JP6562213 | Method for Producing Optically Active 5-Hydroxy-3-ketoesters |
WO/2013/030777 | CO-CRYSTALS OF CYPRODINIL AND DITHIANON |
JP2009524579 | Trisubstituted amine compounds |
TSENG SHI-LIANG (TW)
LIOU BO-SIAN (TW)
CHEN CHUNG CHIN (US)
WO2013067036A1 | 2013-05-10 |
US20110251181A1 | 2011-10-13 | |||
US201962924214P | 2019-10-22 |
DATABASE PubCHEM COMPOUND U.S. National Library of Medicine; 15 January 2016 (2016-01-15), "N-(6-Chloro-7H-purin-2-yl)-5-nitrothiophene-2-carboxamide | C10H5ClN6O3S", XP055819292, Database accession no. CID 108200193
DATABASE PubCHEM COMPOUND U.S. National Library of Medicine; 29 July 2006 (2006-07-29), "5-Nitro-N-thieno[2,3-d]pyrimidin-4-ylthiophene-2-carboxamide | C11H6N4O3S2", XP055819295, Database accession no. CID 7615364
DATABASE PubCHEM COMPOUND U.S. National Library of Medicine; 7 September 2016 (2016-09-07), "N-{5,6-Dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-5-nitrothiophene-2-carboxamide | C13H11N5O3S", XP055819305, Database accession no. CID 121564559
R. LAROCK: "Comprehensive Organic Transformations", 1999, VCH PUBLISHERS
P. G. M. WUTST. W. GREENE: "Greene's Protective Groups in Organic Synthesis", 2007, JOHN WILEY AND SONS
L. FIESERM. FIESER: "Fieser and Fieser's Reagents for Organic Synthesis", 1994, JOHN WILEY AND SONS
"Encyclopedia of Reagents for Organic Synthesis", 2009, JOHN WILEY AND SONS
P. ROSZKOWSKIJ.K. MAURINZ. CZARNOCKI: "Enantioselective synthesis of (R)-(-)-praziquantel (PZQ", TETRAHEDRON: ASYMMETRY, vol. 17, 2006, pages 1415 - 1419
NAT. REV. CANCER, vol. 6, 2006, pages 813 - 823
See also references of EP 4048656A4
WHAT IS CLAIMED IS: A c 1o.m Ap cooumnpodun odf o tfh foerm Fuolarm (I)u:la Formula I or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein each of X1, X2 and X3 independently is C, N, O or S, with the proviso that no more than two of X1, X2 and X3 are N, O or S; each of R1 independently is selected from the group consisting of hydrogen, halogen, alkyl, alkyloxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein each of alkyl, alkyloxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally substituted with one to three moieties selected from the group consisting of halogen, hydroxyl, nitro, cyano, –NRaRb, – C(=O)Rc, –C(=O)ORd, heterocycloalkyl optionally substituted with one to four halogen, aryl optionally substituted with one to three halogen or –NRaRb, alkyl optionally substituted with one to three halogen, and alkyloxy optionally substituted with one to three halogen or alkyloxy, in which each of Ra and Rb independently is hydrogen, alkyl or acrylamide, and each of Rc and Rd independently is hydrogen, alkenyl, or alkyl optionally substituted with one to three halogen or alkyloxy optionally further substituted with alkyloxy; one of R and R2 is the other of R and R2 is –OR3, –NHR4, –SR5, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aryl fused with heterocycloalkyl, cycloalkenyl or cycloamine, wherein each of alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl and cycloalkenyl is optionally substituted with one to three moieties selected from the group consisting of halogen, hydroxyl, nitro, cyano, –NReRf, –C(=O)Rg, –C(=O)ORh, –SO2Ri, –OSiRj, alkenyl, heterocycloalkyl, aryl optionally substituted with alkyl optionally substituted with one to three halogen or alkyloxy optionally substituted with one to three halogen, alkyl optionally substituted with one to three halogen, –NReRf or –ORk, and alkyloxy optionally substituted with one to four halogen, hydroxyl, –NReRf or alkyloxy optionally further substituted with alkyloxy, in which each of Re and Rf independently is hydrogen or alkyl optionally substituted with alkyloxy, each of Rg and Rh independently is hydrogen, alkyl or alkenyl, Ri is alkyl, Rj is alkyl, and Rk is hydrogen, aryl, or alkyl optionally substituted with alkyloxy optionally further substituted with alkyloxy; each of R3 and R5 independently is alkyl, cycloalkyl or aryl, wherein alkyl, cycloalkyl or aryl is optionally substituted with one to four moieties selected from the group consisting of halogen, alkyl optionally susbstituted with one to four halogen, alkyloxy optionally substituted with one to three halogen or alkyloxy, –NRlRm, and heterocycloalkyl, in which each of Rl and Rm independently is hydrogen or alkyl; R4 is alkyl, cycloalkyl or –SO2Rn, in which Rn is hydrogen, alkyl or aryl, and each of alkyl or aryl is optionally substituted with one to three halogen; and n is 1, 2 or 3. 2. The compound of claim 1, wherein in which n is 1 or 2. 3. The compound of claim 1, wherein in which each of R1a and R1b independently is selected from the group consisting of hydrogen, halogen, alkyl, alkyloxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein each of alkyl, alkyloxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally substituted with one to three moieties selected from the group consisting of halogen, hydroxyl, nitro, cyano, –NRaRb, –C(=O)Rc, –C(=O)ORd, heterocycloalkyl optionally substituted with one to four halogen, aryl optionally substituted with one to three halogen or – NRaRb, alkyl optionally substituted with one to three halogen, and alkyloxy optionally substituted with one to three halogen or alkyloxy, in which each of Ra and Rb independently is hydrogen, alkyl or acrylamide, and each of Rc and Rd independently is hydrogen, alkenyl, or alkyl optionally substituted with one to three halogen or alkyloxy optionally further substituted with alkyloxy. 4. The compound of claim 3, wherein R1b is hygrogen or alkyl. 5. The compound of claim 4, wherein R1b is hygrogen. 6. The compound of claim 5, wherein R1a is alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl, wherein each of alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally substituted with one to three moieties selected from the group consisting of F, Cl, hydroxyl, cyano, –NRaRb, –C(=O)Rc, –C(=O)ORd, heterocycloalkyl optionally substituted with one to four F or Cl , aryl optionally substituted with one to three F, Cl or –NRaRb, alkyl optionally substituted with one to three F, Cl, and alkyloxy optionally substituted with one to three F, Cl or alkyloxy, in which Ra is hydrogen or alkyl, Rb is alkyl or acrylamide, Rc is alkyl or alkenyl, Rd is alkyl optionally substituted with one to three F, Cl or alkyloxy optionally further substituted with alkyloxy. 7. The compound of claim 6, wherein R1a is alkyl, benzyl, phenyl, pyridinyl, pyrrolidinyl, cyclopentyl, cyclohexyl, cycloheptyl or piperidinyl; wherein alkyl is optionally substituted with hydroxyl, cyano, dialkylamino, heterocycloalkyl optionally substituted with one or two F, or alkyloxy optionally substituted with alkyloxy; benzyl is optionally substituted with one F; phenyl is optionally substituted with one or two F, Cl, –NRaRb, alkyl optionally substituted with three F, or alkyloxy optionally substituted with one to three F; pyridinyl is optionally substituted with alkyl optionally substituted with three F; pyrrolidinyl is substituted with alkyl, –C(=O)Rc or –C(=O)ORd; cyclopentyl, cyclohexyl and cycloheptyl is optionally substituted with one or two F, Cl or alkyl; and piperidinyl is optionally substituted with alkyl, – C(=O)Rc, or –C(=O)ORd; wherein Ra is hydrogen, Rb is acrylamide, Rc is alkyl or alkenyl, Rd is alkyl optionally substituted with one to three F, Cl or alkyloxy optionally further substituted with alkyloxy. 8. The compound of claim 7, wherein R1a is benzyl, phenyl, pyridinyl, pyrrolidinyl, cyclopentyl, cyclohexyl, cycloheptyl or piperidinyl; wherein benzyl is optionally substituted with one F; phenyl is optionally substituted with one or two F, Cl, –NRaRb, alkyl optionally substituted with three F, or alkyloxy optionally substituted with one to three F; pyridinyl is optionally substituted with alkyl optionally substituted with three F; pyrrolidinyl is substituted with alkyl, –C(=O)Rc or –C(=O)ORd; cyclopentyl, cyclohexyl and cycloheptyl is optionally substituted with one or two F or alkyl; and piperidinyl is optionally substituted with alkyl, – C(=O)Rc, or –C(=O)ORd; wherein Ra is hydrogen, Rb is acrylamide, Rc is alkyl or alkenyl, Rd is alkyl optionally substituted with one to three F or alkyloxy optionally further substituted with alkyloxy. 9. The compound of claim 3, wherein R is . 10. The compound of claim 9, wherein R2 is –OR3, –NHR4, –SR5, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aryl fused with heterocycloalkyl or cycloalkenyl, wherein each of alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl and cycloalkenyl is optionally substituted with one to three moieties selected from the group consisting of F, Cl, hydroxyl, cyano, –NReRf, –C(=O)Rg, –C(=O)ORh, –SO2Ri, –OSiRj, alkenyl, heterocycloalkyl, aryl optionally substituted with alkyl optionally substituted with one to three F, Cl or alkyloxy optionally substituted with one to three F, Cl, alkyl optionally substituted with one to three F, Cl, –NReRf or –ORk, and alkyloxy optionally substituted with one to four F, Cl, hydroxyl, – NReRf or alkyloxy optionally further substituted with alkyloxy, in which each of Re and Rf independently is hydrogen or alkyl optionally substituted with alkyloxy, each of Rg and Rh independently is hydrogen, alkyl or alkenyl, Ri is alkyl, Rj is alkyl, and Rk is hydrogen, aryl, or alkyl optionally substituted with alkyloxy optionally further substituted with alkyloxy; each of R3 and R5 independently is alkyl, cycloalkyl or aryl, wherein alkyl, cycloalkyl or aryl is optionally substituted with one to four moieties selected from the group consisting of F, Cl, alkyl optionally susbstituted with one to four F or Cl, alkyloxy optionally substituted with one to three F, Cl or alkyloxy, –NRlRm, and heterocycloalkyl, in which each of Rl and Rm independently is hydrogen or alkyl; and R4 is alkyl, cycloalkyl or –SO2Rn, in which Rn is hydrogen, alkyl or aryl, and each of alkyl or aryl is optionally substituted with one to three F or Cl. 11. The compound of claim 10, wherein R2 is –OR3, –NHR4, –SR5, styryl, phenylethnyl, cyclohexyl, cyclohexenyl, phenyl, benzodioxolyl, benzodioxinyl, benzofuranyl, furanyl, thiophenyl, xazolyl, imidazole, pyrazolyl, oxadiazolyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyrimidinyl, or pyridinyl, wherein styryl is optionally substituted with alkyl substituted with one to three F or alkoxy; phenylethynyl is optionally substituted with alkyl optionally substituted with one to three F or alkoxy optionally substituted with one to three F; cyclohexyl is optionally substituted with one to three alkyl; cyclohexenyl is optionally substituted with one to three alkyl; phenyl is optionally substituted with one to three moieties selected from the group consisting of F, Cl, cyano, dialkylamino, –C(=O)Rg, –C(=O)ORh, – SO2Ri, alkyl optionally substituted with one to three F, dialkylamin or alkyloxy, and alkyloxy optionally substituted with one to three F or alkyloxy optionally further substithted with alkyloxy; thiophenyl is optionally substituted with Cl or alkyl; xazolyl is optionally subsitiuted with one or two alkyl; pyrazolyl is optionally substituted with alkyl optionally substituted with one to three F; oxadiazolyl is optionally substituted with alkyl; azetidinyl is optionally substituted with one or two F or –OSiRj; pyrrolidinyl is optionally substituted with hydroxyl, cyano, alkenyl, – C(=O)ORh, one to two F, or alkyl optionally substituted with hydroxyl, phenoxy or alkyloxy optionally substituted with alkyloxy optionally further substituted with alkyloxy; piperidinyl is optionally substituted with alkyl, one or two F, –C(=O)Rg; morpholinyl is optionally substituted with one to three alkyl; piperazinyl is optionally substituted with alkyl; and pyridinyl is optionally substituted with one or two moieties selected from the group consisting of F, Cl, cyano, piperidinyl, morpholinyl, –NReRf, alkyl optionally substituted with three to four F, and alkyloxy optionally substituted with one to four F, hydroxyl, dialkylamino or alkyloxy optionally further substituted with alkyloxy; in which R e is alkyl, Rf is alkyl optionally substituted with alkyloxy, Rg is hydrogen, alkyl or alkenyl, Rh is hydrogen or alkyl, Ri is alkyl, and Rj is alkyl; R3 is phenyl, cycloalkyl or alkyl, wherein phenyl is optionally substituted with F, morpholinyl, alkyloxy optionally substituted with one to three F, or alkyl optionally substituted with one to three F; and alkyl is optionally substituted with one to four F, morpholinyl, dialkylamino, or alkyloxy optionally substituted with alkyloxy; R4 is alkyl, cycloalkyl or –SO2Rn, in which Rn is phenyl optionally subistuted with one to three Cl; and R5 is phenyl optionally substituted with Cl. 12. The compound of claim 3, wherein R2 is . 13. The compound of claim 12, wherein R is phenyl or morpholinyl, and phenyl is optionally substituted with alkyl or alkyloxy optionally substituted with one to three F. 14. The compound of claim 1, wherein , in which R1a is alkyl and R1b is hygrogen; R2 is styryl or phenyl, in which phenyl is substituted with alkyl substituted with one to three F or alkyloxy substituted with one to three F; and styryl is substituted with alkyl substituted with one to three F. (R1)n X X 2 1 X 15. The compound of claim 1, wherein 3 is , in which R1b is hygrogen, and R1a is phenyl optionally substituted with one or two F, Cl, acrylamido, alkyl optionally substituted with three F or alkyloxy optionally substituted with three F; R2 is –OR3, phenyl, benzodioxolyl, thiophenyl, pyrazolyl, pyrrolidinyl, pyrimidinyl, or pyridinyl, wherein phenyl is optionally substituted with one or two moieties selected from the group consisting of F, Cl, cyano, alkyl substituted with one to three F, and alkyloxy substituted with one to three F; pyrazolyl is optionally substituted with alkyl; pyrrolidinyl is substituted with –C(=O)ORh, one to two F, or alkyl substituted with hydroxyl, phenoxy or alkyloxy; pyridinyl is optionally substituted with one or two moieties selected from the group consisting of F, Cl, cyano, piperidinyl, alkyl, and alkyloxy optionally substituted with dialkylamino or alkyloxy optionally further substituted with alkyloxy; R3 is alkyl optionally substituted with dialkylamino; and Rh is alkyl. 16. The compound of claim 1, wherein , in which R1b is hygrogen, and R1a is pyridinyl substituted with alkyl substituted with one to three F; R2 is phenyl substituted with one or two F or Cl. 17. The compound of claim 1, wherein in which R1b is hygrogen, R1a is piperidinyl substituted with –C(=O)ORd, and Rd is alkyl; R2 is phenyl substituted with Cl or –C(=O)ORh, in which Rh is alkyl. 18. The compound of claim 1, wherein , in which R1b is hygrogen, and R1a is cyclohexyl optionally subsisuted with one or two F or alkyl; R2 is phenyl or pyridinyl, wherein phenyl is substituted with one or two F, Cl, or – C(=O)ORh, in which Rh is alkyl; and pyridinyl is substituted with F, Cl or alkyloxy. 19. The compound of claim 1, wherein which R1c and R1d are respectively alkyl. 20. The compound of claim 19, wherein R is , and R2 is phenyl, wherein phenyl is optionally substituted with F, alkyl optionally substituted with one to three F or alkyloxy optionally substituted with one to three F. 21. The compound of claim 1, wherein , in which R1e is alkyl. 22. The compound of claim 21, wherein R is , and R2 is phenyl optionally substituted with alkyl. 23. The compound of claim 1, wherein , in which R1f is alkyl or aryl optionally substituted with halogen or alkyl. 24. The compound of claim 23, wherein R1f is alkyl, R2 is , and R is phenyl, in which phenyl is optionally substituted with alkoxy optionally substituted with one to three F. 25. The compound of claim 23, wherein R1f is alkyl or phenyl optionally substituted with F or alkyl, R is , and R2 is –OR3, pyrrolidinyl or phenyl, in which pyrrolidinyl is optionally substituted with one or two F, phenyl is optionally substituted with one to three moieties selected from the group consisting of F, Cl dialkylamino, alkyl optionally substituted with one to three F, and alkoxy optionally substituted with one to three F, and R3 is phenyl optionally substituted with alkyl. 26. The compound of claim 1, wherein n which R1f is alkyl; R is ; and R2 is phenyl, in whicn phenyl is substituted with alkyl substituted with one to three F or alkyloxy substituted with one to three F. 27. The compound of claim 1, wherein in which R1g is cycloalkyl or heterocycloalkyl optionally substituted with –C(=O)ORd, and Rd is alkyl. 28. The compound of claim 27, wherein R1g is piperidinyl or cyclohexyl, R is , and R2 is phenyl optionally substituted with F or pyridinyl optionally substituted with F or alkyloxy. 29. The compound claim 1, wherein the compound is any one selected from the group consisting of Compounds 1-1 to 1-33, Compounds 2-1 to 2-8, Compounds 3-1 to 3-12, Compounds 4-1 to 4-22, Compounds 5-1 to 5-57, Compounds 6-1 to 6-145, Compounds 7-1 to 7-19, Compounds 8-1 to 8-16, Compounds 9-1 to 9-13 and Compounds 10-1 to 10-72. 30. The compound claim 1, wherein the compound is any one selected from the group consisting of compounds 1-4 to 1-5, compound 1-11, compound 1-22, compound 1-27, compound 4-2, compound 4-5, compound 5-6, compound 5-18, compounds 5-28 to 5-33, compound 5-35, compound 5-39, compound 5-40, compound 5-42, compound 5-44, compound 5-45, compound 5-47, compound 5-49, compound 5-56, compound 6-4, compound 6-11, compound 6-18, compound 6-19, compounds 6-24 to 6-28, compound 6-35, compound 6-36, compound 6-39, compound 6-43, compound 6-45, compound 6-46, compounds 6-50 to 6-54, compounds 6-57 to 6-58, compound 6-66, compound 6-69, compound 6-71, compound 6-75, compound 6-85, compounds 6-89 to 6-91, compound 6-104, compound 6-106, compound 6-108, compounds 6-110 to 6-112, compounds 6-114 to 6-121, compound 6-125, compounds 6-127 to 6-128, compound 6-130, compound 6-133, compound 6-135, compound 6-137, compound 7-1, compound 7-3, compound 7-6, compound 7-13, compound 7-19, compound 9-3, compound 9-5, compound 10-13, compound 10-14, compound 10-18, compound 10-23, compound 10-32, compound 10-40, compound 10-55, compound 10-57, and compound 10-64. 31. A pharmaceutical composition comprising: a compound of claim 1 or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. 32. A method for treating a cancer, comprising: administering to a subject in need thereof an effective amount of a compound of claim 1 or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof. 33. The method of claim 32, wherein the cancer is selected from the group consisting of gastric cancer, colon cancer, colorectal cancer, breast cancer, lung cancer, prostate cancer, bladder cancer, pancreatic cancer, liver cancer, uterine cancer, cervical caner, endometrial cancer, esophageal cancer, leukemia, lymphoma, kidney cancer, osteosarcoma, ovarian cancer, skin cancer, small intestine cancer, thymus cancer, thyroid cancer, nervous system cancers, bone cancer, brain cancer, and head and neck cancer. |
Experimental Procedure Step1: Cyclization To a solution of the 2,4,6-trichloropyrimidine-5-carbaldehyde (3.71 g, 17.5 mmol) dissolved in EtOH (50 ml) cooled to -78°C was added methyl hydrazine (0.93 ml, 17.5 mmol) and TEA (8 ml). The mixture was stirred for 30 minutes at -78°C, and then 2 hr at 0°C. The solution was concentrated in vacuum without heating. To the reduced volume solution EtOAc was added and the solution washed with a saturated NaHCO 3 solution and concentrated in vacuum without heating. Filtration over a small silica gel plug (2:1 = EtOAc:Hex) and concentration afforded the desired product 4,6-Dichloro-1-methyl- 1H-pyrazolo[3,4- d]pyrimidine as a yellow solid (2.84g, 80%). Step2: Amination To a suspension of 4,6-Dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (2.84g, 14 mmol) in the reaction flask and then add THF(56ml) to wait for the solid to dissolve completely. Then add 20g 30% ammonium solution and react at room temperature (25 °C) for 24h and poured 60ml water into the solution, filtration by suction to afford the 6-chloro-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-4-amine (2.17g, 85%) as a yellow solid powder. Step3: Suzuki coupling reaction To a suspension of 6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.84g, 10 mmol), 4-(tert-butyl)phenyl boronic acid (2.67 g, 15 mmol), Tetrakis (triphenylphosphine) palladium (0) (1.16g, 1 mmol), 1,4-dioxane (40 ml), water (2 ml) and aqueous Cesium carbonate solution (2.0 M, 20 ml, 40 mmol) in a 100 ml glass flask was deoxygenated using 6 alternate vacuum/Nitrogen flush cycles. The reaction mixture was heated to 100°C for 16 hrs. After cooling to room temperature, poured the Celite powder into the flask and stirred for 10min at room temperature then filter by suction and the filtrate was partitioned between ethyl acetate (80 ml) and saturated aqueous sodium bicarbonate solution (30 ml). The layers were separated and the organic layer was washed with brine (30 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-25% n-Hexanes/Ethyl acetate, linear gradient) to afford 6-(4-(tert-butyl)phenyl)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-4-amine (2.25g, 80%) as a yellow powder. Step4: Amidation reaction N-(6-(4-(tert-butyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrim idin-4-yl)-5-nitrothiophene-2- carboxamide formation by amidation of carbonyl acid To a solution of 6-(4-(tert-butyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidi n-4-amine (843mg, 3.00 mmol) in pyridine (6 ml), was added 5-nitrothiophene-2- carbonyl chloride (900 mg, 4.68 mmol). The reaction mixture was stirred at ambient temperature for 15 hr. Water was added and the product extracted with ethyl acetate. The organic layer was separated, dried (anhydrous sodium sulfate) and evaporated in vacuo. The product was purified by column chromatography on silica gel (hexane- ethyl acetate gradient eluent) and recrystallization with hexane and acetone to yield the title compound. Yield 980 mg (75%). N-(6-(4-(tert- butyl)phenyl)-1-methyl-1H -pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxami de as a yellow powder. Experimental Procedure Cyclization via condensation and closure ring reactions To a solution of the 2,4,6-trichloropyrimidine-5-carbaldehyde (3.7 g, 17.5 mmol) dissolved in 50 ml EtOH and cooled to 0°C by ice bath was added phenylhydrazine hydrochloride (2.53g, 17.5 mmol) and 8 ml TEA. The mixture was stirred for 30 minutes at 0°C and spontaneous to ambient temperature. The solution was concentrated in vacuum without heating. To the reduced volume solution EtOAc was added and the solution washed with a saturated NaHCO 3 solution and concentrated in vacuum without heating. Filtration over a small silica gel plug (EtOAc : Hex = 2:1) and concentration afforded the desired product 4,6-dichloro- 1-phenyl-1H-pyrazolo[3,4-d] pyrimidine as a yellow solid (3.94g, 85%).
*a: Use TEA or DIPEA as base N-C bond formation with Mitsunobu reaction Formation of tert-butyl 4-(6-chloro-4-((4-methoxybenzyl)amino)-1H-pyrazolo[3,4-d] pyrimidin- 1-yl)piperidine-1-carboxylate To a flame dried round bottom flask under N 2 was added 6-chloro-N-(4-methoxy benzyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-amine (4.35 g, 15 mmol), t-butyl 4-hydroxy-1- piperidinecarboxylate (3.96 g, 20 mmol), and PPh 3 (5.24g, 20mmol) in anhydrous tetrahydrofuran (175 ml). The mixture was cooled to 0°C and diisoproyl azodicarboxylate (DIAD) (4.0 ml, 20 mmol) in tetrahydrofuran (30 ml) was added dropwise. The mixture was allowed to warm to room temperature and stirred overnight. The reaction was then filtered and taken up in DCM. The insoluble material was filtered off. The filtrate was concentrated, taken up in DCM, and put in the freezer for 5 hr. The crystals that formed were filtered off and the filtrate was purified by silica gel chromatography (5-12% methanol/DCM) to give pure tert-butyl 4-(6- chloro-4-((4-methoxybenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidi n-1-yl)piperidine-1-carboxylate (4.78g, 70%). Suzuki coupling reaction Formation of 4-(6-(4-chlorophenyl)-4-((4-methoxybenzyl)amino)-1H-pyrazolo [3,4-d] pyrimidin- 1-yl)piperidine-1-carboxylate To a suspension solution of tert-butyl 4-(6-chloro-4-((4-methoxybenzyl)amino) -1H- pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (4.73g, 10 mmol), 4-chlorophenyl boronic acid (1.87g, 12 mmol), Tetrakis (triphenylphosphine) palladium (0) (1.16g, 1 mmol), 1,4-dioxane (100 ml), water (40 ml), and aqueous Cesium carbonate solution (1.0 M, 40 ml, 40 mmol) in a 100 ml glass flask was deoxygenated using 6 alternate vacuum/Nitrogen flush cycles. The reaction mixture was heated to 90°C for 16 hrs. After cooling to room temperature, poured the Celite powder into the flask and stirred for 10min at room temperature then filter by suction and the filtrate was partitioned between ethyl acetate (160 ml) and saturated aqueous sodium bicarbonate solution (80 ml). The layers were separated and the organic layer was washed with brine (80 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-35% n-Hexanes/Ethyl acetate, linear gradient) to afford tert-butyl 4-(6-(4-chloro phenyl)-4-((4-methoxybenzyl)amino)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (4.23g, 77%) as a yellow powder. Deprotection by DDQ Formation of tert-butyl 4-(4-amino-6-(4-chlorophenyl)-1H-pyrazolo[3,4-d] pyrimidin-1- yl)piperidine-1-carboxylate To a mixture of tert-butyl 4-(6-(4-chlorophenyl)-4-((4-methoxybenzyl)amino)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (4.12 g, 7.5mmol) and DDQ (2.04g, 9.0mmol) in the reaction flask, poured 125 ml DCM, 25 ml H 2 O, and stir overnight at room temperature. After the reaction is over, then add DCM and NaHCO 3 (aq) to extract, use DCM (150 ml x 3) to extract the water layer, use anhydrous MgSO 4 to remove water and use Celite to filter and concentrate, then use silica gel column chromatography (10% EA/DCM) to afford tert- butyl 4-(4-amino -6-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperid ine-1- carboxylate 2.54g (yield 79%) as a white solid. Deprotection by TFA Formation of (S)-6-(6-fluoropyridin-3-yl)-1-(pyrrolidin-3-yl)-1H-pyrazolo [3,4-d] pyrimidin-4- amine To a solution of tert-butyl (S)-3-(4-amino-6-(6-fluoropyridin-3-yl)-1H -pyrazolo[3,4- d]pyrimidin-1-yl)pyrrolidine-1-carboxylate (2.00g, 5mmol) in 20 ml DCM then added 5 ml TFA dropwised at room temperature for 1 h. After the reaction is judged by LCMS, concentrate to remove the solvent, add EA and adjusted to pH=11 by addition of 10% NaOH, use EA (100 ml x3) to extract the water layer, use anhydrous MgSO 4 to remove water from the collected organic layer, and filter it concentrate to obtain (S)-6-(6-fluoropyridin-3-yl)-1-(pyrrolidin-3 -yl)-1H- pyrazolo[3,4-d]pyrimidin-4-amine 1.28 g (86%) as yellow solid. Amidation with acyloyl chloride Formation of (S)-1-(3-(4-amino-6-(6-fluoropyridin-3-yl)-1H-pyrazolo[3,4-d ] pyrimidin-1- yl)pyrrolidin-1-yl)prop-2-en-1-one Add TEA (2.02 g, 20 mmol) and acryloyl chloride (1.00 g, 11 mmol) to a solution of (S)- 6-(6-fluoropyridin-3-yl)-1-(pyrrolidin-3-yl)-1H-pyrazolo [3,4-d]pyrimidin-4-amine (1.20 g, 4 mmol) in 50 ml THF at 0 °C by ice bath. stir the resulting mixture for 50 minutes and quench the mixture by 8 ml MeOH then extraction and concentrate the mixture and purify by silica gel column chromatography (0-10% MeOH in DCM) to obtain (S)-1-(3-(4-amino-6-(6 - fluoropyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrroli din-1-yl)prop-2-en-1-one 1.06g (75%) as pale yellow solid. Amination To a suspension solution of 4,6-Dichloro-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine (3.71 g, 14 mmol) in the reaction flask and then add 60ml THF to wait for the solid to dissolve completely. Then add 20g, 30% ammonium solution and react at room temperature (25 °C) for 24h. Poured 60ml water into the solution, filtration by suction to afford the 6-chloro- 1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-4-amine (2.93g, 85%) as a yellow solid powder. N-Alkylation 6-(3,3-difluoropyrrolidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-d]p yrimidin-4-amine formation A suspension solution of 6-chloro-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2.46 g, 10 mmol), 3,3-Difluoropyrrolidine hydrochloride (2.15 g, 15 mmol), 1,4-dioxane (50 ml), Cesium carbonate (13.03g, 40 mmol) in a 100 ml glass flask. The reaction mixture was heated to 100°C for 16 hrs. then cooling to ambient temperature, and filter by suction and the filtrate was removed and extract with ethyl acetate (60 ml) three time. The layers were separated and the organic layer was washed with brine (30 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (n-Hexanes/0-30% Ethyl acetate, linear gradient) to afford 6-(3,3-difluoropyrrolidin-1-yl)-1- phenyl-1H-pyrazolo[3,4-d] pyrimidin-4-amine (2.66 g, 83%) as a pale yellow powder. Amidation N-(6-(3,3-difluoropyrrolidin-1-yl)-1-phenyl-1H-pyrazolo[3,4- d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide formation by amidation of carbonyl acid To a solution of 6-(3,3-difluoropyrrolidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-d]p yrimidin - 4-amine (948mg, 3.00 mmol) and triethyamine(2.06 ml) in 30ml THF, was added 5- nitrothiophene-2-carbonyl chloride (900 mg, 4.68 mmol). The reaction mixture was stirred at ambient temperature for 15 hr. Water was added and the product extracted with ethyl acetate. The organic layer was separated, dried (anhydrous sodium sulfate) and evaporated in vacuo. The product was purified by column chromatography on silica gel (hexane-ethyl acetate gradient) and recrystallization (DCM and MeOH) to yield the title compound. Yield 1060 mg (75%) N-(6-(4- (tert-butyl)phenyl)-1-methyl-1H-pyrazolo [3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2- carboxamide as a yellow powder. Alkoxylation 6-(4-fluorophenoxy)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-a mine formation To a suspension solution of 6-chloro-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin- 4-amine (2.46 g, 10 mmol), 4-fluorophenol (1.68g, 15 mmol), 1,4-dioxane (50 ml), Cesium carbonate (13.03g, 40 mmol) in a 100 ml glass flask. The reaction mixture was heated to 100°C for 16 hrs. After cooling to room temperature, then filter by suction and the filtrate was removed and extract with ethyl acetate (60 ml*3). The layers were separated and the organic layer was washed with brine (30 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (n-Hexanes/0-25% Ethyl acetate, linear gradient) to afford 6-(4-fluorophenoxy) -1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2.60g, 81%) as a pale yellow powder. Amidation N-(6-(4-fluorophenoxy)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin- 4-yl)-5-nitrothiophene-2- carboxamide formation by amidation of carbonyl acid To a solution of 6-(3,3-difluoropyrrolidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-d]p yrimidin- 4-amine (948mg, 3.00 mmol) and triethyamine(2.06 ml) in 30ml THF, was added 5- nitrothiophene-2- carbonyl chloride (900 mg, 4.68 mmol). The reaction mixture was stirred at ambient temperature for 15 hr. Water was added and the product extracted with ethyl acetate. The organic layer was separated, dried (anhydrous sodium sulfate) and evaporated in vacuo. The product was purified by column chromatography on silica gel (hexane-ethyl acetate gradient eluent) and recrystallization with DCM and MeOH to yield the title compound. Yield 1100 mg (77%) N-(6-(4-fluorophenoxy)-1-phenyl-1H-pyrazolo [3,4-d]pyrimidin-4-yl)-5-nitrothiophene- 2-carboxamide formation as a yellow powder. Experimental Procedure To a solution of the 2,4,6-trichloropyrimidine-5-carbaldehyde (3.7 g, 17.5 mmol) dissolved in EtOH (50 ml) cooled to -78°C. was added methyl hydrazine (0.93 ml, 17.5 mmol) and TEA (8 ml). The mixture was stirred for 30 minutes at -78°C. then 2 hr at 0°C. The solution was concentrated in vacuum without heating. To the reduced volume solution EtOAc was added and the solution washed with a saturated NaHCO 3 solution and concentrated in vacuum without heating. Filtration over a small silica gel plug (2:1 EtOAc:Hex) and concentration afforded the desired product.4,6-Dichloro-1-methyl- 1H-pyrazolo[3,4-d]pyrimidine as a yellow solid (2.84g, 80% ) 4-(4-(tert-butyl)phenyl)-6-chloro-1-methyl-1H-pyrazolo[3,4-d ]pyrimidine formation Suzuki coupling reaction A suspension of 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (2.03g, 10 mmol), 4-(tert-butyl)phenyl boronic acid (2.67 g, 15 mmol), Tetrakis (triphenylphosphine) palladium (0) (1.16g, 1 mmol), 1,4-dioxane (40 ml), water (2 ml), and aqueous Cesium carbonate solution (2.0 M, 20 ml, 40 mmol) in a 100 mL glass flask was deoxygenated using 5 alternate vacuum/Nitrogen flush cycles. The reaction mixture was heated to 90°C for 15 hrs. After cooling to room temperature, poured the Celite powder into the flask and stirred for 10min at room temperature then filter by suction and the filtrate was partitioned between ethyl acetate (80 ml) and saturated aqueous sodium bicarbonate solution (30 ml). The layers were separated and the organic layer was washed with brine (30 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-25% n-Hexanes/Ethyl acetate, linear gradient) to afford 4-(4-(tert-butyl)phenyl)-6-chloro-1- methyl-1H-pyrazolo[3,4-d]pyrimidine (2.55g, 85%) as a yellow powder. 4-(4-(tert-butyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidi n-6-amine Amination To a suspension of 4,6-Dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (2.11g, 7 mmol) in the reaction flask and then add 32ml THF to wait for the solid to dissolve completely. Then add 10g, 30% ammonium solution and react at room temperature (25 °C) for 24h. Poured 60ml water into the solution, filtration by suction to afford the 4-(4-(tert-butyl)phenyl)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-amine (1.58g, 80%) as a yellow solid powder. Amidation N-(4-(4-(tert-butyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrim idin-6-yl)-5-nitrothiophene-2- carboxamide formation by amidation of carbonyl acid To a solution of 4-(4-(tert-butyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidi n -6-amine (843mg, 3.00 mmol) in pyridine (6 ml), was added 5-nitrothiophene-2- carbonyl chloride (900 mg, 4.68 mmol). The reaction mixture was stirred at ambient temperature for 15 hr. Water was added and the product extracted with ethyl acetate. The organic layer was separated, dried (anhydrous sodium sulfate) and evaporated in vacuo. The product was purified by column chromatography on silica gel (hexane- ethyl acetate gradient) and recrystallization (hexane and acetone) to yield the title compound. Yield 1021 mg (78%) N-(4-(4-(tert-butyl)phenyl)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-5-nitrothiophene-2- carboxamide as a yellow powder. Evaluation of compounds of formula (I) in in vitro MTS assays The cell viability measurement is based on the NCI-60 screening methodology (Nat. Rev. Cancer 6, 813–823, 2006). Briefly, cells are inoculated into 96-well plates at the optimal plating density. After 24 h, one of the two plates for Hep3B cell line is processed to determine a time zero cell viability (Tz) by MTS assay (Promega). Compounds are added over a 2-fold serial dilution to provide a total five drug concentrations plus DMSO control. Plates are incubated for a further 2 days, then measured cell viability by MTS assay [control growth (C) and test growth in the presence of drug at the five concentration levels (Ti)]. The LC 50 is calculated from [(Ti- Tz)/Tz] x 100 = -50, which is the drug concentration resulting in a 50% reduction at the end of the drug treatment as compared to that at the beginning. The compounds prepared in Tables 1-10 were tested in three in vitro assays, and the results are shown in Tables 1-10 for Hep3B and Table 11 for SW480 and NCI-H460 shown below. Herein, Hep3B refers to hepatocellular carcinoma cell line, SW480 refers to colon adenocarcinoma cell line, and NCI-H460 refers to human lung cancer cell line. In the compounds shown in Tables 1 to 10, the detail synthesized procedures of some compounds are not repeated again if the synthesized procedures thereof are similar to those of the forgoing compounds. Shown in following Tables 1 to10 are the structures and in vitro activities of exemplary compounds of formula (I). Most of the disclosed compounds were found to inhibit the growth of Hep3B cells (hepatocellular carcinoma cell line). Table 1 Compound 1-1 N-(6-(4-(tert-butyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrim idin-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, CDCl 3 ): δ 15.33 (br. s., 1H), 8.36 (br. s., 1H), 8.13-8.26 (m, 2H), 7.90 (d, J = 4.4 Hz, 1H), 7.77 (d, J = 4.4 Hz, 1H), 7.58 (d, J = 8.3 Hz, 2H), 4.13 (s, 3H), 1.37 (s, 9H). MS(M+1):437. Compound 1-2 N-(6-(4-ethoxyphenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4 -yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.82 (br. s., 1H), 8.43-8.54 (m, J = 8.8 Hz, 2H), 8.30-8.40 (m, 2H), 8.24 (d, J = 4.4 Hz, 1H), 7.02-7.13 (m, 2H), 4.13 (q, J = 7.2 Hz, 2H), 4.07 (s, 3H), 1.37 (t, J = 6.8 Hz, 3H). MS(M+1):425. Compound 1-3 N-(6-(benzofuran-2-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin- 4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.18 (br. s., 1H), 8.29-8.41 (m, 2H), 8.24 (d, J = 4.4 Hz, 1H), 7.79-7.89 (m, 2H), 7.76 (d, J = 7.8 Hz, 1H), 7.47 (t, J = 7.8 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 4.10 (s, 3H). MS(M+1):421. Compound 1-4 N-(1-methyl-6-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-d] pyrimidin-4-yl)-5-nitrothiophene- 2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.99 (br. s., 1H), 8.69-8.77 (m, J = 8.3 Hz, 2H), 8.40 (s, 1H), 8.36 (d, J = 4.4 Hz, 1H), 8.24 (d, J = 4.4 Hz, 1H), 7.89-7.99 (m, J = 8.3 Hz, 2H), 4.11 (s, 3H). MS(M+1):449. Compound 1-5 N-(1-methyl-6-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-d ]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.94 (br. s., 1H), 8.57-8.68 (m, 2H), 8.32-8.41 (m, 2H), 8.24 (d, J = 4.4 Hz, 1H), 7.50-7.61 (m, J = 8.3 Hz, 2H), 4.09 (s, 3H). MS(M+1) :465 Compound 1-6 N-(1-methyl-6-(3-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-d ]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.85 (br. s., 1H), 8.55 (d, J = 7.8 Hz, 1H), 8.42 (s, 1H), 8.38 (s, 1H), 8.34 (d, J = 4.4 Hz, 1H), 8.23 (d, J = 4.4 Hz, 1H), 7.71 (t, J = 8.1 Hz, 1H), 7.55-7.60 (m, 1H), 4.08 (s, 3H).MS(M+1):465. Compound 1-7 N-(6-(4-(tert-butoxy)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyri midin-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.88 (br. s., 1H), 8.41-8.50 (m, J = 8.8 Hz, 2H), 8.32-8.40 (m, 2H), 8.24 (d, J = 4.4 Hz, 1H), 7.08-7.19 (m, 2H), 4.08 (s, 3H), 1.39 (s, 9H). MS(M+1):453. Compound 1-8 N-(1-methyl-6-(2-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-d ]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.09 (br. s., 1H), 8.43 (s, 1H), 8.34 (d, J = 4.4 Hz, 1H), 8.22 (d, J = 4.4 Hz, 1H), 8.13 (dd, J = 7.8, 2.0 Hz, 1H), 7.64-7.72 (m, 1H), 7.48-7.64 (m, 2H), 4.05 (s, 3H). MS(M+1):465. Compound 1-9 N-(1-methyl-6-(4-(tert-pentyl)phenyl)-1H-pyrazolo[3,4-d]pyri midin-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.93 (br. s., 1H), 8.46 (d, J = 8.3 Hz, 2H), 8.31-8.43 (m, 2H), 8.25 (d, J = 4.4 Hz, 1H), 7.52 (d, J = 8.3 Hz, 2H), 4.09 (s, 3H), 1.60-1.76 (m, 2H), 1.31 (s, 6H), 0.66 (t, J = 7.3 Hz, 3H). MS(M+1):451. Compound 1-10 N-(6-(4-(dimethylamino)phenyl)-1-methyl-1H-pyrazolo[3,4-d]py rimidin-4-yl)-5-nitrothiophene- 2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.73 (s, 1H), 8.32-8.45 (m, 3H), 8.27 (s, 1H), 8.24 (d, J = 4.4 Hz, 1H), 6.82 (d, J = 8.8 Hz, 2H), 4.04 (s, 3H), 3.03 (s, 6H). MS(M+1): 424. Compound 1-11 (E)-N-(1-methyl-6-(4-(trifluoromethyl)styryl)-1H-pyrazolo[3, 4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.98 (br. s., 1H), 8.28-8.38 (m, 2H), 8.20 (d, J = 4.4 Hz, 1H), 8.07 (d, J = 16.1 Hz, 1H), 7.89-7.98 (m, J = 8.3 Hz, 2H), 7.72-7.80 (m, J = 8.3 Hz, 2H), 7.41 (d, J = 16.1 Hz, 1H), 4.03 (s, 3H). MS(M+1):475. Compound 1-12 (E)-N-(6-(4-methoxystyryl)-1-methyl-1H-pyrazolo[3,4-d]pyrimi din-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.92 (br. s., 1H), 8.32 (s, 2H), 8.22 (d, J = 4.4 Hz, 1H), 8.03 (d, J = 16.1 Hz, 1H), 7.60-7.73 (m, 2H), 7.16 (d, J = 16.1 Hz, 1H), 6.88 - 7.08 (m, 2H), 4.03 (s, 3H), 3.81 (s, 3H). MS(M+1):437. Compound 1-13 N-(1-methyl-6-((4-(trifluoromethyl)phenyl)ethynyl)-1H-pyrazo lo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ):δ 12.28 (s, 1H), 8.40 (s, 1H), 8.34 (d, J = 4.4 Hz, 1H), 8.18 (d, J = 4.4 Hz, 1H), 7.72-7.92 (m, 4H), 4.03 (s, 3H). MS(M+1):473. Compound 1-14 N-(1-methyl-6-((4-(trifluoromethoxy)phenyl)ethynyl)-1H-pyraz olo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ):δ 12.32 (br. s., 1H), 8.42 (s, 1H), 8.35 (d, J = 4.4 Hz, 1H), 8.21 (d, J = 4.4 Hz, 1H), 7.77-7.86 (m, 2H), 7.49 (d, J = 7.8 Hz, 2H), 4.05 (s, 3H). MS(M+1):489. Compound 1-15 N-(1-methyl-6-phenoxy-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-ni trothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.17 (s, 1H), 8.31-8.34 (m, 2H), 8.21 (d, J = 4.4 Hz, 1H), 7.43-7.50 (m, 2H), 7.24-7.32 (m, 3H), 3.80 (s, 3H). MS (M+1) : 397. Compound 1-16 N-(6-(4-fluorophenoxy)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin- 4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.14 (s, 1H), 8.29-8.33 (m, 2H), 8.20 (d, J = 4.9 Hz, 1H), 7.24-7.38 (m, 5H), 3.79 (s, 3H). MS (M+1) : 415. Compound 1-17 N-(1-methyl-6-(4-(trifluoromethoxy)phenoxy)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.15 (s, 1H), 8.33 (s, 1H), 8.31 (d, J = 4.9 Hz, 1H), 8.20 (d, J = 4.4 Hz, 1H), 7.46 (s, 4H), 3.81 (s, 3H). MS (M+1): 481. Compound 1-18 N-(1-methyl-6-(3-(trifluoromethyl)phenoxy)-1H-pyrazolo[3,4-d ]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.20 (s, 1H), 8.34 (s, 1H), 8.31 (d, J = 4.9 Hz, 1H), 8.21 (d, J = 4.4 Hz, 1H), 7.62-7.77 (m, 4H), 3.80 (s, 3H). MS (M+1) : 465. Compound 1-19 N-(6-(2-(dimethylamino)ethoxy)-1-methyl-1H-pyrazolo[3,4-d]py rimidin-4-yl)-5-nitrothiophene- 2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 8.28-8.33 (m, 2H), 8.22 (d, J = 4.4 Hz, 1H), 4.71-4.79 (m, 2H), 3.95 (s, 3H), 3.52-3.60 (m, 2H), 2.87 (s, 6H). MS (M+1) : 392. Compound 1-20 N-(1-methyl-6-(4-morpholinophenoxy)-1H-pyrazolo[3,4-d]pyrimi din-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.12 (br. s., 1H), 8.31 (d, J = 4.4 Hz, 1H), 8.30 (s, 1H), 8.20 (d, J = 4.4 Hz, 1H), 7.12-7.19 (m, J = 9.3 Hz, 2H), 6.96-7.03 (m, J = 9.3 Hz, 2H), 3.80 (s, 3H), 3.72-3.78 (m, 4H), 3.08-3.15 (m, 4H). MS (M+1) : 482. Compound 1-21 N-(1-methyl-6-morpholino-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5 -nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.36 (br. s., 1H), 8.27 (d, J = 4.4 Hz, 1H), 8.20 (d, J = 4.4 Hz, 1H), 8.07 (s, 1H), 3.77-3.88 (m, 7H), 3.66-3.72 (m, 4H). MS(M+1):390. Compound 1-22 N-(1-isopropyl-6-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3, 4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.94 (s, 1H), 8.53-8.74 (m, 2H), 8.34-8.50 (m, 2H), 8.24 (d, J = 4.4 Hz, 1H), 7.57 (d, J = 7.8 Hz, 2H), 5.13-5.43 (m, 1H), 1.55 (d, J = 6.8 Hz, 6H). MS(M+1):493. Compound 1-23 N-(6-(4-(tert-butyl)phenyl)-1-isopropyl-1H-pyrazolo[3,4-d]py rimidin-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.90 (s, 1H), 8.43-8.53 (m, J = 8.3 Hz, 2H), 8.31-8.43 (m, 2H), 8.25 (d, J = 4.4 Hz, 1H), 7.47-7.67 (m, J = 8.3 Hz, 2H), 5.18-5.37 (m, 1H), 1.56 (d, J = 6.8 Hz, 6H), 1.35 (s, 9H). MS(M+1):465. Compound 1-24 N-(1-isopropyl-6-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4 -d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.95 (s, 1H), 8.62-8.78 (m, J = 8.3 Hz, 2H), 8.30-8.44 (m, 2H), 8.22 (d, J = 4.4 Hz, 1H), 7.86-7.99 (m, J = 8.3 Hz, 2H), 5.29 (quin, J = 6.7 Hz, 1H), 1.56 (d, J = 6.8 Hz, 6H). MS(M+1):477. Compound 1-25 N-(1-(tert-butyl)-6-(4-(tert-butyl)phenyl)-1H-pyrazolo[3,4-d ]pyrimidin-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.91 (br. s., 1H), 8.36-8.58 (m, J = 8.3 Hz, 2H), 8.17-8.36 (m, 3H), 7.51-7.76 (m, J = 8.3 Hz, 2H), 1.84 (s, 9H), 1.35 (s, 9H). MS(M+1):479. Compound 1-26 N-(1-(tert-butyl)-6-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[ 3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.95 (s, 1H), 8.59-8.76 (m, J = 7.8 Hz, 2H), 8.29-8.42 (m, 2H), 8.23 (d, J = 4.4 Hz, 1H), 7.87-8.11 (m, J = 8.3 Hz, 2H), 1.84 (s, 9H). MS(M+1): 491. Compound 1-27 N-(1-(tert-butyl)-6-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo [3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.87 (br. s., 1H), 8.59 (d, J = 8.8 Hz, 2H), 8.34 (d, J = 4.4 Hz, 1H), 8.29 (d, J = 1.5 Hz, 1H), 8.18-8.24 (m, 1H), 7.50-7.60 (m, 2H), 1.82 (s, 9H). MS(M+1):507. Compound 1-28 N-(1-(2-hydroxyethyl)-6-(4-(trifluoromethoxy)phenyl)-1H-pyra zolo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.95 (br. s., 1H), 8.59-8.69 (m, 2H), 8.41 (s, 1H), 8.37 (d, J = 4.4 Hz, 1H), 8.25 (d, J = 4.4 Hz, 1H), 7.57 (d, J = 7.8 Hz, 2H), 4.90 (t, J = 5.6 Hz, 1H), 4.55 (t, J = 5.6 Hz, 2H), 3.92 (d, J = 5.9 Hz, 2H). MS(M+1):495. Compound 1-29 N-(1-(2-cyanoethyl)-6-(4-(trifluoromethoxy)phenyl)-1H-pyrazo lo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.01 (br. s., 1H), 8.57-8.73 (m, 2H), 8.47 (s, 1H), 8.37 (d, J = 4.9 Hz, 1H), 8.25 (d, J = 4.4 Hz, 1H), 7.49-7.64 (m, J = 8.3 Hz, 2H), 4.71-4.83 (m, 2H), 3.25 (t, J = 6.4 Hz, 2H). MS(M+1):504. Compound 1-30 N-(1-(2-morpholinoethyl)-6-(4-(trifluoromethoxy)phenyl)-1H-p yrazolo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ):δ 11.95 (br. s., 1H), 8.57-8.68 (m, 2H), 8.40 (s, 1H), 8.36 (d, J = 4.4 Hz, 1H), 8.25 (d, J = 4.9 Hz, 1H), 7.46-7.64 (m, J = 8.3 Hz, 2H), 4.64 (t, J = 6.1 Hz, 2H), 3.37-3.50 (m, 4H), 2.84 (t, J = 6.1 Hz, 2H), 2.45-2.55 (m, 4H). MS(M+1):564 Compound 1-31 N-(1-(2-(dimethylamino)ethyl)-6-(4-(trifluoromethoxy)phenyl) -1H-pyrazolo[3,4-d]pyrimidin-4- yl)-5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ):δ 12.08 (br. s., 1H), 10.38 (br. s., 1H), 8.61-8.78 (m, 2H), 8.47- 8.58 (m, 1H), 8.37-8.47 (m, 1H), 8.26 (d, J = 4.4 Hz, 1H), 7.58 (d, J = 7.8 Hz, 2H), 4.95 (t, J = 6.1 Hz, 2H), 3.71 (t, J = 6.1 Hz, 2H), 2.87 (s, 6H).MS(M+1):558. Compound 1-32 N-(1-(2-(3,3-difluoropyrrolidin-1-yl)ethyl)-6-(4-(trifluorom ethoxy)phenyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ):δ 11.95 (br. s., 1H), 8.54-8.73 (m, 2H), 8.41 (s, 1H), 8.36 (d, J = 4.4 Hz, 1H), 8.25 (d, J = 4.4 Hz, 1H), 7.50-7.61 (m, 2H), 4.62 (t, J = 6.1 Hz, 2H), 2.92-3.06 (m, 4H), 2.77 (t, J = 7.1 Hz, 2H), 2.01-2.19 (m, 2H). MS(M+1):584. Compound 1-33 N-(1-(2-(2-ethoxyethoxy)ethyl)-6-(4-fluorophenyl)-1H-pyrazol o[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.86 (s, 1H), 8.58-8.54 (m, 2H), 8.38-8.34 (m, 2H), 8.22 (d, J = 4.4 Hz, 1H), 7.38 (t, J = 8.8 Hz, 2H), 4.64 (t, J = 5.6 Hz, 2H), 3.95 (t, J = 5.6 Hz, 2H), 3.54- 3.51 (m, 2H), 3.35-3.32 (m, 2H), 3.25 (q, J = 6.8 Hz, 2H), 0.93 (t, J = 6.8 Hz, 3H). MS(M+1): 501. Yellow solid. Table 2 Compound 2-1 N-(4-(4-(tert-butyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrim idin-6-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.66 (s, 1H), 8.66 (s, 1H), 8.27-8.35 (m, 2H), 8.17-8.27 (m, 2H), 7.61-7.70 (m, 2H), 4.04 (s, 3H), 1.36 (s, 9H). MS(M+1):437. Compound 2-2 N-(1-methyl-4-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-d ]pyrimidin-6-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.72 (s, 1H), 8.69 (s, 1H), 8.43-8.52 (m, 2H), 8.17-8.28 (m, 2H), 7.57-7.67 (m, J = 8.3 Hz, 2H), 4.04 (s, 3H). MS(M+1):465. Compound 2-3 N-(1-isopropyl-4-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3, 4-d]pyrimidin-6-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.71 (s, 1H), 8.68 (s, 1H), 8.37-8.57 (m, 2H), 8.11-8.29 (m, 2H), 7.51-7.71 (m, 2H), 5.01-5.24 (m, 1H), 1.54 (d, J = 6.8 Hz, 6H). MS(M+1):493. Compound 2-4 N-(1-(tert-butyl)-4-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo [3,4-d]pyrimidin-6-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.63 (s, 1H), 8.58 (s, 1H), 8.42 (d, J = 8.8 Hz, 2H), 8.14-8.34 (m, 2H), 7.63 (d, J = 7.8 Hz, 2H), 1.80 (s, 9H). MS(M+1):507. Compound 2-5 N-(1-(tert-butyl)-4-(4-(tert-butyl)phenyl)-1H-pyrazolo[3,4-d ]pyrimidin-6-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.58 (s, 1H), 8.55 (s, 1H), 8.11-8.32 (m, 4H), 7.57-7.72 (m, 2H), 1.80 (s, 9H), 1.36 (s, 9H). MS(M+1):479. Compound 2-6 N-(1-methyl-4-morpholino-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-5 -nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.10 (s, 1H), 8.25 (s, 1H), 8.16 (d, J = 3.4 Hz, 2H), 3.93 (d, J = 4.9 Hz, 4H), 3.88 (s, 3H), 3.68-3.78 (m, 4H). MS(M+1):390. Compound 2-7 N-(7-methyl-4-(3-(trifluoromethoxy)phenyl)thieno[3,2-d]pyrim idin-2-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.73 (br. s., 1H), 8.27 (d, J = 1.5 Hz, 1H), 8.18-8.26 (m, 3H), 8.14 (s, 1H), 7.84 (t, J = 8.1 Hz, 1H), 7.63-7.73 (m, 1H), 2.47 (d, J = 1.0 Hz, 3H). MS(M+1): 481. Compound 2-8 N-(7-methyl-4-(4-(trifluoromethoxy)phenyl)thieno[3,2-d]pyrim idin-2-yl)-5-nitrothiop hene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.74 (br. s., 1H), 8.31-8.38 (m, 2H), 8.27 (d, J = 1.0 Hz, 1H), 8.22 (q, J = 4.4 Hz, 2H), 7.69 (d, J = 7.8 Hz, 2H), 2.47 (d, J = 1.0 Hz, 3H), MS(M+1): 481. Table 3 Compound 3-1 N-(1,3-dimethyl-5-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4, 3-d]pyrimidin-7-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.89 (br. s., 1H), 8.61 (br. s., 2H), 8.07-8.26 (m, 2H), 7.91 (d, J = 7.8 Hz, 2H), 4.20 (s, 3H), 2.72 (s, 3H). MS(M+1): 463. Compound 3-2 N-(1,3-dimethyl-5-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4, 3-d]pyrimidin-7-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.91 (br. s., 1H), 8.69 (br. s., 2H), 8.10-8.35 (m, 2H), 7.87 (d, J = 7.8 Hz, 1H), 7.79 (t, J = 7.8 Hz, 1H), 4.19 (s, 3H), 2.72 (s, 3H). MS(M+1): 463. Compound 3-3 N-(1,3-dimethyl-5-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[4 ,3-d]pyrimidin-7-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.87 (br. s., 1H), 8.50 (br. s., 2H), 8.04-8.29 (m, 2H), 7.53 (d, J = 7.8 Hz, 2H), 4.18 (s, 3H), 2.70 (s, 3H). MS(M+1): 479. Compound 3-4 N-(1,3-dimethyl-5-(3-(trifluoromethoxy)phenyl)-1H-pyrazolo[4 ,3-d]pyrimidin-7-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.84 (br. s., 1H), 8.46 (br. s., 1H), 8.30 (br. s., 1H), 8.06-8.26 (m, 2H), 7.68 (t, J = 7.6 Hz, 1H), 7.50 (d, J = 6.8 Hz, 1H), 4.19 (s, 3H), 2.71 (s, 3H). MS(M+1): 479. Compound 3-5 N-(1-methyl-3-propyl-5-(4-(trifluoromethoxy)phenyl)-1H-pyraz olo[4,3-d]pyrimidin-7-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ):δ8.42 (d, J = 7.3 Hz, 2H), 8.21 (d, J = 4.4 Hz, 1H), 8.02 (br. s., 1H), 7.57 (d, J = 8.8 Hz, 2H), 4.20 (br. s., 3H), 2.97 (t, J = 7.3 Hz, 2H), 1.87 (dq, J = 14.8, 7.6 Hz, 2H), 1.00 (t, J = 7.3 Hz, 3H). MS(M+1): 507. Compound 3-6 N-(1-methyl-3-propyl-5-(4-(trifluoromethyl)phenyl)-1H-pyrazo lo[4,3-d]pyrimidin-7-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ):δ 12.13 (br. s., 1H), 8.54 (br. s., 2H), 8.25 (d, J = 4.4 Hz, 1H), 8.13 (br. s., 1H), 7.96 (d, J = 8.3 Hz, 2H), 4.16 (br. s., 3H), 3.00 (t, J = 7.3 Hz, 2H), 2.00-1.80 (m, 2H), 1.01 (t, J = 7.3 Hz, 3H). MS(M+1): 491. Compound 3-7 N-(5-(4-(tert-butyl)phenyl)-1-methyl-3-propyl-1H-pyrazolo[4, 3-d]pyrimidin-7-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ):δ 8.21 (br. s., 2H), 8.05-8.17 (m, 1H), 7.75 (s, 1H), 7.56 (br. s., 2H), 4.26 (br. s., 3H), 2.91 (t, J = 7.3 Hz, 2H), 1.77-1.94 (m, 2H), 1.34 (s, 9H), 0.99 (t, J = 7.3 Hz, 3H). MS(M+1): 479. Compound 3-8 N-(1-methyl-5-phenyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7- yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 8.26 (br. s., 2H), 8.01-8.22 (m, 1H), 7.92 (br. s., 1H), 7.58 (d, J = 6.8 Hz, 3H), 4.27 (br. s., 3H), 2.95 (t, J = 7.6 Hz, 2H), 1.86 (sxt, J = 7.5 Hz, 2H), 0.99 (t, J = 7.3 Hz, 3H). MS(M+1): 423. Yellow solid. Compound 3-9 N-(5-(4-fluorophenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]py rimidin-7-yl)-5-nitrothiophene- 2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 8.31 (br. s., 2H), 8.22 (d, J = 4.4 Hz, 1H), 8.03 (br. s., 1H), 7.44 (br. s., 2H), 4.22 (br. s., 3H), 2.96 (t, J = 7.3 Hz, 2H), 1.86 (sxt, J = 7.3 Hz, 2H), 1.00 (t, J = 7.3 Hz, 3H). MS(M+1): 441. Yellow solid. Compound 3-10 N-(2-(4-(tert-butyl)phenyl)-6-methyl-6H-pyrrolo[3,4-d]pyrimi din-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 8.07-8.13 (m, J = 7.8 Hz, 2H), 8.05 (d, J = 4.4 Hz, 1H), 7.89 (d, J = 2.0 Hz, 1H), 7.85 (br. s., 1H), 7.66-7.73 (m, J = 8.3 Hz, 2H), 7.43 (d, J = 2.0 Hz, 1H), 4.14 (s, 3H), 1.40 (s, 9H). MS (M+1) : 436. Pale yellow solid. Compound 3-11 N-(2-(4-(tert-butyl)phenyl)-6-ethyl-6H-pyrrolo[3,4-d]pyrimid in-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 14.36 (br. s., 1H), 8.24 (s, 1H), 8.13 (br. s., 1H), 7.88-8.08 (m, 2H), 7.80 (br. s., 1H), 7.44-7.73 (m, 3H), 4.30 (d, J = 6.8 Hz, 2H), 1.49 (t, J = 7.1 Hz, 3H), 1.23- 1.41 (m, 9H). MS(M+1):450. Yellow solid. Compound 3-12 N-(2-(4-(tert-butyl)phenyl)-6-isopropyl-6H-pyrrolo[3,4-d]pyr imidin-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 14.24 (s, 1H), 8.17 (d, J = 4.4 Hz, 1H), 8.07 (br. s., 2H), 7.99 (br. s., 1H), 7.94 (br. s., 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.62 (d, J = 8.3 Hz, 2H), 4.71 (quin, J = 6.6 Hz, 1H), 1.56 (d, J = 6.4 Hz, 6H), 1.34 (s, 9H). MS(M+1): 464. Yellow solid. Table 4
Synthesis of 2-choloro-7-methylthieno[3,2-d]pyrimidin-4-amine Synthesis of 2-chloro-7-methylthieno[3,2-d]pyrimidin-4-amine by three steps To a solution of methyl 3-amino-4-methylthiophene-2-carboxylate(20.6 g, 120mmol) was added 36 g (600 mmol) of urea, and the resulting mixture was heated at 200 oC for 1.5 hours. The mixture was allowed to resume room temperature, and DMF (360 ml) was added thereto, followed by heating under reflux for one hour. After completion of the reaction, ice water was added to the reaction mixture, and crystals thus precipitated were filtered to give (19.8 g, 90%) of 7-methylthieno[3,2-d]-pyrimidine-2,4(1H,3H)-dione. To a solution of 7-methylthieno[3,2-d]-pyrimidine-2,4(1H,3H)-dione (18.3 g, 100 mmol) were added 153.0 g (1 mol) of phosphorus oxychloride and the resulting mixture was subjected to heating under reflux for 8 hours. After completion of the reaction, ice water was added to the reaction mixture, and crystals thus precipitated were filtered to give (15.4 g, 70 %) of 2,4- dichloro-7-methylthieno[3,2-d]pyrimidine. To a suspension solution of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine (8.8 g, 40 mmol) in the reaction flask and then add 100ml THF to wait for the solid to dissolve completely. Then add 100g, 30% ammonium solution and react at room temperature for 24h. Poured 60ml water into the solution, filtration by suction to afford the 2-chloro- 7-methylthieno[3,2- d]pyrimidin-4-amine (6.8 g, 85%) as a yellow solid powder. Compound 4-1 N-(2-(4-(tert-butyl)phenyl)-7-methylthieno[3,2-d]pyrimidin-4 -yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.97 (br. s., 1H), 8.46 (d, J = 8.3 Hz, 2H), 8.24 (d, J = 4.4 Hz, 1H), 8.08 (d, J = 1.5 Hz, 1H), 7.59 (d, J = 8.3 Hz, 2H), 3.28 (br. s., 3H), 1.35 (s, 9H), MS(M+1): 453. Compound 4-2 N-(7-methyl-2-(4-(trifluoromethyl)phenyl)thieno[3,2-d]pyrimi din-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.06 (br. s., 1H), 8.68-8.80 (m, J = 7.8 Hz, 2H), 8.32 (d, J = 4.4 Hz, 1H), 8.25 (d, J = 4.4 Hz, 1H), 8.14 (d, J = 1.5 Hz, 1H), 7.91-8.02 (m, J = 8.3 Hz, 2H), 2.53 (d, J = 1.0 Hz, 3H). MS(M+1): 465 Compound 4-3 N-(7-methyl-2-(3-(trifluoromethyl)phenyl)thieno[3,2-d]pyrimi din-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ):δ 12.01 (br. s., 1H), 8.73-8.93 (m, 2H), 8.32 (d, J = 4.4 Hz, 1H), 8.25 (d, J = 4.4 Hz, 1H), 8.14 (d, J = 1.0 Hz, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.84 (t, J = 7.6 Hz, 1H), 2.52 (d, J = 1.0 Hz, 3H). MS(M+1): 465. Compound 4-4 N-(7-methyl-2-(4-(trifluoromethoxy)phenyl)thieno[3,2-d]pyrim idin-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.03 (br. s., 1H), 8.50-8.78 (m, 2H), 8.16-8.38 (m, 2H), 8.11 (d, J = 1.0 Hz, 1H), 7.57 (d, J = 7.8 Hz, 2H), 2.49 (br. s., 3H). MS(M+1): 481. Compound 4-5 N-(7-methyl-2-(3-(trifluoromethoxy)phenyl)thieno[3,2-d]pyrim idin-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.97 (s, 1H), 8.58 (d, J = 7.8 Hz, 1H), 8.43 (s, 1H), 8.31 (d, J = 4.4 Hz, 1H), 8.25 (d, J = 4.4 Hz, 1H), 8.14 (d, J = 1.0 Hz, 1H), 7.73 (t, J = 8.1 Hz, 1H), 7.52- 7.60 (m, 1H), 2.51 (d, J = 1.0 Hz, 7H). MS(M+1): 481. Compound 4-6 N-(2-(3,5-bis(trifluoromethyl)phenyl)-7-methylthieno[3,2-d]p yrimidin-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.01 (br. s., 1H), 9.07 (s, 2H), 8.30 (d, J = 4.4 Hz, 2H), 8.24 (d, J = 4.4 Hz, 1H), 8.15 (d, J = 1.0 Hz, 1H), 2.52 (s, 2H). MS(M+1): 533. Compound 4-7 N-(2-(3-fluorophenyl)-7-methylthieno[3,2-d]pyrimidin-4-yl)-5 -nitrothiophene-2-carboxamide d 6 ): δ 11.94 (br. s., 1H), 8.39 (d, J = 7.8 Hz, 1H), 8.18 - 8.33 (m, 3H), 8.11 (d, J = 1.0 Hz, 1H), 7.63 (td, J = 8.1, 6.4 Hz, 1H), 7.33-7.45 (m, 1H), 2.51 (s, 3H). MS(M+1): 415. Compound 4-8 N-(2-(4-fluorophenyl)-7-methylthieno[3,2-d]pyrimidin-4-yl)-5 -nitrothiophene-2-carboxamide d 6 ): δ 11.95 (br. s., 1H), 8.50-8.66 (m, 2H), 8.30 (d, J = 4.4 Hz, 1H), 8.24 (d, J = 4.4 Hz, 1H), 8.10 (d, J = 1.0 Hz, 1H), 7.31-7.50 (m, 2H), 2.50 (s, 3H). MS(M+1): 415. Compound 4-9 N-(7-methyl-2-(3,4,5-trifluorophenyl)thieno[3,2-d]pyrimidin- 4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.94 (br. s., 1H), 8.28-8.36 (m, 3H), 8.25-8.27 (m, 1H), 8.14 (d, J = 1.0 Hz, 1H), 2.50 (s, 3H). MS(M+1): 451. Compound 4-10 N-(2-(4-(dimethylamino)phenyl)-7-methylthieno[3,2-d]pyrimidi n-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.85 (br. s., 1H), 8.33-8.51 (m, 2H), 8.30 (br. s., 1H), 8.24 (d, J = 3.9 Hz, 1H), 8.01 (br. s., 1H), 6.84 (d, J = 8.8 Hz, 2H), 3.02 (s, 6H), 2.47 (d, J = 1.0 Hz, 3H). MS(M+1): 440. Compound 4-11 N-(2-(3,3-difluoropyrrolidin-1-yl)-7-methylthieno[3,2-d]pyri midin-4-yl)-5-nitrothiophene-2- carboxamide 11.59 (br. s., 1H), 8.16-8.30 (m, 2H), 7.87 (d, J = 1.0 Hz, 1H), 3.89-4.07 (m, 2H), 3.84 (t, J = 7.3 Hz, 2H), 2.52-2.67 (m, 3H), 2.30 (d, J = 1.0 Hz, 3H), MS(M+1): 426. Compound 4-12 N-(2-(4-(tert-butyl)phenoxy)-7-methylthieno[3,2-d]pyrimidin- 4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ):δ 12.07 (s, 1H), 8.21-8.25 (m, 1H), 8.18-8.21 (m, 1H), 8.05 (d, J = 1.0 Hz, 1H), 7.34-7.55 (m, 2H), 7.10-7.25 (m, 2H), 2.26 (s, 3H), 1.31 (s, 9H). MS(M+1): 469. Compound 4-13 N-(2-(2-fluoro-5-(trifluoromethyl)phenyl)-7-methylthieno[3,2 -d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.12 (br. s., 1H), 8.48 (dd, J = 6.8, 2.4 Hz, 1H), 8.27 (d, J = 4.4 Hz, 1H), 8.17-8.25 (m, 1H), 8.16 (d, J = 1.5 Hz, 1H), 7.88-8.05 (m, 1H), 7.65 (t, J = 9.5 Hz, 1H), 2.47 (d, J = 1.0 Hz, 3H). MS(M+1): 483. Yellow solid Compound 4-14 N-(2-(2-fluoro-4-(trifluoromethyl)phenyl)-7-methylthieno[3,2 -d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.18 (br. s., 1H), 8.32 (t, J = 7.8 Hz, 1H), 8.23-8.28 (m, 1H), 8.18-8.23 (m, 1H), 8.15 (d, J = 1.0 Hz, 1H), 7.86 (d, J = 10.3 Hz, 1H), 7.79 (d, J = 8.3 Hz, 1H), 2.46 (d, J = 1.0 Hz, 3H). MS(M+1): 483. Yellow solid. Compound 4-15 N-(2-(4-fluorophenyl)-7-phenylthieno[3,2-d]pyrimidin-4-yl)-5 -nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.08 (s, 1H), 8.69 (s, 1H), 8.56 (dd, J = 8.8, 5.4 Hz, 2H), 8.34 (d, J = 4.4 Hz, 1H), 8.27 (d, J = 4.4 Hz, 1H), 8.09-8.21 (m, 2H), 7.51-7.62 (m, 2H), 7.36-7.49 (m, 3H). MS(M+1): 477. Yellow solid. Compound 4-16 N-(2-(4-chloro-3-fluorophenyl)-7-phenylthieno[3,2-d]pyrimidi n-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.09 (s, 1H), 8.69-8.74 (m, 1H), 8.31-8.40 (m, 3H), 8.23-8.30 (m, 1H), 8.06-8.18 (m, 2H), 7.76-7.88 (m, 1H), 7.51-7.64 (m, 2H), 7.40-7.50 (m, 1H). MS(M+1): 511. Yellow solid. Compound 4-17 N-(2-(2-fluoro-5-(trifluoromethyl)phenyl)-7-phenylthieno[3,2 -d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.21 (br. s., 1H), 8.77 (s, 1H), 8.58 (dd, J = 6.8, 2.4 Hz, 1H), 8.32 (d, J = 4.4 Hz, 1H), 8.25 (d, J = 4.4 Hz, 1H), 8.14-8.20 (m, 2H), 8.00 (dt, J = 8.2, 3.5 Hz, 1H), 7.63-7.73 (m, 1H), 7.47-7.56 (m, 2H), 7.38-7.46 (m, 1H). MS(M+1):545. Ashy solid. Compound 4-18 N-(7-(3-fluorophenyl)-2-(4-fluorophenyl)thieno[3,2-d]pyrimid in-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.09 (s, 1H), 8.81 (s, 1H), 8.55 (dd, J = 8.8, 5.9 Hz, 2H), 8.34 (d, J = 4.4 Hz, 1H), 8.26 (d, J = 4.4 Hz, 1H), 8.04-8.09 (m, 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.60 (td, J = 7.9, 6.6 Hz, 1H), 7.38-7.49 (m, 2H), 7.17-7.33 (m, 1H) MS(M+1): 495. Orange solid. Compound 4-19 N-(7-(4-(tert-butyl)phenyl)-2-(4-fluorophenyl)thieno[3,2-d]p yrimidin-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.09 (br. s., 1H), 8.63 (s, 1H), 8.57 (dd, J = 8.8, 5.9 Hz, 2H), 8.28-8.35 (m, 1H), 8.19-8.28 (m, 1H), 8.04-8.17 (m, 2H), 7.52-7.65 (m, 2H), 7.43 (t, J = 8.8 Hz, 2H), 1.37 (s, 9H). MS(M+1): 533. Yellow solid. Compound 4-20 tert-butyl 4-(2-(4-fluorophenyl)-6-(5-nitrothiophene-2-carboxamido)-9H- purin-9-yl) piperidine-1-carboxylate 1H NMR (400MHz, DMSO-d 6 ): δ 11.76 (br. s., 1H), 8.65 (s, 1H), 8.43-8.58 (m, 2H), 8.15-8.28 (m, 2H), 7.27-7.46 (m, 2H), 4.73-4.89 (m, 1H), 4.16 (d, J = 11.7 Hz, 2H), 3.00 (br. s., 2H), 2.06- 2.25 (m, 4H). MS(M+1):568. Yellow solid. Compound 4-21 N-(9-cyclohexyl-2-(6-fluoropyridin-3-yl)-9H-purin-6-yl)-5-ni trothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.82 (s, 1H), 9.22 (d, J = 2.4 Hz, 1H), 8.89 (td, J = 8.3, 2.4 Hz, 1H), 8.68 (s, 1H), 8.23 (q, J = 4.4 Hz, 2H), 7.38 (dd, J = 8.8, 2.4 Hz, 1H), 4.56- 4.69 (m, 1H), 1.99-2.18 (m, 4H), 1.82-1.97 (m, 2H), 1.75 (d, J = 13.2 Hz, 1H), 1.41-1.61 (m, 2H), 1.25-1.40 (m, 1H). MS(M+1): 468. Khaki solid. Compound 4-22 N-(9-cyclohexyl-2-(6-ethoxypyridin-3-yl)-9H-purin-6-yl)-5-ni trothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.76 (br. s., 1H), 9.18 (d, J = 2.4 Hz, 1H), 8.55-8.68 (m, 2H), 8.16-8.27 (m, 2H), 6.90-7.02 (m, 1H), 4.52-4.68 (m, 1H), 4.33-4.46 (m, 2H), 1.97-2.20 (m, 4H), 1.91 (t, J = 6.6 Hz, 2H), 1.75 (d, J = 12.2 Hz, 1H), 1.52 (q, J = 12.9 Hz, 2H), 1.30-1.42 (m, 4H). MS(M+1): 494. Khaki solid. Table 5
Compound 5-1 5-nitro-N-(1-phenyl-6-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyr imidin-4-yl)thiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 8.36 (s, 1H), 8.29-8.24 (m, 2H), 8.07 (d, J = 4.4 Hz, 1H), 7.66 (d, J = 3.9 Hz, 1H), 7.54 (t, J = 7.9 Hz, 2H), 7.31 (t, J = 7.3 Hz, 1H), 3.38- 3.36 (m, 2H), 3.07- 3.02 (m, 3H), 2.15-2.02 (m, 4H). MS(M+1): 450. Yellow solid. Compound 5-2 N-(6-(1-acryloylpiperidin-4-yl)-1-phenyl-1H-pyrazolo[3,4-d]p yrimidin-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.11 (s, 1H), 8.58 (s, 1H), 8.30 (brs, 1H), 8.23- 8.20 (m, 3H), 7.60 (t, J = 7.8 Hz, 2H), 7.40 (t, J = 7.4 Hz, 1H), 6.87 (dd, J =16.6, 10.3 Hz, 1H), 6.12 (dd, J = 16.6, 2.5 Hz, 1H), 5.69 (dd, J = 10.3, 2.5 Hz, 1H), 4.55-4.52 (m, 1H), 4.21-4.17 (m, 1H), 3.27- 3.21 (m, 2H), 2.91-2.84 (m, 1H), 2.12-2.08 (m, 2H), 1.83-1.78 (m, 2H). MS(M+1): 504. Yellow solid. Compound 5-3 5-nitro-N-(1-phenyl-6-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-d]py rimidin-4-yl)thiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 8.35 (dd, J = 8.8, 1.0 Hz, 2H), 8.05 (t, J = 2.2 Hz, 2H), 7.64 (d, J = 4.4 Hz, 1H), 7.44-7.52 (m, 2H), 7.21 (t, J = 7.3 Hz, 1H), 3.54-3.62 (m, 4H), 1.90-1.97 (m, 4H). MS(M+1):436. Compound 5-4 (S)-N-(6-(3-hydroxypyrrolidin-1-yl)-1-phenyl-1H-pyrazolo[3,4 -d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.56 (s, 1H), 8.30-8.20 (m ,5H), 7.53 (t, J = 7.8 Hz, 2H), 7.29 (t, J = 7.3 Hz, 1H), 5.00 (d, J = 3.5 Hz, 1H), 4.42 (s, 1H), 3.70-3.60 (m, 4H), 2.09-1.99 (m, 1H), 1.94 (brm, 1H). MS(M+1): 452. Yellow solid. Compound 5-5 (R)-N-(6-(3-cyanopyrrolidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-d ]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H-NMR (DMSO-d 6 , 400 MHz) : δ 11.62 (s, 1H), 8.31-8.22 (m, 5H), 7.55 (t, J = 7.8 Hz, 2H), 7.32 (t, J = 7.4 Hz, 1H), 4.00-3.59 (m, 5H), 2.52-2.38 (m, 1H), 2.33-1.91 (m, 2H). MS(M+1): 461. Yellow solid. Compound 5-6 N-(6-(3,3-difluoropyrrolidin-1-yl)-1-phenyl-1H-pyrazolo[3,4- d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.63 (br. s., 1H), 8.33 (s, 1H), 8.30 (d, J = 4.4 Hz, 1H), 8.25 (d, J = 7.3 Hz, 2H), 8.22 (d, J = 4.4 Hz, 1H), 7.55 (dd, J = 8.3, 7.3 Hz, 2H), 7.29 - 7.35 (m, 1H), 4.05 (t, J = 13.2 Hz, 2H), 3.88 (t, J = 7.1 Hz, 2H), 2.59 (tt, J = 14.2, 7.3 Hz, 2H). MS(M+1):472. Compound 5-7 N-(6-morpholino-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5 -nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.52 (br. s., 1H), 8.33 (s, 1H), 8.29 (d, J = 4.4 Hz, 1H), 8.23 (d, J = 4.4 Hz, 1H), 8.19 (dd, J = 8.8, 1.0 Hz, 2H), 7.50-7.58 (m, 2H), 7.28- 7.35 (m, 1H), 3.82- 3.90 (m, 4H), 3.68-3.76 (m, 4H). MS (M+1) : 452. Compound 5-8 N-(6-((2S,6R)-2,6-dimethylmorpholino)-1-phenyl-1H-pyrazolo[3 ,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.46 (s, 1H), 8.30 (s, 1H), 8.28 (d, J = 4.4 Hz, 1H), 8.20 (d, J = 4.4 Hz, 1H), 8.17 (d, J = 7.3 Hz, 2H), 7.54 (t, J = 8.1 Hz, 2H), 7.31 (t, J = 7.6 Hz, 1H), 4.62 (d, J = 12.2 Hz, 2H), 3.55-3.67 (m, 2H), 2.64 (dd, J = 13.2, 10.8 Hz, 2H), 1.19 (s, 3H), 1.18 (s, 3H). MS(M+1):480. Orange solid. Compound 5-9 N-(6-((4-chlorophenyl)sulfonamido)-1-phenyl-1H-pyrazolo[3,4- d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.06 (br. s., 1H), 11.95 (br. s., 1H), 8.42 (s, 1H), 8.29 (br. s., 1H), 8.23 (d, J = 4.4 Hz, 1H), 8.04 (d, J = 8.3 Hz, 2H), 7.96 (d, J = 7.8 Hz, 2H), 7.52-7.66 (m, 4H), 7.35-7.46 (m, 1H). MS(M+1):590. Cream solid. Compound 5-10 N-(6-(2-(2-ethoxyethoxy)ethoxy)-1-phenyl-1H-pyrazolo[3,4-d]p yrimidin-4-yl)-5-nitrothiophene- 2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.12 (br. s., 1H), 8.52 (s, 1H), 8.32 (d, J = 4.4 Hz, 1H), 8.21 (d, J = 4.4 Hz, 1H), 8.17 (dd, J = 8.8, 1.0 Hz, 2H), 7.53-7.61 (m, 2H), 7.33- 7.41 (m, 1H), 4.50- 4.59 (m, 2H), 3.77-3.85 (m, 2H), 3.59 (dd, J = 5.9, 3.9 Hz, 2H), 3.45-3.50 (m, 2H), 3.40 (q, J = 6.8 Hz, 2H), 1.03-1.10 (m, 3H). MS(M+1):499. Yellow solid. Compound 5-11 N-(6-(2-(dimethylamino)ethoxy)-1-phenyl-1H-pyrazolo[3,4-d]py rimidin-4-yl)-5-nitrothiophene- 2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 8.57 (s, 1H), 8.32 (d, J = 4.9 Hz, 1H), 8.24 (d, J = 4.4 Hz, 1H), 8.16 (d, J = 7.8 Hz, 2H), 7.60 (t, J = 7.8 Hz, 2H), 7.38-7.45 (m, 1H), 4.74 -4.83 (m, 2H), 3.57- 3.65 (m, 2H), 2.88 (s, 6H). MS (M+1) : 454. Compound 5-12 N-(6-(2-morpholinoethoxy)-1-phenyl-1H-pyrazolo[3,4-d]pyrimid in-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 8.54 (s, 1H), 8.34 (d, J = 4.4 Hz, 1H), 8.23 (d, J = 4.4 Hz, 1H), 8.17 (dd, J = 8.8, 1.0 Hz, 2H), 7.54-7.62 (m, 2H), 7.39 (t, J = 7.3 Hz, 1H), 4.58 (t, J = 5.4 Hz, 2H), 3.56 (br. s., 4H), 2.82 (br. s., 2H). MS(M+1):496. Compound 5-13 5-nitro-N-(6-phenoxy-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4- yl)thiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.29 (s, 1H), 8.56 (s, 1H), 8.33 (d, J = 4.4 Hz, 1H), 8.21 (d, J = 4.4 Hz, 1H), 7.98 (dd, J = 8.6, 1.2 Hz, 2H), 7.45-7.55 (m, 2H), 7.38-7.45 (m, 2H), 7.25-7.38 (m, 4H). MS(M+1):459. gray solid. Compound 5-14 N-(6-(4-fluorophenoxy)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin- 4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.29 (br. s., 1H), 8.56 (s, 1H), 8.33 (d, J = 4.4 Hz, 1H), 8.22 (d, J = 4.4 Hz, 1H), 7.96-8.00 (m, 2H), 7.37-7.48 (m, 4H), 7.28-7.37 (m, 3H). MS(M+1):477. gray solid. Compound 5-15 5-nitro-N-(1-phenyl-6-(phenylthio)-1H-pyrazolo[3,4-d]pyrimid in-4-yl)thiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.27 (s, 1H), 8.50 (s, 1H), 8.33 (d, J = 4.4 Hz, 1H), 8.19 (d, J = 4.4 Hz, 1H), 7.81-7.91 (m, 2H), 7.69-7.81 (m, 2H), 7.53-7.69 (m, 3H), 7.18-7.39 (m, 3H). MS(M+1):475. Yellow-brown solid. Compound 5-16 N-(6-((4-chlorophenyl)thio)-1-phenyl-1H-pyrazolo[3,4-d]pyrim idin-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.44 (s, 1H), 8.47 (s, 1H), 8.04-8.21 (m, 2H), 7.82-7.99 (m, 2H), 7.68-7.81 (m, 2H), 7.56-7.68 (m, 2H), 7.22-7.43 (m, 3H). MS(M+1):509. Yellow solid. Compound 5-17 N-(6-(furan-2-yl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl) -5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.20 (br. s., 1H), 8.57 (s, 1H), 8.38 (d, J = 4.4 Hz, 1H), 8.19- 8.32 (m, 3H), 8.01 (d, J = 1.0 Hz, 1H), 7.58-7.68 (m, 2H), 7.47 (d, J = 2.9 Hz, 1H), 7.39-7.46 (m, 1H), 6.77 (dd, J = 3.4, 2.0 Hz, 1H). MS(M+1):433. Light khaki solid. Compound 5-18 5-nitro-N-(1-phenyl-6-(thiophen-2-yl)-1H-pyrazolo[3,4-d]pyri midin-4-yl)thiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.07 (br. s., 1H), 8.57 (s, 1H), 8.38 (d, J = 4.4 Hz, 1H), 8.25- 8.30 (m, 2H), 8.24 (d, J = 4.4 Hz, 1H), 8.11 (dd, J = 3.7, 1.2 Hz, 1H), 7.84 (dd, J = 4.9, 1.5 Hz, 1H), 7.59-7.67 (m, 2H), 7.39-7.45 (m, 1H), 7.27 (dd, J = 5.1, 3.7 Hz, 1H). MS(M+1):449. Light khaki solid. Compound 5-19 N-(6-(5-chlorothiophen-2-yl)-1-phenyl-1H-pyrazolo[3,4-d]pyri midin-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.07 (br. s., 1H), 8.58 (s, 1H), 8.36 (d, J = 4.4 Hz, 1H), 8.22- 8.28 (m, 3H), 7.93 (d, J = 3.9 Hz, 1H), 7.60-7.66 (m, 2H), 7.38-7.45 (m, 1H), 7.29 (d, J = 4.4 Hz, 1H). MS(M+1): 483. Yellow solid. Compound 5-20 5-nitro-N-(1-phenyl-6-(thiophen-3-yl)-1H-pyrazolo[3,4-d]pyri midin-4-yl)thiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.01 (br. s., 1H), 8.57 (s, 1H), 8.51 (dd, J = 2.9, 1.0 Hz, 1H), 8.37 (d, J = 4.4 Hz, 1H), 8.28-8.33 (m, 2H), 8.23 (d, J = 4.4 Hz, 1H), 7.94 (dd, J = 4.9, 1.0 Hz, 1H), 7.71 (dd, J = 5.1, 3.2 Hz, 1H), 7.59-7.67 (m, 2H), 7.37-7.45 (m, 1H). MS(M+1):449. Yellow-brown solid. Compound 5-21 N-(6-(3,5-dimethylisoxazol-4-yl)-1-phenyl-1H-pyrazolo[3,4-d] pyrimidin-4-yl)-5-nitrothiophene- 2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.78 (s, 1H), 8.61 (s, 1H), 8.29-8.33 (m, 1H), 8.25-8.29 (m, 1H), 8.18 (d, J = 8.3 Hz, 2H), 7.61 (t, J = 7.8 Hz, 2H), 7.38-7.47 (m, 1H), 2.90 (s, 3H), 2.63 (s, 3H). MS(M+1):462. Brown solid. Compound 5-22 5-nitro-N-(1-phenyl-6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)- 1H-pyrazolo[3,4-d]pyrimidin-4- yl)thiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.40 (s, 1H), 8.90-8.94 (m, 1H), 8.61 (s, 1H), 8.37 (d, J = 4.4 Hz, 1H), 8.21 (d, J = 4.4 Hz, 1H), 8.18 (dd, J = 8.6, 1.2 Hz, 2H), 7.57-7.65 (m, 2H), 7.39-7.46 (m, 1H), 7.12 (d, J = 2.9 Hz, 1H). MS(M+1):501. Light Yellow solid. Compound 5-23 N-(1,6-diphenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothi ophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.00 (br. s., 1H), 8.61 (s, 1H), 8.50-8.57 (m, 2H), 8.37 (d, J = 4.4 Hz, 1H), 8.29 (dd, J = 8.8, 1.0 Hz, 2H), 8.23 (d, J = 4.4 Hz, 1H), 7.61-7.67 (m, 2H), 7.54- 7.61 (m, 3H), 7.38-7.45 (m, 1H). MS(M+1):443. Yellow solid. Compound 5-24 5-nitro-N-(1-phenyl-6-(pyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyr imidin-4-yl)thiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.10 (br. s., 1H), 9.72 (s, 2H), 9.37 (s, 1H), 8.67 (s, 1H), 8.36 (d, J = 4.4 Hz, 1H), 8.22-8.33 (m, 3H), 7.57-7.72 (m, 2H), 7.36-7.50 (m, 1H). MS(M+1):445. Light khaki solid. Compound 5-25 N-(6-(2-fluorophenyl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4 -yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.21 (br. s., 1H), 8.66 (s, 1H), 8.38 (d, J = 3.9 Hz, 1H), 8.30 (d, J = 7.8 Hz, 2H), 8.22-8.25 (m, 1H), 8.18-8.22 (m, 1H), 7.6 (t, J = 8.1 Hz, 3H), 7.40 (t, J = 7.6 Hz, 3H). MS(M+1):461. Compound 5-26 N-(6-(3-fluorophenyl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4 -yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.99 (s, 1H), 8.64 (s, 1H), 8.34-8.40 (m, 2H), 8.21-8.30 (m, 4H), 7.59-7.68 (m, 3H), 7.39-7.46 (m, 2H). MS(M+1):461. Compound 5-27 N-(6-(4-fluorophenyl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4 -yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.95 (s, 1H), 8.59 (s, 1H), 8.55 (dd, J = 8.8, 5.9 Hz, 2H), 8.36 (d, J = 4.4 Hz, 1H), 8.20-8.28 (m, 3H), 7.62 (t, J = 7.8 Hz, 2H), 7.35-7.45 (m, 3H), MS(M+1):461. Compound 5-28 N-(6-(6-fluoropyridin-3-yl)-1-phenyl-1H-pyrazolo[3,4-d]pyrim idin-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.06 (br. s., 1H), 9.30 (d, J = 2.4 Hz, 1H), 8.93 (td, J = 8.3, 2.4 Hz, 1H), 8.65 (s, 1H), 8.36 (d, J = 4.4 Hz, 1H), 8.21-8.34 (m, 3H), 7.55- 7.70 (m, 2H), 7.35- 7.48 (m, 2H). MS(M+1): 462. Yellow solid. Compound 5-29 N-(6-(3-chlorophenyl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4 -yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.04 (s, 1H), 8.66 (s, 1H), 8.50-8.56 (m, 1H), 8.48 (dt, J = 7.0, 1.9 Hz, 1H), 8.39 (d, J = 4.4 Hz, 1H), 8.21-8.32 (m, 3H), 7.55-7.75 (m, 4H), 7.32-7.51 (m, 1H). MS(M+1): 477. Yellow solid. Compound 5-30 N-(6-(4-chlorophenyl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4 -yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ):δ 12.06 (br. s., 1H), 8.64 (s, 1H), 8.51-8.58 (m, 2H), 8.37 (d, J = 4.4 Hz, 1H), 8.25-8.31 (m, 3H), 7.61-7.71 (m, 4H), 7.38-7.49 (m, 1H) MS(M+1):474. Compound 5-31 N-(6-(6-chloropyridin-3-yl)-1-phenyl-1H-pyrazolo[3,4-d]pyrim idin-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.13 (s, 1H), 9.49 (d, J = 2.4 Hz, 1H), 8.83 (dd, J = 8.3, 2.4 Hz, 1H), 8.70 (s, 1H), 8.40 (d, J = 4.4 Hz, 1H), 8.25-8.32 (m, 3H), 7.79 (d, J = 8.3 Hz, 1H), 7.64- 7.69 (m, 2H), 7.42-7.48 (m, 1H). MS(M+1): 478. Orange solid. Compound 5-32 N-(6-(4-cyanophenyl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4- yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.07 (br. s., 1H), 8.62-8.69 (m, 3H), 8.36 (d, J = 4.4 Hz, 1H), 8.21-8.28 (m, 3H), 8.01-8.09 (m, 2H), 7.61-7.68 (m, 2H), 7.41-7.48 (m, 1H). MS(M+1): 468. Light khaki solid. Compound 5-33 N-(6-(6-cyanopyridin-3-yl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimi din-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.00 (br. s., 1H), 9.66 (d, J = 1.5 Hz, 1H), 8.83- 8.91 (m, 1H), 8.61 (s, 1H), 8.33 (d, J = 4.4 Hz, 1H), 8.17-8.25 (m, 4H), 7.55-7.64 (m, 2H), 7.36-7.45 (m, 1H). MS(M+1):469. Red solid. Compound 5-34 N-(6-(6-methylpyridin-3-yl)-1-phenyl-1H-pyrazolo[3,4-d]pyrim idin-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.06 (br. s., 1H), 9.54 (d, J = 2.0 Hz, 1H), 8.59 -8.70 (m, 2H), 8.37 (d, J = 4.4 Hz, 1H), 8.16-8.34 (m, 3H), 7.64 (t, J = 8.1 Hz, 2H), 7.30-7.54 (m, 2H), 2.52- 2.61 (m, 3H). MS(M+1): 458. Dark orange solid. Compound 5-35 N-(6-(6-methoxypyridin-3-yl)-1-phenyl-1H-pyrazolo[3,4-d]pyri midin-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.87 (s, 1H), 9.22 (d, J = 2.4 Hz, 1H), 8.54-8.64 (m, 2H), 8.26-8.20 (m, 4H), 7.60 (t, J = 7.8 Hz, 2H), 7.39 (t, J = 7.8 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 3.94 (s, 3H). MS(M+1): 474. Yellow solid. Compound 5-36 N-(6-(4-methoxyphenyl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin- 4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.98 (br. s., 1H), 8.60 (s, 1H), 8.40-8.58 (m, J = 8.8 Hz, 2H), 8.38 (d, J = 4.4 Hz, 1H), 8.30 (dd, J = 8.8, 1.0 Hz, 2H), 8.26 (d, J = 4.4 Hz, 1H), 7.58-7.70 (m, 2H), 7.38-7.48 (m, 1H), 7.08-7.20 (m, 2H), 3.87 (s, 3H) MS(M+1): 473. Yellow solid. Compound 5-37 N-(6-(4-(tert-butyl)phenyl)-1-phenyl-1H-pyrazolo[3,4-d]pyrim idin-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.04 (br. s., 1H), 8.62 (s, 1H), 8.48 (d, J = 8.8 Hz, 2H), 8.40 (d, J = 4.4 Hz, 1H), 8.32 (d, J = 7.8 Hz, 2H), 8.26 (d, J = 4.4 Hz, 1H), 7.58 -7.68 (m, 4H), 7.40- 7.47 (m, 1H), 1.35 (s, 9H). MS (M+1) : 499. Yellow solid. Compound 5-38 5-nitro-N-(1-phenyl-6-(3-(trifluoromethyl)phenyl)-1H-pyrazol o[3,4-d]pyrimidin-4-yl)thiophene- 2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.07 (br. s., 1H), 8.77-8.85 (m, 2H), 8.66 (s, 1H), 8.38 (d, J = 4.4 Hz, 1H), 8.23-8.31 (m, 3H), 7.96 (d, J = 7.8 Hz, 1H), 7.85 (t, J = 7.8 Hz, 1H), 7.65 (t, J = 8.1 Hz, 2H), 7.41-7.48 (m, 1H). MS(M+1):511. Yellow solid. Compound 5-39 5-nitro-N-(1-phenyl-6-(4-(trifluoromethyl)phenyl)-1H-pyrazol o[3,4-d]pyrimidin-4-yl)thiophene- 2-carboxamide 12.05 (s, 1H), 8.64-8.70 (m, J = 7.8 Hz, 2H), 8.61 (s, 1H), 8.37 (d, J = 4.4 Hz, 1H), 8.21-8.27 (m, 3H), 7.90-7.96 (m, J = 8.3 Hz, 2H), 7.58-7.66 (m, 2H), 7.40-7.46 (m, 1H). MS (M+1) : 511. Pale yellow solid. Compound 5-40 5-nitro-N-(1-phenyl-6-(4-(trifluoromethoxy)phenyl)-1H-pyrazo lo[3,4-d]pyrimidin-4- yl)thiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.08 (s, 1H), 8.60-8.68 (m, 3H), 8.38 (d, J = 4.4 Hz, 1H), 8.23-8.32 (m, 3H), 7.61-7.68 (m, 2H), 7.59 (d, J = 8.3 Hz, 2H), 7.40-7.48 (m, 1H), MS (M+1) : 527. Pale yellow solid. Compound 5-41 N-(6-(3-(dimethylamino)phenyl)-1-phenyl-1H-pyrazolo[3,4-d]py rimidin-4-yl)-5-nitrothiophene- 2-carboxamide 11.95 (br. s., 1H), 8.60 (br. s., 1H), 8.27-8.48 (m, 3H), 8.23 (br. s., 1H), 7.94 (br. s., 1H), 7.86 (d, J = 7.3 Hz, 1H), 7.63 (t, J = 7.3 Hz, 2H), 7.30-7.53 (m, 2H), 6.94 (d, J = 8.3 Hz, 1H), 3.02 (s, 6H). MS(M+1): 486. Brick red solid. Compound 5-42 5-nitro-N-(1-phenyl-6-(6-(piperidin-1-yl)pyridin-3-yl)-1H-py razolo[3,4-d]pyrimidin-4- yl)thiophene-2-carboxamide 11.92 (br. s., 1H), 9.23 (d, J = 2.0 Hz, 1H), 8.55 (s, 1H), 8.49 (dd, J = 9.3, 2.4 Hz, 1H), 8.35 (d, J = 4.4 Hz, 1H), 8.31 (d, J = 7.3 Hz, 2H), 8.25 (d, J = 4.4 Hz, 1H), 7.59-7.67 (m, 2H), 7.36-7.44 (m, 1H), 6.97 (d, J = 8.8 Hz, 1H), 3.61-3.72 (m, 4H), 1.65 (d, J = 4.9 Hz, 2H), 1.58 (d, J = 3.9 Hz, 4H). MS(M+1): 527. Yellow solid. Compound 5-43 N-(6-(6-morpholinopyridin-3-yl)-1-phenyl-1H-pyrazolo[3,4-d]p yrimidin-4-yl)-5-nitrothiophene- 2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.82 (br. s., 1H), 9.22 (d, J = 2.0 Hz, 1H), 8.52 (s, 1H), 8.50 (dd, J = 9.3, 2.4 Hz, 1H), 8.34 (d, J = 4.4 Hz, 1H), 8.27 (dd, J = 8.6, 1.2 Hz, 2H), 8.21 (d, J = 4.4 Hz, 1H), 7.57-7.64 (m, 2H), 7.35-7.42 (m, 1H), 6.95 (d, J = 9.3 Hz, 1H), 3.68-3.75 (m, 4H), 3.55-3.64 (m, 4H). MS(M+1):529. Yellow green solid. Compound 5-44 N-(6-(3,4-difluorophenyl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimid in-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.96 (br. s., 1H), 8.63 (s, 1H), 8.41 (ddd, J = 12.0, 8.1, 2.0 Hz, 1H), 8.32-8.38 (m, 2H), 8.21-8.30 (m, 3H), 7.60-7.69 (m, 3H), 7.39-7.46 (m, 1H). MS(M+1):479. Yellow solid. Compound 5-45 N-(6-(2,4-difluorophenyl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimid in-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.13 (br. s., 1H), 8.64 (s, 1H), 8.33-8.42 (m, 1H), 8.24-8.33 (m, 3H), 8.22 (d, J = 4.4 Hz, 1H), 7.54-7.66 (m, 2H), 7.36-7.49 (m, 2H), 7.23-7.36 (m, 1H). MS(M+1):479. Yellow solid. Compound 5-46 N-(6-(4-chloro-3-fluorophenyl)-1-phenyl-1H-pyrazolo[3,4-d]py rimidin-4-yl)-5-nitrothiophene- 2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.97 (br. s., 1H), 8.63 (s, 1H), 8.28-8.42 (m, 4H), 8.19-8.28 (m, 3H), 7.80 (t, J = 7.8 Hz, 1H), 7.57-7.69 (m, 2H), 7.37-7.48 (m, 1H). MS(M+1):495. Yellow solid. Compound 5-47 N-(6-(4-chloro-2-fluorophenyl)-1-phenyl-1H-pyrazolo[3,4-d]py rimidin-4-yl)-5-nitrothiophene- 2-carboxamide 1H NMR (DMSO-d 6 ) : δ 12.11 (br. s., 1H), 8.62 (d, J = 1.0 Hz, 1H), 8.34 (d, J = 4.4 Hz, 1H), 8.23-8.31 (m, 3H), 8.21 (d, J = 4.4 Hz, 1H), 7.55-7.65 (m, 3H), 7.46-7.52 (m, 1H), 7.36-7.43 (m, 1H). MS(M+1): 495. Yellow-brown solid. Compound 5-48 N-(6-(3,4-dichlorophenyl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimid in-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.96 (br. s., 1H), 8.60 (d, J = 2.0 Hz, 1H), 8.59 (s, 1H), 8.36- 8.39 (m, 1H), 8.35 (d, J = 4.4 Hz, 1H), 8.23 (d, J = 4.4 Hz, 1H), 8.16-8.21 (m, 2H), 7.80 (d, J = 8.8 Hz, 1H), 7.57-7.64 (m, 2H), 7.38-7.44 (m, 1H). MS(M+1) :511. Brown solid. Compound 5-49 N-(6-(2,4-dichlorophenyl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimid in-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.32 (br. s., 1H), 8.69 (s, 1H), 8.36 (d, J = 4.4 Hz, 1H), 8.19- 8.26 (m, 3H), 7.94 (d, J = 8.3 Hz, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.55-7.66 (m, 3H), 7.37-7.44 (m, 1H). MS(M+1):512. Yellow solid. Compound 5-50 N-(6-(2-fluoro-5-(trifluoromethyl)phenyl)-1-phenyl-1H-pyrazo lo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.20 (br. s., 1H), 8.69 (s, 1H), 8.62 (dd, J = 6.8, 2.4 Hz, 1H), 8.36 (d, J = 4.4 Hz, 1H), 8.30 (dd, J = 8.6, 1.2 Hz, 2H), 8.25 (d, J = 4.4 Hz, 1H), 7.98-8.08 (m, 1H), 7.65-7.73 (m, 1H), 7.58-7.65 (m, 2H), 7.39-7.45 (m, 1H) MS(M+1): 529. Pale yellow solid. Compound 5-51 N-(6-(2-fluoro-4-(trifluoromethyl)phenyl)-1-phenyl-1H-pyrazo lo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.16 (br. s., 1H), 8.60 (s, 1H), 8.28-8.46 (m, 2H), 8.13-8.28 (m, 3H), 7.85 (d, J = 10.8 Hz, 1H), 7.76 (d, J = 8.3 Hz, 1H), 7.50-7.63 (m, 2H), 7.32-7.43 (m, 1H). MS(M+1):529. Light khaki solid. Compound 5-52 N-(6-(3-fluoro-4-(trifluoromethyl)phenyl)-1-phenyl-1H-pyrazo lo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.10 (br. s., 1H), 8.69 (s, 1H), 8.41-8.55 (m, 2H), 8.35 (d, J = 4.4 Hz, 1H), 8.21-8.31 (m, 3H), 8.04 (t, J = 8.1 Hz, 1H), 7.61-7.72 (m, 2H), 7.41-7.51 (m, 1H). MS(M+1):529. Yellow solid. Compound 5-53 5-nitro-N-(1-phenyl-6-(3,4,5-trifluorophenyl)-1H-pyrazolo[3, 4-d]pyrimidin-4-yl)thiophene-2- carboxamide 1H NMR (DMSO-d 6 ): δ 11.79 (br. s., 1H), 8.56 (s, 1H), 8.30 (d, J = 4.4 Hz, 1H), 8.22 (d, J = 4.4 Hz, 1H), 8.10-8.21 (m, 4H), 7.59 (t, J = 7.8 Hz, 2H), 7.35-7.43 (m, 1H) MS(M+1):497. Yellow-brown solid. Compound 5-54 N-(6-(6-(2-methoxyethoxy)pyridin-3-yl)-1-phenyl-1H-pyrazolo[ 3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.96 (br. s., 1H), 9.26 (d, J = 2.4 Hz, 1H), 8.68 (dd, J = 8.8, 2.4 Hz, 1H), 8.60 (s, 1H), 8.36 (d, J = 4.4 Hz, 1H), 8.28 (d, J = 7.3 Hz, 2H), 8.25 (d, J = 4.4 Hz, 1H), 7.59-7.68 (m, 2H), 7.37-7.46 (m, 1H), 7.02 (d, J = 8.8 Hz, 1H), 4.43-4.52 (m, 2H), 3.70 (dd, J = 5.4, 3.9 Hz, 2H). MS(M+1):518. Yellow solid. Compound 5-55 N-(6-(6-(2-ethoxyethoxy)pyridin-3-yl)-1-phenyl-1H-pyrazolo[3 ,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.84 (br. s., 1H), 9.20 (d, J = 2.4 Hz, 1H), 8.62 (dd, J = 8.3, 2.4 Hz, 1H), 8.54 (s, 1H), 8.32 (d, J = 4.4 Hz, 1H), 8.24 (dd, J = 8.8, 1.0 Hz, 2H), 8.20 (d, J = 4.4 Hz, 1H), 7.55-7.64 (m, 2H), 7.34-7.42 (m, 1H), 6.97 (d, J = 7.8 Hz, 1H), 4.44 (dd, J = 5.6, 4.4 Hz, 2H), 3.68-3.77 (m, 2H), 3.51 (q, J = 7.0 Hz, 2H), 1.14 (t, J = 7.0 Hz, 3H). MS(M+1):532. Yellow solid. Compound 5-56 5-nitro-N-(1-phenyl-6-(6-(2,2,3,3-tetrafluoropropoxy)pyridin -3-yl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)thiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.03 (br. s., 1H), 9.31 (d, J = 2.4 Hz, 1H), 8.77- 8.82 (m, 1H), 8.65 (s, 1H), 8.37 (d, J = 4.4 Hz, 1H), 8.28-8.34 (m, 2H), 8.25-8.28 (m, 1H), 7.62-7.70 (m, 2H), 7.40-7.48 (m, 1H), 7.18 (d, J = 9.3 Hz, 1H), 6.71 (t, J = 5.4 Hz, 1H), 4.98 (t, J = 13.9 Hz, 2H). MS(M+1):574. Yellow solid. Compound 5-57 N-(6-(6-(2-(2-ethoxyethoxy)ethoxy)pyridin-3-yl)-1-phenyl-1H- pyrazolo[3,4-d]pyrimidin-4-yl)- 5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.88 (br. s., 1H), 9.22 (d, J = 2.0 Hz, 1H), 8.64 (dd, J = 8.8, 2.4 Hz, 1H), 8.56 (s, 1H), 8.33 (d, J = 4.4 Hz, 1H), 8.25 (dd, J = 8.8, 1.0 Hz, 2H), 8.21 (d, J = 4.4 Hz, 1H), 7.57-7.65 (m, 2H), 7.35-7.43 (m, 1H), 6.99 (d, J = 9.3 Hz, 1H), 4.46 (dd, J = 5.4, 3.9 Hz, 2H), 3.78 (dd, J = 5.4, 3.9 Hz, 2H), 3.57-3.63 (m, 2H), 3.48-3.53 (m, 2H), 3.44 (q, J = 6.8 Hz, 2H), 1.05-1.13 (m, 3H). MS(M+1):576. Beige solid. Table 6
Compound 6-1 (S)-N-(6-(2-(hydroxymethyl)pyrrolidin-1-yl)-1-(o-tolyl)-1H-p yrazolo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.46 (br. s., 1H), 8.29 (br. s., 1H), 8.23 (br. s., 2H), 7.30-7.47 (m, 4H), 4.62 (br. s., 1H), 4.23 (br. s., 1H), 4.01 (br. s., 1H), 3.50 (br. s., 4H), 2.17 (s, 3H), 1.85- 2.07 (m, 3H), 1.76-1.85 (m, 1H). MS(M+1): 480. Yellow solid. Compound 6-2 N-(6-(6-fluoropyridin-3-yl)-1-(o-tolyl)-1H-pyrazolo[3,4-d]py rimidin-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ):δ 12.11 (br. s., 1H), 9.17 (d, J = 2.4 Hz, 1H), 8.76 (td, J = 8.3, 2.4 Hz, 1H), 8.66 (s, 1H), 8.38 (d, J = 4.4 Hz, 1H), 8.27 (d, J = 4.4 Hz, 1H), 7.49-7.59 (m, 3H), 7.41-7.49 (m, 1H), 7.35 (dd, J = 8.8, 2.4 Hz, 1H), 2.16 (s, 3H) MS(M+1):476. Light yellow solid. Compound 6-3 (S)-N-(6-(2-(hydroxymethyl)pyrrolidin-1-yl)-1-(p-tolyl)-1H-p yrazolo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.46 (br. s., 1H), 8.26 (br. s., 1H), 8.19-8.24 (m, 2H), 8.08- 8.15 (m, J = 8.3 Hz, 2H), 7.24-7.38 (m, J = 8.3 Hz, 2H), 4.73 (br. s., 1H), 4.25 (br. s., 1H), 3.49- 3.74 (m, 4H), 2.32-2.43 (m, 3H), 1.93-2.13 (m, 3H), 1.91 (br. s., 1H). MS(M+1): 480. Yellow solid. Compound 6-4 N-(6-(4-fluorophenyl)-1-(p-tolyl)-1H-pyrazolo[3,4-d]pyrimidi n-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.03 (br. s., 1H), 8.51-8.66 (m, 3H), 8.36 (d, J = 4.4 Hz, 1H), 8.26 (d, J = 4.4 Hz, 1H), 8.06-8.19 (m, 2H), 7.35-7.52 (m, 4H), 2.41 (s, 3H). MS(M+1):475. Yellow solid. Compound 6-5 N-(6-(6-fluoropyridin-3-yl)-1-(p-tolyl)-1H-pyrazolo[3,4-d]py rimidin-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.11 (br. s., 1H), 9.30 (d, J = 2.4 Hz, 1H), 8.94 (td, J = 8.3, 2.4 Hz, 1H), 8.63 (s, 1H), 8.31 (d, J = 4.4 Hz, 1H), 8.25 (d, J = 4.4 Hz, 1H), 8.10-8.20 (m, 2H), 7.39-7.49 (m, 3H), 2.41 (s, 3H). MS(M+1):476. Light khaki solid. Compound 6-6 N-(6-(6-methoxypyridin-3-yl)-1-(p-tolyl)-1H-pyrazolo[3,4-d]p yrimidin-4-yl)-5-nitrothiophene- 2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.97 (br. s., 1H), 9.27 (d, J = 2.4 Hz, 1H), 8.67 (dd, J = 8.6, 2.2 Hz, 1H), 8.57 (s, 1H), 8.35 (d, J = 4.4 Hz, 1H), 8.25 (d, J = 4.9 Hz, 1H), 8.09-8.18 (m, J = 8.8 Hz, 2H), 7.38-7.47 (m, J = 8.3 Hz, 2H), 7.01 (d, J = 8.3 Hz, 1H), 3.96 (s, 3H), 2.40 (s, 3H). MS(M+1):488. Yellow solid. Compound 6-7 N-(6-(4-chlorophenyl)-1-(p-tolyl)-1H-pyrazolo[3,4-d]pyrimidi n-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.05 (br. s., 1H), 8.61 (s, 1H), 8.49-8.57 (m, 2H), 8.34 (d, J = 4.4 Hz, 1H), 8.26 (d, J = 4.4 Hz, 1H), 8.08-8.16 (m, 2H), 7.63-7.71 (m, 2H), 7.45 (d, J = 7.8 Hz, 2H), 2.42 (s, 3H). MS(M+1):491. Silver solid. Compound 6-8 5-nitro-N-(1-(p-tolyl)-6-(4-(trifluoromethyl)phenyl)-1H-pyra zolo[3,4-d]pyrimidin-4- yl)thiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.10 (br. s., 1H), 8.70 (d, J = 8.3 Hz, 2H), 8.63 (s, 1H), 8.37 (d, J = 4.4 Hz, 1H), 8.26 (d, J = 4.4 Hz, 1H), 8.08-8.17 (m, 2H), 7.91-7.99 (m, J = 8.3 Hz, 2H), 7.44 (d, J = 8.3 Hz, 2H), 2.42 (s, 3H). MS(M+1):525. Silver solid. Compound 6-9 N-(6-(benzo[d][1,3]dioxol-5-yl)-1-(p-tolyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.84 (br. s., 1H), 8.54 (s, 1H), 8.34 (d, J = 4.4 Hz, 1H), 8.24 (d, J = 4.4 Hz, 1H), 8.06-8.16 (m, 3H), 7.96 (d, J = 1.5 Hz, 1H), 7.42 (d, J = 8.3 Hz, 2H), 7.09 (d, J = 8.3 Hz, 1H), 6.14 (s, 2H), 2.40 (s, 3H). MS(M+1):501. Yellow solid. Compound 6-10 N-(6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(p-tolyl)-1H-py razolo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.91 (br. s., 1H), 8.55 (s, 1H), 8.35 (d, J = 4.4 Hz, 1H), 8.25 (d, J = 4.4 Hz, 1H), 8.06-8.15 (m, J = 8.3 Hz, 2H), 7.98-8.06 (m, 2H), 7.40-7.49 (m, J = 8.3 Hz, 2H), 7.03 (d, J = 8.3 Hz, 1H), 4.24-4.39 (m, 4H), 2.40 (s, 3H).MS(M+1): 515. Khaki solid. Compound 6-11 N-(6-(2,4-difluorophenyl)-1-(p-tolyl)-1H-pyrazolo[3,4-d]pyri midin-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.14 (br. s., 1H), 8.61 (s, 1H), 8.34 (d, J = 4.4 Hz, 1H), 8.29 (td, J = 8.8, 6.8 Hz, 1H), 8.23 (d, J = 4.4 Hz, 1H), 8.06-8.17 (m, 2H), 7.44 (ddd, J = 11.4, 9.2, 2.4 Hz, 1H), 7.35-7.41 (m, J = 8.3 Hz, 2H), 7.22-7.34 (m, 1H), 2.38 (s, 4H). MS(M+1):493. Light yellow solid. Compound 6-12 N-(6-(6-(2-methoxyethoxy)pyridin-3-yl)-1-(p-tolyl)-1H-pyrazo lo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ11.91 (br. s., 1H), 9.23 (d, J = 2.4 Hz, 1H), 8.64 (dd, J = 8.8, 2.4 Hz, 1H), 8.55 (s, 1H), 8.33 (d, J = 4.9 Hz, 1H), 8.23 (d, J = 4.4 Hz, 1H), 8.04- 8.15 (m, J = 8.3 Hz, 2H), 7.36-7.46 (m, J = 8.8 Hz, 2H), 7.00 (d, J = 8.3 Hz, 1H), 4.33- 4.55 (m, 2H), 3.63- 3.77 (m, 2H), 3.32 (s, 3H), 2.39 (s, 3H). MS(M+1): 532. Khaki solid. Compound 6-13 N-(6-(6-(2-ethoxyethoxy)pyridin-3-yl)-1-(p-tolyl)-1H-pyrazol o[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.89 (br. s., 1H), 9.22 (d, J = 2.4 Hz, 1H), 8.63 (dd, J = 8.6, 2.2 Hz, 1H), 8.54 (s, 1H), 8.34 (d, J = 4.4 Hz, 1H), 8.23 (d, J = 4.4 Hz, 1H), 8.05- 8.13 (m, J = 8.3 Hz, 2H), 7.36-7.47 (m, J = 8.3 Hz, 2H), 7.00 (d, J = 8.8 Hz, 1H), 4.46 (dd, J = 5.6, 4.2 Hz, 2H), 3.70-3.78 (m, 2H), 3.51 (q, J = 6.8 Hz, 2H), 2.39 (s, 3H), 1.14 (t, J = 6.8 Hz, 3H). MS(M+1): 546. Yellow solid. Compound 6-14 N-(6-(6-(2-(2-ethoxyethoxy)ethoxy)pyridin-3-yl)-1-(p-tolyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-yl)- 5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ):δ 11.87 (br. s., 1H), 9.21 (d, J = 2.0 Hz, 1H), 8.62 (dd, J = 8.8, 2.4 Hz, 1H), 8.53 (s, 1H), 8.33 (d, J = 4.4 Hz, 1H), 8.22 (d, J = 4.4 Hz, 1H), 8.03-8.15 (m, 2H), 7.36-7.44 (m, J = 8.3 Hz, 2H), 6.98 (d, J = 9.3 Hz, 1H), 4.46 (dd, J = 5.4, 3.9 Hz, 2H), 3.78 (dd, J = 5.4, 3.9 Hz, 2H), 3.58-3.64 (m, 2H), 3.47-3.55 (m, 2H), 3.44 (q, J = 6.8 Hz, 2H), 2.38 (s, 3H), 1.10 (t, J = 6.8 Hz, 3H). MS(M+1):590. Yellow solid. Compound 6-15 N-(6-(cyclohexylamino)-1-(4-methoxyphenyl)-1H-pyrazolo[3,4-d ]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.68 (br., 1H), 8.12-8.29 (m, 2H), 8.05 (d, J = 8.3 Hz, 3H), 7.29 (br., 1H), 7.08 (d, J = 8.8 Hz, 2H), 3.82 (s, 4H), 1.93 (d, J = 18.6 Hz, 2H), 1.68- 1.83 (m, 2H), 1.62 (d, J = 11.7 Hz, 1H), 1.34 (br. s., 4H), 1.23 (br. s., 1H). MS(M+1):494. Yellow solid. Compound 6-16 N-(6-(cyclohexyloxy)-1-(4-methoxyphenyl)-1H-pyrazolo[3,4-d]p yrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.08 (br. s., 1H), 8.48 (s, 1H), 8.32 (d, J = 4.4 Hz, 1H), 8.23 (d, J = 4.4 Hz, 1H), 7.98-8.07 (m, J = 9.3 Hz, 2H), 7.09-7.18 (m, J = 9.3 Hz, 2H), 5.02-5.15 (m, 1H), 3.83 (s, 3H), 2.00 (d, J = 3.9 Hz, 2H), 1.75 (d, J = 5.9 Hz, 2H), 1.50- 1.67 (m, 3H), 1.34- 1.50 (m, 3H). MS(M+1):495. Yellow solid. Compound 6-17 N-(1-(4-methoxyphenyl)-6-(6-methylpyridin-3-yl)-1H-pyrazolo[ 3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.91 (s, 1H), 9.47 (d, J = 2.4 Hz, 1H), 8.59 (dd, J = 8.1, 2.2 Hz, 1H), 8.52 (s, 1H), 8.34 (d, J = 4.4 Hz, 1H), 8.21 (d, J = 4.4 Hz, 1H), 8.09 (d, J = 9.3 Hz, 2H), 7.42 (d, J = 8.3 Hz, 1H), 7.15 (d, J = 8.8 Hz, 2H), 3.84 (s, 3H), 2.55 (s, 3H). MS(M+1):488. Orange solid. Compound 6-18 N-(6-(4-fluorophenyl)-1-(4-methoxyphenyl)-1H-pyrazolo[3,4-d] pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.04 (br. s., 1H), 8.54-8.62 (m, 3H), 8.36 (d, J = 4.4 Hz, 1H), 8.26 (d, J = 4.4 Hz, 1H), 8.09-8.17 (m, 2H), 7.37-7.47 (m, 2H), 7.17-7.24 (m, 2H), 3.86 (s, 3H). MS(M+1):491. Yellow solid. Compound 6-19 N-(6-(6-fluoropyridin-3-yl)-1-(4-methoxyphenyl)-1H-pyrazolo[ 3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.06 (br. s., 1H), 9.30 (d, J = 2.0 Hz, 1H), 8.93 (td, J = 8.2, 2.2 Hz, 1H), 8.63 (s, 1H), 8.37 (d, J = 4.4 Hz, 1H), 8.26 (d, J = 4.4 Hz, 1H), 8.09-8.18 (m, J = 9.3 Hz, 2H), 7.42 (dd, J = 8.8, 2.4 Hz, 1H), 7.15-7.24 (m, J = 9.3 Hz, 2H), 3.86 (s, 3H). MS(M+1):492. Yellow solid. Compound 6-20 N-(6-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazolo[3,4-d] pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.98 (br. s., 1H), 8.56 (s, 1H), 8.46-8.52 (m, J = 8.3 Hz, 2H), 8.37 (d, J = 4.4 Hz, 1H), 8.24 (d, J = 4.4 Hz, 1H), 8.06-8.12 (m, J = 8.8 Hz, 2H), 7.63 (d, J = 8.3 Hz, 2H), 7.17 (d, J = 9.3 Hz, 2H), 3.85 (s, 3H). MS(M+1) : 507. Yellow solid. Compound 6-21 N-(6-(6-chloropyridin-3-yl)-1-(4-methoxyphenyl)-1H-pyrazolo[ 3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.07 (br. s., 1H), 9.44 (d, J = 2.4 Hz, 1H), 8.79 (dd, J = 8.3, 2.4 Hz, 1H), 8.63 (s, 1H), 8.38 (d, J = 4.4 Hz, 1H), 8.08-8.17 (m, 2H), 7.76 (d, J = 8.8 Hz, 1H), 7.15-7.23 (m, 2H), 3.79-3.90 (m, 3H). MS(M+1):508. Black solid. Compound 6-22 N-(6-(4-chloro-2-fluorophenyl)-1-(4-methoxyphenyl)-1H-pyrazo lo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.12 (br. s., 1H), 8.59 (s, 1H), 8.35 (d, J = 4.4 Hz, 1H), 8.19- 8.27 (m, 2H), 8.11 (d, J = 8.8 Hz, 2H), 7.62 (dd, J = 10.8, 2.0 Hz, 1H), 7.49 (dd, J = 8.3, 2.0 Hz, 1H), 7.13 (d, J = 9.3 Hz, 2H), 3.83 (s, 3H). MS(M+1):525. Yellow solid. Compound 6-23 N-(6-(3,4-difluorophenyl)-1-(4-methoxyphenyl)-1H-pyrazolo[3, 4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.89 (br. s., 1H), 8.56 (s, 1H), 8.28-8.41 (m, 3H), 8.24 (d, J = 4.4 Hz, 1H), 8.04-8.11 (m, 2H), 7.62 (dt, J = 10.3, 8.6 Hz, 1H), 7.11-7.21 (m, 2H), 3.85 (s, 3H). MS(M+1):509. Orange solid. Compound 6-24 N-(6-(benzo[d][1,3]dioxol-5-yl)-1-(4-methoxyphenyl)-1H-pyraz olo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.87 (s, 1H), 8.56 (s, 1H), 8.37 (d, J = 4.4 Hz, 1H), 8.26 (d, J = 4.4 Hz, 1H), 8.08-8.18 (m, 3H), 7.98 (d, J = 1.5 Hz, 1H), 7.19 (d, J = 9.3 Hz, 2H), 7.11 (d, J = 8.3 Hz, 1H), 6.15 (s, 2H), 3.86 (s, 3H). MS(M+1):517. Orange solid Compound 6-25 N-(1-(4-methoxyphenyl)-6-(6-propoxypyridin-3-yl)-1H-pyrazolo [3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.90 (br. s., 1H), 9.23 (d, J = 2.0 Hz, 1H), 8.64 (dd, J = 8.8, 2.4 Hz, 1H), 8.54 (s, 1H), 8.35 (d, J = 4.4 Hz, 1H), 8.24 (d, J = 4.4 Hz, 1H), 8.09-8.15 (m, 2H), 7.13-7.21 (m, 2H), 6.96 (d, J = 8.8 Hz, 1H), 4.30 (t, J = 6.6 Hz, 2H), 3.85 (s, 3H), 1.77 (sxt, J = 7.1 Hz, 2H), 0.99 (t, J = 7.6 Hz, 3H). MS(M+1):532. Orange solid. Compound 6-26 N-(6-(6-(2-methoxyethoxy)pyridin-3-yl)-1-(4-methoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-4- yl)-5-nitrothiophene-2-carboxamide d 6 ): δ 11.90 (br. s., 1H), 9.23 (d, J = 2.0 Hz, 1H), 8.65 (dd, J = 8.8, 2.4 Hz, 1H), 8.54 (s, 1H), 8.35 (d, J = 4.4 Hz, 1H), 8.24 (d, J = 4.4 Hz, 1H), 8.08-8.15 (m, 2H), 7.13-7.20 (m, 2H), 7.00 (d, J = 8.8 Hz, 1H), 4.42-4.52 (m, 2H), 3.85 (s, 3H), 3.66-3.72 (m, 2H). MS(M+1):548. Orange solid. Compound 6-27 N-(6-(6-(2-ethoxyethoxy)pyridin-3-yl)-1-(4-methoxyphenyl)-1H -pyrazolo[3,4-d]pyrimidin-4- yl)-5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.85 (br. s., 1H), 9.21 (d, J = 2.0 Hz, 1H), 8.62 (dd, J = 8.6, 2.2 Hz, 1H), 8.51 (s, 1H), 8.33 (d, J = 4.4 Hz, 1H), 8.22 (d, J = 4.4 Hz, 1H), 8.05-8.14 (m, 2H), 7.10-7.19 (m, 2H), 6.98 (d, J = 8.8 Hz, 1H), 4.45 (dd, J = 5.4, 3.9 Hz, 2H), 3.84 (s, 3H), 3.73 (dd, J = 5.4, 3.9 Hz, 2H), 3.51 (q, J = 6.8 Hz, 2H), 1.09- 1.17 (m, 3H). MS(M+1):562. Yellow solid. Compound 6-28 N-(6-(6-(2-(2-ethoxyethoxy)ethoxy)pyridin-3-yl)-1-(4-methoxy phenyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.79 (br. s., 1H), 9.17 (d, J = 2.0 Hz, 1H), 8.59 (dd, J = 8.8, 2.4 Hz, 1H), 8.48 (s, 1H), 8.31 (d, J = 4.4 Hz, 1H), 8.20 (d, J = 4.4 Hz, 1H), 8.04-8.11 (m, J = 8.8 Hz, 2H), 7.09-7.16 (m, J = 9.3 Hz, 2H), 6.95 (d, J = 8.3 Hz, 1H), 4.44 (dd, J = 5.6, 4.2 Hz, 2H), 3.83 (s, 3H), 3.75-3.80 (m, 2H), 3.57-3.62 (m, 2H), 3.48-3.53 (m, 2H), 3.43 (q, J = 6.8 Hz, 2H), 1.10 (t, J = 7.1 Hz, 3H). MS(M+1):606. Yellow solid. Compound 6-29 N-(6-(4,4-dimethylcyclohex-1-en-1-yl)-1-(4-methoxyphenyl)-1H -pyrazolo[3,4-d]pyrimidin-4- yl)-5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ):δ 11.78 (br. s., 1H), 8.49 (s, 1H), 8.32 (br. s., 1H), 8.22 (d, J = 4.4 Hz, 1H), 8.02-8.18 (m, J = 8.8 Hz, 2H), 7.37 (br. s., 1H), 7.07-7.21 (m, 2H), 3.83 (s, 3H), 2.63 (br. s., 2H), 2.02-2.19 (m, 2H), 1.52 (t, J = 6.4 Hz, 2H), 0.96 (s, 6H). MS(M+1): 505. Yellow solid. Compound 6-30 N-(6-(4,4-dimethylcyclohexyl)-1-(4-methoxyphenyl)-1H-pyrazol o[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ):δ 12.07 (br. s., 1H), 8.52 (s, 1H), 8.28 (br. s., 1H), 8.21 (d, J = 4.4 Hz, 1H), 7.96-8.11 (m, J = 8.8 Hz, 2H), 7.06-7.20 (m, 2H), 3.84 (s, 3H), 2.76-2.85 (m, 1H), 1.77-1.94 (m, 4H), 1.50 (d, J = 12.7 Hz, 2H), 1.34 (td, J = 12.6, 5.1 Hz, 2H), 0.97 (d, J = 3.4 Hz, 6H). MS(M+1): 507. Yellow solid. Compound 6-31 (S)-N-(1-(3-chlorophenyl)-6-(2-(hydroxymethyl)pyrrolidin-1-y l)-1H-pyrazolo[3,4-d]pyrimidin- 4-yl)-5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.53 (br. s., 1H), 8.44 (br. s., 1H), 8.25-8.36 (m, 3H), 8.18- 8.25 (m, 1H), 7.56 (t, J = 8.3 Hz, 1H), 7.30-7.38 (m, 1H), 4.73 (br. s., 1H), 4.26 (br. s., 1H), 3.66 (br. s., 4H), 2.06 (d, J = 13.2 Hz, 3H), 1.92 (d, J = 6.8 Hz, 1H). MS(M+1):500. Orange solid. Compound 6-32 methyl (1-(3-chlorophenyl)-4-(5-nitrothiophene-2-carboxamido)-1H-py razolo[3,4-d] pyrimidin- 6-yl)-L-prolinate 1H NMR (400MHz, DMSO-d 6 ): δ 11.66 (br. s., 1H), 8.24-8.35 (m, 3H), 8.16-8.24 (m, 2H), 7.53 (t, J = 8.1 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), 4.57-4.64 (m, 1H), 3.71-3.88 (m, 2H), 3.57-3.71 (m, 3H), 2.41 (dt, J = 8.2, 4.0 Hz, 1H), 1.93-2.15 (m, 3H). MS(M+1): 528. Yellow solid. Compound 6-33 N-(1-(3-chlorophenyl)-6-(thiophen-3-yl)-1H-pyrazolo[3,4-d]py rimidin-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.10 (s, 1H), 8.63 (s, 1H), 8.53 (dd, J = 2.9, 1.0 Hz, 1H), 8.37-8.43 (m, 3H), 8.27 (d, J = 4.4 Hz, 1H), 7.91-7.97 (m, 1H), 7.73-7.78 (m, 1H), 7.68 (t, J = 8.1 Hz, 1H), 7.49 (dd, J = 7.8, 2.4 Hz, 1H). MS(M+1): 483. Pale green solid. Compound 6-34 N-(1-(3-chlorophenyl)-6-(3-fluorophenyl)-1H-pyrazolo[3,4-d]p yrimidin-4-yl)-5-nitrothiophene- 2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.06 (br. s., 1H), 8.67 (s, 1H), 8.39 (t, J = 2.0 Hz, 1H), 8.33- 8.38 (m, 3H), 8.22-8.28 (m, 2H), 7.62-7.72 (m, 2H), 7.48-7.52 (m, 1H), 7.45 (td, J = 8.6, 2.4 Hz, 1H). MS(M+1): 495. Yellow solid. Compound 6-35 N-(1-(3-chlorophenyl)-6-(4-fluorophenyl)-1H-pyrazolo[3,4-d]p yrimidin-4-yl)-5-nitrothiophene- 2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.01 (br. s., 1H), 8.60 (s, 1H), 8.48-8.57 (m, 2H), 8.30-8.37 (m, 3H), 8.24 (d, J = 4.4 Hz, 1H), 7.60-7.68 (m, 1H), 7.44-7.49 (m, 1H), 7.37-7.44 (m, 2H). MS(M+1): 495. Yellow solid. Compound 6-36 N-(1-(3-chlorophenyl)-6-(6-fluoropyridin-3-yl)-1H-pyrazolo[3 ,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.06 (br. s., 1H), 9.27 (d, J = 2.4 Hz, 1H), 8.89 (td, J = 8.1, 2.4 Hz, 1H), 8.64 (s, 1H), 8.28-8.40 (m, 3H), 8.25 (d, J = 4.4 Hz, 1H), 7.66 (t, J = 8.1 Hz, 1H), 7.45-7.49 (m, 1H), 7.43 (dd, J = 8.6, 2.7 Hz, 1H). MS(M+1): 496. Pale yellow solid. Compound 6-37 N-(1,6-bis(3-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl) -5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.07 (br. s., 1H), 8.67 (s, 1H), 8.51-8.55 (m, 1H), 8.45 (dt, J = 7.0, 1.9 Hz, 1H), 8.39 (t, J = 2.2 Hz, 1H), 8.37 (d, J = 4.4 Hz, 1H), 8.32 (ddd, J = 8.3, 2.0, 1.0 Hz, 1H), 8.26 (d, J = 4.4 Hz, 1H), 7.61-7.71 (m, 3H), 7.47-7.52 (m, 1H). MS(M+1): 511. Pale yellow solid. Compound 6-38 N-(1-(3-chlorophenyl)-6-(4-chlorophenyl)-1H-pyrazolo[3,4-d]p yrimidin-4-yl)-5-nitrothiophene- 2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.02 (br. s., 1H), 8.62 (s, 1H), 8.44-8.54 (m, 2H), 8.37 (d, J = 4.4 Hz, 1H), 8.29-8.35 (m, 2H), 8.25 (d, J = 4.4 Hz, 1H), 7.60-7.71 (m, 3H), 7.43-7.50 (m, 1H). MS(M+1): 511. Pale yellow solid. Compound 6-39 N-(6-(benzo[d][1,3]dioxol-5-yl)-1-(3-chlorophenyl)-1H-pyrazo lo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.93 (br. s., 1H), 8.59 (s, 1H), 8.39 (t, J = 2.0 Hz, 1H), 8.29- 8.35 (m, 2H), 8.25 (d, J = 4.4 Hz, 1H), 8.13 (dd, J = 8.3, 1.5 Hz, 1H), 7.96 (d, J = 1.5 Hz, 1H), 7.66 (t, J = 8.3 Hz, 1H), 7.41-7.50 (m, 1H), 7.12 (d, J = 8.3 Hz, 1H), 6.15 (s, 2H). MS(M+1):521. Orange solid. Compound 6-40 N-(1-(3-chlorophenyl)-6-(3-(trifluoromethoxy)phenyl)-1H-pyra zolo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.02 (s, 1H), 8.64 (s, 1H), 8.51 (dt, J = 7.8, 1.2 Hz, 1H), 8.38-8.45 (m, 2H), 8.36 (d, J = 4.4 Hz, 1H), 8.17-8.31 (m, 2H), 7.74 (t, J = 8.1 Hz, 1H), 7.65 (t, J = 8.1 Hz, 1H), 7.55-7.62 (m, 1H), 7.40-7.52 (m, 1H). MS(M+1): 561. Yellow solid. Compound 6-41 N-(1-(3-chlorophenyl)-6-(2-fluoro-4-(trifluoromethyl)phenyl) -1H-pyrazolo[3,4-d]pyrimidin-4- yl)-5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.27 (br. s., 1H), 8.69 (s, 1H), 8.43-8.50 (m, 2H), 8.36 (d, J = 4.4 Hz, 1H), 8.29 (dd, J = 8.3, 1.5 Hz, 1H), 8.24 (d, J = 4.4 Hz, 1H), 7.92 (d, J = 10.8 Hz, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.63 (t, J = 8.1 Hz, 1H), 7.44-7.49 (m, 1H). MS(M+1):563. Ashy solid. Compound 6-42 N-(6-(2,4-bis(trifluoromethyl)phenyl)-1-(3-chlorophenyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.43 (s, 1H), 8.77 (s, 1H), 8.32-8.40 (m, 2H), 8.27-8.32 (m, 2H), 8.23 (d, J = 4.4 Hz, 1H), 8.14-8.22 (m, 2H), 7.58-7.64 (m, 1H), 7.42-7.51 (m, 1H). MS(M+1): 613. White solid. Compound 6-43 N-(1-(3-chlorophenyl)-6-(6-(2-methoxyethoxy)pyridin-3-yl)-1H -pyrazolo[3,4-d]pyrimidin-4-yl)- 5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.88 (br. s., 1H), 9.18 (d, J = 2.0 Hz, 1H), 8.60 (dd, J = 8.8, 2.4 Hz, 1H), 8.56 (s, 1H), 8.26-8.38 (m, 3H), 8.23 (d, J = 4.4 Hz, 1H), 7.63 (t, J = 8.3 Hz, 1H), 7.38-7.47 (m, 1H), 6.99 (d, J = 8.8 Hz, 1H), 4.43-4.53 (m, 2H), 3.65-3.78 (m, 2H), 3.34 (s, 3H). MS(M+1): 552. Light yellow solid. Compound 6-44 N-(1-(3-chlorophenyl)-6-(6-(2-ethoxyethoxy)pyridin-3-yl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.91 (br. s., 1H), 9.19 (d, J = 2.4 Hz, 1H), 8.61 (dd, J = 8.8, 2.4 Hz, 1H), 8.56 (s, 1H), 8.28 - 8.37 (m, 3H), 8.23 (d, J = 4.4 Hz, 1H), 7.63 (t, J = 8.3 Hz, 1H), 7.41-7.49 (m, 1H), 7.00 (d, J = 8.8 Hz, 1H), 4.46 (dd, J = 5.6, 4.2 Hz, 2H), 3.70-3.79 (m, 2H), 3.52 (q, J = 6.8 Hz, 2H), 1.14 (t, J = 7.1 Hz, 3H). MS(M+1): 566. Light yellow solid. Compound 6-45 N-(1-(3-chlorophenyl)-6-(6-(2-(2-ethoxyethoxy)ethoxy)pyridin -3-yl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.80 (br. s., 1H), 9.12 (d, J = 2.4 Hz, 1H), 8.40- 8.59 (m, 2H), 8.13-8.40 (m, 4H), 7.51-7.69 (m, 1H), 7.33-7.49 (m, 1H), 6.95 (d, J = 8.8 Hz, 1H), 4.38- 4.50 (m, 2H), 3.74-3.83 (m, 2H), 3.57-3.63 (m, 2H), 3.48-3.54 (m, 2H), 3.44 (q, J = 6.8 Hz, 2H), 1.10 (t, J = 7.1 Hz, 3H). MS(M+1): 610. Brown solid. Compound 6-46 N-(1-(4-chlorophenyl)-6-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazo lo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.34 (br. s., 1H), 8.56-8.73 (m, 2H), 8.20-8.41 (m, 4H), 7.65- 7.73 (m, 2H), 6.44-6.52 (m, 1H), 2.32-2.36 (m, 3H). MS(M+1): 481. Yellow solid. Compound 6-47 N-(1-(4-chlorophenyl)-6-(piperidin-1-yl)-1H-pyrazolo[3,4-d]p yrimidin-4-yl)-5-nitrothiophene-2- carboxamide 11.49 (br. s., 1H), 8.27-8.34 (m, 2H), 8.19-8.27 (m, 3H), 7.58- 7.65 (m, 2H), 3.89 (d, J = 5.4 Hz, 4H), 1.64-1.72 (m, 2H), 1.53-1.64 (m, 4H). MS(M+1): 484. Orange solid. Compound 6-48 N-(1-(4-chlorophenyl)-6-(4-fluorophenyl)-1H-pyrazolo[3,4-d]p yrimidin-4-yl)-5-nitrothiophene- 2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 8.64 (s, 1H), 8.54-8.63 (m, 2H), 8.29-8.41 (m, 3H), 8.26 (d, J = 4.4 Hz, 1H), 7.71 (d, J = 8.8 Hz, 2H), 7.43 (t, J = 8.8 Hz, 2H). MS(M+1): 495. Yellow orange solid. Compound 6-49 N-(1,6-bis(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl) -5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.14 (br. s., 1H), 8.65 (s, 1H), 8.55 (d, J = 8.3 Hz, 2H), 8.34 (d, J = 8.8 Hz, 3H), 8.25 (d, J = 4.4 Hz, 1H), 7.71 (d, J = 8.8 Hz, 2H), 7.66 (d, J = 8.3 Hz, 2H), MS(M+1): 511., Khaki solid. Compound 6-50 N-(6-(benzo[d][1,3]dioxol-5-yl)-1-(4-chlorophenyl)-1H-pyrazo lo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.94 (br. s., 1H), 8.62 (s, 1H), 8.33-8.38 (m, 3H), 8.23 (d, J = 4.4 Hz, 1H), 8.18 (dd, J = 8.3, 2.0 Hz, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.65-7.75 (m, 2H), 7.09 (d, J = 8.3 Hz, 1H), 6.15 (s, 2H). MS(M+1):521. Light orange solid. Compound 6-51 N-(1-(4-chlorophenyl)-6-(6-(2-methoxyethoxy)pyridin-3-yl)-1H -pyrazolo[3,4-d]pyrimidin-4-yl)- 5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.97 (br. s., 1H), 9.27 (d, J = 2.0 Hz, 1H), 8.69 (dd, J = 8.8, 2.4 Hz, 1H), 8.60 (s, 1H), 8.29-8.39 (m, 3H), 8.25 (d, J = 4.4 Hz, 1H), 7.66- 7.75 (m, 2H), 7.01 (d, J = 8.3 Hz, 1H), 4.48 (dd, J = 5.6, 3.7 Hz, 2H), 3.66-3.77 (m, 2H), 3.32 (s, 3H). MS(M+1):552. Khaki solid. Compound 6-52 N-(1-(4-chlorophenyl)-6-(6-(2-ethoxyethoxy)pyridin-3-yl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.92 (br. s., 1H), 9.23 (d, J = 2.4 Hz, 1H), 8.65 (dd, J = 8.8, 2.4 Hz, 1H), 8.57 (s, 1H), 8.28-8.37 (m, 3H), 8.24 (d, J = 4.4 Hz, 1H), 7.61-7.72 (m, 2H), 6.99 (d, J = 8.8 Hz, 1H), 4.37-4.50 (m, 2H), 3.69-3.80 (m, 2H), 3.52 (q, J = 7.2 Hz, 2H), 1.08-1.19 (m, 3H). MS(M+1): 566. Khaki solid. Compound 6-53 N-(1-(4-chlorophenyl)-6-(6-(2-(2-ethoxyethoxy)ethoxy)pyridin -3-yl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ):δ 11.91 (br. s., 1H), 9.23 (d, J = 2.0 Hz, 1H), 8.64 (dd, J = 8.3, 2.4 Hz, 1H), 8.56 (s, 1H), 8.26-8.39 (m, 3H), 8.23 (d, J = 4.4 Hz, 1H), 7.60 -7.71 (m, 2H), 6.98 (d, J = 8.3 Hz, 1H), 4.42-4.52 (m, 2H), 3.74-3.84 (m, 2H), 3.58 -3.66 (m, 2H), 3.49-3.55 (m, 2H), 3.44 (q, J = 6.8 Hz, 2H), 1.07-1.13 (m, 3H). MS (M+1):610. Brown solid. Compound 6-54 N-(6-(6-fluoropyridin-3-yl)-1-(4-(trifluoromethyl)phenyl)-1H -pyrazolo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ):δ 12.08 (s, 1H), 9.38 (s, 1H), 8.94-9.07 (m, 1H), 8.73 (s, 1H), 8.57-8.66 (m, J = 8.3 Hz, 2H), 8.40 (d, J = 4.4 Hz, 1H), 8.20-8.17 (d, J = 4.4 Hz, 1H), 7.88-7.99 (m, J = 8.3 Hz, 2H), 7.33 (d, J = 7.3 Hz, 1H). MS(M+1):530. White brown solid. Compound 6-55 N-(6-(4-chlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-pyraz olo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.12 (br. s., 1H), 8.70 (s, 2H), 8.59 (t, J = 7.8 Hz, 3H), 8.37 (br. s., 1H), 8.27 (br. s., 1H), 8.02 (d, J = 7.8 Hz, 2H), 7.67 (d, J = 8.3 Hz, 2H). MS(M+1):545. Lavender solid. Compound 6-56 N-(6-(6-(2-(2-ethoxyethoxy)ethoxy)pyridin-3-yl)-1-(4-(triflu oromethyl)phenyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamid e 1H NMR (400MHz, DMSO-d 6 ): δ 11.98 (br. s., 1H), 9.29 (br. s., 1H), 8.71 (d, J = 7.8 Hz, 1H), 8.64 (s, 1H), 8.54-8.63 (m, J = 7.8 Hz, 2H), 8.35 (d, J = 3.9 Hz, 1H), 8.25 (d, J = 3.9 Hz, 1H), 7.93-8.06 (m, J = 7.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 1H), 4.48 (br. s., 2H), 3.79 (br. s., 2H), 3.57- 3.62 (m, 2H), 3.50-3.54 (m, 2H), 3.44 (d, J = 6.8 Hz, 2H), 1.10 (t, J = 6.8 Hz, 3H). MS(M+1):644. Yellow solid. Compound 6-57 N-(1-(4-(tert-butyl)phenyl)-6-methoxy-1H-pyrazolo[3,4-d]pyri midin-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.14 (br. s., 1H), 8.50 (s, 1H), 8.33 (d, J = 4.4 Hz, 1H), 8.21 (d, J = 4.4 Hz, 1H), 8.08-8.14 (m, J = 8.8 Hz, 2H), 7.56-7.63 (m, J = 8.8 Hz, 2H), 4.05 (s, 3H), 1.34 (s, 9H). MS (M+1) : 453. Light yellow solid. Compound 6-58 N-(1-(4-(tert-butyl)phenyl)-6-(2-(dimethylamino)ethoxy)-1H-p yrazolo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.14 (br. s., 1H), 9.58 (br. s., 1H), 8.55 (s, 1H), 8.32 (d, J = 4.4 Hz, 1H), 8.24 (d, J = 4.4 Hz, 1H), 8.03-8.10 (m, J = 8.8 Hz, 2H), 7.57-7.63 (m, J = 8.8 Hz, 2H), 4.78 (dd, J = 5.6, 4.2 Hz, 2H), 3.58-3.66 (m, 2H), 2.89 (s, 6H), 1.35 (s, 9H). MS (M+1) : 510. Yellow solid. Compound 6-59 N-(1-(4-(tert-butyl)phenyl)-6-(2,2,3,3-tetrafluoropropoxy)-1 H-pyrazolo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.24 (s, 1H), 8.58 (s, 1H), 8.34 (d, J = 4.4 Hz, 1H), 8.23 (d, J = 4.4 Hz, 1H), 8.03-8.09 (m, J = 8.3 Hz, 2H), 7.57-7.63 (m, J = 8.8 Hz, 2H), 6.68 (t, J = 5.4 Hz, 1H), 5.03 (t, J = 13.9 Hz, 2H), 1.35 (s, 9H). MS(M+1):553. Compound 6-60 N-(1-(4-(tert-butyl)phenyl)-6-(2-morpholinoethoxy)-1H-pyrazo lo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 8.51 (s, 1H), 8.32 (d, J = 4.4 Hz, 1H), 8.22 (d, J = 4.4 Hz, 1H), 8.04-8.11 (m, J = 8.8 Hz, 2H), 7.56-7.62 (m, J = 8.8 Hz, 2H), 4.55 (t, J = 5.6 Hz, 2H), 3.52-3.58 (m, 4H), 2.76 (t, J = 5.6 Hz, 2H), 1.34 (s, 9H). MS(M+1):552. Compound 6-61 N-(1-(4-(tert-butyl)phenyl)-6-(2-(2-ethoxyethoxy)ethoxy)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.11 (br. s., 1H), 8.51 (s, 1H), 8.32 (d, J = 4.9 Hz, 1H), 8.21 (d, J = 4.4 Hz, 1H), 8.05-8.10 (m, J = 8.8 Hz, 2H), 7.56-7.61 (m, J = 8.8 Hz, 2H), 4.52-4.59 (m, 2H), 3.79-3.85 (m, 2H), 3.57-3.63 (m, 2H), 3.46-3.51 (m, 2H), 3.41 (q, J = 7.2 Hz, 2H), 1.34 (s, 9H), 1.04-1.10 (m, 3H). MS(M+1):555. Light green solid Compound 6-62 N-(1-(4-(tert-butyl)phenyl)-6-(pyrrolidin-1-yl)-1H-pyrazolo[ 3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 8.20-8.28 (m, J = 8.8 Hz, 2H), 8.04 (d, J = 4.4 Hz, 1H), 8.02 (s, 1H), 7.61 (d, J = 3.9 Hz, 1H), 7.46-7.52 (m, J = 8.8 Hz, 2H), 3.58 (t, J = 6.6 Hz, 4H), 1.89-1.99 (m, 4H), 1.32 (s, 9H). MS(M+1):492. Compound 6-63 N-(1-(4-(tert-butyl)phenyl)-6-(piperidin-1-yl)-1H-pyrazolo[3 ,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.46 (br. s., 1H), 8.29 (d, J = 4.4 Hz, 1H), 8.26 (s, 1H), 8.23 (d, J = 4.4 Hz, 1H), 8.06-8.15 (m, 2H), 7.49-7.60 (m, 2H), 3.89 (d, J = 4.9 Hz, 4H), 1.66 (br. s., 2H), 1.53-1.64 (m, 4H), 1.33 (s, 9H). MS(M+1):506. Compound 6-64 N-(1-(4-(tert-butyl)phenyl)-6-(3-methylpiperidin-1-yl)-1H-py razolo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.45 (s, 1H), 8.20-8.32 (m, 3H), 8.06-8.16 (m, 2H), 7.49 - 7.62 (m, 2H), 4.68 (d, J = 12.7 Hz, 2H), 3.01 (t, J = 11.7 Hz, 1H), 2.64 -2.79 (m, 1H), 1.82 (d, J = 12.2 Hz, 1H), 1.67-1.79 (m, 1H), 1.61 (dd, J = 10.5, 3.7 Hz, 1H), 1.47 (q, J = 12.2 Hz, 1H), 1.14- 1.29 (m, 1H), 0.96 (d, J = 6.4 Hz, 3H). MS(M+1) : 520. Compound 6-65 N-(1-(4-(tert-butyl)phenyl)-6-(3,3-difluoroazetidin-1-yl)-1H -pyrazolo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.90 (s, 1H), 8.34 (s, 1H), 8.31 (d, J = 4.4 Hz, 1H), 8.20 (d, J = 4.9 Hz, 1H), 8.06-8.12 (m, J = 8.8 Hz, 2H), 7.51-7.58 (m, J = 8.8 Hz, 2H), 4.60 (t, J = 12.5 Hz, 4H), 1.33 (s, 9H). MS(M+1):514. Compound 6-66 N-(1-(4-(tert-butyl)phenyl)-6-(3,3-difluoropyrrolidin-1-yl)- 1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.62 (br. s., 1H), 8.28-8.33 (m, 2H), 8.23 (d, J = 4.9 Hz, 1H), 8.13-8.19 (m, J = 8.8 Hz, 2H), 7.53-7.60 (m, J = 8.8 Hz, 2H), 4.06 (t, J = 13.0 Hz, 2H), 3.88 (t, J = 7.3 Hz, 2H), 2.59 (tt, J = 14.3, 7.2 Hz, 2H), 1.34 (s, 9H). MS (M+1) : 528. Yellow solid. Compound 6-67 N-(1-(4-(tert-butyl)phenyl)-6-(4,4-difluoropiperidin-1-yl)-1 H-pyrazolo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.56 (br. s., 1H), 8.32 (s, 1H), 8.30 (d, J = 4.4 Hz, 1H), 8.23 (d, J = 4.4 Hz, 1H), 8.09 (d, J = 8.8 Hz, 2H), 7.57 (d, J = 8.8 Hz, 2H), 4.03 (t, J = 5.4 Hz, 4H), 1.99-2.17 (m, 4H), 1.34 (s, 9H). MS(M+1):542. Yellow solid. Compound 6-68 N-(1-(4-(tert-butyl)phenyl)-6-(2-methylenepyrrolidin-1-yl)-1 H-pyrazolo[3,4-d]pyrimidin-4-yl)- 5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 8.55 (s, 1H), 8.12 (d, J = 4.4 Hz, 1H), 7.87-8.00 (m, J = 8.3 Hz, 2H), 7.78 (d, J = 4.4 Hz, 1H), 7.53-7.61 (m, J = 8.8 Hz, 2H), 4.39-4.52 (m, 1H), 4.27-4.37 (m, 1H), 4.14-4.26 (m, 1H), 3.61-3.75 (m, 1H), 2.06-2.19 (m, 1H), 2.02 (br. s., 1H), 1.85-1.99 (m, 1H), 1.57-1.74 (m, 1H), 1.33 (s, 9H). MS(M+1):504. Yellow solid. Compound 6-69 methyl(1-(4-(tert-butyl)phenyl)-4-(5-nitrothiophene-2-carbox amido)-1H-pyrazolo[3,4- d]pyrimidin-6-yl)-L-prolinate 1H NMR (400MHz, DMSO-d 6 ): δ 11.64 (br. s., 1H), 8.21-8.35 (m, 3H), 8.03-8.13 (m, J = 8.8 Hz, 2H), 7.46-7.60 (m, 2H), 4.57 (dd, J = 8.6, 3.7 Hz, 1H), 3.82 (br. s., 2H), 3.61-3.68 (m, 3H), 2.40 (br. s., 1H), 2.03 (d, J = 3.4 Hz, 3H), 1.34 (s, 9H). MS(M+1):550. Yellow solid. Compound 6-70 (1-(4-(tert-butyl)phenyl)-4-(5-nitrothiophene-2-carboxamido) -1H-pyrazolo[3,4-d]pyrimidin-6- yl)-L-proline 1H NMR (400MHz, DMSO-d 6 ): δ 12.63 (br. s., 1H), 11.63 (br. s., 1H), 8.12-8.36 (m, 5H), 7.39- 7.62 (m, 2H), 4.48 (dd, J = 8.6, 3.7 Hz, 1H), 3.80 (t, J = 5.4 Hz, 2H), 3.61-3.74 (m, 1H), 2.25- 2.45 (m, 2H), 1.87-2.16 (m, 3H), 1.33 (s, 9H). MS(M+1):536 Yellow solid. Compound 6-71 (S)-N-(1-(4-(tert-butyl)phenyl)-6-(2-(hydroxymethyl)pyrrolid in-1-yl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.48 (br. s., 1H), 8.15-8.38 (m, 5H), 7.54 (d, J = 9.3 Hz, 2H), 4.77 (br. s., 1H), 4.26 (br. s., 1H), 3.53-3.83 (m, 4H), 1.84-2.14 (m, 4H), 1.33 (s, 9H). MS(M+1):522. Yellow solid. Compound 6-72 (S)-N-(1-(4-(tert-butyl)phenyl)-6-(2-((2-(2-ethoxyethoxy)eth oxy)methyl)pyrrolidin-1-yl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamid e 1H NMR (400MHz, DMSO-d 6 ): δ 11.51 (br. s., 1H), 8.28 (br. s., 1H), 8.24 (s, 1H), 8.21 (d, J = 3.9 Hz, 1H), 8.12-8.19 (m, J = 8.3 Hz, 2H), 7.46-7.57 (m, J = 8.3 Hz, 2H), 4.36 (br. s., 1H), 3.78 (br. s., 1H), 3.63 (br. s., 3H), 3.53 (br. s., 3H), 3.44-3.50 (m, 3H), 3.42 (d, J = 4.9 Hz, 2H), 3.37 (q, J = 7.0 Hz, 2H), 2.03 (br. s., 3H), 1.92 (br. s., 1H), 1.33 (s, 9H), 1.05 (t, J = 7.1 Hz, 3H). MS(M+1):638. Orange solid. Compound 6-73 N-(1-(4-(tert-butyl)phenyl)-6-(4-(tert-butyl)piperazin-1-yl) -1H-pyrazolo[3,4-d]pyrimidin-4-yl)- 5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ):δ 11.68 (br. s., 1H), 8.31-8.37 (m, 2H), 8.23 (d, J = 4.4 Hz, 1H), 8.06-8.12 (m, 2H), 7.49-7.60 (m, 2H), 4.91 (d, J = 11.7 Hz, 2H), 3.65 (br. s., 4H), 3.06 (d, J = 8.8 Hz, 2H), 1.38 (br. s., 9H), 1.34 (s, 9H). MS(M+1):563. Yellow solid. Compound 6-74 N-(1-(4-(tert-butyl)phenyl)-6-(1H-imidazol-1-yl)-1H-pyrazolo [3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.16 (br. s., 1H), 8.69 (s, 1H), 8.64 (s, 1H), 8.34 (d, J = 4.4 Hz, 1H), 8.26 (d, J = 4.4 Hz, 1H), 8.11-8.18 (m, J = 8.8 Hz, 2H), 8.05 (t, J = 1.2 Hz, 1H), 7.61- 7.68 (m, J = 8.8 Hz, 2H), 7.19 (s, 1H), 1.36 (s, 9H). MS(M+1):489 Yellow solid. Compound 6-75 N-(1-(4-(tert-butyl)phenyl)-6-(1H-pyrazol-1-yl)-1H-pyrazolo[ 3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 8.81 (br. s., 1H), 8.51 (br. s., 1H), 8.14-8.24 (m, J = 8.8 Hz, 2H), 8.09 (br. s., 1H), 7.74 (br. s., 2H), 7.55-7.67 (m, J = 8.3 Hz, 2H), 6.65 (br. s., 1H), 1.36 (s, 9H). MS(M+1):489. Yellow solid. Compound 6-76 N-(6-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)-1-(4-(tert-butyl) phenyl)-1H-pyrazolo[3,4-d]pyrimidin- 4-yl)-5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.52 (s, 1H), 8.68 (s, 1H), 8.36 (br. s., 1H), 8.23 (d, J = 4.4 Hz, 1H), 8.01-8.19 (m, J = 8.8 Hz, 2H), 7.55-7.77 (m, J = 8.3 Hz, 2H), 1.48 (s, 9H), 1.36 (s, 9H). MS(M+1):547. White solid. Compound 6-77 N-(1-(4-(tert-butyl)phenyl)-6-(3-methyl-1H-pyrazol-1-yl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.31 (br. s., 1H), 8.65 (d, J = 2.9 Hz, 1H), 8.56 (s, 1H), 8.35 (d, J = 4.4 Hz, 1H), 8.23 (d, J = 4.4 Hz, 1H), 7.90-8.15 (m, 2H), 7.44-7.69 (m, 2H), 6.47 (d, J = 2.4 Hz, 1H), 2.33 (s, 3H), 1.36 (s, 9H). MS(M+1): 503. Yellow solid. Compound 6-78 N-(1-(4-(tert-butyl)phenyl)-6-(4-(trifluoromethyl)-1H-pyrazo l-1-yl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.33 (br. s., 1H), 9.25 (s, 1H), 8.66 (s, 1H), 8.37 (s, 1H), 8.21-8.31 (m, 2H), 8.11-8.19 (m, 2H), 7.61-7.69 (m, 2H), 1.37 (s, 9H). MS(M+1) :557. Compound 6-79 N-(1-(4-(tert-butyl)phenyl)-6-(2-fluorophenyl)-1H-pyrazolo[3 ,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.17 (br. s., 1H), 8.64 (s, 1H), 8.36 (d, J = 4.4 Hz, 1H), 8.13- 8.31 (m, 4H), 7.55-7.68 (m, 3H), 7.35-7.47 (m, 2H), 1.35 (s, 9H). MS(M+1):517. Compound 6-80 N-(1-(4-(tert-butyl)phenyl)-6-(3-fluorophenyl)-1H-pyrazolo[3 ,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.03 (br. s., 1H), 8.53 - 8.66 (m, 3H), 8.36 (d, J = 4.4 Hz, 1H), 8.26 (d, J = 4.4 Hz, 1H), 8.12-8.23 (m, 2H), 7.60-7.71 (m, 2H), 7.39-7.49 (m, 2H), 1.37 (s, 9H). MS(M+1):517. Compound 6-81 N-(1-(4-(tert-butyl)phenyl)-6-(4-fluorophenyl)-1H-pyrazolo[3 ,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.00 (br. s., 1H), 8.63 (s, 1H), 8.33-8.42 (m, 2H), 8.21-8.29 (m, 2H), 8.14-8.21 (m, 2H), 7.60-7.69 (m, 3H), 7.37-7.47 (m, 1H), 1.37 (s, 9H). MS(M+1):517. Compound 6-82 N-(1-(4-(tert-butyl)phenyl)-6-(6-methoxypyridin-3-yl)-1H-pyr azolo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.90 (d, J = 6.3 Hz, 1H), 9.52-9.24 (m ,1H), 8.66-8.53 (m, 2H), 8.34-8.14 (m, 4H), 7.61 (d, J = 6.8 Hz, 2H), 6.99-6.96 (m, 1H), 3.94 (s, 3H), 1.35 (s, 9H). MS(M+1): 530. Yellow-brown solid. Compound 6-83 N-(1-(4-(tert-butyl)phenyl)-6-(6-(2-(2-ethoxyethoxy)ethoxy)p yridin-3-yl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.92 (br. s., 1H), 9.25 (d, J = 2.0 Hz, 1H), 8.67 (dd, J = 8.8, 2.4 Hz, 1H), 8.56 (s, 1H), 8.34 (d, J = 4.4 Hz, 1H), 8.23 (d, J = 4.4 Hz, 1H), 8.08-8.20 (m, 2H), 7.57-7.69 (m, 2H), 7.01 (d, J = 8.8 Hz, 1H), 4.47 (dd, J = 5.6, 4.2 Hz, 2H), 3.78 (dd, J = 5.4, 3.9 Hz, 2H), 3.56-3.64 (m, 2H), 3.47-3.53 (m, 2H), 3.43 (q, J = 6.8 Hz, 2H), 1.36 (s, 9H), 1.10 (t, J = 7.1 Hz, 3H). MS(M+1):632. White solid. Compound 6-84 N-(6-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)-1-(4-(t rifluoromethoxy)phenyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamid e 1H NMR (400MHz, DMSO-d 6 ):δ 11.75 (br. s., 1H), 8.33-8.42 (m, 2H), 8.27-8.33 (m, 2H), 8.21 (d, J = 4.4 Hz, 1H), 7.55 (d, J = 8.3 Hz, 2H), 4.74-4.87 (m, 1H), 4.44 (dd, J = 9.8, 6.4 Hz, 2H), 3.93 (dd, J = 9.8, 4.4 Hz, 2H), 0.82-0.96 (m, 9H), 0.05-0.13 (m, 6H). MS(M+1):636. Compound 6-85 N-(6-(3,3-difluoropyrrolidin-1-yl)-1-(4-(trifluoromethoxy)ph enyl)-1H-pyrazolo[3,4-d]pyrimidin- 4-yl)-5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.65 (br. s., 1H), 8.40 (d, J = 9.3 Hz, 2H), 8.35 (s, 1H), 8.31 (d, J = 4.4 Hz, 1H), 8.22 (d, J = 4.4 Hz, 1H), 7.55 (d, J = 8.8 Hz, 2H), 4.06 (t, J = 13.2 Hz, 2H), 3.88 (t, J = 7.3 Hz, 2H), 2.52-2.68 (m, 2H). MS(M+1):556. Compound 6-86 N-(6-(4-(tert-butyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1 H-pyrazolo[3,4-d]pyrimidin-4-yl)- 5-nitrothiophene-2-carboxamide 12.06 (br. s., 1H), 8.62 (s, 1H), 8.43-8.55 (m, 4H), 8.38 (d, J = 4.4 Hz, 1H), 8.25 (d, J = 4.4 Hz, 1H), 7.54-7.73 (m, 4H), 1.35 (s, 9H). MS(M+1):583. Compound 6-87 5-nitro-N-(6-(4-(tert-pentyl)phenyl)-1-(4-(trifluoromethoxy) phenyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)thiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ):δ 12.04 (br. s., 1H), 8.63 (s, 1H), 8.42-8.51 (m, 4H), 8.38 (d, J = 4.4 Hz, 1H), 8.25 (d, J = 4.4 Hz, 1H), 7.65 (d, J = 8.3 Hz, 2H), 7.55 (d, J = 8.3 Hz, 2H), 1.69 (q, J = 7.3 Hz, 2H), 1.32 (s, 6H), 0.67 (t, J = 7.3 Hz, 3H). MS(M+1) :597. Compound 6-88 5-nitro-N-(1-(4-(trifluoromethoxy)phenyl)-6-(4-(trifluoromet hyl)phenyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)thiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ):δ 12.15 (br. s., 1H), 8.70-8.78 (m, J = 7.8 Hz, 2H), 8.68 (s, 1H), 8.40-8.48 (m, 2H), 8.38 (d, J = 4.4 Hz, 1H), 8.26 (d, J = 4.4 Hz, 1H), 7.91-8.00 (m, J = 8.3 Hz, 2H), 7.65 (d, J = 8.3 Hz, 2H). MS(M+1):595. Light yellow solid. Compound 6-89 N-(1-(3-fluorophenyl)-6-(4-fluorophenyl)-1H-pyrazolo[3,4-d]p yrimidin-4-yl)-5-nitrothiophene- 2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.99 (br. s., 1H), 8.43-8.64 (m, 3H), 8.35 (d, J = 4.4 Hz, 1H), 8.07-8.29 (m, 3H), 7.58-7.77 (m, 1H), 7.41 (t, J = 8.8 Hz, 2H), 7.12-7.35 (m, 1H). MS(M+1):479. Light yellow solid. Compound 6-90 N-(1-(3-fluorophenyl)-6-(6-fluoropyridin-3-yl)-1H-pyrazolo[3 ,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ) :δ 11.97 (br. s., 1H), 9.21 (d, J = 2.4 Hz, 1H), 8.84 (td, J = 8.1, 2.4 Hz, 1H), 8.54-8.64 (m, 1H), 8.28 (d, J = 4.4 Hz, 1H), 8.19-8.24 (m, 1H), 8.17 (dd, J = 8.3, 1.5 Hz, 1H), 8.06 (dt, J = 11.0, 2.1 Hz, 1H), 7.63 (td, J = 8.3, 6.4 Hz, 1H), 7.38 (dd, J = 8.6, 2.7 Hz, 1H), 7.22 (td, J = 8.6, 2.4 Hz, 1H). MS(M+1): 480. Light yellow solid. Compound 6-91 N-(6-(4-chlorophenyl)-1-(3-fluorophenyl)-1H-pyrazolo[3,4-d]p yrimidin-4-yl)-5-nitrothiophene- 2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.99 (br. s., 1H), 8.61 (s, 1H), 8.45-8.51 (m, 2H), 8.36 (d, J = 4.4 Hz, 1H), 8.24 (d, J = 4.4 Hz, 1H), 8.18 (dd, J = 8.3, 1.5 Hz, 1H), 8.11 (dt, J = 10.8, 2.4 Hz, 1H), 7.60-7.70 (m, 3H), 7.19-7.29 (m, 1H). MS(M+1):495. Yellow-green solid Compound 6-92 N-(6-(benzo[d][1,3]dioxol-5-yl)-1-(3-fluorophenyl)-1H-pyrazo lo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.84 (s, 1H), 8.56 (s, 1H), 8.34 (d, J = 4.4 Hz, 1H), 8.23 (d, J = 4.4 Hz, 1H), 8.16-8.21 (m, 1H), 8.07-8.15 (m, 2H), 7.93 (d, J = 1.5 Hz, 1H), 7.65 (td, J = 8.3, 6.8 Hz, 1H), 7.23 (td, J = 8.1, 2.4 Hz, 1H), 7.09 (d, J = 8.3 Hz, 1H), 6.14 (s, 2H). MS(M+1):505. Yellow solid. Compound 6-93 N-(1-(3-fluorophenyl)-6-(6-((2-methoxyethyl)(methyl)amino)py ridin-3-yl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ):δ 11.86 (br. s., 1H), 9.20 (d, J = 2.4 Hz, 1H), 8.54 (s, 1H), 8.45 (dd, J = 9.0, 2.2 Hz, 1H), 8.35 (d, J = 4.4 Hz, 1H), 8.20-8.26 (m, 2H), 8.16 (dt, J = 10.9, 2.4 Hz, 1H), 7.66 (td, J = 8.3, 6.8 Hz, 1H), 7.18-7.26 (m, 1H), 6.79 (d, J = 9.3 Hz, 1H), 3.80 (t, J = 5.6 Hz, 2H), 3.56 (t, J = 5.6 Hz, 2H), 3.28 (s, 3H), 3.13 (s, 3H). MS(M+1): 549. Orange solid. Compound 6-94 N-(1-(3-fluorophenyl)-6-(6-(2-methoxyethoxy)pyridin-3-yl)-1H -pyrazolo[3,4-d]pyrimidin-4-yl)- 5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.00 (br. s., 1H), 9.25 (d, J = 1.5 Hz, 1H), 8.66 (dd, J = 8.8, 2.4 Hz, 1H), 8.61 (s, 1H), 8.36 (d, J = 4.4 Hz, 1H), 8.20-8.26 (m, 2H), 8.13 (dt, J = 10.9, 2.4 Hz, 1H), 7.67 (td, J = 8.3, 6.8 Hz, 1H), 7.20-7.29 (m, 1H), 7.03 (d, J = 8.8 Hz, 1H), 4.43-4.52 (m, 2H), 3.65-3.73 (m, 2H), 3.33 (s, 3H). MS(M+1):536. Bright yellow solid. Compound 6-95 N-(6-(6-(2-ethoxyethoxy)pyridin-3-yl)-1-(3-fluorophenyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.96 (br. s., 1H), 9.23 (d, J = 2.4 Hz, 1H), 8.65 (dd, J = 8.8, 2.4 Hz, 1H), 8.59 (s, 1H), 8.33 (d, J = 4.4 Hz, 1H), 8.18-8.26 (m, 2H), 8.12 (dt, J = 10.9, 2.4 Hz, 1H), 7.66 (td, J = 8.3, 6.4 Hz, 1H), 7.24 (td, J = 8.2, 2.2 Hz, 1H), 7.03 (d, J = 8.8 Hz, 1H), 4.47 (dd, J = 5.4, 3.9 Hz, 2H), 3.74 (dd, J = 5.4, 3.9 Hz, 2H), 3.52 (q, J = 7.2 Hz, 2H), 1.10-1.19 (m, 3H). MS(M+1):550. Yellow solid. Compound 6-96 N-(6-(6-(2-(2-ethoxyethoxy)ethoxy)pyridin-3-yl)-1-(3-fluorop henyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ) :δ 11.80 (br. s., 1H), 9.12 (d, J = 2.4 Hz, 1H), 8.55 (dd, J = 8.8, 2.4 Hz, 1H), 8.49 (s, 1H), 8.11-8.35 (m, 4H), 7.49-7.64 (m, 1H), 7.32-7.41 (m, 1H), 6.95 (d, J = 8.8 Hz, 1H), 4.37-4.50 (m, 2H), 3.69-3.85 (m, 2H), 3.56-3.64 (m, 2H), 3.48- 3.54 (m, 2H), 3.44 (q, J = 6.8 Hz, 2H), 1.10 (t, J = 7.1 Hz, 3H). MS(M+1): 594. Yellow solid. Compound 6-97 N-(6-(3,3-difluoropyrrolidin-1-yl)-1-(4-fluorophenyl)-1H-pyr azolo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ):δ 11.65 (br. s., 1H), 8.15-8.41 (m, 5H), 7.27-7.46 (m, 2H), 4.05 (t, J = 13.0 Hz, 2H), 3.88 (t, J = 7.3 Hz, 2H), 2.54-2.68 (m, 2H). MS(M+1):490. Compound 6-98 N-(6-(4,4-difluoropiperidin-1-yl)-1-(4-fluorophenyl)-1H-pyra zolo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.57 (s, 1H), 8.27-8.37 (m, 2H), 8.12-8.27 (m, 3H), 7.29-7.45 (m, 2H), 4.03 (t, J = 5.6 Hz, 4H), 1.95-2.16 (m, 4H). MS(M+1):504. Compound 6-99 N-(6-((2S,6R)-2,6-dimethylmorpholino)-1-(4-fluorophenyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)- 5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.50 (s, 1H), 8.26-8.37 (m, 2H), 8.10-8.26 (m, 3H), 7.23-7.53 (m, 2H), 4.63 (d, J = 10.8 Hz, 2H), 3.61 (ddd, J = 10.6, 6.2, 2.7 Hz, 2H), 2.65 (dd, J = 13.2, 10.8 Hz, 2H), 1.09-1.28 (m, 6H). MS(M+1):498. Dark yellow solid. Compound 6-100 methyl (1-(4-fluorophenyl)-4-(5-nitrothiophene-2-carboxamido)-1H-py razolo [3,4-d]pyrimidin- 6-yl)-L-prolinate 1H NMR (400MHz, DMSO-d 6 ): δ 11.65 (br. s., 1H), 8.15-8.34 (m, 5H), 7.30-7.44 (m, 2H), 4.56 (dd, J = 8.6, 3.7 Hz, 1H), 3.81 (t, J = 6.1 Hz, 2H), 3.64 (s, 3H), 2.28-2.46 (m, 1H), 1.88-2.14 (m, 3H). MS(M+1):512. yellow solid. Compound 6-101 ethyl (1-(4-fluorophenyl)-4-(5-nitrothiophene-2-carboxamido)-1H-py razolo[3,4-d] pyrimidin-6- yl)-L-prolinate 1 H NMR (400MHz, DMSO-d 6 ): δ 11.60 (br. s., 1H), 8.13-8.36 (m, 5H), 7.26-7.44 (m, 2H), 4.58 (dd, J = 8.3, 3.4 Hz, 1H), 3.94-4.19 (m, 2H), 3.65-3.90 (m, 2H), 2.29-2.47 (m, 1H), 2.02 (d, J = 3.4 Hz, 3H), 1.04-1.22 (m, 3H). MS(M+1):526. Orange solid. Compound 6-102 (S)-N-(1-(4-fluorophenyl)-6-(2-(hydroxymethyl)pyrrolidin-1-y l)-1H-pyrazolo[3,4-d]pyrimidin- 4-yl)-5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.54 (br. s., 1H), 8.24-8.35 (m, 4H), 8.22 (d, J = 4.4 Hz, 1H), 7.37 (t, J = 8.8 Hz, 2H), 4.26 (br. s., 1H), 3.51-3.80 (m, 5H), 1.85-2.15 (m, 4H). MS(M+1):484. Yellow solid. Compound 6-103 (S)-N-(1-(4-fluorophenyl)-6-(2-(methoxymethyl)pyrrolidin-1-y l)-1H-pyrazolo[3,4-d]pyrimidin- 4-yl)-5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.51 (br. s., 1H), 8.23-8.33 (m, 4H), 8.20 (d, J = 4.4 Hz, 1H), 7.35 (t, J = 8.8 Hz, 2H), 4.35 (br. s., 1H), 3.52-3.76 (m, 3H), 3.39-3.49 (m, 1H), 2.02 (br. s., 3H), 1.78-1.97 (m, 1H). MS(M+1):498. Yellow solid. Compound 6-104 (S)-N-(6-(2-(ethoxymethyl)pyrrolidin-1-yl)-1-(4-fluorophenyl )-1H-pyrazolo[3,4-d]pyrimidin-4- yl)-5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.52 (br. s., 1H), 8.23-8.38 (m, 4H), 8.19-8.23 (m, 1H), 7.35 (t, J = 8.1 Hz, 2H), 4.36 (br. s., 1H), 3.72 (d, J = 7.8 Hz, 1H), 3.63 (br. s., 2H), 3.38-3.56 (m, 3H), 2.03 (br. s., 3H), 1.92 (d, J = 6.4 Hz, 1H), 1.11 (t, J = 7.1 Hz, 3H). MS(M+1):512. Yellow solid. Compound 6-105 (S)-N-(1-(4-fluorophenyl)-6-(2-(propoxymethyl)pyrrolidin-1-y l)-1H-pyrazolo[3,4-d]pyrimidin- 4-yl)-5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.51 (br. s., 1H), 8.16-8.36 (m, 5H), 7.25-7.43 (m, 2H), 4.25- 4.46 (m, 1H), 3.71 (dd, J = 9.0, 2.7 Hz, 1H), 3.63 (br. s., 2H), 3.33-3.51 (m, 3H), 1.96-2.15 (m, 3H), 1.92 (br. s., 1H), 1.43-1.56 (m, 2H), 0.85 (t, J = 7.3 Hz, 3H). MS(M+1):526. Orange solid. Compound 6-106 (S)-N-(1-(4-fluorophenyl)-6-(2-(phenoxymethyl)pyrrolidin-1-y l)-1H-pyrazolo[3,4-d]pyrimidin- 4-yl)-5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.51 (br. s., 1H), 8.27 (s, 2H), 8.20 (d, J = 3.9 Hz, 2H), 7.37 (br. s., 1H), 7.20-7.29 (m, 2H), 7.06 (br. s., 1H), 6.97 (d, J = 7.8 Hz, 2H), 6.91 (t, J = 6.8 Hz, 1H), 4.41 (br. s., 1H), 4.32 (d, J = 4.9 Hz, 1H), 4.06 (t, J = 8.6 Hz, 1H), 3.71 (br. s., 2H), 2.14 (br. s., 3H), 1.99 (br. s., 1H). MS(M+1):560. Yellow solid. Compound 6-107 N-(1-(4-fluorophenyl)-6-(thiophen-3-yl)-1H-pyrazolo[3,4-d]py rimidin-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.03 (s, 1H), 8.57 (s, 1H), 8.52-8.51 (m, 1H), 8.36 (d, J = 7.8 Hz, 1H), 8.35-8.29 (m, 2H), 8.24 (d, J = 8.8 Hz, 1H), 7.96-7.94 (m, 1H), 7.73-7.71 (m, 1H), 7.48-7.43 (m, 2H). MS(M+1): 467. Yellow solid. Compound 6-108 N-(1-(4-fluorophenyl)-6-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazo lo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.33 (br. s., 1H), 8.66 (d, J = 2.4 Hz, 1H), 8.59 (s, 1H), 8.36 (d, J = 4.4 Hz, 1H), 8.15-8.33 (m, 3H), 7.34-7.58 (m, 2H), 6.48 (d, J = 2.4 Hz, 1H), 2.33 (s, 3H). MS(M+1): 465. Yellow solid. Compound 6-109 N-(1-(4-fluorophenyl)-6-(3-(trifluoromethyl)-1H-pyrazol-1-yl )-1H-pyrazolo[3,4-d]pyrimidin-4- yl)-5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.47 (s, 1H), 8.91-9.06 (m, 1H), 8.67 (s, 1H), 8.39 (d, J = 4.4 Hz, 1H), 8.14-8.29 (m, 3H), 7.37-7.55 (m, 2H), 7.15 (d, J = 2.9 Hz, 1H). MS(M+1):519. Light yellow solid. Compound 6-110 N-(1-(4-fluorophenyl)-6-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4 -yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.02 (br. s., 1H), 8.62 (s, 1H), 8.44-8.59 (m, 2H), 8.16-8.44 (m, 4H), 7.55-7.69 (m, 3H), 7.40-7.55 (m, 2H). MS(M+1):461. Compound 6-111 N-(1-(4-fluorophenyl)-6-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyr imidin-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.08 (br. s., 1H), 9.65-9.69 (m, 1H), 8.77-8.81 (m, 1H), 8.74- 8.77 (m, 1H), 8.65 (s, 1H), 8.37 (d, J = 4.4 Hz, 1H), 8.28-8.34 (m, 2H), 8.26 (d, J = 4.4 Hz, 1H), 7.59-7.65 (m, 1H), 7.45-7.53 (m, 2H). MS(M+1):462. Yellow solid Compound 6-112 N-(1-(4-fluorophenyl)-6-(pyrimidin-5-yl)-1H-pyrazolo[3,4-d]p yrimidin-4-yl)-5-nitrothiophene- 2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.12 (br. s., 1H), 9.74 (s, 2H), 9.38 (s, 1H), 8.68 (s, 1H), 8.18-8.45 (m, 4H), 7.38 - 7.59 (m, 2H). MS(M+1): 463. Khaki solid. Compound 6-113 N-(6-(2-fluorophenyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]p yrimidin-4-yl)-5-nitrothiophene- 2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.19 (br. s., 1H), 8.65 (s, 1H), 8.13-8.41 (m, 5H), 7.54-7.67 (m, 1H), 7.33-7.54 (m, 4H). MS(M+1):479. White solid. Compound 6-114 N-(6-(3-fluorophenyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]p yrimidin-4-yl)-5-nitrothiophene- 2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.97 (br. s., 1H), 8.61 (s, 1H), 8.14-8.39 (m, 6H), 7.62 (td, J = 8.1, 5.9 Hz, 1H), 7.36-7.55 (m, 3H). MS(M+1):479. Khaki solid. Compound 6-115 N-(1,6-bis(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl) -5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.02 (br. s., 1H), 8.52-8.66 (m, 3H), 8.37 (d, J = 4.4 Hz, 1H), 8.17-8.33 (m, 3H), 7.31-7.55 (m, 4H). MS(M+1):479. Yellow solid. Compound 6-116 N-(1-(4-fluorophenyl)-6-(6-fluoropyridin-3-yl)-1H-pyrazolo[3 ,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.05 (s, 1H), 9.28 (s, 1H), 8.94-8.90 (m, 1H), 8.83 (d, J = 7.8 Hz, 1H), 8.63 (s, 1H), 8.39 (d, J = 8.8 Hz, 1H), 8.30-8.25 (m, 3H), 7.91-7.88 (m, 1H), 7.42-7.39 (m, 1H). MS(M+1): 480. Yellow solid. Compound 6-117 N-(6-(3-chlorophenyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]p yrimidin-4-yl)-5-nitrothiophene- 2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.01 (s, 1H), 8.64 (s, 1H), 8.53-8.52 (m, 1H), 8.47-8.45 (m, 1H), 8.38 (d, J = 7.8 Hz, 1H), 8.29-8.26 (m, 3H), 7.67-7.60 (m, 2H), 7.51-7.47 (m, 2H). MS(M+1): 495. Yellow solid. Compound 6-118 N-(6-(4-chlorophenyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]p yrimidin-4-yl)-5-nitrothiophene- 2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.00 (br. s., 1H), 8.60 (s, 1H), 8.47-8.53 (m, 2H), 8.37 (d, J = 4.4 Hz, 1H), 8.23-8.29 (m, 3H), 7.60-7.67 (m, 2H), 7.43-7.50 (m, 2H). MS(M+1): 495. Yellow solid. Compound 6-119 N-(6-(6-chloropyridin-3-yl)-1-(4-fluorophenyl)-1H-pyrazolo[3 ,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.06 (br. s., 1H), 9.43 (d, J = 2.4 Hz, 1H), 8.77 (dd, J = 8.3, 2.4 Hz, 1H), 8.63 (s, 1H), 8.36 (d, J = 4.4 Hz, 1H), 8.23-8.30 (m, 3H), 7.73 (d, J = 8.3 Hz, 1H), 7.46 (t, J = 8.8 Hz, 2H). MS(M+1):496. yellow solid. Compound 6-120 N-(1-(4-fluorophenyl)-6-(6-methylpyridin-3-yl)-1H-pyrazolo[3 ,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.05 (br. s., 1H), 9.54 (d, J = 2.0 Hz, 1H), 8.66 (dd, J = 8.1, 2.2 Hz, 1H), 8.63 (s, 1H), 8.38 (d, J = 4.4 Hz, 1H), 8.27-8.34 (m, 2H), 8.26 (d, J = 4.4 Hz, 1H), 7.43-7.54 (m, 3H), 2.58 (s, 3H). MS(M+1): 476. Amber solid. Compound 6-121 N-(1-(4-fluorophenyl)-6-(6-methoxypyridin-3-yl)-1H-pyrazolo[ 3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.90 (s, 1H), 9.24 (d, J = 2.4 Hz, 1H), 8.63 (dd, J = 8.8, 2.4 Hz, 1H), 8.55 (s, 1H), 8.34 (d, J = 4.4 Hz, 1H), 8.28 (dd, J = 9.3, 4.9 Hz, 2H), 8.23 (d, J = 4.4 Hz, 1H), 7.44 (t, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 1H), 3.94 (s, 3H). MS(M+1): 492. Yellow solid. Compound 6-122 N-(1-(4-fluorophenyl)-6-(4-(trifluoromethyl)phenyl)-1H-pyraz olo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.06 (s, 1H), 8.62-8.69 (m, J = 8.3 Hz, 2H), 8.60 (s, 1H), 8.37 (d, J = 4.4 Hz, 1H), 8.13-8.28 (m, 3H), 7.84-7.99 (m, J = 8.3 Hz, 2H), 7.45 (t, J = 8.8 Hz, 2H). MS(M+1):529. Compound 6-123 N-(1-(4-fluorophenyl)-6-(4-(trifluoromethoxy)phenyl)-1H-pyra zolo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ):δ 12.11 (br. s., 1H), 8.52-8.74 (m, 3H), 8.22-8.42 (m, 4H), 7.58 (d, J = 7.8 Hz, 2H), 7.49 (t, J = 8.8 Hz, 2H). MS(M+1):545. Yellow solid. Compound 6-124 N-(6-(benzo[d][1,3]dioxol-5-yl)-1-(4-fluorophenyl)-1H-pyrazo lo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.90 (br. s., 1H), 8.58 (s, 1H), 8.35 (d, J = 4.4 Hz, 1H), 8.23- 8.34 (m, 3H), 8.14 (dd, J = 8.3, 1.5 Hz, 1H), 7.98 (d, J = 1.5 Hz, 1H), 7.43-7.53 (m, 2H), 7.10 (d, J = 7.8 Hz, 1H), 6.15 (s, 2H). MS(M+1): 505. Light yellow solid. Compound 6-125 N-(6-(3,4-difluorophenyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4 -d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.95 (br. s., 1H), 8.61 (s, 1H), 8.31-8.44 (m, 3H), 8.18-8.30 (m, 3H), 7.58-7.70 (m, 1H), 7.47 (t, J = 8.8 Hz, 2H). MS(M+1):497. Brown solid. Compound 6-126 N-(6-(2,4-difluorophenyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4 -d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.20 (br. s., 1H), 8.60 (s, 1H), 8.23-8.35 (m, 3H), 8.18-8.23 (m, 2H), 7.38-7.49 (m, 3H), 7.29 (td, J = 8.3, 2.4 Hz, 1H). MS(M+1):497. ashy solid. Compound 6-127 N-(6-(4-chloro-3-fluorophenyl)-1-(4-fluorophenyl)-1H-pyrazol o[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.97 (br. s., 1H), 8.61 (s, 1H), 8.29-8.39 (m, 3H), 8.20-8.29 (m, 3H), 7.78 (t, J = 8.1 Hz, 1H), 7.36-7.53 (m, 2H). MS(M+1):513. Light khaki solid. Compound 6-128 N-(6-(4-chloro-2-fluorophenyl)-1-(4-fluorophenyl)-1H-pyrazol o[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.15 (br. s., 1H), 8.63 (s, 1H), 8.36 (d, J = 4.4 Hz, 1H), 8.20- 8.32 (m, 4H), 7.63 (dd, J = 11.0, 2.2 Hz, 1H), 7.50 (dd, J = 8.3, 2.0 Hz, 1H), 7.39-7.48 (m, 2H). MS(M+1): 513. Yellow-brown solid. Compound 6-129 N-(6-(4-chloro-2-ethoxyphenyl)-1-(4-fluorophenyl)-1H-pyrazol o[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 8.53 (s, 1H), 8.33 (dd, J = 9.0, 5.1 Hz, 2H), 7.82-8.20 (m, 3H), 7.41 (t, J = 8.8 Hz, 2H), 7.27 (s, 1H), 7.14 (d, J = 8.8 Hz, 1H), 4.19 (br. s., 2H), 1.30 (t, J = 7.1 Hz, 3H). MS(M+1): 539. Light yellow solid. Compound 6-130 N-(6-(6-(2-(dimethylamino)ethoxy)pyridin-3-yl)-1-(4-fluoroph enyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide 1H NMR (400MHz, D 2 O+DMSO-d 6 ) : δ 9.14 (d, J = 2.1 Hz, 1H), 8.62 (dd, J = 8.8, 2.1 Hz, 1H), 8.43 (s, 1H), 8.22 (d, J = 4.4 Hz, 1H), 8.18-8.14 (m, 2H), 8.10 (d, J = 4.4 Hz, 1H), 7.36 (t, J = 8.8 Hz, 2H), 6.99 (d, J = 8.8 Hz, 1H), 4.66-4.63 (m, 2H), 3.56-3.53 (m, 2H), 2.88 (s, 6H). MS- ESI (M+1): 549. Yellow solid. Compound 6-131 N-(1-(4-fluorophenyl)-6-(6-((2-methoxyethyl)(methyl)amino)py ridin-3-yl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.82 (br. s., 1H), 9.18 (d, J = 2.0 Hz, 1H), 8.50 (s, 1H), 8.44 (dd, J = 9.3, 2.4 Hz, 1H), 8.24-8.37 (m, 3H), 8.22 (d, J = 4.4 Hz, 1H), 7.44 (t, J = 8.8 Hz, 2H), 6.75 (d, J = 9.3 Hz, 1H), 3.78 (t, J = 5.6 Hz, 2H), 3.55 (t, J = 5.9 Hz, 2H), 3.27 (s, 3H), 3.12 (s, 3H). MS(M+1):549. Orange solid. Compound 6-132 N-(1-(4-fluorophenyl)-6-(4-propoxyphenyl)-1H-pyrazolo[3,4-d] pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.99 (br. s., 1H), 8.58 (s, 1H), 8.39 - 8.54 (m, 2H), 8.29 - 8.39 (m, 3H), 8.26 (d, J = 4.4 Hz, 1H), 7.38 - 7.65 (m, 2H), 6.99 - 7.23 (m, 2H), 4.04 (t, J = 6.6 Hz, 2H), 1.79 (tt, J = 7.0, 6.6 Hz, 2H), 1.02 (t, J = 7.0 Hz, 3H). MS(M+1): 519. Yellow solid. Compound 6-133 N-(1-(4-fluorophenyl)-6-(6-propoxypyridin-3-yl)-1H-pyrazolo[ 3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ) : δ 11.84 (brs, 1H), 9.19 (d, J = 2.1 Hz, 1H), 8.60 (dd, J = 8.8, 2.1 Hz, 1H), 8.52 (s, 1H), 8.32 (d, J = 4.4 Hz, 1H), 8.28-8.23 (m, 2H), 8.21 (d, J = 4.4 Hz, 1H), 7.42 (t, J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 1H), 4.28 (t, J = 6.8 Hz, 2H), 1.80- 1.71 (m, 2H), 0.99 (t, J = 6.8 Hz, 3H). MS(M+1): 520. Yellow solid. Compound 6-134 N-(1-(4-fluorophenyl)-6-(6-(2-hydroxyethoxy)pyridin-3-yl)-1H -pyrazolo[3,4-d]pyrimidin-4-yl)- 5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ) : δ 9.21 (d, J = 2.0 Hz, 1H), 8.62 - 8.76 (m, 1H), 8.37 - 8.43 (m, 2H), 8.33 - 8.37 (m, 1H), 8.06 (d, J = 3.9 Hz, 1H), 7.58 (d, J = 3.9 Hz, 1H), 7.37 - 7.48 (m, 2H), 6.93 (d, J = 9.3 Hz, 1H), 4.88 (br. s., 1H), 4.30 - 4.44 (m, 2H), 3.76 (t, J = 4.9 Hz, 2H). MS(M+1): 522. Orange solid. Compound 6-135 N-(1-(4-fluorophenyl)-6-(6-(2-methoxyethoxy)pyridin-3-yl)-1H -pyrazolo[3,4-d]pyrimidin-4-yl)- 5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.62 (s, 1H), 9.04 (d, J = 1.0 Hz, 1H), 8.45 (dd, J = 8.3, 1.8 Hz, 1H), 8.37 (s, 1H), 8.24-8.12 (m ,4H),7.32 (t, J = 8.3 Hz, 2H), 6.85 (d, J = 8.8 Hz, 1H), 4.40- 4.38 (m, 2H), 3.69-3.66 (m, 2H), 3.34 (s, 3H). MS(M+1): 536. Yellow solid. Compound 6-136 N-(6-(6-(2-ethoxyethoxy)pyridin-3-yl)-1-(4-fluorophenyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ) : δ 11.89 (br. s., 1H), 9.21 (d, J = 2.0 Hz, 1H), 8.63 (dd, J = 8.8, 2.4 Hz, 1H), 8.54 (s, 1H), 8.18-8.38 (m, 4H), 7.34 - 7.52 (m, 2H), 6.98 (d, J = 8.3 Hz, 1H), 4.45 (dd, J = 5.6, 4.2 Hz, 2H), 3.73 (dd, J = 5.6, 4.2 Hz, 2H), 3.52 (q, J = 6.8 Hz, 2H), 1.14 (t, J = 6.8 Hz, 3H). MS(M+1): 550. Yellow solid. Compound 6-137 N-(6-(6-(2-(2-ethoxyethoxy)ethoxy)pyridin-3-yl)-1-(4-fluorop henyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.95 (s, 1H), 9.23 (d, J = 2.4 Hz, 1H), 8.66 (dd, J = 8.8, 2.4 Hz, 1H), 8.56 (s, 1H), 8.33-8.22 (m, 4H), 7.45 (t, J = 8.8 Hz, 2H), 6.99 (d, J = 8.8 Hz, 1H), 4.47- 4.45 (m, 2H), 3.79-3.77 (m, 2H), 3.60-3.58 (m, 2H), 3.51-3.49 (m, 2H), 3.43 (q, J = 6.8 Hz, 2H), 1.09 (t, J = 6.8 Hz, 3H). MS(M+1): 594. Yellow solid. Compound 6-138 N-(6-(2-fluoro-4-(2-methoxyethoxy)phenyl)-1-(4-fluorophenyl) -1H-pyrazolo[3,4-d]pyrimidin-4- yl)-5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.14 (br. s., 1H), 8.61 (s, 1H), 8.18-8.42 (m, 5H), 7.37-7.53 (m, 2H), 6.92-7.08 (m, 2H), 4.22 (dd, J = 5.1, 3.7 Hz, 2H), 3.62-3.76 (m, 2H), 3.33 (s, 3H). MS(M+1): 553. Bright yellow solid. Compound 6-139 N-(6-(6-(2-(2-ethoxyethoxy)ethoxy)-4-methylpyridin-3-yl)-1-( 4-fluorophenyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.93 (s, 1H), 8.11 (s, 1H), 8.55 (s, 1H), 8.30 (d, J = 4.2 Hz, 1H), 8.19-8.15 (m, 1H), 7.42-7.38 (m, 2H), 6.79 (s, 1H), 4.43-4.41 (m, 2H), 3.77-3.74 (m, 2H), 3.60-3.57 (m, 2H), 3.51-3.49 (m, 2H), 3.43 (q, J = 6.8 Hz, 2H), 2.63(s, 3H), 1.10 (t, J = 6.8 Hz, 3H). MS(M+1): 608. Yellow solid. Compound 6-140 N-(6-(4-chloro-2-(2-(2-ethoxyethoxy)ethoxy)phenyl)-1-(4-fluo rophenyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.26 (br. s., 1H), 8.65 (s, 1H), 8.13-8.41 (m, 4H), 7.83 (br. s., 1H), 7.45 (t, J = 8.8 Hz, 2H), 7.37 (br. s., 1H), 7.20 (d, J = 7.3 Hz, 1H), 4.26 (br. s., 2H), 3.70 (br. s., 2H), 3.38 (br. s., 2H), 3.15-3.26 (m, 4H), 0.91 (t, J = 6.8 Hz, 3H). MS(M+1): 628. Yellow solid. Compound 6-141 N-(1-(4-fluorophenyl)-6-(6-morpholinopyridin-3-yl)-1H-pyrazo lo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.95 (br. s., 1H), 9.27 (d, J = 2.0 Hz, 1H), 8.53-8.58 (m, 2H), 8.30-8.37 (m, 3H), 8.25 (d, J = 4.4 Hz, 1H), 7.44-7.52 (m, 2H), 7.00 (d, J = 8.8 Hz, 1H), 3.69- 3.78 (m, 4H), 3.58-3.67 (m, 4H). MS(M+1):547. brown solid. Compound 6-142 N-(1-(4-fluorophenyl)-6-(4-methylcyclohex-1-en-1-yl)-1H-pyra zolo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ):δ 11.85 (br. s., 1H), 8.52 (s, 1H), 8.15-8.41 (m, 4H), 7.32-7.53 (m, 3H), 2.82 (d, J = 17.1 Hz, 1H), 2.36-2.48 (m, 2H), 1.81-2.03 (m, 2H), 1.74 (br. s., 1H), 1.23- 1.42 (m, 1H), 1.02 (d, J = 6.4 Hz, 3H). MS(M+1): 479. Pale yellow solid. Compound 6-143 N-(1-(4-fluorophenyl)-6-(4-methylcyclohexyl)-1H-pyrazolo[3,4 -d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 )(cis and trans):δ 12.03 (br. s., 1H), 8.55 (s, 2H), 8.31 (br. s., 2H), 8.09-8.28 (m, 7H), 7.37-7.53 (m, 4H), 3.04 (tt, J = 7.9, 4.0 Hz, 1H), 2.84 (tt, J = 11.9, 3.2 Hz, 1H), 2.14 (br. s., 2H), 2.06 (d, J = 11.2 Hz, 2H), 1.57-1.86 (m, 9H), 1.34- 1.52 (m, 3H), 1.03- 1.18 (m, 2H), 0.89-1.00 (m, 6H). MS(M+1): 481. Pale yellow solid. Compound 6-144 N-(6-(4,4-dimethylcyclohex-1-en-1-yl)-1-(4-fluorophenyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)- 5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.90 (br. s., 1H), 8.54 (s, 1H), 8.17-8.42 (m, 4H), 7.34-7.57 (m, 3H), 2.66 (br. s., 2H), 2.13 (br. s., 2H), 1.54 (t, J = 6.4 Hz, 2H), 0.98 (s, 6H). MS(M+1): 493. Pale yellow solid. Compound 6-145 N-(6-(4,4-dimethylcyclohexyl)-1-(4-fluorophenyl)-1H-pyrazolo [3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.23 (br. s., 1H), 8.55 (s, 1H), 8.16-8.41 (m, 4H), 7.37-7.55 (m, 2H), 2.73-2.90 (m, 1H), 1.75-1.99 (m, 4H), 1.51 (d, J = 12.7 Hz, 2H), 1.36 (td, J = 12.5, 4.9 Hz, 2H), 0.98 (d, J = 4.9 Hz, 6H). MS(M+1): 495. White solid. Table 7 Compound 7-1 N-(6-(4-fluorophenyl)-1-(5-(trifluoromethyl)pyridin-2-yl)-1H -pyrazolo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.11 (s, 1H), 9.08 (s, 1H), 8.47-8.76 (m, 5H), 8.39 (d, J = 4.4 Hz, 1H), 8.28 (d, J = 4.4 Hz, 1H), 7.43 (t, J = 8.6 Hz, 2H). MS(M+1):530. Light yellow solid. Compound 7-2 N-(6-(6-fluoropyridin-3-yl)-1-(5-(trifluoromethyl)pyridin-2- yl)-1H-pyrazolo[3,4-d]pyrimidin-4- yl)-5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.17 (brs, 1H), 9.36 (d, J = 2.4 Hz, 1H), 9.09 (s, 1H), 9.02- 8.97 (m, 1H), 8.76 (s, 1H), 8.68 (d, J = 8.8 Hz, 1H), 8.57-8.55 (m, 1H), 8.37 (d, J = 4.4 Hz, 1H), 8.27 (d, J = 4.4 Hz, 2H), 7.45-7.42 (m, 1H). MS(M+1): 531. White solid. Compound 7-3 N-(6-(4-chlorophenyl)-1-(5-(trifluoromethyl)pyridin-2-yl)-1H -pyrazolo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.12 (s, 1H), 9.08 (s, 1H), 8.72 (s, 1H), 8.60-8.69 (m, 1H), 8.50-8.60 (m, 3H), 8.39 (d, J = 4.4 Hz, 1H), 8.27 (d, J = 4.4 Hz, 1H), 7.61- 7.74 (m, 2H). MS(M+1):546. Light yellow solid. Compound 7-4 5-nitro-N-(6-(4-(trifluoromethyl)phenyl)-1-(5-(trifluorometh yl)pyridin-2-yl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)thiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.21 (br. s., 1H), 9.08 (s, 1H), 8.74 (t, J = 4.2 Hz, 3H), 8.64 (d, J = 8.8 Hz, 1H), 8.51-8.60 (m, 1H), 8.38 (d, J = 4.4 Hz, 1H), 8.27 (d, J = 4.4 Hz, 1H), 7.96 (d, J = 8.3 Hz, 2H). MS(M+1):580. White milky solid. Compound 7-5 5-nitro-N-(6-(4-(trifluoromethoxy)phenyl)-1-(5-(trifluoromet hyl)pyridin-2-yl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)thiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.16 (br. s., 1H), 9.08 (s, 1H), 8.72 (s, 1H), 8.66 (dd, J = 9.0, 2.2 Hz, 3H), 8.55 (dd, J = 8.6, 2.2 Hz, 1H), 8.38 (d, J = 4.4 Hz, 1H), 8.27 (d, J = 4.4 Hz, 1H), 7.58 (d, J = 7.8 Hz, 2H). MS(M+1):596. White solid. Compound 7-6 N-(6-(2,4-difluorophenyl)-1-(5-(trifluoromethyl)pyridin-2-yl )-1H-pyrazolo[3,4-d]pyrimidin-4- yl)-5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.25 (br. s., 1H), 9.05 (s, 1H), 8.73 (s, 1H), 8.67 (d, J = 8.3 Hz, 1H), 8.54 (dd, J = 8.8, 2.4 Hz, 1H), 8.37 (d, J = 4.4 Hz, 1H), 8.17-8.34 (m, 2H), 7.46 (t, J = 2.2 Hz, 1H), 7.32 (d, J = 2.4 Hz, 1H). MS(M+1):548. White solid. Compound 7-7 N-(6-(6-(2-(2-ethoxyethoxy)ethoxy)pyridin-3-yl)-1-(5-(triflu oromethyl)pyridin-2-yl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamid e 1H NMR (400MHz, DMSO-d 6 ): δ 11.96 (s, 1H), 9.25 (d, J = 2.4 Hz, 1H), 9.02 (s, 1H), 8.68-8.64 (m, 3H), 8.53-8.50 (m, 1H), 8.34 (d, J = 8.8 Hz, 1H), 8.23 (d, J = 8.8 Hz, 1H), 6.98 (d, J = 8.8 Hz, 1H), 4.47-4.45 (m, 2H), 3.79-3.77 (m, 2H), 3.60-3.58 (m, 2H), 3.52-3.49 (m, 2H), 3.43 (q, J = 6.8 Hz, 2H), 1.10 (t, J = 6.8 Hz, 3H). MS(M+1): 645. Yellow solid. Compound 7-8 N-(6-(4-fluorophenyl)-1-(pyridin-2-yl)-1H-pyrazolo[3,4-d]pyr imidin-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ):δ 12.04 (br. s., 1H), 8.67-8.71 (m, 1H), 8.65 (s, 1H), 8.53-8.60 (m, 2H), 8.39 (d, J = 4.4 Hz, 1H), 8.23-8.30 (m, 2H), 8.11-8.18 (m, 1H), 7.52 (ddd, J = 7.3, 4.9, 1.0 Hz, 1H), 7.35-7.45 (m, 2H). MS(M+1):462. Yellow solid. Compound 7-9 N-(1-(2,4-dichlorophenyl)-6-(4-fluorophenyl)-1H-pyrazolo[3,4 -d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.10 (br. s., 1H), 8.65 (s, 1H), 8.39-8.48 (m, 2H), 8.37 (d, J = 4.4 Hz, 1H), 8.26 (d, J = 4.4 Hz, 1H), 8.02 (d, J = 2.4 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.73 (dd, J = 8.8, 2.4 Hz, 1H), 7.32-7.41 (m, 2H). MS(M+1):530. Light khaki solid. Compound 7-10 N-(1-(2,4-dichlorophenyl)-6-(6-fluoropyridin-3-yl)-1H-pyrazo lo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.19 (br. s., 1H), 9.18 (d, J = 2.4 Hz, 1H), 8.78 (td, J = 8.3, 2.4 Hz, 1H), 8.68 (s, 1H), 8.31 (d, J = 4.4 Hz, 1H), 8.26 (d, J = 4.4 Hz, 1H), 8.02 (d, J = 2.4 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.68-7.78 (m, 1H), 7.35 (dd, J = 8.8, 2.4 Hz, 1H). MS(M+1): 530. Light khaki solid. Compound 7-11 (S)-N-(1-(3,4-dichlorophenyl)-6-(2-(hydroxymethyl)pyrrolidin -1-yl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.54 (br. s., 1H), 8.63 (br. s., 1H), 8.25-8.34 (m, 2H), 8.18- 8.25 (m, 1H), 7.77 (d, J = 8.8 Hz, 1H), 4.73 (br. s., 1H), 4.25 (d, J = 16.6 Hz, 1H), 3.65 (br. s., 4H), 1.98-2.18 (m, 3H), 1.91 (br. s., 1H). MS(M+1): 534. Khaki solid. Compound 7-12 N-(1-(2,4-difluorophenyl)-6-(4-fluorophenyl)-1H-pyrazolo[3,4 -d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ):δ 12.08 (br. s., 1H), 8.65 (s, 1H), 8.42-8.51 (m, 2H), 8.37 (d, J = 4.4 Hz, 1H), 8.26 (d, J = 4.4 Hz, 1H), 7.88 (td, J = 8.8, 5.9 Hz, 1H), 7.63-7.73 (m, 1H), 7.32-7.44 (m, 3H). MS(M+1): 497. Yellow solid. Compound 7-13 N-(1-(2,4-difluorophenyl)-6-(6-fluoropyridin-3-yl)-1H-pyrazo lo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.14 (br. s., 1H), 9.21 (d, J = 2.4 Hz, 1H), 8.80 (td, J = 8.4, 2.4 Hz, 1H), 8.69 (s, 1H), 8.38 (d, J = 4.4 Hz, 1H), 8.27 (d, J = 4.4 Hz, 1H), 7.90 (td, J = 8.4, 6.0 Hz, 1H), 7.60-7.76 (m, 1H), 7.31-7.47 (m, 2H). MS(M+1): 498. White solid. Compound 7-14 N-(6-(4-chlorophenyl)-1-(2,4-difluorophenyl)-1H-pyrazolo[3,4 -d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.09 (br. s., 1H), 8.65 (s, 1H), 8.31-8.50 (m, 3H), 8.25 (d, J = 4.4 Hz, 1H), 7.88 (td, J = 8.8, 5.9 Hz, 1H), 7.55-7.73 (m, 3H), 7.31-7.45 (m, 1H). MS(M+1): 513. Yellow solid. Compound 7-15 N-(1-benzyl-6-(6-chloropyridin-3-yl)-1H-pyrazolo[3,4-d]pyrim idin-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ):δ 12.03 (br. s., 1H), 9.48 (d, J = 2.0 Hz, 1H), 8.85 (dd, J = 8.3, 2.4 Hz, 1H), 8.46 (s, 1H), 8.32 (d, J = 4.4 Hz, 1H), 8.24 (d, J = 4.4 Hz, 1H), 7.75 (d, J = 8.3 Hz, 1H), 7.19-7.46 (m, 5H), 5.74 (s, 2H). MS(M+1): 492. Lemon Chiffon solid. Compound 7-16 N-(1-benzyl-6-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4 -yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.97 (br. s., 1H), 8.49-8.61 (m, 2H), 8.43 (s, 1H), 8.36 (d, J = 4.4 Hz, 1H), 8.25 (d, J = 4.4 Hz, 1H), 7.57-7.72 (m, 2H), 7.22-7.39 (m, 5H), 5.73 (s, 2H). MS(M+1): 491. Bright yellow solid. Compound 7-17 N-(1-benzyl-6-(6-methylpyridin-3-yl)-1H-pyrazolo[3,4-d]pyrim idin-4-yl)-5-nitrothiophene-2- carboxamide d 6 ): δ 11.97 (s, 1H), 9.56 (d, J = 2.0 Hz, 1H), 8.66-8.79 (m, 1H), 8.44 (s, 1H), 8.38 (d, J = 4.4 Hz, 1H), 8.25 (d, J = 4.4 Hz, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.22- 7.41 (m, 5H), 5.73 (s, 2H), 2.58 (s, 3H). MS(M+1): 472. Khaki solid. Compound 7-18 N-(1-(3-fluorobenzyl)-6-(6-methoxypyridin-3-yl)-1H-pyrazolo[ 3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.94 (br. s., 1H), 9.31 (d, J = 2.4 Hz, 1H), 8.72 (dd, J = 8.8, 2.4 Hz, 1H), 8.43 (s, 1H), 8.36 (d, J = 4.4 Hz, 1H), 8.25 (d, J = 4.4 Hz, 1H), 7.39 (td, J = 7.9, 6.1 Hz, 1H), 7.06-7.23 (m, 3H), 7.01 (d, J = 9.3 Hz, 1H), 5.74 (s, 2H), 3.96 (s, 3H). MS(M+1): 506. Bright yellow solid. Compound 7-19 N-(1-(4-acrylamidophenyl)-6-(4-fluorophenyl)-1H-pyrazolo[3,4 -d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.97 (br. s., 1H), 10.34 (s, 1H), 8.51-8.61 (m, 3H), 8.37 (d, J = 4.4 Hz, 1H), 8.24 (d, J = 4.4 Hz, 1H), 8.16-8.22 (m, J = 8.8 Hz, 2H), 7.87- 7.95 (m, J = 8.8 Hz, 2H), 7.40 (t, J = 9.0 Hz, 2H), 6.49 (dd, J = 17.1, 10.3 Hz, 1H), 6.31 (dd, J = 17.1, 2.0 Hz, 1H), 5.80 (dd, J = 9.8, 2.0 Hz, 1H). MS(M+1):530. Yellow solid. Table 8
Compound 8-1 (S)-N-(6-(6-fluoropyridin-3-yl)-1-(1-isopropylpyrrolidin-3-y l)-1H-pyrazolo[3,4-d]pyrimidin-4- yl)-5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 11.84 (br. s., 1H), 9.30 (d, J = 2.4 Hz, 1H), 8.96 (td, J = 8.3, 2.4 Hz, 1H), 8.42 (s, 1H), 8.25-8.32 (m, 1H), 8.18-8.25 (m, 1H), 7.40 (dd, J = 8.6, 2.7 Hz, 1H), 5.51-5.69 (m, 1H), 2.90 (d, J = 19.1 Hz, 3H), 2.58 (br. s., 1H), 2.25-2.47 (m, 3H), 1.09 (d, J = 6.4 Hz, 6H). MS(M+1): 497. Dark orange solid. Compound 8-2 (S)-N-(1-(1-acetylpyrrolidin-3-yl)-6-(6-fluoropyridin-3-yl)- 1H-pyrazolo[3,4-d]pyrimidin-4-yl)- 5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.01 (br. s., 1H), 9.32 (dd, J = 5.4, 2.4 Hz, 1H), 8.89-9.05 (m, 1H), 8.45 (d, J = 5.4 Hz, 1H), 8.33 (d, J = 4.4 Hz, 1H), 8.25 (d, J = 4.4 Hz, 1H), 7.42 (dd, J = 8.6, 2.7 Hz, 1H), 3.57-4.11 (m, 5H), 2.38-2.60 (m, 2H), 1.99 (s, 3H). MS(M+1): 497. White solid. Compound 8-3 (S)-N-(1-(1-acryloylpyrrolidin-3-yl)-6-(6-fluoropyridin-3-yl )-1H-pyrazolo[3,4-d]pyrimidin-4- yl)-5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.01 (br. s., 1H), 9.21-9.43 (m, 1H), 8.86-9.06 (m, 1H), 8.45 (d, J = 3.4 Hz, 1H), 8.34 (dd, J = 4.4, 1.5 Hz, 1H), 8.25 (d, J = 4.4 Hz, 1H), 7.42 (dd, J = 8.6, 2.7 Hz, 1H), 6.51-6.75 (m, 1H), 6.18 (ddd, J = 17.1, 7.8, 2.4 Hz, 1H), 5.62- 5.83 (m, 2H), 3.59-4.23 (m, 4H), 2.25-2.64 (m, 2H). MS(M+1): 509. Rosy brown solid. Compound 8-4 (S)-N-(6-(6-fluoropyridin-3-yl)-1-(1-pivaloylpyrrolidin-3-yl )-1H-pyrazolo[3,4-d]pyrimidin-4- yl)-5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.93 (br. s., 1H), 9.29 (d, J = 2.4 Hz, 1H), 8.94 (td, J = 8.3, 2.4 Hz, 1H), 8.41 (s, 1H), 8.34 (d, J = 4.4 Hz, 1H), 8.23 (d, J = 4.4 Hz, 1H), 7.40 (dd, J = 8.6, 2.7 Hz, 1H), 5.65 (br. s., 1H), 4.00 (br. s., 2H), 3.83 (br. s., 2H), 2.44 (br. s., 2H), 1.19 (s, 9H). MS(M+1): 539. White solid. Compound 8-5 ethyl (S)-3-(6-(6-fluoropyridin-3-yl)-4-(5-nitrothiophene-2-carbox amido)-1H- pyrazolo[3,4- d]pyrimidin-1-yl)pyrrolidine-1-carboxylate 1H NMR (400MHz, DMSO-d 6 ): δ 11.94 (s, 1H), 9.28 (d, J = 2.4 Hz, 1H), 8.93 (td, J = 8.3, 2.4 Hz, 1H), 8.41 (s, 1H), 8.34 (d, J = 4.4 Hz, 1H), 8.23 (d, J = 4.4 Hz, 1H), 7.40 (dd, J = 8.6, 2.7 Hz, 1H), 5.68 (br. s., 1H), 4.06 (quin, J = 7.1 Hz, 2H), 3.86-3.95 (m, 1H), 3.75 (dd, J = 11.2, 4.4 Hz, 1H), 3.48-3.71 (m, 2H), 2.30-2.48 (m, 2H), 1.19 (dt, J = 16.6, 7.3 Hz, 3H). MS(M+1):527. Burly wood soild. Compound 8-6 ethyl (R)-3-(6-(6-fluoropyridin-3-yl)-4-(5-nitrothiophene-2-carbox amido)-1H-pyrazolo [3,4- d]pyrimidin-1-yl)pyrrolidine-1-carboxylate 1H NMR (400MHz, DMSO-d 6 ): δ 11.99 (br. s., 1H), 9.31 (d, J = 2.4 Hz, 1H), 8.95 (td, J = 8.3, 2.4 Hz, 1H), 8.44 (s, 1H), 8.34 (d, J = 4.4 Hz, 1H), 8.25 (d, J = 4.4 Hz, 1H), 7.41 (dd, J = 8.6, 2.7 Hz, 1H), 5.70 (br. s., 1H), 4.01-4.15 (m, 2H), 3.85-3.97 (m, 1H), 3.71-3.78 (m, 1H), 3.64 (d, J = 6.8 Hz, 1H), 3.57 (d, J = 6.4 Hz, 1H), 2.26-2.48 (m, 2H), 1.19 (dt, J = 16.9, 7.0 Hz, 3H). MS(M+1):527. Light yellow solid. Compound 8-7 tert-butyl (S)-3-(6-(6-fluoropyridin-3-yl)-4-(5-nitrothiophene-2-carbox amido)-1H- pyrazolo[3,4- d]pyrimidin-1-yl)pyrrolidine-1-carboxylate 1H NMR (400MHz, DMSO-d 6 ): δ 12.01 (br. s., 1H), 9.32 (d, J = 2.4 Hz, 1H), 8.96 (td, J = 8.3, 2.4 Hz, 1H), 8.44 (s, 1H), 8.32 (d, J = 4.4 Hz, 1H), 8.25 (d, J = 4.4 Hz, 1H), 7.41 (dd, J = 8.6, 2.7 Hz, 1H), 5.68 (br. s., 1H), 3.82-3.91 (m, 1H), 3.56-3.72 (m, 2H), 3.50 (br. s., 1H), 2.34-2.48 (m, 2H), 1.38-1.48 (m, 9H). MS(M+1): 555. Pale yellow solid. Compound 8-8 N-(1-cyclopentyl-6-(6-fluoropyridin-3-yl)-1H-pyrazolo[3,4-d] pyrimidin-4-yl)-5-nitrothiophene- 2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.91 (br. s., 1H), 9.30 (d, J = 2.4 Hz, 1H), 8.95 (td, J = 8.3, 2.4 Hz, 1H), 8.41 (s, 1H), 8.31-8.39 (m, 1H), 8.24 (d, J = 4.4 Hz, 1H), 7.40 (dd, J = 8.6, 2.7 Hz, 1H), 5.46 (quin, J = 7.3 Hz, 1H), 2.13-2.27 (m, 2H), 2.00-2.13 (m, 2H), 1.83- 2.00 (m, 2H), 1.68- 1.83 (m, 2H). MS(M+1): 454. Khaki solid. Compound 8-9 N-(6-(4-chlorophenyl)-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimi din-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.87 (br. s., 1H), 8.45-8.62 (m, 2H), 8.30-8.45 (m, 2H), 8.21 (d, J = 4.4 Hz, 1H), 7.56-7.71 (m, 2H), 5.43 (quin, J = 7.2 Hz, 1H), 2.12- 2.26 (m, 2H), 1.99-2.12 (m, 2H), 1.82-1.99 (m, 2H), 1.63-1.82 (m, 2H). MS(M+1): 469. Light yellow solid. Compound 8-10 N-(1-cycloheptyl-6-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimi din-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.91 (br. s., 1H), 8.54-8.62 (m, 2H), 8.37 (s, 1H), 8.33 (d, J = 4.4 Hz, 1H), 8.24 (d, J = 4.4 Hz, 1H), 7.34-7.46 (m, 2H), 5.12 (tt, J = 9.6, 4.8 Hz, 1H), 2.10-2.24 (m, 2H), 2.00-2.10 (m, 2H), 1.79-1.95 (m, 2H), 1.56-1.79 (m, 6H). MS(M+1):481. Khaki solid. Compound 8-11 N-(1-cycloheptyl-6-(6-fluoropyridin-3-yl)-1H-pyrazolo[3,4-d] pyrimidin-4-yl)-5-nitrothiophene- 2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.92 (br. s., 1H), 9.31 (d, J = 2.4 Hz, 1H), 8.95 (td, J = 8.3, 2.4 Hz, 1H), 8.40 (s, 1H), 8.35 (d, J = 4.4 Hz, 1H), 8.24 (d, J = 4.4 Hz, 1H), 7.40 (dd, J = 8.6, 2.7 Hz, 1H), 5.13 (tt, J = 9.6, 4.8 Hz, 1H), 2.10-2.23 (m, 2H), 1.98-2.10 (m, 2H), 1.78-1.91 (m, 2H), 1.55-1.78 (m, 6H). MS(M+1):482. Khaki solid. Compound 8-12 methyl 4-(1-cycloheptyl-4-(5-nitrothiophene-2-carboxamido)-1H-pyraz olo[3,4-d] pyrimidin-6- yl)benzoate 1H NMR (400MHz, DMSO-d 6 ): δ 11.97 (br. s., 1H), 8.64-8.71 (m, J = 8.8 Hz, 2H), 8.39 (s, 1H), 8.36 (d, J = 4.4 Hz, 1H), 8.24 (d, J = 4.4 Hz, 1H), 8.09-8.20 (m, J = 8.3 Hz, 2H), 5.15 (tt, J = 9.5, 4.9 Hz, 1H), 3.91 (s, 3H), 2.10-2.22 (m, 2H), 1.99-2.10 (m, 2H), 1.78-1.92 (m, 2H), 1.55-1.78 (m, 6H). MS(M+1):521. Gray solid. Compound 8-13 N-(6-(4-fluorophenyl)-1-((1R,5S)-3,3,5-trimethylcyclohexyl)- 1H-pyrazolo[3,4-d]pyrimidin-4- yl)-5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.88 (br. s., 1H), 8.57 (dd, J = 8.8, 5.9 Hz, 2H), 8.32- 8.42 (m, 2H), 8.25 (d, J = 4.4 Hz, 1H), 7.35-7.48 (m, 2H), 5.04-5.17 (m, 1H), 2.37-2.47 (m, 2H), 2.32 (dd, J = 14.2, 5.9 Hz, 1H), 1.67 (dd, J = 13.7, 4.4 Hz, 1H), 1.53-1.62 (m, 1H), 1.47 (dd, J = 12.7, 3.9 Hz, 1H), 1.10-1.16 (m, 1H), 1.08 (d, J = 6.8 Hz, 3H), 0.99 (s, 3H), 0.59 (s, 3H). MS(M+1): 509. Yellow solid. Compound 8-14 N-(6-(6-fluoropyridin-3-yl)-1-((1R,5S)-3,3,5-trimethylcycloh exyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.94 (br. s., 1H), 9.29 (d, J = 2.4 Hz, 1H), 8.93 (td, J = 8.3, 2.4 Hz, 1H), 8.41 (s, 1H), 8.33 (d, J = 4.4 Hz, 1H), 8.24 (d, J = 4.4 Hz, 1H), 7.42 (dd, J = 8.8, 2.4 Hz, 1H), 5.09-5.18 (m, 1H), 2.36-2.45 (m, 2H), 2.29 (dd, J = 13.9, 6.1 Hz, 1H), 1.68 (dd, J = 13.7, 3.9 Hz, 1H), 1.54-1.63 (m, 1H), 1.47 (d, J = 9.3 Hz, 1H), 1.11-1.18 (m, 1H), 1.08 (d, J = 6.8 Hz, 3H), 0.99 (s, 3H), 0.60 (s, 3H). MS(M+1): 510. Light yellow solid. Compound 8-15 N-(6-(4-chlorophenyl)-1-((1R,5S)-3,3,5-trimethylcyclohexyl)- 1H-pyrazolo[3,4-d]pyrimidin-4- yl)-5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.89 (s, 1H), 8.45-8.59 (m, J = 8.8 Hz, 2H), 8.31-8.42 (m, 2H), 8.24 (d, J = 4.4 Hz, 1H), 7.56-7.72 (m, 2H), 5.04-5.20 (m, 1H), 2.36-2.45 (m, 2H), 2.31 (dd, J = 13.7, 5.9 Hz, 1H), 1.67 (dd, J = 13.7, 4.4 Hz, 1H), 1.51-1.62 (m, 1H), 1.46 (dd, J = 13.0, 3.2 Hz, 1H), 1.09-1.16 (m, 1H), 1.07 (d, J = 6.8 Hz, 3H), 0.98 (s, 3H), 0.58 (s, 3H).MS(M+1): 525. Yellow solid. Compound 8-16 N-(6-(6-chloropyridin-3-yl)-1-((1R,5S)-3,3,5-trimethylcycloh exyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.96 (s, 1H), 9.45 (d, J = 2.0 Hz, 1H), 8.80 (dd, J = 8.3, 2.4 Hz, 1H), 8.43 (s, 1H), 8.36 (d, J = 4.4 Hz, 1H), 8.25 (d, J = 4.4 Hz, 1H), 7.77 (d, J = 8.3 Hz, 1H), 5.04-5.22 (m, 1H), 2.35-2.45 (m, 2H), 2.29 (dd, J = 13.9, 6.1 Hz, 1H), 1.68 (dd, J = 13.9, 4.2 Hz, 1H), 1.59 (s, 1H), 1.43-1.50 (m, 1H), 1.05-1.17 (m, 4H), 0.99 (s, 3H), 0.60 (s, 3H). MS(M+1): 526. Yellow-green solid. Table 9 Compound 9-1 N-(6-(6-fluoropyridin-3-yl)-1-(1-isopropylpiperidin-4-yl)-1H -pyrazolo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.63 (br. s., 1H),9.30 (d, J = 2.0 Hz, 1H), 8.94 (td, J = 8.3, 2.4 Hz, 1H), 8.38 (s, 1H), 8.14-8.31 (m, 2H), 7.39 (dd, J = 8.6, 2.7 Hz, 1H), 4.92 (br. s., 1H), 3.05 (br. s., 2H), 2.93 (br. s., 1H), 2.45-2.65 (m, 2H), 2.17-2.29 (m, 2H), 1.94- 2.07 (m, 2H), 1.08 (d, J = 6.8 Hz, 6H). MS(M+1): 511.Light yellow solid. Compound 9-2 ethyl 4-(6-(6-fluoropyridin-3-yl)-4-(5-nitrothiophene-2-carboxamid o)-1H-pyrazolo [3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate 1H NMR (400MHz, DMSO-d 6 ): δ 12.05 (br. s., 1H), 9.31 (s, 1H), 8.96 (t, J = 7.6 Hz, 1H), 8.40 (s, 1H), 8.23 (br. s., 2H), 7.41 (d, J = 8.3 Hz, 1H), 5.15 (br. s., 1H), 3.98-4.26 (m, 4H), 3.13 (br. s., 2H), 2.08-2.03 (m., 4H), 1.22 (t, J = 7.1 Hz, 3H). MS(M+1): 541. Yellow-green solid. Compound 9-3 tert-butyl 4-(6-(4-(methoxycarbonyl)phenyl)-4-(5-nitrothiophene-2-carbo xamido)- 1H- pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate 1H NMR (DMSO-d 6 , 400 MHz): δ 11.97 (br. s., 1H), 8.57-8.70 (m, 2H), 8.38 (s, 1H), 8.36 (d, J = 4.4 Hz, 1H), 8.23 (d, J = 4.4 Hz, 1H), 8.07-8.17 (m, 2H), 4.97-5.21 (m, 1H), 4.12 (d, J = 12.2 Hz, 2H), 3.90 (s, 3H), 3.07 (brs., 2H), 1.94-2.14 (m, 4H), 1.45 (s, 9H). MS(M+1): 608. Yellow solid. Compound 9-4 tert-butyl 4-(6-(6-fluoropyridin-3-yl)-4-(5-nitrothiophene-2-carboxamid o)-1H- pyrazolo[3,4- d]pyrimidin-1-yl)piperidine-1-carboxylate 1H NMR (400MHz, DMSO-d 6 ): δ 11.90 (s, 1H), 9.28 (d, J = 2.4 Hz, 1H), 8.92 (t, J = 8.3, 1H), 8.38 (s, 1H), 8.32 (d, J = 4.4 Hz, 1H), 8.21 (d, J = 4.4 Hz, 1H), 7.38 (dd, J = 8.3 , 2.7 Hz, 1H), 5.15-5.07 (m, 1H), 4.13-4.10 (brm, 2H), 3.06 (brs, 2H), 2.08-1.98 (m, 4H), 1.44 (s, 9H). MS(M+1): 569. Yellow solid. Compound 9-5 tert-butyl 4-(6-(4-chlorophenyl)-4-(5-nitrothiophene-2-carboxamido)-1H- pyrazolo [3,4- d]pyrimidin-1-yl)piperidine-1-carboxylate 1H NMR (400MHz, DMSO-d 6 ): δ 11.96 (br. s., 1H), 8.48-8.61 (m, 2H), 8.40 (s, 1H), 8.34 (d, J = 4.9 Hz, 1H), 8.24 (d, J = 4.4 Hz, 1H), 7.61-7.69 (m, 2H), 5.02-5.19 (m, 1H), 4.12 (d, J = 12.2 Hz, 2H), 3.07 (br. s., 2H), 1.94-2.13 (m, 4H), 1.45 (s, 9H). MS(M+1): 584. Light yellow solid. Compound 9-6 N-(1-(1-acryloylpiperidin-4-yl)-6-(6-fluoropyridin-3-yl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.98 (br. s., 1H), 9.32 (d, J = 2.4 Hz, 1H), 8.96 (td, J = 8.3, 2.4 Hz, 1H), 8.43 (s, 1H), 8.34 (d, J = 4.4 Hz, 1H), 8.25 (d, J = 4.4 Hz, 1H), 7.42 (dd, J = 8.8, 2.4 Hz, 1H), 6.90 (dd, J = 16.6, 10.8 Hz, 1H), 6.16 (dd, J = 16.6, 2.4 Hz, 1H), 5.75 (s, 1H), 5.72 (dd, J = 10.3, 2.4 Hz, 1H), 5.25 (t, J = 7.1 Hz, 1H), 4.58 (d, J = 13.7 Hz, 1H), 4.25 (d, J = 13.2 Hz, 1H), 3.43 (td, J = 7.1, 4.9 Hz, 1H), 2.92-3.10 (m, 1H), 1.97-2.20 (m, 4H). MS(M+1): 523. Goldenrod powder. Compound 9-7 N-(1-(1-butyrylpiperidin-4-yl)-6-(6-fluoropyridin-3-yl)-1H-p yrazolo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.95 (br. s., 1H), 9.31 (d, J = 2.4 Hz, 1H), 8.95 (td, J = 8.3, 2.4 Hz, 1H), 8.41 (s, 1H), 8.34 (d, J = 4.4 Hz, 1H), 8.24 (d, J = 4.4 Hz, 1H), 7.41 (dd, J = 8.6, 2.7 Hz, 1H), 5.13-5.31 (m, 1H), 4.57 (d, J = 13.2 Hz, 1H), 4.06 (d, J = 13.7 Hz, 1H), 2.87 (t, J = 11.5 Hz, 1H), 2.28-2.44 (m, 2H), 1.57 (sxt, J = 7.3 Hz, 2H), 0.93 (t, J = 7.3 Hz, 3H). MS(M+1):539. Khaki solid. Compound 9-8 N-(6-(6-fluoropyridin-3-yl)-1-(1-pivaloylpiperidin-4-yl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.92 (br. s., 1H), 9.29 (d, J = 2.4 Hz, 1H), 8.93 (td, J = 8.3, 2.4 Hz, 1H), 8.39 (s, 1H), 8.34 (d, J = 4.9 Hz, 1H), 8.23 (d, J = 4.4 Hz, 1H), 7.40 (dd, J = 8.6, 2.7 Hz, 1H), 5.13-5.26 (m, 1H), 4.45 (d, J = 13.2 Hz, 2H), 3.05-3.18 (m, 2H), 1.99-2.13 (m, 4H), 1.25 (s, 9H). MS(M+1): 553. Light khaki solid. Compound 9-9 4,4,4-trifluorobutyl 4-(6-(4-chlorophenyl)-4-(5-nitrothiophene-2-carboxamido)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate 1H NMR (400MHz, DMSO-d 6 ): δ 11.95 (br. s., 1H), 8.50-8.61 (m, 2H), 8.40 (s, 1H), 8.35 (d, J = 4.4 Hz, 1H), 8.24 (d, J = 4.4 Hz, 1H), 7.57-7.70 (m, 2H), 5.15 (dt, J = 10.4, 5.3 Hz, 1H), 4.04- 4.25 (m, 4H), 3.15 (br. s., 2H), 2.27-2.45 (m, 2H), 1.96-2.19 (m, 4H), 1.75-1.90 (m, 2H). MS(M+1): 638. Light yellow solid. Compound 9-10 2-(2-ethoxyethoxy)ethyl 4-(4-(5-nitrothiophene-2-carboxamido)-6-(thiophen-2-yl)- 1H- pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate 1H NMR (400MHz, DMSO-d 6 ): δ 11.93 (s, 1H), 8.36 (d, J = 4.4 Hz, 1H), 8.33 (s, 1H), 8.23 (d, J = 4.4 Hz, 1H), 8.06-8.10 (m, 1H), 7.80 (dd, J = 5.1, 1.2 Hz, 1H), 7.25 (dd, J = 4.9, 3.4 Hz, 1H), 4.91-5.13 (m, 1H), 4.05-4.27 (m, 4H), 3.60-3.68 (m, 2H), 3.53- 3.59 (m, 2H), 3.46-3.50 (m, 2H), 3.43 (q, J = 7.2 Hz, 2H), 3.14 (br. s., 2H), 1.97-2.14 (m, 4H), 1.09 (t, J = 7.1 Hz, 3H). MS(M+1): 616. Yellow solid. Compound 9-11 2-(2-ethoxyethoxy)ethyl 4-(6-(4-chlorophenyl)-4-(5-nitrothiophene-2-carboxamido) -1H- pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate 1H NMR (400MHz, DMSO-d 6 ): δ 11.95 (s, 1H), 8.55 (d, J = 8.8 Hz, 2H), 8.4 (s, 1H), 8.34 (d, J = 4.4 Hz, 1H), 8.24 (d, J = 4.4 Hz, 1H), 7.65 (d, J = 8.8 Hz, 2H), 5.19-5.12 (m, 1H), 4.18-4.14 (m, 4H), 3.65-3.4 (m, 8H), 3.15 (br. s, 1H), 2.09-2.01 (m 4H), 1.09 (t, J = 6.9 Hz, 3H). MS(M+1): 644. Yellow-brown solid. Compound 9-12 2-methoxyethyl 4-(6-(4-chlorophenyl)-4-(5-nitrothiophene-2-carboxamido)-1H- pyrazolo[3,4- d]pyrimidin-1-yl)piperidine-1-carboxylate 1H NMR (400MHz, DMSO-d 6 ): δ 11.93 (br. s., 1H), 8.48-8.58 (m, 2H), 8.39 (s, 1H), 8.35 (d, J = 4.4 Hz, 1H), 8.24 (d, J = 4.4 Hz, 1H), 7.58-7.69 (m, 2H), 5.15 (dt, J = 10.3, 5.1 Hz, 1H), 4.06- 4.23 (m, 4H), 3.48-3.61 (m, 2H), 3.29 (s, 3H), 3.13 (d, J = 16.1 Hz, 2H), 1.97- 2.13 (m, 4H). MS(M+1): 586. Yellow solid. Compound 9-13 2-ethoxyethyl 4-(6-(4-chlorophenyl)-4-(5-nitrothiophene-2-carboxamido)-1H- pyrazolo [3,4- d]pyrimidin-1-yl)piperidine-1-carboxylate 1H NMR (400MHz, DMSO-d 6 ): δ 11.93 (br. s., 1H), 8.47-8.59 (m, 2H), 8.30-8.44 (m, 2H), 8.23 (d, J = 4.4 Hz, 1H), 7.59-7.70 (m, 2H), 5.06-5.22 (m, 1H), 4.05-4.28 (m, 4H), 3.52-3.67 (m, 2H), 3.48 (q, J = 7.2 Hz, 2H), 3.15 (br. s., 2H), 1.96-2.14 (m, 4H), 1.03-1.16 (m, 3H). MS(M+1): 600. Light yellow solid. Table 10
Compound 10-1 N-(1-cyclohexyl-6-(3,3-difluoropyrrolidin-1-yl)-1H-pyrazolo[ 3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.50 (br. s., 1H), 8.28 (d, J = 4.4 Hz, 1H), 8.21 (d, J = 4.4 Hz, 1H), 8.06 (s, 1H), 4.50-4.60 (m, 1H), 4.01 (t, J = 13.2 Hz, 2H), 3.83 (t, J = 7.3 Hz, 2H), 2.52-2.63 (m, 2H), 1.82-1.97 (m, 6H), 1.70 (d, J = 12.7 Hz, 1H), 1.38-1.52 (m, 2H), 1.19-1.34 (m, 1H). MS(M+1):478. Light yellow solid. Compound 10-2 N-(1-cyclohexyl-6-(4,4-difluoropiperidin-1-yl)-1H-pyrazolo[3 ,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.44 (br. s., 1H), 8.24-8.30 (m, 1H), 8.22 (d, J = 4.4 Hz, 1H), 8.07 (s, 1H), 4.54 (dt, J = 9.8, 4.9 Hz, 1H), 4.00 (t, J = 5.6 Hz, 4H), 1.96-2.14 (m, 4H), 1.80-1.96 (m, 6H), 1.66-1.76 (m, 1H), 1.37-1.51 (m, 2H), 1.18-1.31 (m, 1H). MS(M+1):492. Light yellow solid. Compound 10-3 (S)-N-(1-cyclohexyl-6-(2-(hydroxymethyl)pyrrolidin-1-yl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)- 5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 8.12-8.38 (m, 2H), 7.98 (s, 1H), 4.78 (br. s., 1H), 4.40 -4.58 (m, 1H), 4.21 (br. s., 1H), 3.66 (br. s., 1H), 3.45-3.63 (m, 3H), 1.79-2.08 (m, 10H), 1.69 (d, J = 13.2 Hz, 1H), 1.32-1.51 (m, 2H), 1.15-1.32 (m, 1H). MS(M+1):472. Orange solid. Compound 10-4 N-(1-cyclohexyl-6-(furan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4 -yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.06 (br. s., 1H), 8.35 (d, J = 4.4 Hz, 1H), 8.32 (s, 1H), 8.22 (d, J = 4.4 Hz, 1H), 7.98 (s, 1H), 7.40 (d, J = 2.9 Hz, 1H), 6.74 (dd, J = 3.4, 2.0 Hz, 1H), 4.75- 4.87 (m, 1H), 1.92-2.05 (m, 4H), 1.89 (d, J = 13.2 Hz, 2H), 1.73 (d, J = 12.7 Hz, 1H), 1.45-1.62 (m, 2H), 1.23-1.38 (m, 1H). MS(M+1):439. Khaki solid. Compound 10-5 N-(1-cyclohexyl-6-(thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidi n-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.96 (br. s., 1H), 8.33 (d, J = 4.4 Hz, 1H), 8.30 (s, 1H), 8.23 (d, J = 4.4 Hz, 1H), 8.07 (dd, J = 3.9, 1.5 Hz, 1H), 7.79 (dd, J = 4.9, 1.0 Hz, 1H), 7.20-7.28 (m, 1H), 4.77 (dt, J = 15.6, 7.8 Hz, 1H), 1.81-2.04 (m, 6H), 1.74 (d, J = 12.7 Hz, 1H), 1.43-1.60 (m, 2H), 1.21-1.38 (m, 1H). MS(M+1):455. Khaki solid. Compound 10-6 N-(1-cyclohexyl-6-(thiophen-3-yl)-1H-pyrazolo[3,4-d]pyrimidi n-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.93 (br. s., 1H), 8.46 (d, J = 2.9 Hz, 1H), 8.29- 8.37 (m, 2H), 8.24 (d, J = 4.4 Hz, 1H), 7.94 (d, J = 4.9 Hz, 1H), 7.69 (dd, J = 5.1, 3.2 Hz, 1H), 4.78-4.91 (m, 1H), 1.94-2.06 (m, 4H), 1.89 (d, J = 12.7 Hz, 2H), 1.74 (d, J = 12.7 Hz, 1H), 1.45-1.60 (m, 2H), 1.23-1.39 (m, 1H). MS(M+1):455. Khaki solid. Compound 10-7 N-(1-cyclohexyl-6-(5-methylthiophen-2-yl)-1H-pyrazolo[3,4-d] pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.86 (br. s., 1H), 8.32-8.40 (m, 1H), 8.27 (s, 1H), 8.17-8.24 (m, 1H), 7.87 (d, J = 3.4 Hz, 1H), 6.93 (dd, J = 3.4, 1.0 Hz, 1H), 4.66-4.79 (m, 1H), 2.53 (s, 3H), 1.93-2.04 (m, 4H), 1.89 (d, J = 13.2 Hz, 2H), 1.73 (d, J = 12.7 Hz, 1H), 1.42-1.56 (m, 2H), 1.20- 1.36 (m, 1H). MS(M+1):469. Yellow solid. Compound 10-8 N-(6-(5-chlorothiophen-2-yl)-1-cyclohexyl-1H-pyrazolo[3,4-d] pyrimidin-4-yl)-5-nitrothiophene- 2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.91 (br. s., 1H), 8.28-8.41 (m, 2H), 8.23 (d, J = 4.4 Hz, 1H), 7.90 (d, J = 3.9 Hz, 1H), 7.26 (d, J = 3.9 Hz, 1H), 4.75 (t, J = 7.3 Hz, 1H), 1.93-2.08 (m, 4H), 1.89 (d, J = 13.2 Hz, 2H), 1.73 (d, J = 12.7 Hz, 1H), 1.40-1.60 (m, 2H), 1.15-1.36 (m, 1H). MS(M+1):489. Yellow solid. Compound 10-9 N-(1-cyclohexyl-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrazolo[3, 4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.65 (br. s., 1H), 8.34 (s, 1H), 8.23-8.30 (m, 2H), 4.74 (dt, J = 15.7, 7.8 Hz, 1H), 2.88 (s, 3H), 2.60-2.69 (m, 3H), 1.94-2.05 (m, 4H), 1.89 (d, J = 13.2 Hz, 2H), 1.73 (d, J = 13.2 Hz, 1H), 1.41-1.57 (m, 2H), 1.24-1.36 (m, 1H). MS(M+1):468. Khaki solid. Compound 10-10 N-(1-cyclohexyl-6-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin -4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.95 (br. s., 1H), 9.67 (d, J = 1.5 Hz, 1H), 8.69 -8.86 (m, 2H), 8.41 (s, 1H), 8.36 (d, J = 4.4 Hz, 1H), 8.25 (d, J = 4.4 Hz, 1H), 7.55 -7.67 (m, 1H), 4.80-5.01 (m, 1H), 1.94-2.08 (m, 4H), 1.83-1.94 (m, 2H), 1.74 (d, J = 13.2 Hz, 1H), 1.48-1.66 (m, 2H), 1.23- 1.39 (m, 1H). MS(M+1):450. Khaki solid. Compound 10-11 N-(1-cyclohexyl-6-(2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimid in-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.08 (br. s., 1H), 8.41 (s, 1H), 8.34 (br. s., 1H), 8.22 (d, J = 4.4 Hz, 1H), 8.01-8.12 (m, 1H), 7.55-7.67 (m, 1H), 7.30-7.43 (m, 2H), 4.81 (dt, J = 15.4, 7.9 Hz, 1H), 1.92-2.09 (m, 4H), 1.88 (d, J = 13.2 Hz, 2H), 1.66 -1.79 (m, 1H), 1.43- 1.57 (m, 2H), 1.22- 1.35 (m, 1H). MS(M+1):467. Light khaki solid. Compound 10-12 N-(1-cyclohexyl-6-(3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimid in-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 8.34-8.47 (m, 2H), 8.18-8.34 (m, 3H), 7.62 (td, J = 7.9, 6.1 Hz, 1H), 7.40 (td, J = 8.4, 2.2 Hz, 1H), 4.84-4.96 (m, 1H), 1.94-2.08 (m, 4H), 1.85- 1.94 (m, 2H), 1.74 (d, J = 12.7 Hz, 1H), 1.56 (d, J = 8.3 Hz, 2H), 1.25-1.37 (m, 1H). MS(M+1):467. Khaki solid. Compound 10-13 N-(1-cyclohexyl-6-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimid in-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.88 (br. s., 1H), 8.53-8.64 (m, 2H), 8.32-8.42 (m, 2H), 8.25 (d, J = 4.4 Hz, 1H), 7.34-7.47 (m, 2H), 4.83-4.96 (m, 1H), 1.95-2.10 (m, 4H), 1.91 (d, J = 13.2 Hz, 2H), 1.69-1.81 (m, 1H), 1.46-1.64 (m, 2H), 1.24-1.39 (m, 1H). MS(M+1):467. Compound 10-14 N-(1-cyclohexyl-6-(6-fluoropyridin-3-yl)-1H-pyrazolo[3,4-d]p yrimidin-4-yl)-5-nitrothiophene- 2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.95 (br. s., 1H), 9.31 (d, J = 2.4 Hz, 1H), 8.96 (td, J = 8.3, 2.4 Hz, 1H), 8.41 (s, 1H), 8.34 (d, J = 4.4 Hz, 1H), 8.25 (d, J = 4.4 Hz, 1H), 7.41 (dd, J = 8.6, 2.7 Hz, 1H), 4.91 (t, J = 6.8 Hz, 1H), 1.94-2.05 (m, 4H), 1.85-1.94 (m, 2H), 1.74 (d, J = 12.7 Hz, 1H), 1.47-1.61 (m, 2H), 1.30 (d, J = 12.7 Hz, 1H). MS(M+1): 468. Light yellow solid. Compound 10-15 N-(1-cyclohexyl-6-(2-fluoropyridin-4-yl)-1H-pyrazolo[3,4-d]p yrimidin-4-yl)-5-nitrothiophene- 2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.00 (br. s., 1H), 8.43-8.52 (m, 2H), 8.31-8.38 (m, 2H), 8.25 (d, J = 4.4 Hz, 1H), 8.09 (s, 1H), 4.88-4.99 (m, 1H), 1.96-2.06 (m, 4H), 1.90 (d, J = 12.7 Hz, 2H), 1.71-1.80 (m, 1H), 1.49-1.61 (m, 2H), 1.26-1.38 (m, 1H). MS (M+1): 468. Light yellow solid. Compound 10-16 N-(6-(3-chlorophenyl)-1-cyclohexyl-1H-pyrazolo[3,4-d]pyrimid in-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.90 (br. s., 1H), 8.50-8.63 (m, 1H), 8.45-8.50 (m, 1H), 8.39 (s, 1H), 8.34 (d, J = 4.4 Hz, 1H), 8.24 (d, J = 4.4 Hz, 1H), 7.53-7.69 (m, 2H), 4.82-4.97 (m, 1H), 1.93-2.10 (m, 4H), 1.90 (d, J = 13.2 Hz, 2H), 1.74 (d, J = 13.2 Hz, 1H), 1.45-1.64 (m, 2H), 1.21- 1.41 (m, 1H). MS(M+1): 483. White solid. Compound 10-17 N-(6-(4-chlorophenyl)-1-cyclohexyl-1H-pyrazolo[3,4-d]pyrimid in-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.88 (br. s., 1H), 8.49-8.55 (m, 2H), 8.30-8.41 (m, 2H), 8.22 (d, J = 4.4 Hz, 1H), 7.58-7.69 (m, 2H), 4.82-4.92 (m, 1H), 1.92-2.03 (m, 4H), 1.89 (d, J = 13.7 Hz, 2H), 1.69-1.81 (m, 1H), 1.44-1.62 (m, 2H), 1.22-1.37 (m, 1H).MS(M+1): 483. Yellow solid. Compound 10-18 N-(6-(6-chloropyridin-3-yl)-1-cyclohexyl-1H-pyrazolo[3,4-d]p yrimidin-4-yl)-5-nitrothiophene- 2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.97 (br. s., 1H), 9.46 (d, J = 2.4 Hz, 1H), 8.82 (dd, J = 8.3, 2.4 Hz, 1H), 8.42 (s, 1H), 8.35 (d, J = 4.4 Hz, 1H), 8.25 (d, J = 4.4 Hz, 1H), 7.75 (d, J = 8.3 Hz, 1H), 4.77-5.01 (m, 1H), 1.94-2.07 (m, 4H), 1.83-1.94 (m, 2H), 1.74 (d, J = 12.7 Hz, 1H), 1.44- 1.64 (m, 2H), 1.20-1.39 (m, 1H). MS(M+1): 484. Light yellow solid. Compound 10-19 N-(1-cyclohexyl-6-(6-methylpyridin-3-yl)-1H-pyrazolo[3,4-d]p yrimidin-4-yl)-5-nitrothiophene- 2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.95 (br. s., 1H), 9.54 (d, J = 2.0 Hz, 1H), 8.68 (dd, J = 8.1, 2.2 Hz, 1H), 8.38 (s, 1H), 8.34 (d, J = 4.4 Hz, 1H), 8.24 (d, J = 4.4 Hz, 1H), 7.46 (d, J = 8.3 Hz, 1H), 4.81-4.98 (m, 1H), 2.58 (s, 3H), 1.95-2.05 (m, 4H), 1.90 (d, J = 13.2 Hz, 2H), 1.74 (d, J = 12.7 Hz, 1H), 1.46-1.62 (m, 2H), 1.21-1.36 (m, 1H). MS(M+1): 464. Yellow solid. Compound 10-20 N-(6-(4-cyanophenyl)-1-cyclohexyl-1H-pyrazolo[3,4-d]pyrimidi n-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.96 (br. s., 1H), 8.65-8.73 (m, 2H), 8.41 (s, 1H), 8.35 (d, J = 4.4 Hz, 1H), 8.24 (d, J = 4.4 Hz, 1H), 8.01-8.09 (m, 2H), 4.84-4.96 (m, 1H), 1.95- 2.07 (m, 4H), 1.90 (d, J = 13.2 Hz, 2H), 1.70-1.81 (m, 1H), 1.48-1.62 (m, 2H), 1.25-1.40 (m, 1H). MS(M+1): 474. Light khaki solid. Compound 10-21 N-(1-cyclohexyl-6-(6-methoxypyridin-3-yl)-1H-pyrazolo[3,4-d] pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.85 (br. s., 1H), 9.28 (d, J = 2.0 Hz, 1H), 8.69 (dd, J = 8.8, 2.4 Hz, 1H), 8.31-8.39 (m, 2H), 8.23 (d, J = 4.4 Hz, 1H), 7.00 (d, J = 8.8 Hz, 1H), 4.79-4.93 (m, 1H), 3.95 (s, 3H), 1.93-2.08 (m, 4H), 1.89 (d, J = 13.2 Hz, 2H), 1.70-1.79 (m, 1H), 1.43-1.61 (m, 2H), 1.20-1.36 (m, 1H). MS(M+1): 480. Light khaki solid. Compound 10-22 N-(1-cyclohexyl-6-(5-methoxypyridin-3-yl)-1H-pyrazolo[3,4-d] pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ) : δ 11.92 (br. s., 1H), 9.29 (s, 1H), 8.47 (d, J = 2.4 Hz, 1H), 8.41 (s, 1H), 8.36 (d, J = 4.4 Hz, 1H), 8.27-8.34 (m, 1H), 8.25 (d, J = 4.4 Hz, 1H), 4.92 (t, J = 7.1 Hz, 1H), 3.97 (s, 3H), 1.95-2.03 (m, 4H), 1.90 (d, J = 12.7 Hz, 2H), 1.74 (d, J = 13.2 Hz, 1H), 1.48- 1.61 (m, 2H), 1.24-1.36 (m, 1H). MS(M+1): 480. Goldenrod powder. Compound 10-23 N-(1-cyclohexyl-6-(6-ethoxypyridin-3-yl)-1H-pyrazolo[3,4-d]p yrimidin-4-yl)-5-nitrothiophene- 2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.84 (br. s., 1H), 9.26 (d, J = 2.0 Hz, 1H), 8.68 (dd, J = 8.8, 2.4 Hz, 1H), 8.30-8.41 (m, 2H), 8.23 (d, J = 4.4 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 4.86 (t, J = 6.8 Hz, 1H), 4.40 (q, J = 7.3 Hz, 2H), 1.93-2.07 (m, 4H), 1.89 (d, J = 13.7 Hz, 2H), 1.74 (d, J = 12.7 Hz, 1H), 1.44-1.63 (m, 2H), 1.36 (t, J = 6.8 Hz, 3H), 1.20-1.33 (m, 1H). MS(M+1):494. Brown solid. Compound 10-24 N-(1-cyclohexyl-6-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3, 4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.99 (br. s., 1H), 8.69-8.78 (m, J = 8.3 Hz, 2H), 8.41 (s, 1H), 8.36 (d, J = 4.4 Hz, 1H), 8.24 (d, J = 4.4 Hz, 1H), 7.91-7.99 (m, J = 8.3 Hz, 2H), 4.86-4.97 (m, 1H), 1.94-2.09 (m, 4H), 1.83-1.94 (m, 2H), 1.75 (d, J = 12.7 Hz, 1H), 1.46 -1.62 (m, 2H), 1.25- 1.41 (m, 1H). MS(M+1):517. Yellow-brown solid. Compound 10-25 N-(1-cyclohexyl-6-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyraz olo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.01 (br. s., 1H), 9.72-9.83 (m, 1H), 9.03 (dd, J = 8.1, 1.7 Hz, 1H), 8.41-8.49 (m, 1H), 8.36 (d, J = 4.4 Hz, 1H), 8.24 (d, J = 4.4 Hz, 1H), 8.10-8.16 (m, 1H), 4.83-5.00 (m, 1H), 1.95-2.11 (m, 4H), 1.90 (d, J = 13.2 Hz, 2H), 1.75 (d, J = 12.7 Hz, 1H), 1.45- 1.62 (m, 2H), 1.25-1.39 (m, 1H). MS(M+1): 518. Khaki solid. Compound 10-26 N-(1-cyclohexyl-6-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3 ,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.94 (br. s., 1H), 8.59-8.68 (m, 2H), 8.30-8.40 (m, 2H), 8.23 (d, J = 4.4 Hz, 1H), 7.49-7.63 (m, J = 8.3 Hz, 2H), 4.81-4.95 (m, 1H), 1.94-2.09 (m, 4H), 1.89 (d, J = 12.7 Hz, 2H), 1.69-1.82 (m, 1H), 1.44-1.61 (m, 2H), 1.23-1.37 (m, 1H). MS(M+1):533. Khaki solid. Compound 10-27 N-(1-cyclohexyl-6-(4-formylphenyl)-1H-pyrazolo[3,4-d]pyrimid in-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.98 (br. s., 1H), 10.13 (s, 1H), 8.66-8.79 (m, J = 8.3 Hz, 2H), 8.34-8.47 (m, 2H), 8.25 (d, J = 4.4 Hz, 1H), 8.03-8.20 (m, J = 8.3 Hz, 2H), 4.79- 5.03 (m, 1H), 1.96-2.09 (m, 4H), 1.83-1.96 (m, 2H), 1.75 (d, J = 13.2 Hz, 1H), 1.43-1.68 (m, 2H), 1.21-1.41 (m, 1H). MS(M+1): 477. Yellow solid. Compound 10-28 N-(6-(4-acetylphenyl)-1-cyclohexyl-1H-pyrazolo[3,4-d]pyrimid in-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (DMSO-d6, 400 MHz): δ 11.97 (brs., 1H), 8.56-8.74 (m, J = 8.3 Hz, 2H), 8.31 -8.45 (m, 2H), 8.25 (d, J = 4.4 Hz, 1H), 8.05-8.20 (m, J = 8.3 Hz, 2H), 4.83-4.99 (m, 1H), 2.66 (s, 3H), 1.95-2.06 (m, 4H), 1.91 (d, J = 12.7 Hz, 2H), 1.75 (d, J = 13.2 Hz, 1H), 1.43-1.66 (m, 2H), 1.21- 1.40 (m, 1H). MS(M+1): 491. Yellow solid. Compound 10-29 N-(1-cyclohexyl-6-(4-((dimethylamino)methyl)phenyl)-1H-pyraz olo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.93 (br. s., 1H), 8.53-8.66 (m, J = 8.3 Hz, 2H), 8.32-8.49 (m, 2H), 8.26 (d, J = 4.4 Hz, 1H), 7.65-7.79 (m, J = 7.8 Hz, 2H), 4.91 (dt, J = 15.3, 7.8 Hz, 1H), 4.32 (br. s., 2H), 2.71 (s, 6H), 1.94-2.08 (m, 4H), 1.90 (d, J = 13.2 Hz, 2H), 1.75 (d, J = 13.2 Hz, 1H), 1.43-1.63 (m, 2H), 1.26-1.41 (m, 1H). MS(M+1): 506. Khaki solid. Compound 10-30 N-(1-cyclohexyl-6-(4-(methoxymethyl)phenyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.91 (br. s., 1H), 8.48-8.59 (m, J = 8.3 Hz, 2H), 8.33-8.41 (m, 2H), 8.24 (d, J = 4.4 Hz, 1H), 7.44-7.57 (m, J = 8.3 Hz, 2H), 4.82-4.99 (m, 1H), 4.52 (s, 2H), 3.35 (s, 3H), 1.93-2.09 (m, 4H), 1.90 (d, J = 13.2 Hz, 2H), 1.71-1.81 (m, 1H), 1.47-1.62 (m, 2H), 1.26-1.37 (m, 1H). MS(M+1): 493. Khaki solid. Compound 10-31 methyl 3-(1-cyclohexyl-4-(5-nitrothiophene-2-carboxamido)-1H-pyrazo lo[3,4-d] pyrimidin-6-yl)benzoate 1H NMR (400MHz, DMSO-d 6 ): δ 12.01 (br. s., 1H), 9.10 (t, J = 1.7 Hz, 1H), 8.73-8.84 (m, 1H), 8.31-8.42 (m, 2H), 8.24 (d, J = 4.9 Hz, 1H), 8.10-8.17 (m, 1H), 7.73 (t, J = 7.8 Hz, 1H), 4.85- 4.98 (m, 1H), 3.93 (s, 3H), 1.96-2.12 (m, 4H), 1.90 (d, J = 13.2 Hz, 2H), 1.75 (d, J = 12.7 Hz, 1H), 1.46-1.64 (m, 2H), 1.25-1.39 (m, 1H). MS(M+1):507. Khaki solid. Compound 10-32 methyl 4-(1-cyclohexyl-4-(5-nitrothiophene-2-carboxamido)-1H-pyrazo lo[3,4-d] pyrimidin-6- yl)benzoate 1H NMR (400MHz, DMSO-d 6 ): δ 12.02 (br. s., 1H), 8.61-8.71 (m, J = 8.3 Hz, 2H), 8.38-8.45 (m, 1H), 8.34 (d, J = 4.4 Hz, 1H), 8.24 (d, J = 4.4 Hz, 1H), 8.10-8.20 (m, 2H), 4.83-5.01 (m, 1H), 3.82-3.98 (m, 3H), 1.95-2.07 (m, 4H), 1.84-1.95 (m, 2H), 1.75 (d, J = 13.2 Hz, 1H), 1.48-1.63 (m, 2H), 1.23-1.39 (m, 1H). MS(M+1):507. Light khaki solid. Compound 10-33 ethyl 4-(1-cyclohexyl-4-(5-nitrothiophene-2-carboxamido)-1H-pyrazo lo[3,4-d] pyrimidin-6- yl)benzoate 1285 1H NMR (400MHz, DMSO-d 6 ): δ 12.00 (br. s., 1H), 8.61-8.72 (m, J = 8.3 Hz, 2H), 8.39 (s, 1H), 8.35 (d, J = 4.4 Hz, 1H), 8.24 (d, J = 4.4 Hz, 1H), 8.11-8.20 (m, J = 8.3 Hz, 2H), 4.86-4.98 (m, 1H), 4.37 (q, J = 7.2 Hz, 2H), 1.96-2.14 (m, 4H), 1.90 (d, J = 13.2 Hz, 2H), 1.75 (d, J = 13.2 Hz, 1H), 1.47-1.65 (m, 2H), 1.36 (t, J = 7.1 Hz, 3H), 1.24-1.34 (m, 1H). MS(M+1): 521. Yellow solid. Compound 10-34 N-(1-cyclohexyl-6-(4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4 -d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.00 (br. s., 1H), 8.67-8.80 (m, 2H), 8.40 (s, 1H), 8.36 (d, J = 4.4 Hz, 1H), 8.24 (d, J = 4.4 Hz, 1H), 8.10-8.18 (m, 2H), 4.85-4.96 (m, 1H), 3.30 (s, 3H), 1.95- 2.09 (m, 4H), 1.90 (d, J = 13.2 Hz, 2H), 1.68-1.82 (m, 1H), 1.47-1.64 (m, 2H), 1.23-1.40 (m, 1H). MS(M+1):527. Pale yellow solid. Compound 10-35 N-(6-(4-(tert-butyl)phenyl)-1-cyclohexyl-1H-pyrazolo[3,4-d]p yrimidin-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.89 (br. s., 1H), 8.45 (d, J = 8.3 Hz, 2H), 8.35- 8.39 (m, 1H), 8.34 (s, 1H), 8.23 (d, J = 4.4 Hz, 1H), 7.53-7.63 (m, 2H), 4.86 (dt, J = 15.3, 7.8 Hz, 1H), 1.94- 2.09 (m, 4H), 1.90 (d, J = 13.2 Hz, 2H), 1.68-1.81 (m, 1H), 1.46-1.60 (m, 2H), 1.31-1.40 (m, 9H), 1.23-1.31 (m, 1H). MS(M+1): 505. Pale yellow solid. Compound 10-36 N-(6-(benzo[d][1,3]dioxol-5-yl)-1-cyclohexyl-1H-pyrazolo[3,4 -d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.78 (br. s., 1H), 8.27-8.39 (m, 2H), 8.24 (d, J = 4.4 Hz, 1H), 8.15 (dd, J = 8.1, 1.7 Hz, 1H), 8.02 (d, J = 1.5 Hz, 1H), 7.10 (d, J = 8.3 Hz, 1H), 6.14 (s, 2H), 4.81-4.94 (m, 1H), 1.94-2.06 (m, 4H), 1.89 (d, J = 13.2 Hz, 2H), 1.70-1.81 (m, 1H), 1.45-1.62 (m, 2H), 1.23-1.37 (m, 1H). MS(M+1): 493. Light orange solid. Compound 10-37 N-(1-cyclohexyl-6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H-p yrazolo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1 H NMR (400MHz, DMSO-d 6 ): δ 11.80 (br. s., 1H), 8.30-8.40 (m, 2H), 8.24 (d, J = 4.4 Hz, 1H), 8.01-8.08 (m, 2H), 7.00-7.06 (m, 1H), 4.85 (dt, J = 15.3, 7.8 Hz, 1H), 4.27-4.40 (m, 4H), 1.95- 2.05 (m, 4H), 1.89 (d, J = 13.2 Hz, 2H), 1.70-1.79 (m, 1H), 1.45-1.64 (m, 2H), 1.19-1.39 (m, 1H). MS(M+1): 507. Yellow solid. Compound 10-38 N-(1-cyclohexyl-6-(6-morpholinopyridin-3-yl)-1H-pyrazolo[3,4 -d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.82 (br. s., 1H), 9.26 (d, J = 2.4 Hz, 1H), 8.55 (dd, J = 8.8, 2.4 Hz, 1H), 8.28-8.38 (m, 2H), 8.23 (d, J = 4.4 Hz, 1H), 6.98 (d, J = 8.8 Hz, 1H), 4.76-4.91 (m, 1H), 3.66-3.82 (m, 4H), 3.55-3.66 (m, 4H), 1.92-2.08 (m, 4H), 1.89 (d, J = 12.7 Hz, 2H), 1.69- 1.81 (m, 1H), 1.46-1.61 (m, 2H), 1.22-1.40 (m, 1H). MS(M+1):535. Yellow solid. Compound 10-39 N-(1-cyclohexyl-6-(2,4-difluorophenyl)-1H-pyrazolo[3,4-d]pyr imidin-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.05 (br. s., 1H), 8.39 (s, 1H), 8.33 (d, J = 3.9 Hz, 1H), 8.10- 8.25 (m, 2H), 7.41 (td, J = 10.3, 2.4 Hz, 1H), 7.22-7.34 (m, 1H), 4.79 (dt, J = 15.3, 7.8 Hz, 1H), 1.92-2.05 (m, 4H), 1.88 (d, J = 13.2 Hz, 2H), 1.65-1.77 (m, 1H), 1.39-1.61 (m, 2H), 1.17-1.35 (m, 1H). MS(M+1):485. Khaki solid. Compound 10-40 N-(1-cyclohexyl-6-(3,4-difluorophenyl)-1H-pyrazolo[3,4-d]pyr imidin-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.90 (br. s., 1H), 8.47 (ddd, J = 12.0, 8.1, 2.0 Hz, 1H), 8.35- 8.43 (m, 2H), 8.32 (d, J = 4.4 Hz, 1H), 8.25 (d, J = 4.4 Hz, 1H), 7.65 (dt, J = 10.4, 8.5 Hz, 1H), 4.83-4.98 (m, 1H), 1.94-2.04 (m, 4H), 1.90 (d, J = 12.7 Hz, 2H), 1.74 (d, J = 13.2 Hz, 1H), 1.47- 1.61 (m, 2H), 1.25-1.36 (m, 1H). MS(M+1):485. Light yellow solid. Compound 10-41 N-(1-cyclohexyl-6-(3,5-difluorophenyl)-1H-pyrazolo[3,4-d]pyr imidin-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.87 (br. s., 1H), 8.42 (s, 1H), 8.34 (d, J = 4.4 Hz, 1H), 8.25 (d, J = 4.4 Hz, 1H), 8.12-8.21 (m, 2H), 7.47 (tt, J = 9.0, 2.4 Hz, 1H), 4.89-5.00 (m, 1H), 1.95- 2.06 (m, 4H), 1.89 (d, J = 12.7 Hz, 2H), 1.74 (d, J = 13.2 Hz, 1H), 1.50-1.63 (m, 2H), 1.24-1.37 (m, 1H). MS(M+1):485. Khaki solid. Compound 10-42 N-(1-cyclohexyl-6-(2,4-dichlorophenyl)-1H-pyrazolo[3,4-d]pyr imidin-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ) : δ 12.17 (br. s., 1H), 8.43 (s, 1H), 8.33 (d, J = 4.4 Hz, 1H), 8.20 (d, J = 4.4 Hz, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.60 (dd, J = 8.3, 2.0 Hz, 1H), 4.64-4.85 (m, 1H), 1.91-2.06 (m, 4H), 1.86 (d, J = 13.2 Hz, 2H), 1.61-1.74 (m, 1H), 1.34- 1.59 (m, 2H), 1.17-1.34 (m, 1H). MS(M+1):517. Yellow solid. Compound 10-43 N-(1-cyclohexyl-6-(3,4-dichlorophenyl)-1H-pyrazolo[3,4-d]pyr imidin-4-yl)-5-nitrothiophene-2- carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.91 (br. s., 1H), 8.69 (d, J = 2.0 Hz, 1H), 8.47 (dd, J = 8.3, 2.0 Hz, 1H), 8.40 (s, 1H), 8.35 (d, J = 4.4 Hz, 1H), 8.24 (d, J = 4.9 Hz, 1H), 7.78- 7.91 (m, 1H), 4.82-4.97 (m, 1H), 1.92-2.09 (m, 4H), 1.89 (d, J = 13.2 Hz, 2H), 1.74 (d, J = 12.7 Hz, 1H), 1.47- 1.65 (m, 2H), 1.26-1.40 (m, 1H). MS(M+1):517. Yellow solid. Compound 10-44 N-(6-(3-chloro-4-ethoxyphenyl)-1-cyclohexyl-1H-pyrazolo[3,4- d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.81 (br. s., 1H), 8.54 (d, J = 2.0 Hz, 1H), 8.44 (dd, J = 8.6, 2.2 Hz, 1H), 8.30-8.39 (m, 2H), 8.23 (d, J = 4.4 Hz, 1H), 7.31 (d, J = 8.8 Hz, 1H), 4.82-4.94 (m, 1H), 4.23 (q, J = 6.8 Hz, 2H), 1.93-2.10 (m, 4H), 1.89 (d, J = 13.2 Hz, 2H), 1.69- 1.79 (m, 1H), 1.47-1.62 (m, 2H), 1.41 (t, J = 6.8 Hz, 3H), 1.23-1.36 (m, 1H). MS(M+1):527. Light khaki solid. Compound 10-45 N-(6-(4-chloro-2-fluorophenyl)-1-cyclohexyl-1H-pyrazolo[3,4- d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.08 (br. s., 1H), 8.40 (s, 1H), 8.32 (d, J = 4.4 Hz, 1H), 8.22 (d, J = 4.4 Hz, 1H), 8.12-8.19 (m, 1H), 7.61 (dd, J = 10.8, 2.0 Hz, 1H), 7.49 (dd, J = 8.3, 2.0 Hz, 1H), 4.79 (dt, J = 15.3, 7.8 Hz, 1H), 1.94-2.07 (m, 4H), 1.88 (d, J = 12.7 Hz, 2H), 1.72 (d, J = 12.7 Hz, 1H), 1.42-1.58 (m, 2H), 1.23-1.39 (m, 1H). MS(M+1):501. Light yellow solid. Compound 10-46 N-(6-(2-chloro-4-fluorophenyl)-1-cyclohexyl-1H-pyrazolo[3,4- d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.17 (br. s., 1H), 8.42 (s, 1H), 8.32 (d, J = 4.4 Hz, 1H), 8.20 (d, J = 4.4 Hz, 1H), 7.87 (dd, J = 8.6, 6.1 Hz, 1H), 7.53-7.67 (m, 1H), 7.39 (td, J = 8.4, 2.7 Hz, 1H), 4.78 (t, J = 7.1 Hz, 1H), 1.92-2.05 (m, 4H), 1.86 (d, J = 12.7 Hz, 2H), 1.65- 1.76 (m, 1H), 1.38-1.58 (m, 2H), 1.21-1.38 (m, 1H). MS(M+1):501. Light yellow solid. Compound 10-47 N-(6-(5-chloro-2-fluorophenyl)-1-cyclohexyl-1H-pyrazolo[3,4- d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.01 (br. s., 1H), 8.40 (s, 1H), 8.33 (d, J = 4.4 Hz, 1H), 8.21 (d, J = 4.4 Hz, 1H), 8.17 (dd, J = 6.4, 2.9 Hz, 1H), 7.60-7.68 (m, 1H), 7.44 (dd, J = 10.3, 8.8 Hz, 1H), 4.72-4.86 (m, 1H), 1.93-2.05 (m, 4H), 1.87 (d, J = 13.2 Hz, 2H), 1.66- 1.77 (m, 1H), 1.40- 1.57 (m, 2H), 1.20-1.36 (m, 1H). MS(M+1):501. Yellow solid. Compound 10-48 N-(1-cyclohexyl-6-(3,4-dimethoxyphenyl)-1H-pyrazolo[3,4-d]py rimidin-4-yl)-5-nitrothiophene- 2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.81 (br. s., 1H), 8.34 (d, J = 4.4 Hz, 1H), 8.32 (s, 1H), 8.22 (d, J = 4.4 Hz, 1H), 8.15 (dd, J = 8.6, 1.7 Hz, 1H), 8.09 (d, J = 2.0 Hz, 1H), 7.13 (d, J = 8.8 Hz, 1H), 4.78-4.92 (m, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 1.94-2.07 (m, 4H), 1.89 (d, J = 13.2 Hz, 2H), 1.68-1.79 (m, 1H), 1.43-1.63 (m, 2H), 1.22-1.36 (m, 1H). MS(M+1):509. Yellow solid. Compound 10-49 N-(1-cyclohexyl-6-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)-1H -pyrazolo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.89 (br. s., 1H), 9.29 (d, J = 2.4 Hz, 1H), 8.79 (dd, J = 8.8, 2.4 Hz, 1H), 8.30-8.44 (m, 2H), 8.25 (d, J = 4.4 Hz, 1H), 7.19 (d, J = 8.3 Hz, 1H), 5.11 (q, J = 8.8 Hz, 2H), 4.79-4.97 (m, 1H), 1.94-2.08 (m, 4H), 1.89 (d, J = 12.2 Hz, 2H), 1.74 (d, J = 12.7 Hz, 1H), 1.46-1.66 (m, 2H), 1.25-1.39 (m, 1H). MS(M+1): 548. Yellow solid. Compound 10-50 N-(1-cyclohexyl-6-(4-(2-methoxyethoxy)phenyl)-1H-pyrazolo[3, 4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.83 (br. s., 1H), 8.45-8.53 (m, J = 8.3 Hz, 2H), 8.37 (d, J = 3.9 Hz, 1H), 8.34 (s, 1H), 8.25 (d, J = 4.4 Hz, 1H), 7.09-7.17 (m, J = 8.8 Hz, 2H), 4.87 (dt, J = 15.9, 7.7 Hz, 1H), 4.20 (dd, J = 5.6, 3.7 Hz, 2H), 3.68-3.75 (m, 2H), 1.95- 2.04 (m, 4H), 1.86- 1.95 (m, 2H), 1.74 (d, J = 13.2 Hz, 1H), 1.46-1.60 (m, 2H), 1.28-1.37 (m, 1H). MS(M+1): 523. Yellow solid. Compound 10-51 N-(1-cyclohexyl-6-(6-(2-methoxyethoxy)pyridin-3-yl)-1H-pyraz olo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.85 (br. s., 1H), 9.25 (d, J = 2.0 Hz, 1H), 8.69 (dd, J = 8.8, 2.4 Hz, 1H), 8.35 (t, J = 2.2 Hz, 2H), 8.23 (d, J = 4.4 Hz, 1H), 7.01 (d, J = 8.8 Hz, 1H), 4.81-4.94 (m, 1H), 4.39-4.54 (m, 2H), 3.70 (dd, J = 5.4, 3.9 Hz, 2H), 3.32 (s, 5H), 1.94-2.07 (m, 4H), 1.89 (d, J = 13.2 Hz, 2H), 1.74 (d, J = 13.2 Hz, 1H), 1.46- 1.61 (m, 2H), 1.24-1.37 (m, 1H). MS(M+1): 524. Yellow solid. Compound 10-52 N-(1-cyclohexyl-6-(6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-y l)-1H-pyrazolo[3,4-d]pyrimidin-4- yl)-5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.94 (br. s., 1H), 9.29 (d, J = 2.0 Hz, 1H), 8.79 (dd, J = 8.6, 2.2 Hz, 1H), 8.37 (s, 1H), 8.29 (d, J = 4.4 Hz, 1H), 8.24 (d, J = 4.4 Hz, 1H), 7.16 (d, J = 8.8 Hz, 1H), 6.71 (t, J = 5.4 Hz, 1H), 4.92-5.05 (m, 2H), 4.81-4.92 (m, 1H), 1.95-2.08 (m, 4H), 1.90 (d, J = 13.2 Hz, 2H), 1.74 (d, J = 12.7 Hz, 1H), 1.45-1.61 (m, 2H), 1.30 (q, J = 13.0 Hz, 1H). MS(M+1):580. Light yellow solid. Compound 10-53 N-(1-cyclohexyl-6-(6-(2-(2-ethoxyethoxy)ethoxy)pyridin-3-yl) -1H-pyrazolo[3,4-d]pyrimidin-4- yl)-5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.88 (br. s., 1H), 9.27 (d, J = 2.4 Hz, 1H), 8.71 (dd, J = 8.8, 2.4 Hz, 1H), 8.29-8.39 (m, 2H), 8.24 (d, J = 4.4 Hz, 1H), 7.02 (d, J = 8.8 Hz, 1H), 4.82-4.92 (m, 1H), 4.48 (dd, J = 5.6, 4.2 Hz, 2H), 3.76-3.83 (m, 2H), 3.57-3.64 (m, 2H), 3.46-3.53 (m, 2H), 3.39-3.46 (m, 2H), 1.94-2.08 (m, 4H), 1.89 (d, J = 12.7 Hz, 2H), 1.69 -1.79 (m, 1H), 1.46-1.62 (m, 2H), 1.23-1.36 (m, 1H), 1.05-1.13 (m, 3H). MS(M+1): 582. Yellow solid. Compound 10-54 N-(1-(4,4-difluorocyclohexyl)-6-(4-fluorophenyl)-1H-pyrazolo [3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.93 (br. s., 1H), 8.53-8.66 (m, 2H), 8.40 (s, 1H), 8.35 (d, J = 4.4 Hz, 1H), 8.25 (d, J = 4.4 Hz, 1H), 7.33-7.47 (m, 2H), 5.06-5.23 (m, 1H), 2.15- 2.36 (m, 6H), 2.09 (br. s., 2H). MS(M+1): 503. Pale yellow solid. Compound 10-55 N-(1-(4,4-difluorocyclohexyl)-6-(6-fluoropyridin-3-yl)-1H-py razolo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.90 (s, 1H), 9.30 (d, J = 2.4 Hz, 1H), 8.93 (td, J = 8.3, 2.4 Hz, 1H), 8.40 (s, 1H), 8.34 (d, J = 4.4 Hz, 1H), 8.22 (d, J = 4.4 Hz, 1H), 7.40 (dd, J = 8.3, 2.4 Hz, 1H), 5.03-5.25 (m, 1H), 2.15-2.34 (m, 6H), 2.01-2.15 (m, 2H). MS(M+1): 504. White solid. Compound 10-56 N-(6-(4-chlorophenyl)-1-(4,4-difluorocyclohexyl)-1H-pyrazolo [3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.93 (br. s., 1H), 8.49-8.62 (m, 2H), 8.29-8.42 (m, 2H), 8.23 (d, J = 4.4 Hz, 1H), 7.59-7.71 (m, 2H), 5.15 (d, J = 3.9 Hz, 1H), 2.15-2.34 (m, 6H), 2.09 (br. s., 2H). MS(M+1): 519. White solid. Compound 10-57 N-(6-(6-chloropyridin-3-yl)-1-(4,4-difluorocyclohexyl)-1H-py razolo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.99 (br. s., 1H), 9.47 (d, J = 2.0 Hz, 1H), 8.83 (dd, J = 8.3, 2.4 Hz, 1H), 8.41-8.48 (m, 1H), 8.35 (d, J = 4.4 Hz, 1H), 8.25 (d, J = 4.4 Hz, 1H), 7.77 (d, J = 8.3 Hz, 1H), 5.12-5.25 (m, 1H), 2.16-2.1 (m, 8H). MS(M+1): 520. Rosy brown solid. Compound 10-58 N-(1-(4,4-difluorocyclohexyl)-6-(4-(trifluoromethyl)phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-yl)- 5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.02 (br. s., 1H), 8.65-8.81 (m, J = 8.3 Hz, 2H), 8.43 (s, 1H), 8.36 (d, J = 4.4 Hz, 1H), 8.24 (d, J = 4.4 Hz, 1H), 7.86-8.02 (m, J = 8.3 Hz, 2H), 5.05-5.28 (m, 1H), 2.16-2.36 (m, 6H), 2.11 (br. s., 2H). MS(M+1): 553. White solid. Compound 10-59 N-(1-(4,4-difluorocyclohexyl)-6-(4-ethoxyphenyl)-1H-pyrazolo [3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.87 (br. s., 1H), 8.428.54 (m, J = 8.8 Hz, 2H), 8.29- 8.39 (m, 2H), 8.24 (d, J = 4.4 Hz, 1H), 7.02-7.15 (m, 2H), 5.04-5.20 (m, 1H), 4.14 (q, J = 6.8 Hz, 2H), 2.15-2.37 (m, 6H), 2.08 (br. s., 2H), 1.37 (t, J = 6.8 Hz, 3H). MS(M+1): 529. Bright yellow solid. Compound 10-60 N-(1-(4,4-difluorocyclohexyl)-6-(4-propoxyphenyl)-1H-pyrazol o[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.89 (br. s., 1H), 8.49 (d, J = 8.8 Hz, 2H), 8.28-8.38 (m, 2H), 8.24 (d, J = 4.4 Hz, 1H), 7.02-7.19 (m, 2H), 5.05-5.20 (m, 1H), 4.04 (t, J = 6.6 Hz, 2H), 2.14- 2.37 (m, 6H), 2.08 (br. s., 2H), 1.68-1.84 (m, 2H), 1.01 (t, J = 7.6 Hz, 3H). MS(M+1): 543. Bright yellow solid. Compound 10-61 N-(1-(4,4-dimethylcyclohexyl)-6-(4-fluorophenyl)-1H-pyrazolo [3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.90 (br. s., 1H), 8.48-8.64 (m, 2H), 8.29-8.40 (m, 2H), 8.24 (d, J = 4.4 Hz, 1H), 7.32-7.49 (m, 2H), 4.74-4.90 (m, 1H), 2.23 (qd, J = 12.5, 4.6 Hz, 2H), 1.73- 1.86 (m, 2H), 1.43-1.62 (m, 4H), 1.04-1.12 (m, 3H), 1.01 (s, 3H). MS(M+1): 495. Bright yellow solid. Compound 10-62 N-(1-(4,4-dimethylcyclohexyl)-6-(6-fluoropyridin-3-yl)-1H-py razolo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.96 (s, 1H), 9.30 (d, J = 2.4 Hz, 1H), 8.94 (t, J = 8.3, 1H), 8.41 (s, 1H), 8.34 (d, J = 4.4 Hz, 1H), 8.23 (d, J = 4.4 Hz, 1H), 7.40 (dd, J = 8.3 , 2.7 Hz, 1H), 4.89-4.82 (m, 1H), 2.27-2.20 (m, 2H), 1.82-1.80 (m, 2H), 1.54-1.48 (m, 4H), 1.07 (s, 3H), 1.01 (s, 3H). MS(M+1): 496. Yellow solid. Compound 10-63 N-(6-(4-chlorophenyl)-1-(4,4-dimethylcyclohexyl)-1H-pyrazolo [3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.89 (br. s., 1H), 8.45-8.58 (m, 2H), 8.30-8.40 (m, 2H), 8.22 (d, J = 4.4 Hz, 1H), 7.54-7.71 (m, 2H), 4.72-4.89 (m, 1H), 2.09-2.31 (m, 2H), 1.70-1.86 (m, 2H), 1.42-1.59 (m, 4H), 1.03-1.11 (m, 3H), 1.00 (s, 3H). MS(M+1): 511. Bright yellow solid. Compound 10-64 N-(6-(6-chloropyridin-3-yl)-1-(4,4-dimethylcyclohexyl)-1H-py razolo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.96 (s, 1H), 9.44 (d, J = 1.7 Hz, 1H), 8.81 (dd, J = 8.8, 2.4 Hz, 1H), 8.41 (s,1H), 8.35 (d, J = 4.4 Hz, 1H), 8.24 (d, J = 4.4 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 4.88-4.80 (m, 1H), 2.26-2.16 (m, 2H), 1.82-1.79 (m, 2H), 1.54-1.48 (m, 4H), 1.06 (s, 3H), 1.01 (s, 3H). MS(M+1): 512. Yellow solid. Compound 10-65 N-(6-(4-chloro-2-fluorophenyl)-1-(4,4-dimethylcyclohexyl)-1H -pyrazolo[3,4-d]pyrimidin-4-yl)- 5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.05 (br. s., 1H), 8.37-8.46 (m, 1H), 8.34 (d, J = 4.4 Hz, 1H), 8.09-8.27 (m, 2H), 7.61 (dd, J = 10.8, 2.0 Hz, 1H), 7.49 (dd, J = 8.3, 2.0 Hz, 1H), 4.73 (tt, J = 11.9, 4.3 Hz, 1H), 2.24 (qd, J = 12.7, 3.9 Hz, 2H), 1.73-1.87 (m, 2H), 1.39- 1.60 (m, 4H), 1.05 (s, 3H), 0.99 (s, 3H). MS(M+1): 529. Yellow solid. Compound 10-66 N-(6-(benzo[d][1,3]dioxol-5-yl)-1-(4,4-dimethylcyclohexyl)-1 H-pyrazolo[3,4-d]pyrimidin-4-yl)- 5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.76 (br. s., 1H), 8.27-8.40 (m, 2H), 8.23 (d, J = 4.4 Hz, 1H), 8.14 (dd, J = 8.3, 1.5 Hz, 1H), 8.01 (d, J = 1.5 Hz, 1H), 7.09 (d, J = 8.3 Hz, 1H), 6.13 (s, 2H), 4.72-4.85 (m, 1H), 2.22 (qd, J = 12.2, 5.4 Hz, 2H), 1.71-1.86 (m, 2H), 1.42-1.61 (m, 4H), 1.07 (s, 3H), 1.00 (s, 3H). MS(M+1): 521. Yellow solid. Compound 10-67 N-(1-(3,5-dimethylcyclohexyl)-6-(4-fluorophenyl)-1H-pyrazolo [3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.88 (br. s., 1H), 8.52-8.66 (m, 2H), 8.32-8.40 (m, 2H), 8.24 (d, J = 4.4 Hz, 1H), 7.32-7.46 (m, 2H), 4.97 (tt, J = 11.7, 3.9 Hz, 1H), 1.94 (d, J = 11.7 Hz, 2H), 1.68-1.86 (m, 3H), 1.60 (q, J = 12.1 Hz, 2H), 0.97 (d, J = 6.4 Hz, 6H), 0.64-0.80 (m, 1H). MS(M+1):495. Light green solid. Compound 10-68 N-(1-(3,5-dimethylcyclohexyl)-6-(6-fluoropyridin-3-yl)-1H-py razolo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.94 (br. s., 1H), 9.31 (d, J = 2.4 Hz, 1H), 8.96 (td, J = 8.3, 2.4 Hz, 1H), 8.41 (s, 1H), 8.34 (d, J = 4.4 Hz, 1H), 8.25 (d, J = 4.4 Hz, 1H), 7.41 (dd, J = 8.8, 2.4 Hz, 1H), 4.90-5.08 (m, 1H), 1.86-2.05 (m, 2H), 1.74 (t, J = 9.3 Hz, 3H), 1.61 (q, J = 11.9 Hz, 2H), 0.97 (d, J = 6.4 Hz, 6H), 0.74 (d, J = 11.7 Hz, 1H) MS(M+1): 496. Light yellow solid. Compound 10-69 N-(6-(4-chlorophenyl)-1-(3,5-dimethylcyclohexyl)-1H-pyrazolo [3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.90 (br. s., 1H), 8.47-8.56 (m, J = 8.3 Hz, 2H), 8.29- 8.42 (m, 2H), 8.24 (d, J = 4.4 Hz, 1H), 7.56-7.73 (m, J = 8.8 Hz, 2H), 4.84-5.08 (m, 1H), 1.93 (d, J = 12.2 Hz, 2H), 1.72 (d, J = 11.2 Hz, 3H), 1.60 (q, J = 12.1 Hz, 2H), 0.96 (d, J = 6.4 Hz, 6H), 0.65- 0.80 (m, 1H). MS(M+1):511. Light yellow solid. Compound 10-70 N-(6-(6-chloropyridin-3-yl)-1-(3,5-dimethylcyclohexyl)-1H-py razolo[3,4-d]pyrimidin-4-yl)-5- nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 11.94 (br. s., 1H), 9.44 (d, J = 2.4 Hz, 1H), 8.80 (dd, J = 8.3, 2.4 Hz, 1H), 8.40 (s, 1H), 8.34 (d, J = 4.4 Hz, 1H), 8.24 (d, J = 4.4 Hz, 1H), 7.60- 7.81 (m, 1H), 4.98 (tt, J = 11.7, 3.9 Hz, 1H), 1.94 (d, J = 12.2 Hz, 2H), 1.68-1.82 (m, 3H), 1.60 (q, J = 12.2 Hz, 2H), 0.97 (d, J = 6.4 Hz, 6H), 0.66-0.79 (m, 1H). MS(M+1): 512. Light yellow solid. Compound 10-71 methyl 4-(1-(3,5-dimethylcyclohexyl)-4-(5-nitrothiophene-2-carboxam ido)-1H- pyrazolo[3,4-d]pyrimidin-6-yl)benzoate 1H NMR (400MHz, DMSO-d 6 ): δ 12.00 (br. s., 1H), 8.57-8.71 (m, J = 7.8 Hz, 2H), 8.31-8.44 (m, 2H), 8.25 (d, J = 4.4 Hz, 1H), 8.09-8.21 (m, J = 7.8 Hz, 2H), 5.01 (t, J = 11.2 Hz, 1H), 3.91 (s, 3H), 1.95 (d, J = 11.7 Hz, 2H), 1.68-1.84 (m, 3H), 1.49-1.68 (m, 2H), 0.98 (d, J = 5.9 Hz, 6H), 0.74 (d, J = 12.2 Hz, 1H). MS(M+1): 535. Light yellow solid. Compound 10-72 N-(6-(4-chloro-2-fluorophenyl)-1-(3,5-dimethylcyclohexyl)-1H -pyrazolo[3,4-d]pyrimidin-4-yl)- 5-nitrothiophene-2-carboxamide 1H NMR (400MHz, DMSO-d 6 ): δ 12.08 (br. s., 1H), 8.36-8.45 (m, 1H), 8.32 (d, J = 4.4 Hz, 1H), 8.22 (d, J = 4.4 Hz, 1H), 8.15 (t, J = 8.3 Hz, 1H), 7.61 (dd, J = 10.8, 2.0 Hz, 1H), 7.49 (dd, J = 8.6, 1.7 Hz, 1H), 4.78-4.97 (m, 1H), 1.93 (d, J = 11.7 Hz, 2H), 1.52-1.81 (m, 5H), 0.95 (d, J = 5.9 Hz, 6H), 0.61-0.83 (m, 1H). MS(M+1):529. Light yellow solid. Shown in Tables 11 are in vitro activities of exemplary compounds of formula (I). The results indicate that the compounds of the present disclosure indeed have efficacy for inhibiting the growth of various tumor celles. Table 11 OTHER EMBODIMENTS All of the features disclosed in this specification may be combined in any combination. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Thus, unless expressly stated otherwise, each feature disclosed is only an example of a generic series of equivalent or similar features. Further, from the above description, one skilled in the art can easily ascertain the essential characteristics of the present disclosure, and without departing from the spirit and scope thereof, can make various changes and modifications of the disclosure to adapt it to various usages and conditions. Thus, other embodiments are also within the claims.