
or its phNmaceutically acceptable salts, phNmaceutically acceptable solvNes, stereoisomers,
tautomers, geometR1c isomers, racemNes. regioisomers, prodrugs, metabolites, polymorphs or N-
oxides. thereof.
3. A phNmaceutical composition compR1sing a therapeutically effective amount of a compound as defined in claim 1 or 2 along with one or more of phNmaceutically acceptable cNR1ers, excipients or diluents.
4. A phNmaceutical composition compR1sing a therapeutically effective amount of a compound of claim 1 or 2, along with one or more of phNmaceutically acceptable cNR1ers, excipients or diluents and N least one other compound selected from B2- agonists, corticosteroids, leukotR1ene antagonists, 5-lipoxygenase inhibitors, chemokine inhibitors, p38 kinase inhibitors, anticholinergics, antiallergics, PN (plNelet activNing factor) antagonists, EGFR (epidermal growth factor receptor) kinase inhibitors, muscN1nic receptor antagonists or combinNion(s) thereof.
5. Use of a compound of claim 1 or 2 or a phNmaceutical composition of claim 3 or 4 in the manufacture of a medicament for treNing, preventing, inhibiting or suppressing inflammNory diseases, CNS diseases or autoimmune diseases, in a mammal.
6. Use of a compound of claim 1 or 2 or a phNmaceutical composition of claim 3 or 4 in the manufacture of a medicament for the treNment, prevention, inhibition or suppression of multiple sclerosis, AIDS, rejection of transplant, rheumNoid NthR1tis, bronchitis, chronic obstructive pulmonNy disease (COPD), asthma, psoR1asis, allergic rhinitis, shock, Nopic dermNitis, Crohn's disease, adult respirNory distress syndrome (NDS), eosinophilic granuloma, allergic conjunctivitis, osteoNthR1tis, colitis, pancreNitis, and cancer in a mammal.
7. The use according to claim 5 or 6, wherein the disease is mediNed through phosphodiesterase type 4 and/or 7.
8. A method for the prepNNion of a compound of Formula I,
the method compR1sing,
(a) reacting a compound of Formula II with a compound of Formula III to give a
compound of Formula IV.
(FORMULA REMOVED)
(b) heNing the compound of Formula IV to give a compound of Formula V(a),
reacting the compound of Formula V(a) with phosphorous oxy halide to give a compound
of Formula V,
or reacting the compound of Formula IV with phosphorous oxy halide to give a compound of Formula V,
(FORMULA REMOVED)
(c) reacting the compound of Formula V with a compound of Formula VI to give a
compound of Formula VII,
hydrolysing the compound of Formula VII
to give a compound of Formula VIII, or hydrolysing the compound of Formula V to give a compound of Formula VII (a), reacting the compound of Formula VII (a) with a compound of Formula VI to give a compound of Formula VIII,
(FORMULA REMOVED)
(d) reacting the compound of Formula VIII with a compound of Formula IX to give a
compound of Formula X,
(FORMULA REMOVED)
(e) reducing the compound of Formula X to give a compound of Formula XI,
(FORMULA REMOVED)
(f) reacting the compound of Formula XI with hydroxylamine hydrochloR1de to give a
compound of Formula XII,
(FORMULA REMOVED)
(g) reacting the compound of Formula XII with a compound of Formula XIII
(FORMULA REMOVED)
to give a compound of Formula 1,
wherein Ru is alkyl, X is a halogen, and Rt, R2, R3 and M Ne the same as defined in claim
1.
9. A method for the prepNNion of compounds of Formulae XVI (a), XVIII, XIX and XX,
(FORMULA REMOVED)
the method compR1sing,
(a) reacting a compound of Formula XII with a compound of Formula XIV to give a
compound of Formula XV,
(FORMULA REMOVED)
(b) reducing the compound of Formula XV to a give a compound of Formula XVI or
reacting the compound of Formula XII with a compound of Formula XIV (a) to give a
compound of Formula XVI.
(FORMULA REMOVED)
(c) (i) cyclizing the compound of Formula XVI to give a compound of Formula
XVI (a),
(ii) mesylNing the compound of Formula XVI to give a compound of Formula XVII,
cyclizing the compound of Formula XVII to give a compound of Formula XVIII, oxidising the compound of Formula XVIII to give a compound of Formula XIX or compound of Formula XX,
wherein R)a is alkyl, m is an integer from 0-2 and R1, R2, R3 Ne the same as defined in claim 1.
10. A method for the prepNNion of compounds of Formulae XXII and XXIII,

the method compR1sing,
(a) oxidising a compound of Formula XXI
(FORMULA REMOVED)
to give a compound of Formula XXII.
(b) reacting the compound of Formula XXII with hydroxylamine hydrochloR1de to give
a compound of Formula XXIII.
wherein R3 and M Ne the same as defined in claim 1.
11, A method for the prepNNion of a compound of Formula XXVII,
(FORMULA REMOVED)
the method compR1sing
(a) reacting a compound of Formula XII with a compound of Formula XXIV to give a
compound of Formula XXV,
(FORMULA REMOVED)
(b) reducing the compound of Formula XXV to give a compound of Formula XXVI,
(FORMULA REMOVED)
(c) cyclizing the compound of Formula XXVI to give a compound of Formula XXVII, wherein R]a is alkyl, X is halogen, R(, R? and R3 Ne the same as defined in claim 1.
12. A method for the prepNNion of compounds of Formulae XXIX and XXXI,
(FORMULA REMOVED)
the method compR1sing,
(a) deprotecting a compound of Formula XXVIII to give a compound of Formula
XXIX,
(b) reacting the compound
(FORMULA REMOVED)
of Formula XXIX with a compound of Formula XXX
to give a compound of Formula XXXI.
wherein R|a is alkyl, X is halogen, R is alkyl, cycloalkyl, cycloalkylalkyl, -COR4 or -SO2R4 and R1, R2, R3 and R4 Ne the same as defined in claim 1.
13. A method for the prepNNion of compounds of Formulae XXXIII, XXXHI (a), and XXXIII
(c),
(FORMULA REMOVED)
(a) hydrolysing a compound of Formula XXXII to give a compound of Formula
XXXIII,
(b) (i) reducing the compound of Formula XXXIII to give a compound of Formula
XXXIII (a),
(ii) reacting the compound of Formula XXXIII with chloroacetonitR1le to give a compound of XXXIII (b)
(FORMULA REMOVED)
and hydrolysing the compound of XXXIII (b) to give a compound of Formula XXXIII (c),
wherein A is a 3-7 membered sNurNed, pNtially sNurNed or unsNurNed R1ng containing cNbon Noms and R;, R2 and R3 Ne the same as defined in claim 1.
14. A method for the prepNNion of compounds of Formulae XXXIV and XXXVI,
(FORMULA REMOVED)
the method compR1sing,
(a) deprotecting a compound of Formula XXXIV (a)
(FORMULA REMOVED)
to give a compound of Formula XXXIV.
(b) reacting the compound of Formula XXXIV with a compound of Formula XXXV
(FORMULA REMOVED)
to give a compound ot hormula XXXVI,
wherein Pr is a protecting group, X is halogen, R' is alkyl, cycloalkyl or cycloalkylalkyl, and R1, R2, R3 and M Ne the same as defined in claim 1.
15. A method for the prepNNion of compounds of Formulae XXXVIII and XXXIX,
(FORMULA REMOVED)
the method compR1sing,
(a) deprotecting a compound of Formula XXXVII
(FORMULA REMOVED)
to give a compound of Formula XXXVIII,
(b) reacting the compound of Formula XXXVIII with a compound of Formula XXX
(FORMULA REMOVED)
to give a compound of Formula XXXIX.
wherein R1a is alkyl, X is halogen, R is alkyl, cycloalkyl, cycloalkylalkyl, -COR4 or -SO2R4 and R3, R4 and M Ne the same as defined in claim 1.
16. A method for the prepNNion of compounds of Formulae XLI, XLII and XLIII,
(FORMULA REMOVED)
the method compR1sing,
(a) deprotecting a compound of Formula XL
(FORMULA REMOVED)
to give a compound of Formula XLI,
(b) reacting the compound of Formula XLI with a compound of Formula XXXV
(FORMULA REMOVED)
to give a compound of Formula XLI I,
(c) debenzylNing the compound of Formula XLII to give a compound of Formula
XLIII,
wherein Pr is a protecting group, X is a halogen. R' is alkyl, cycloalkyl or cycloalkylalkyl and R|, R2, R3, M and m Ne the same as defined in claim 1.
17. A method for the prepNNion of a compound of Formula L,
(FORMULA REMOVED)
the method compR1sing,
(a) reacting a compound of Formula V with a compound of Formula VI (a) to give a compound of Formula XLIV,
(FORMULA REMOVED)
(b) oxidising the compound of Formula XLIV to give a compound of Formula XLV,
(FORMULA REMOVED)
(c) hydrolysing the compound of Formula XLV to give a compound of Formula XLVI,
(FORMULA REMOVED)
(d) reacting the compound of Formula XLVI with a compound of Formula IX to give a
compound of Formula XLV II.
(FORMULA REMOVED)
(e) reducing the compound of Formula XLVII to give a compound of Formula XLVIII,
(FORMULA REMOVED)
(f) reacting the compound of Formula XLVIII with hydroxylamine hydrochloR1de to
give a compound of Formula XLIX,
(FORMULA REMOVED)
(g) reacting the compound of Formula XLIX with a compound of Formula XIII
(FORMULA REMOVED)
to give a compound of Formula L. wherein X is halogen, R!a is alkyl and R; amd M Ne the same as defined in claim 1.
18. A method for the prepNNion of a compound of Formula LXVI,
(FORMULA REMOVED)
the method compR1sing,
(a) heNing a compound of Formula LI to give a compound of Formula LII,
(FORMULA REMOVED)
(b) reacting the compound of Formula LII with phosphorous oxy halide to give a
compound of Formula LII I.
(FORMULA REMOVED)
(c) reacting the compound of Formula LIII with a compound of Formula LIV to give a
compound of Formula LV.
(FORMULA REMOVED)
(d) hydrolysing the compound of Formula LV to give a compound of Formula LVI,
(FORMULA REMOVED)
(e) reacting the compound of Formula LVI with a compound of Formula IX to give a
compound of Formula LVII,
(FORMULA REMOVED)
(f) deprotecting the compound of Formula LVII to give a compound of Formula LVIII,
(FORMULA REMOVED)
(g) reacting the compound of Formula LVIII with a compound of Formula LIX to give a
compound of Formula LX.
(FORMULA REMOVED)
(h) reducing the compound of Formula LX to give a compound of Formula LXI,
(FORMULA REMOVED)
(i) reacting the compound of Formula LXI with hydroxylamine hydrochloR1de to give a compound of Formula LXII,
(FORMULA REMOVED)
(j) reacting the compound of Formula LXII with a compound of Formula XIII to give a compound of Formula LXIII,
(FORMULA REMOVED)
(k) deprotecting the compound of Formula LXIII to give a compound of Formula LXIV,
(FORMULA REMOVED)
(1) reacting the compound of Formula LXIV with a compound of Formula LXV
(FORMULA REMOVED)
to give a compound of Formula LXVI.
vherein R1a is alkyl, Pr is a protecting group, X is a halogen, R3b is alkyl or cycloalkyl, RT,C is Nyl ir heteroNyl and R3 and M Ne the same as defined in claim 1.
9. A method for the prepNNion of a compound of Formula LXIII (a),
(FORMULA REMOVED)
the method compR1sing,
(a) reacting a compound of Formula LIII with a compounds of Formula VI to give a
compound of Formula LV (a),
(FORMULA REMOVED)
(b) hydrolysing the compound of Formula LV(a) to give a compound of Formula LVI
(a), (FORMULA REMOVED)
(c) reacting the compound of Formula LVI (a) with a compound of Formula IX to give
a compound of Formula LVII (a),
(FORMULA REMOVED)
(d) deprotecting the compound of Formula LVII (a) to give a compound of Formula
LVIII (a),
(FORMULA REMOVED)
(e) reacting the compound of Formula LVUI (a) with a compound of Formula LIX to
give a compound of Formula LX (a),
(FORMULA REMOVED)
(f) reducing the compound of Formula LX (a) to give a compound of Formula LXI (a),
(FORMULA REMOVED)
(g) reacting the compound of Formula LXI (a) with hydroxylamine hydrochloR1de to
give a compound of Formula LXII (a).
(FORMULA REMOVED)
(h) reacting the compound of Formula LXII (a) with a compound of Formula XIII
(FORMULA REMOVED)
to give a compound of Formula LXIII (a), wherein X is halogen, R|a is alkyl, Pr is a protecting group, R3b is alkyl or cycloalkyl and R|, R2, R3 and M Ne the same as defined in claim 1.20. A method for the prepNNion of a compound of Formula LXVII,
(FORMULA REMOVED)
the method compR1sing hydrolysing a compound of Formula LXVII (a)
(FORMULA REMOVED)
to give a compound of Formula LXVII,
wherein Rla is alkyl, R1ng D is cyclobutyl or cyclohexyl R1ng and R3 and M Ne the same as defined in claim 1.
21. A method for the prepNNion of compounds of Formulae LXX, LXXI, LXXII and LXXIV,
(FORMULA REMOVED)
the method compR1sing,
(a) (i) protecting a compound of Formula LXVIII to give a compound of
Formula LXIX.
(FORMULA REMOVED)
(ii) reacting the compound of Formula LXIX with sodium cyanide to give a compound of Formula LXX.
(iii) hydrolysing the compound of Formula LXX to give a compound of Formula LXXI,
(iv) cyclizing the compound of Formula LXX to give a compound of Formula LXXII, (b) reacting the compound of Formula LXVIII with a compound of Formula LXXIII
(FORMULA REMOVED)
to give a compound of Formula LXXIV.
wherein X is halogen, PR1 is a protecting group and R1, R2, R3, R4, mand M Ne the same as defined in claim 1.
22. A method for the prepNNion of compounds of Formulae LXXI, LXXV (a) and LXXV (b),
(FORMULA REMOVED)
the method compR1sing,
(a) hydrolysing a compound of Formula LXXVI
(FORMULA REMOVED)
to give a compound of Formula LXXI.
(b) reacting the compound of Formula LXXI with ammonium cNbonNe or a compound
of Formula LXXV
to give a compound of Formula LXXV (a) or a compound of LXXV (b) repectively,
wherein R,a is alky], and R1, R2, R3, R4, R'4. m and M Ne the same as defined in claim 1.
23. A method for the prepNNion of compounds of Formulae LXXYIII, LXXX and
LXXXI,
(FORMULA REMOVED)
the method compR1sing,
(a) reacting a compound of Formula LXIX with sodium azide to give a compound of
Formula LXXVII,
(FORMULA REMOVED)
(b) reducing the compound of Formula LXXVII to give a compound of Formula
LXXVIII,
(i) reacting the compound of Formula LXXVIII with a compound of Formula LXXIX
(FORMULA REMOVED)
to give a compound of Formula LXXX,
(ii) reacting the compound of Formula LXXVIII with a compound of Formula
LXXIII
(FORMULA REMOVED)
to give a compound of Formula LXXXI,
wherein PR1 is a protecting group, X is halogen and R|, R2, R3, R4, m and M Ne the same as defined in claim 1.
24. Use of a PDE type 7 inhibitor or dual PDE type 4 /PDE type 7 inhibitor having the structure
of Formula la,
(FORMULA REMOVED)
or its phNmaceutically acceptable salts, wherein
R'ia is hydrogen, alky], alkenyl, alkynyl, acyl, Nyl, Nalkenyl, Nalkyl, cycloalkyl alkyl, heteroNyl,
heterocyclylalkyl, heteroNylalkyl, cycloalkyl or heterocyclyl;
R'2a is cyclopropyl, cyclopentyl, alkyl, alkenyl, alkynyl, acyl, Nalkenyl, Nalkyl, cycloalkylalkyl,
heterocyclylalkyl, heteroNylalkyl or heterocyclyl;
R3 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, Nyl, Nalkyl, Nalkenyl, cycloalkylalkyl,
heterocyclyl, heteroNyl, heterocyclylalkyl or heteroNylalkyl;
Ma is a 3-7 membered sNurNed, pNtially sNurNed or unsNurNed R1ng containing cNbon Noms
wherein one or more cNbon Noms optionally Ne replaced by heteroNoms selected from 0, S(O)m
{wherein m is an integer from 0-2} or NR7 {wherein R7 is hydrogen, alkyl, alkenyl, alkynyl,
cycloalkyl, Nyl, heteroNyl or heterocyclyl}, in the manufacture of a medicament for treNing,
preventing, inhibiting or suppressing inflammNory diseases, CNS diseases or autoimmune
diseases, in a mammal.
25. Use of a PDE type 7 inhibitor or dual PDE type 4 /PDE type 7 inhibitor having the structure
of Formula la,
(FORMULA REMOVED)
or its phNmaceutically acceptable salts, wherein
R'ia is hydrogen, alkyl, alkenyl, alkynyl, acyl, Nyl, Nalkenyl, Nalkyl, cycloalkyl alkyl, heteroNyl,
heterocyclylalkyl, heteroNylalkyl. cycloalkyl or heterocyclyl;
RSa is cyclopropyl, cyclopentyl, alkyl, alkenyl, alkynyl, acyl, Nalkenyl, Nalkyl, cycloalkylalkyl,
heterocyclylalkyl, heteroNylalkyl or heterocyclyl;
R3 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, Nyl, Nalkyl, Nalkenyl, cycloalkylalkyl,
heterocyclyl, heteroNyl, heterocyclylalkyl or heteroNylalkyl;
Ma is a 3-7 membered sNurNed, pNtially sNurNed or unsNurNed R1ng containing cNbon Noms
wherein one or more cNbon Noms optionally Ne replaced by heteroNoms selected from O, S(O)m
{wherein m is an integer from 0-2} or NR7 {wherein R7 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, Nyl, heteroNyl or heterocyclyl), in the manufacture of a medicament for the treNment, prevention, inhibition or suppression of multiple sclerosis, AIDS, rejection of transplant, rheumNoid NthR1tis, bronchitis, chronic obstructive pulmonNy disease (COPD), asthma, psoR1asis, allergic rhinitis, shock, Nopic dermNitis, Crohn's disease, adult respirNory distress syndrome (NDS). eosinophilic granuloma, allergic conjunctivitis, osteoNthR1tis, colitis, pancreNitis, and cancer in a mammal.
26. The use according to claim 24 or 25, wherein the PDE type 7 inhibitor or dual PDE type 4 /PDE type 7 inhibitor is selected from
- N-cyclopropyl-l-ethyl-5- (l-oxa-2-azaspiro [4.5] dec-2-en-3-yl)-lH-pyrazolo[3,4-b] pyR1din-4-amine (Compound No. 29).
- N-cyclopropyl-l-ethyl-5- (l-oxa-2-azaspiro [4.4] non-2-en-3-yl)-lH-pyrazolo[3,4-b] pyR1din-4-amine (Compound No. 3O),
- N-cyclopropyl-l-ethyl-5- (5-oxa-6-azaspiro [3.4] oct-6-en-7-yl)-lH-pyrazolo[3,4-b] pyR1din-4-amine (Compound No. 31),
- N-cyclopentyl-1, 3-dimethyl-5- (5-oxa-6-azaspiro [3.4] oct-6-en-7-yl)-lH-pyrazolo[3,4-b] pyR1din-4-amine (Compound No. 32),
- N-cyclopentyl-1, 3-dimethyl-5- (1 -oxa-2-azaspiro [4.4] non-2-en-3-yl)-lH-pyrazolo[3,4-b] pyR1din-4-amine (Compound No. 33).
- N-cyclopentyl-1, 3-dimethyl-5- (l-oxa-2-azaspiro [4.5] dec-2-en-3-yl)-lH-pyrazolo[3,4-b] pyR1din-4-amine (Compound No. 34),
N-cyclopropyl-1, 3-dimethyl-5- (l-oxa-2-azaspiro [4.4] non-2-en-3-yl)-lH-pyrazolo[3,4- b] pyR1din-4-amine (Compound No. 35),
N-cyclopropyl-1, 3-dimethyl-5- (5-oxa-6-azaspiro [3.4] oct-6-en-7-yl)-lH-pyrazolo[3,4-b] pyR1din-4-amine (Compound No. 36),
N-cyclopropyl-1, 3-dimethyl-5- (l-oxa-2-azaspiro [4.5] dec-2-en-3-yl)-lH-pyrazolo[3,4-b] pyR1din-4-amine (Compound No. 37),
N-cyclopentyl-1-ethyl-5- (5-oxa-6-azaspiro [3.4] oct-6-en-7-yl)-lH-pyrazolo[3,4-b] pyR1din-4-amine (Compound No. 38),
N-cyclopentyl-1-ethyl-5- (1-oxa-2-azaspiro [4.4] non-2-en-3-yl)-lH-pyrazolo[3,4-b] pyR1din-4-amine (Compound No. 39).
- N-cyclopentyl-5- (l,7-dioxa-2-azaspiro [4.4] non-2-en-3-yl)-l,3-dimethyl-lH-pyrazolo
[3,4-b] pyR1din-4-amine (Compound No. 4O),
or its phNmaceutically acceptable salts, phNmaceutically acceptable solvNes, stereoisomers,
tautomers. racemNes, regioisomeis. geometR1c isomers, prodrugs, metabolites, polymorphs orN-
oxides.
27. An intermediNe having the structure of Formula lb:
(FORMULA REMOVED)
or its phNmaceutically acceptable salts, phNmaceutically acceptable solvNes, stereoisomers, tautomers, geometR1c isomers, racemNes, regioisomers, prodrugs, metabolites, polymorphs or N-oxides, wherein
R1 and R2 independently Ne hydrogen, Nyl, Nalkyl, heteroNyl, -COR4, -S(O)mR4 (wherein R4 is hydrogen, alkyl, cycloalkyl, Nyl, Nalkyl, heteroNyl or heterocyclyl and m is an integer from 0-
(FORMULA REMOVED)
wherein X is -0-, S(O)m (wherein m is an integer from 0-2), C(=O), C=NOH, CRfRq (wherein Rf and Rq independently Ne hydrogen, hydroxy, cNboxy or cyano) or NR5 {wherein R5 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, Nyl, heteroNyl, heterocyclyl, -COR4, -S(O)mR4, -COOR4 or -CONR4R'4 (wherein R4 and R'4 independently Ne hydrogen, alkyl, cycloalkyl, Nyl, Nalkyl, heteroNyl or heterocyclyl and m is an integer from 0-
2)};
R3 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, Nyl, Nalkyl, Nalkenyl, cycloalkylalkyl,
heterocyclyl, heteroNyl, heterocyclylalkyl or heteroNylalkyl;
(FORMULA REMOVED)
(wherein R!a is alkyl), -CHO or -CH=NORx (wherein Rx is hydrogen, alkyl or cycloalkyl).
28. An intermediNe, which is selected from
4-(Cyclohexylamino)-l-ethyl-N-methoxy-N-methyl-1H-pyrazolo[3,4-b]pyR1dine-5-cNboxamide,
l-Ethyl-N-methoxy-N-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-fr]pyR1dine-5-cNboxamide,
l-Ethyl-4-[(4-hydroxycyclohexyl)amino]-N-methoxy-N-methyl-1H-pyrazolo[3,4-b]pyR1dine-5-cNboxamide.
4-(Cyclohexylamino)-l -ethyl- l#-pyrazo!o[3,4-H]pyR1dine-5-cNbaldehyde,
1 -Ethyl-4-(tetrahydro-2H-pyran-4-yIamino)-1H-pyrazolo[3,4-b]pyR1dine-5-cNbaldehyde,
1 -Ethyl-4-[(4-hydroxycyctohexyl)amino]-1H-pyrazolo[3,4-b]pyR1dine-5-cNba!dehyde,
4-(Cyclohexylamino)-l -ethyl-1H-pyrazolo[3,4-b]pyR1dine-5-cNbaldehyde oxime,
l-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyR1dine-5-cNbaldehyde
oxime,
l-Ethyl-4-[(4-hydroxycyclohexyl)amino]-1H-pyrazolo[3,4-b]pyR1dine-5-cNbaldehyde
oxime,
tert-Butyl 4-({l-ethyl-5-[methoxy(methyl)cNbamoyl]-1H-pyrazolo[3,4-b]pyR1din-4-
y 1} amino)pipeR1dine-1 -cNboxylNe,
l-Ethyl-N-methoxy-4-[(3-methoxyphenyl)amino]-N-methyl-1H-pyrazolo[3,4-b)]pyR1dine-5-
cNboxamide,
4-[( 1,1 -Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-1 -ethyl-N-methoxy-N-methyl-1H-pyrazolo[3,4-b]pyR1dine-5-cNboxamide,
4-(Benzylamino)-l-ethyl-N-Methoxy-N-methyl-1H-pyrazolo[3,4-b)]pyR1dine-5-cNboxamide,
1 -Ethyl-4-[(3-methoxyphenyl)amino]-1H-pyrazolo[3,4-b]pyR1dine-5-cNbaldehyde,
/erf-Butyl 4-[(l-ethyl-5-formyl-1H-pyrazolo[3,4-b]pyR1din-4-yl)amino]pipeR1dine-l-
cNboxylNe,
4-[( 1,1 -Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-1 -ethyl-1H-pyrazolo[3,4-£]pyR1dine-5-cNbaldehyde,
4-(Benzylamino)-l -ethyl- 1H-pyrazolo[3,4-b]pyR1dine-5-cNbaldehyde,
1 -Ethyl-4-[(3-methoxyphenyl)amino]-1 #-pyrazolo[3,4-b]pyR1dine-5-cNbaldehyde oxime,
4-(Benzylamino)-l-ethyl-1H-pyrazolo[3,4-/j]pyR1dine-5-cNbaldehyde oxime,
tert-Butyl 4-[(l-ethyl-5-[(£)-(hydroxyimino)methyl -1H-pyrazolo[3,4-b]pyR1din-4-yl)amino]pipeR1dine-1 -cNboxylNe,
4-[( 1,1 -Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-1 -ethyl-1H-pyrazolo[3,4-b]pyR1dine-5-cNbaldehyde xime.