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Title:
PYRIMIDINE AMIDE COMPOUNDS AND USE THEREOF
Document Type and Number:
WIPO Patent Application WO/2023/244430
Kind Code:
A1
Abstract:
Disclosed are compounds of formula (I) below or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof: in which each of variables R1 and R2 is defined herein. Also disclosed is a method for treating a cancer with a compound of formula (I) or a salt thereof and a pharmaceutical composition containing same.

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Inventors:
CHUNG CHENG-HO (TW)
TSENG SHI-LIANG (TW)
CHEN YEN-FU (TW)
LEE JIAN-BIN (TW)
Application Number:
PCT/US2023/023800
Publication Date:
December 21, 2023
Filing Date:
May 30, 2023
Export Citation:
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Assignee:
ALPHALA CO LTD (TW)
CHEN CHUNG CHIN (US)
International Classes:
A61K31/395; A61K31/04; A61K31/38; A61K31/415; A61K31/505; A61K31/33
Domestic Patent References:
WO2021080980A12021-04-29
WO2006073610A22006-07-13
Foreign References:
US20110251181A12011-10-13
Other References:
DATABASE PUBCHEM COMPOUND ANONYMOUS : "N-(1,6-diphenylpyrazolo[3,4d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide", XP093122335, retrieved from PUBCHEM
MARTÍNEZ ROBERTO, ZAMUDIO GLADYS J. NIEVES, PRETELIN-CASTILLO GUSTAVO, TORRES-OCHOA RUBÉN O., MEDINA-FRANCO JOSÉ L., ESPITIA PINZÓ: "Synthesis and antitubercular activity of new N -[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-(nitroheteroaryl)carboxamides", HETEROCYCLIC COMMUNICATIONS, vol. 25, no. 1, pages 52 - 59, XP093122439, ISSN: 2191-0197, DOI: 10.1515/hc-2019-0007
Attorney, Agent or Firm:
URCIA, Benjamin E. et al. (US)
Download PDF:
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Claims:
Claims 1. A compound of formula (I): or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1 is aryl or heteroaryl, wherein each of aryl and heteroaryl is optionally substituted with one to three moieties selected from the group consisting of halogen, cyano, alkyl, and alkyloxy optionally substituted with alkyloxy; R2 is aryl, heteroaryl, aryl fused with heterocycloalkyl, aryl fused with heteroaryl or heteroaryl fused with heteroaryl, wherein each of aryl, heteroaryl, aryl fused with heterocycloalkyl, aryl fused with heteroaryl or heteroaryl fused with heteroaryl is optionally substituted with one to three moieties selected from the group consisting of halogen, alkyl, alkyloxy, cyano, hydroxyl, -NRaRb, -C(=O)NRaRb, -C(=O)ORc, -C(=O)Rd and an oxy group, wherein alkyloxy is optionally substituted with alkyloxy, hydroxyl, a phosphate group or – OC(=O)Re, and alkyl is optionally substituted with at least one of hydroxyl or alkyloxy; each of Ra and Rb independently is H, alkyl or alkyloxy; Rc is H or alkyl optionally substituted with at least one of hydroxyl or alkyloxy; Rd is alkyl; and Re is alkyl optionally substituted with at least one of an amino group or a carboxyl group. 2. The compound of claim 1, wherein R1 is phenyl or thiophenyl, and each of phenyl or thiophenyl is optionally substituted with one to three moieties selected from the group consisting of halogen, cyano, alkyl, and alkyloxy optionally substituted with alkyloxy. 3. The compound of claim 2, wherein R1 is phenyl optionally substituted with one or two moieties selected from the group consisting of halogen, cyano, alkyl, and alkyloxy optionally substituted with alkyloxy.

4. The compound of claim 2, wherein R1 is thiophenyl optionally substituted with alkyl or cyano. 5. The compound of claim 1, wherein R2 is , X1 is N or C, X2 is N or C, and each of R3 and R4 independently is selected from the group consisting of hydrogen, halogen, alkyl, alkyloxy, cyano, hydroxyl, -NRaRb, -C(=O)NRaRb, -C(=O)ORc, -C(=O)Rd and an oxy group, wherein alkyloxy is optionally substituted with alkyloxy, hydroxyl, a phosphate group or –OC(=O)Re, and alkyl is optionally substituted with hydroxyl or alkyloxy; or R3 and R4 are taken together with their intervening atoms to form a heterocyclic ring optionally substituted with one or two moieties selected from the group consisting of halogen, an oxy group or alkyl optionally substituted with hydroxyl or alkyloxy; or R3 and R4 are taken together with their intervening atoms to form a heteroaryl ring optionally substituted with alkyloxy optionally substituted with alkyloxy or alkyl optionally substituted with hydroxyl or alkyloxy. 6. The compound of claim 5, wherein R2 is and X1 is N or C. 7. The compound of claim 6, wherein R2 is . 8. The compound of claim 7, wherein each of R3 and R4 independently is alkyloxy or cyano. 9. The compound of claim 8, wherein R1 is phenyl substituted with halogen. 10. The compound of claim 5, wherein R2 is benzodioxolyl optionally substituted with one or two moieties selected from the group consisting of halogen and alkyl optionally substituted with hydroxyl; tetrahydroquinolinyl optionally substituted with an oxy group; benzoxazolyl optionally substituted with alkyl optionally substituted with alkyloxy; benzothiophenyl; benzothiazolyl optionally substituted with alkyl or alkyloxy optionally substituted with alkyloxy; or imidazopyridinyl. 11. The compound of claim 1, wherein R2 is each of R5 is hydrogen, halogen, alkyl, alkyloxy, cyano, hydroxyl, -NRaRb, -C(=O)NRaRb, -C(=O)ORc, or -C(=O)Rd, wherein alkyloxy is optionally substituted with alkyloxy, hydroxyl, a phosphate group or –OC(=O)Re, and alkyl is optionally substituted with hydroxyl or alkyloxy. 12. The compound of claim 11, wherein R2 is , , , 13. The compound of claim 12, wherein R2 is . 14. The compound of claim 13, wherein each of R5 is cyano, -C(=O)ORc or alkyloxy optionally substituted with hydroxyl, wherein Rc is alkyl. R5 N 15. The compound of claim 1, wherein R2 is , R5 is -C(=O)ORc, and Rc is alkyl. 16. The compound of claim 15, wherein R1 is phenyl substituted with cyano. 17. The compound of claim 1, wherein R2 is , and R5 is cyano. 18. The compound of claim 17, wherein R1 is phenyl substituted with F. 19. The compound of claim 1, wherein R2 is , and R5 is alkyloxy optionally substituted with hydroxyl. 20. The compound of claim 19, wherein R1 is phenyl substituted with F. 21. The compound of claim 1, wherein the compound is any one selected from the group consisting of Compounds 1-1 to 1-25, Compounds 2-1 to 2-3, Compounds 3-1 to 3-9, Compounds 4-1 to 4-19, Compounds 5-1 to 5-36, and Compounds 6-1 to 6-3. 22. The compound of claim 1, wherein the compound is Compound 1-8, Compound 5-6, Compound 5-8 or Compound 5-16. 23. 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.

24. 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. 25. The method of claim 24, 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 cancer, 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. 26. The method of claim 24, wherein the cancer is liver cancer, colon cancer or lung cancer.
Description:
Pyrimidine amide compounds and use thereof CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of filing date of U. S. Provisional Application Serial Number 63/351,892, filed June 14, 2022 under 35 USC § 119(e)(1). BACKGROUND OF THE INVENTION [0002] Field [0003] The present invention relates to compounds that can inhibit the growth of tumor cells, pharmaceutical compositions comprising the compounds, and the uses of the compounds or compositions. [0004] Description of Related Art [0005] In recent years, it is found that foods or food additives, and environmental pollutions may be a cause or catalyst for promoting cancer in recent years. Not coincidentally, the same event is happening as well in the developed countries and around the world, and the high incidence rates of cancers is an alarming sign. According to the data published by the American Cancer Society, cancer is being proved to be the most significant threat to public health. [0006] The general methods for treating cancer include surgery, radiotherapy, chemotherapy and immune therapy. In recent years, several therapeutic agents for cancer treatments through new anti-cancer mechanisms have been developed, and it has been proven that the survival rate of patients can be increased by treating them with these therapeutic agents. It is known that the therapeutic agents can treat cancers through, for example, inhibition of cell cycle progression, angiogenesis, farnesyl transferase, and tyrosine kinases. [0007] Although it is known that certain agents exhibit therapeutic effects on cancer, these agents still have their limitations. For example, some anti-cancer drugs only have therapeutic effects on specific cancers, e.g. the anti-cancer drugs for lung cancer treatment do not necessarily show effects on breast cancer treatment. In addition, the therapeutic effects of the anti-cancer drugs also depend on the locations of tumor cells, genetic variations of patients, and the side effects of drugs. Furthermore, cancer cells may spread from its original sites to another organ of the patients via the lymphatic system or blood circulatory systems, thereby causing metastatic cancers. [0008] Since the risk of developing cancer generally increases with age, the occurrence rates of cancer are increased as longer lifespan and as mass lifestyle changes. Hence, there is a long unfulfilled need to provide new agents for cancer treatment and prevention. SUMMARY OF THE INVENTION [0009] The present invention relates to certain compounds that can inhibit the growth of tumor cells. [0010] An aspect of this disclosure is drawn to the compounds of formula (I) below or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof: [0011] In this formula, R 1 is aryl or heteroaryl, wherein each of aryl and heteroaryl is optionally substituted with one to three moieties selected from the group consisting of halogen, cyano, alkyl, and alkyloxy optionally substituted with alkyloxy; R 2 is aryl, heteroaryl, aryl fused with heterocycloalkyl, aryl fused with heteroaryl or heteroaryl fused with heteroaryl, wherein each of aryl, heteroaryl, aryl fused with heterocycloalkyl, aryl fused with heteroaryl or heteroaryl fused with heteroaryl is optionally substituted with one to three moieties selected from the group consisting of halogen, alkyl, alkyloxy, cyano, hydroxyl, -NR a R b , -C(=O)NR a R b , -C(=O)OR c , -C(=O)R d and an oxy group, wherein alkyloxy is optionally substituted with alkyloxy, hydroxyl, a phosphate group or –OC(=O)R e , and alkyl is optionally substituted with at least one of hydroxyl or alkyloxy; each of R a and R b independently is H, alkyl or alkyloxy; R c is H or alkyl optionally substituted with at least one of hydroxyl or alkyloxy; R d is alkyl; and R e is alkyl optionally substituted with at least one of an amino group or a carboxyl group. [0012] The term “alkyl” herein refers to a straight or branched hydrocarbon group, containing 1–12 carbon atoms (e.g., C 1 -C 10 , C 1 -C 8 and C 1 -C 6 ). Examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl. [0013] The term “heterocycloalkyl” refers to a nonaromatic 5–8 membered monocyclic, 8–12 membered bicyclic, or 11–14 membered tricyclic ring system having one or more heteroatoms (e.g., O, N, P, and S). Examples include piperazinyl, imidazolidinyl, azepanyl, pyrrolidinyl, dihydrothiadiazolyl, dioxanyl, morpholinyl, tetrahydropuranyl, and tetrahydrofuranyl. [0014] The term “alkoxy” or “alkyloxy” refers to an –O–alkyl group. Examples include methoxy, ethoxy, propoxy, and isopropoxy. [0015] The term “halogen” refers to a fluoro, chloro, bromo, or iodo radical. [0016] The term “amino” refers to a radical derived from amine, which is unsunstituted or mono-/di-substituted with alkyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl. [0017] The term “aryl” refers to a 6-carbon monocyclic, 10-carbon bicyclic, 14-carbon tricyclic aromatic ring system. Examples of aryl groups include phenyl, naphthyl, and anthracenyl. [0018] The term “heteroaryl” refers to an aromatic 5–8 membered monocyclic, 8–12 membered bicyclic, or 11–14 membered tricyclic ring system having one or more heteroatoms (e.g., O, N, P, and S). Examples include thiophenyl, triazolyl, oxazolyl, thiadiazolyl, tetrazolyl, pyrazolyl, pyridyl, furyl, imidazolyl, benzimidazolyl, pyrimidinyl, thienyl, quinolinyl, indolyl, thiazolyl, and benzothiazolyl. [0019] Alkyl, heterocycloalkyl, alkyloxy, aryl, and heteroaryl mentioned herein include both substituted and unsubstituted moieties. Possible substituents on heterocycloalkyl, alkoxy, aryl, and heteroaryl include, but are not limited to, C l-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, C l-12 heterocycloalkyl, C 1-12 heterocycloalkenyl, C 1-6 alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, C l-6 alkylamino, C l-20 dialkylamino, arylamino, diarylamino, C l-6 alkylsulfonamino, arylsulfonamino, C l-6 alkylimino, arylimino, C l-6 alkylsulfonimino, arylsulfonimino, hydroxyl, halo, thio, C l-6 alkylthio, arylthio, C l-6 alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl, amido, amidino, guanidine, ureido, thioureido, cyano, nitro, nitroso, azido, acyl, thioacyl, acyloxy, carboxyl, and carboxylic ester. On the other hand, possible substituents on alkyl include all of the above-recited substituents except C l-6 alkyl. Heterocycloalkyl, aryl, and heteroaryl can also be fused with each other. [0020] In addition to the compounds of formula (I) described above, their pharmaceutically acceptable salts and solvates, where applicable, are also covered by this disclosure. A salt can be formed between an anion and a positively charged group (e.g., amino) on a compound. Examples of a suitable anion include chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, acetate, malate, tosylate, tartrate, fumurate, glutamate, glucuronate, lactate, glutarate, and maleate. A salt can also be formed between a cation and a negatively charged group. Examples of a suitable cation include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion. A salt further includes those containing quaternary nitrogen atoms. A solvate refers to a complex formed between an active compound and a pharmaceutically acceptable solvent. Examples of a pharmaceutically acceptable solvent include water, ethanol, isopropanol, ethyl acetate, acetic acid, and ethanolamine. [0021] Another aspect of this disclosure is a pharmaceutical composition for treating a cancer. [0022] The pharmaceutical composition contains one of the compounds of formula (I) described above or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, excipient or diluent. [0023] This disclosure also covers use of such a composition for the manufacture of a medicament for treating a cancer. [0024] A composition for oral administration can be any orally acceptable dosage form including capsules, tablets, emulsions and aqueous suspensions, dispersions, and solutions. In the case of tablets, commonly used carriers include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions or emulsions are administered orally, the active ingredient can be suspended or dissolved in an oily phase combined with emulsifying or suspending agents. If desired, certain sweetening, flavoring, or coloring agents can be added. Oral solid dosage forms can be prepared by spray dried techniques; hot melt extrusion strategy, micronization, and nano milling technologies. [0025] A nasal aerosol or inhalation composition can be prepared according to techniques well known in the art of pharmaceutical formulation. For example, such a composition can be prepared as a solution in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. A composition having an active compound can also be administered in the form of suppositories for rectal administration. [0026] The carrier, the excipient and the diluent in the pharmaceutical composition must be “acceptable” in the sense that it is compatible with the active ingredient of the composition (and preferably, capable of stabilizing the active ingredient) and not deleterious to the subject to be treated. One or more solubilizing agents can be utilized as pharmaceutical excipients for delivery of an active compound. Examples of other carriers include colloidal silicon oxide, magnesium stearate, cellulose, sodium lauryl sulfate, and D&C Yellow #10. [0027] Still within the scope of the present invention is a method of treating treating a cancer. [0028] The method includes administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. [0029] The above-described compounds or a pharmaceutical composition containing one or more of them can be administered to a subject orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, or via an implanted reservoir. The term “parenteral” as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques. [0030] The term “treating”, “treat” or “treatment” refers to application or administration of the compound to a subject with the purpose to cure, alleviate, relieve, alter, remedy, improve, or affect the disease, the symptom, or the predisposition. “An effective amount” refers to the amount of the compound which is required to confer the desired effect on the subject. Effective amounts vary, as recognized by those skilled in the art, depending on route of administration, excipient usage, and the possibility of co-usage with other therapeutic treatments such as use of other active agents. [0031] The details of one or more embodiments of the disclosure are set forth in the description below. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. DETAILED DESCRIPTION OF THE INVENTION [0032] One embodiment of the present invention is the compounds of formula (I) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof: in which each of variables each of variables R 1 and R 2 is defined as in the SUMMARY section. [0033] R 1 can be produced by condensing various hydrazine derivatives into a fused aromatic heterocyclic five-membered ring. In addition, it can also be constructed by Mitsunobu reaction or by simple substitution reaction. The Mitsunobu reaction uses triphenylphosphine and azodicarboxylate (such as diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD) to convert alcohols into various functional groups (such as the organic reaction of ester). And alcohol reacts with phosphine to form a good leaving group, and then undergoes stereochemical conversion in the classic S N 2 way of nucleophile substitution to form carbon-carbon bond derivatives. [0034] R 2 can be synthesized by Suzuki, and the Sonogashira reaction is a cross-coupling reaction used to form carbon-carbon bonds in organic synthesis. They use a palladium catalyst as a catalyst to form carbon-carbon bonds between the terminal alkynes and the aryl heteroaryl or vinyl halide. And it is substituted by NR, OR, SR nucleophile in heteroaromatic substitution. [0035] Another embodiment of the present invention is the compound of the aforesaid embodiment or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1 may be phenyl or thiophenyl, and each of phenyl or thiophenyl may be optionally substituted with one to three moieties selected from the group consisting of halogen, cyano, alkyl, and alkyloxy optionally substituted with alkyloxy. [0036] Another embodiment of the present invention is the compound of the aforesaid embodiment or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R 1 may be phenyl optionally substituted with one or two moieties selected from the group consisting of halogen, cyano, alkyl, and alkyloxy optionally substituted with alkyloxy. [0037] Another embodiment of the present invention is the compound of the aforesaid embodiment or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R 1 may be thiophenyl optionally substituted with alkyl or cyano. [0038] Another embodiment of the present invention is the compound of the aforesaid embodiment or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R 2 may be may be N or C, X 2 is N or C, and each of R 3 and R 4 independently may be selected from the group consisting of hydrogen, halogen, alkyl, alkyloxy, cyano, hydroxyl, -NRaRb, -C(=O)NRaRb, -C(=O)ORc, -C(=O)Rd and an oxy group, wherein alkyloxy is optionally substituted with alkyloxy, hydroxyl, a phosphate group or –OC(=O)R e , and alkyl is optionally substituted with hydroxyl or alkyloxy; or R 3 and R 4 may be taken together with their intervening atoms to form a heterocyclic ring optionally substituted with one or two moieties selected from the group consisting of halogen, an oxy group or alkyl optionally substituted with hydroxyl or alkyloxy; or R 3 and R 4 may be taken together with their intervening atoms to form a heteroaryl ring optionally substituted with alkyloxy optionally substituted with alkyloxy or alkyl optionally substituted with hydroxyl or alkyloxy. The definitions of R a , R b , R c , R d and R e are the same as those described above, and are not described again. [0039] Another embodiment of the present invention is the compound of the aforesaid embodiment or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, R 2 may be and X 1 may be N or C. The definitions of R 3 and R 4 are the same as those described above, and are not described again. [0040] Another embodiment of the present invention is the compound of the aforesaid embodiment or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, R 2 may be The definitions of R 3 and R 4 are the same as those described above, and are not described again. [0041] Another embodiment of the present invention is the compound of the aforesaid embodiment or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R 2 may be and each of R 3 and R 4 may independently be alkyloxy (for example, methoxy) or cyano. In one embodiment of the present invention, R 1 may be phenyl substituted with halogen. [0042] Another embodiment of the present invention is the compound of the aforesaid embodiment or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R 2 may be benzodioxolyl optionally substituted with one or two moieties selected from the group consisting of halogen and alkyl optionally substituted with hydroxyl; tetrahydroquinolinyl optionally substituted with an oxy group; benzoxazolyl optionally substituted with alkyl optionally substituted with alkyloxy; benzothiophenyl; benzothiazolyl optionally substituted with alkyl or alkyloxy optionally substituted with alkyloxy; or imidazopyridinyl. [0043] Another embodiment of the present invention is the compound of the aforesaid embodiment or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R 2 may be each of R 5 may be hydrogen, halogen, alkyl, alkyloxy, cyano, hydroxyl, -NR a R b , -C(=O)NR a R b , -C(=O)OR c , or -C(=O)R d , wherein alkyloxy is optionally substituted with alkyloxy, hydroxyl, a phosphate group or –OC(=O)R e , and alkyl is optionally substituted with hydroxyl or alkyloxy. [0044] Another embodiment of the present invention is the compound of the aforesaid embodiment or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R 2 may be The definition of R 5 is the same as those described above, and is not described again. [0045] Another embodiment of the present invention is the compound of the aforesaid embodiment or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R 2 may be The definition of R 5 is the same as those described above, and is not described again. [0046] Another embodiment of the present invention is the compound of the aforesaid embodiment or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R 2 may be and each of R 5 may be cyano, -C(=O)ORc or alkyloxy optionally substituted with hydroxyl, wherein Rc is alkyl. [0047] Another embodiment of the present invention is the compound of the aforesaid embodiment or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R 2 may be , R 5 may be -C(=O)OR c , and R c may be alkyl (for example, methyl). In one embodiment of the present invention, R 1 may be phenyl substituted with cyano. [0048] Another embodiment of the present invention is the compound of the aforesaid embodiment or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R2 may be , and R5 may be cyano. In one embodiment of the present invention, R 1 may be phenyl substituted with F. [0049] Another embodiment of the present invention is the compound of the aforesaid embodiment or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R 2 may be , and R 5 may be alkyloxy optionally substituted with hydroxyl (for example, hydroxyethoxy). In one embodiment of the present invention, R 1 may be phenyl substituted with F. [0050] Another embodiment of the present invention can be a compound selected from the group consisting of Compounds 1-1 to 1-25, Compounds 2-1 to 2-3, Compounds 3-1 to 3-9, Compounds 4-1 to 4-19, Compounds 5-1 to 5-36, and Compounds 6-1 to 6-3, which are listed in the following Tables 1 to 6; or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof. [0051] A further another embodiment of the present invention can be a compound of Compound 1-8, Compound 5-6, Compound 5-8 or Compound 5-16; or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.. [0052] The compounds of the present invention may contain asymmetric or chiral centers, and exist in different stereoisomeric forms. Unless specified otherwise, all stereoisomeric forms of the compounds of the present invention as well as mixtures thereof, including racemic mixtures are within the scope of the present invention. In addition, the compounds of the present invention may also exist in different geometric and positional isomers. For example, both the cis- and trans-forms, as well as mixtures of the compound with a double bond or a fused ring, are also within the scope of the present invention. [0053] Diastereomeric mixtures can be separated into their individual diastereoisomers by any methods, such as by chromatography and/or fractional crystallization. Enantiomers can be separated by use of a chiral HPLC column or by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound to separate the diastereoisomers and convert the individual diastereoisomers into pure enantiomers. The specific stereoisomers may be synthesized by converting one stereoisomer into the other by asymmetric transformation, by using an optically active starting material or by asymmetric synthesis using optically active reagents, catalysts, substrates or solvents. [0054] Also within the present invention is a pharmaceutical composition, comprising: (1) the compound of the present invention, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof; and (2) a pharmaceutically acceptable carrier, excipient or diluent. The composition may also comprise at least one additional pharmaceutical agent such as anti-cancer agents. The compound or the pharmaceutically acceptable salt thereof or the composition of the present invention may be used in the manufacture of a medicament of inhibiting the growth of tumor cells or treating cancer. [0055] Also within the present invention is a method for treating a cancer, which includes the step of administering to the subject in need thereof an effective amount of the compound of the present invention or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof. [0056] Further covered by the present invention a method of inhibiting a growth of tumor cells, which includes the step of administering to a subject in need thereof an effective amount of the compound of the present invention or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof. [0057] In the present invention, the aforesaid subject can be mammal, for example, human. [0058] In the present invention, the compound of the present invention or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof can inhibit the growth of tumor cells to achieve the purpose of treating a cancer. Examples of the cancer include, but are not limited to, gastric cancer, colon cancer, colorectal cancer, breast cancer, lung cancer, prostate cancer, bladder cancer, pancreatic cancer, liver cancer, uterine cancer, cervical cancer, 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, or head and neck cancer. In one embodiment of the present invention, the cancer may be liver cancer, colon cancer or lung cancer. [0059] The compounds or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof of the present invention may be administered in combination with at least one additional pharmaceutical agent such as anti-cancer agent. The administration formulation can be, for example, (a) a single formulation comprising the compound of the present invention or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, excipient or diluent and at least one additional pharmaceutical agent; or (b) two formulations administered simultaneously or sequentially and in any order, wherein one comprises the compound of the present invention or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, excipient or diluent and the other one comprises at least one additional pharmaceutical agent. [0060] Suitable anti-cancer agents may include Herceptin, Rituximab, Docetaxel, Capecitabine, Cetuximab, Gefitinib, PD-1, Sorafenib tosylate or Imatinib, but the present invention is not limited thereto. Any other anti-cancer agents known in the art can also be used in the present invention. [0061] Methods for synthesizing the compounds of formula (I) are well known in the art. See, for example, R. Larock, Comprehensive Organic Transformations (2nd Ed., VCH Publishers 1999); P. G. M. Wuts and T. W. Greene, Greene’s Protective Groups in Organic Synthesis (4th Ed., John Wiley and Sons 2007); L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for Organic Synthesis (John Wiley and Sons 1994); L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (2nd ed., John Wiley and Sons 2009); P. Roszkowski, J.K. Maurin, Z. Czarnocki “Enantioselective synthesis of (R)-(–)- praziquantel (PZQ)” Tetrahedron: Asymmetry 17 (2006) 1415‒1419; and L. Hu, S. Magesh, L. Chen, T. Lewis, B. Munoz, L. Wang “Direct inhibitors of keap1-nrf2 interaction as antioxidant inflammation modulators,” WO2013/067036. [0062] The compounds of formula (I) thus prepared can be initially screened using in vitro assays, e.g., NCI-60 screening platform or MTS method. They can be subsequently evaluated using in vivo assays known in the field. The selected compounds can be further tested to verify their efficacy in disease related efficacy and adverse effects models. Based on the results, an appropriate dosage range and administration route can be determined. [0063] The following embodiments are made to clearly exhibit the above-mentioned and other technical contents, features and/or effects of the present invention. Through the exposition by means of the specific embodiments, people would further understand the technical means and effects the present invention adopts to achieve the above-indicated objectives. Moreover, as the contents disclosed herein should be readily understood and can be implemented by a person skilled in the art, all equivalent changes or modifications which do not depart from the concept of the present invention should be encompassed by the appended claims. EXAMPLE [0064] Without further elaboration, it is believed that one skilled in the art can, based on the above description, utilize the present invention to its fullest extent. The following specific examples are therefore to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. All publications cited herein are incorporated by reference in their entirety. [0065] Described below are the procedures used to synthesize the exemplary compounds of the present invention. [0066] Unless otherwise stated, all starting materials used were commercially available and used as supplied. Reactions requiring anhydrous conditions were performed in flame- dried glassware and cooled under an argon or nitrogen atmosphere. Unless otherwise stated, reactions were carried out under argon or nitrogen and monitored by analytical thin-layer chromatography performed on glass-backed plates (5 cm_10 cm) precoated with silica gel 60 F254 as supplied by Merck. Visualization of the resulting chromatograms was done by looking under an ultraviolet lamp (λ=254 nm), followed by dipping in an nBuOH solution of Ninhydrin (0.3% w/v) containing acetic acid (3% v/v) or ethanol solution of phosphomolybdic acid (2.5% w/v) and charring by heat gun. Solvents for reactions were dried under an argon or nitrogen atmosphere prior to use as follows: THF, Toluene, and DCM were dried by the column of Dried molecular Sieve 5A (LC technology solution Inc). DMF dried by calcium hydride or anhydrous is commercial available. Flash chromatography was used routinely for purification and separation of product mixtures using RediSep Rf Silica Gel Disposable Flash Columns, Gold® 20-40 / 40-60 microns silica gel and Reusable RediSep Rf Gold® C18 Reversed Phase columns, 20-40 micronssupplied by RediSep. Eluent systems are given in volume/volume concentrations. 13 C and 1 H NMR spectra were recorded on Bruker AVIII(400 MHz). Chloroform-d or dimethyl sulfoxide-d6 and CD 3 OD was used as the solvent and TMS (δ 0.00 ppm) as an internal standard. Chemical shift values are reported in ppm relative to the TMS in delta (δ) units. Multiplicities are recorded as s (singlet), br s (broad singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublet), dt (doublet of triplet), m (multiplet). Coupling constants (J) are expressed in Hz. Electrospray mass spectra (ESMS) were recorded using a Thermo LTQ XL mass spectrometer. Spectral data were recorded as m/z values. [0067] In the preparation of compounds of the present invention, protection of remote functionality (e.g., primary or secondary amine) of intermediates may be necessary. The need for such protection may vary depending on the nature of the remote functionality and the conditions of the preparation methods. Suitable amino protecting groups (NHPg) include, for example, acetyl, trifluoroacetyl, tbutoxycarbonyl (BOC), 9- fluorenylmethyleneoxycarbonyl (Fmoc) and benzyloxycarbonyl (CBz). Similarly, a “hydroxyl protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable hydroxyl protecting groups (OPg) include, for example, allyl, acetyl, silyl, benzyl, paramethoxy benzyl, trityl, and the like. The need for such protection is readily determined by one skilled in the art. [0068] Experimental Procedure [0069] Step 1: Cyclization [0070] 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%). [0071] Step 2: Amination [0072] 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. [0073] Step 3: Suzuki coupling reaction [0074] 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. [0075] Step 4: Amidation reaction [0076] 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 [0077] 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-carboxamide as a yellow powder. [0078] Experimental Procedure [0079] Cyclization via condensation and closure ring reactions [0080] 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

[0081] N-C bond formation with Mitsunobu reaction [0082] Formation of tert-butyl 4-(6-chloro-4-((4-methoxybenzyl)amino)-1H- pyrazolo[3,4-d] pyrimidin-1-yl)piperidine-1-carboxylate [0083] 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]pyrimidin-1-yl)piperi dine-1-carboxylate (4.78g, 70%). [0084] Suzuki coupling reaction [0085] Formation of 4-(6-(4-chlorophenyl)-4-((4-methoxybenzyl)amino)-1H- pyrazolo[3,4-d] pyrimidin-1-yl)piperidine-1-carboxylate [0086] 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. [0087] Deprotection by DDQ [0088] Formation of tert-butyl 4-(4-amino-6-(4-chlorophenyl)-1H-pyrazolo[3,4-d] pyrimidin-1-yl)piperidine-1-carboxylate [0089] 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)piperidine-1-carboxylate 2.54g (yield 79%) as a white solid. [0090] Deprotection by TFA [0091] Formation of (S)-6-(6-fluoropyridin-3-yl)-1-(pyrrolidin-3-yl)-1H-pyrazolo [3,4-d] pyrimidin-4-amine [0092] 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. [0093] Amidation with acyloyl chloride [0094] 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 [0095] 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)pyrrolidin-1-yl)prop-2-en-1-one 1.06g (75%) as pale yellow solid. [0096] Amination [0097] 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. [0098] N-Alkylation [0099] 6-(3,3-difluoropyrrolidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-d]p yrimidin-4-amine formation [0100] 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. [0101] Amidation [0102] 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 [0103] To a solution of 6-(3,3-difluoropyrrolidin-1-yl)-1-phenyl-1H-pyrazolo[3,4- d]pyrimidin -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. [0104] Alkoxylation [0105] 6-(4-fluorophenoxy)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-a mine formation [0106] 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. [0107] Amidation [0108] N-(6-(4-fluorophenoxy)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin- 4-yl)-5- nitrothiophene-2-carboxamide formation by amidation of carbonyl acid [0109] To a solution of 6-(3,3-difluoropyrrolidin-1-yl)-1-phenyl-1H-pyrazolo[3,4- d]pyrimidin- 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. [0111] 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% ) [0112] 4-(4-(tert-butyl)phenyl)-6-chloro-1-methyl-1H-pyrazolo[3,4-d ]pyrimidine formation [0113] Suzuki coupling reaction [0114] 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. [0115] 4-(4-(tert-butyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidi n-6-amine [0116] Amination [0117] 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-a mine (1.58g, 80%) as a yellow solid powder. [0118] Amidation [0119] 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 [0120] 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]pyrim idin-6-yl)- 5-nitrothiophene-2-carboxamide as a yellow powder. [0121] Evaluation of compounds of formula (I) in in vitro MTS assays [0122] 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 six 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 six 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. [0123] The compounds prepared in Tables 1 to 6 were tested in three in vitro assays, and the results are shown in Table7 for Hep3B, 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. [0124] In the compounds shown in Tables 1 to 6, the detail synthesized procedures of some compounds are not repeated again if the synthesized procedures thereof are similar to those of the forgoing compounds. [0125] Shown in following Tables 1 to 6 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). [0126] Table 1 [0127] Compound 1-1 [0128] N-(1-(4-methoxyphenyl)-6-(5-methoxypyridin-3-yl)-1H-pyrazolo [3,4- d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide [0129] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.01 (br. s., 1H), 9.25 (d, J = 1.5 Hz, 1H), 8.61 (s, 1H), 8.47 (d, J = 2.4 Hz, 1H), 8.37 (d, J = 4.4 Hz, 1H), 8.21-8.29 (m, 2H), 8.07-8.17 (m, 2H), 7.13-7.24 (m, 2H), 3.96 (s, 3H), 3.85 (s, 3H). MS(M+1): 504. Yellow solid. [0130] Compound 1-2 [0131] N-(6-(6-cyanopyridin-3-yl)-1-(4-methoxyphenyl)-1H-pyrazolo[3 ,4-d]pyrimidin- 4-yl)-5-nitrothiophene-2-carboxamide O [0132] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.02 (br. s., 1H), 9.68 (d, J = 1.5 Hz, 1H), 8.88 (dd, J = 8.1, 2.2 Hz, 1H), 8.59 (s, 1H), 8.32 (d, J = 4.4 Hz, 1H), 8.15-8.27 (m, 2H), 7.98- 8.14 (m, 2H), 7.03-7.25 (m, 2H), 3.85 (s, 3H). MS(M+1): 499. Yellow solid. [0133] Compound 1-3 [0134] N-(1-(2,4-difluorophenyl)-6-(6-(2-methoxyethoxy)pyridin-3-yl )-1H-pyrazolo[3,4- d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide

[0135] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.04 (s, 1H), 9.16 (d, J = 2.4 Hz, 1H), 8.64 (s, 1H), 8.56 (dd, J = 8.8, 2.4 Hz, 1H), 8.38 (d, J = 4.4 Hz, 1H), 8.26 (d, J = 4.4 Hz, 1H), 7.88 (td, J = 8.8, 5.9 Hz, 1H), 7.67 (ddd, J = 10.5, 9.0, 2.9 Hz, 1H), 7.30-7.45 (m, 1H), 6.99 (d, J = 9.3 Hz, 1H), 4.38-4.53 (m, 2H), 3.68 (dd, J = 5.4, 3.9 Hz, 2H), 3.30 (s, 3H). MS(M+1): 554. Yellow solid. [0136] Compound 1-4 [0137] N-(6-(4-fluoro-3-methoxyphenyl)-1-(4-fluorophenyl)-1H-pyrazo lo[3,4- d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide [0138] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.04 (br. s., 1H), 8.60 (s, 1H), 8.28-8.36 (m, 3H), 8.23-8.28 (m, 2H), 8.14 (ddd, J = 8.7, 4.5, 2.0 Hz, 1H), 7.36-7.54 (m, 3H), 4.00 (s, 3H). MS(M+1): 509. White solid. [0139] Compound 1-5 [0140] N-(6-(5-methoxy-6-(2-methoxyethoxy)pyridin-3-yl)-1-(4-methox yphenyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamid e

[0141] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.00 (br. s., 1H), 8.84 (d, J = 1.5 Hz, 1H), 8.57 (s, 1H), 8.35 (d, J = 4.4 Hz, 1H), 8.26 (d, J = 4.4 Hz, 1H), 8.19 (d, J = 2.0 Hz, 1H), 8.13- 8.18 (m, 2H), 7.14-7.26 (m, 2H), 4.50 (dd, J = 5.4, 3.9 Hz, 2H), 3.94 (s, 3H), 3.85 (s, 3H), 3.71 (dd, J = 5.4, 3.9 Hz, 2H). MS(M+1): 578. Brown solid. [0142] Compound 1-6 [0143] N-(1-(3-chlorophenyl)-6-(4-fluoro-3-methoxyphenyl)-1H-pyrazo lo[3,4- d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide [0144] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.04 (br. s., 1H), 8.65 (s, 1H), 8.55 (t, J = 2.0 Hz, 1H), 8.36 (d, J = 4.4 Hz, 1H), 8.24-8.32 (m, 3H), 8.14 (ddd, J = 8.3, 4.4, 2.0 Hz, 1H), 7.67 (t, J = 8.1 Hz, 1H), 7.39-7.52 (m, 2H), 4.01 (s, 3H). MS(M+1): 525. Yellow solid. [0145] Compound 1-7 [0146] N-(6-(6-cyano-5-fluoropyridin-3-yl)-1-(4-methoxyphenyl)-1H-p yrazolo[3,4- d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide [0147] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.08 (br. s., 1H), 9.58 (s, 1H), 8.78 (dd, J = 9.5, 1.7 Hz, 1H), 8.66 (s, 1H), 8.34 (d, J = 4.4 Hz, 1H), 8.27 (d, J = 4.4 Hz, 1H), 8.10- 8.16 (m, 2H), 7.18-7.23 (m, 2H), 3.87 (s, 4H). MS(M+1): 517. Yellow solid. [0148] Compound 1-8 [0149] N-(6-(3-cyano-4-methoxyphenyl)-1-(3-fluorophenyl)-1H-pyrazol o[3,4- d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide [0150] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.02 (br. s., 1H), 8.74-8.79 (m, 2H), 8.67 (s, 1H), 8.34 (d, J = 4.4 Hz, 1H), 8.27 (d, J = 4.4 Hz, 1H), 8.23 (dd, J = 8.1, 1.2 Hz, 1H), 8.16 -8.21 (m, 1H), 7.70 (td, J = 8.2, 6.6 Hz, 1H), 7.50-7.55 (m, 1H), 7.28 (td, J = 8.3, 2.4 Hz, 1H), 4.05 (s, 3H). MS(M+1): 516. Yellow solid. [0151] Compound 1-9 [0152] N-(6-(6-cyano-5-ethoxypyridin-3-yl)-1-(3-fluorophenyl)-1H-py razolo[3,4- d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide [0153] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.10 (br. s., 1H), 9.27 (d, J = 1.0 Hz, 1H), 8.68 (s, 1H), 8.50 (s, 1H), 8.36 (d, J = 4.4 Hz, 1H), 8.26 (d, J = 4.4 Hz, 1H), 8.06-8.22 (m, 2H), 7.63-7.72 (m, 1H), 7.27 (td, J = 8.3, 2.4 Hz, 1H), 4.42 (q, J = 6.8 Hz, 2H), 1.49 (t, J = 6.8 Hz, 3H). MS(M+1): 531. Khaki solid. [0154] Compound 1-10 [0155] N-(6-(4-fluoro-3-(2-hydroxyethoxy)phenyl)-1-(4-methoxyphenyl )-1H- pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamid e [0156] 1 H NMR (400MHz, DMSO-d 6 ): δ 11.96 (br. s., 1H), 8.57 (s, 1H), 8.36 (d, J = 4.4 Hz, 1H), 8.22-8.31 (m, 2H), 8.08-8.18 (m, 3H), 7.41 (dd, J = 11.2, 8.8 Hz, 1H), 7.18 (d, J = 9.3 Hz, 2H), 4.98 (t, J = 5.6 Hz, 1H), 4.21 (t, J = 4.9 Hz, 2H), 3.85 (s, 3H), 3.82 (q, J = 5.4 Hz, 2H). MS(M+1): 551. Orange solid. [0157] Compound 1-11 [0158] N-(6-(4-fluoro-3-(3-hydroxypropoxy)phenyl)-1-(4-methoxypheny l)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamid e [0159] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.02 (br. s., 1H), 8.57 (s, 1H), 8.34 (d, J = 4.4 Hz, 1H), 8.20-8.32 (m, 2H), 8.09-8.18 (m, 3H), 7.41 (dd, J = 11.2, 8.8 Hz, 1H), 7.15-7.23 (m, 2H), 4.63 (t, J = 5.1 Hz, 1H), 4.27 (t, J = 6.4 Hz, 2H), 3.85 (s, 3H), 3.63 (q, J = 5.9 Hz, 2H), 1.97 (t, J = 6.1 Hz, 2H). MS(M+1): 565. Yellow solid. [0160] Compound 1-12 [0161] N-(1-(3-cyanophenyl)-6-(4-fluoro-3-(2-hydroxyethoxy)phenyl)- 1H-pyrazolo[3,4- d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide [0162] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.00 (br. s., 1H), 8.81 (t, J = 1.7 Hz, 1H), 8.61-8.66 (m, 1H), 8.59 (dt, J = 8.1, 1.6 Hz, 1H), 8.35 (d, J = 4.9 Hz, 1H), 8.19-8.27 (m, 2H), 8.10 (ddd, J = 8.7, 4.5, 2.0 Hz, 1H), 7.78-7.87 (m, 2H), 7.41 (dd, J = 11.2, 8.8 Hz, 1H), 4.93-5.00 (m, 1H), 4.23 (t, J = 4.9 Hz, 2H), 3.81-3.88 (m, 2H). MS(M+1): 546. Yellow solid. [0163] Compound 1-13 [0164] N-(6-(4-fluoro-3-(2-hydroxyethoxy)phenyl)-1-(4-fluorophenyl) -1H-pyrazolo[3,4- d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide [0165] 1 H NMR (400MHz, DMSO-d 6 ): δ 11.99 (br. s., 1H), 8.60 (s, 1H), 8.35 (d, J = 4.4 Hz, 1H), 8.23-8.32 (m, 4H), 8.12 (ddd, J = 8.4, 4.5, 2.2 Hz, 1H), 7.43-7.50 (m, 2H), 7.41 (dd, J = 11.0, 8.6 Hz, 1H), 4.98 (t, J = 5.4 Hz, 1H), 4.22 (t, J = 4.9 Hz, 2H), 3.83 (q, J = 5.1 Hz, 2H). MS(M+1): 539. Yellow solid. [0166] Compound 1-14 [0167] N-(1-(4-cyanophenyl)-6-(4-fluoro-3-(2-hydroxyethoxy)phenyl)- 1H-pyrazolo[3,4- d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide

[0168] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.08 (br. s., 1H), 8.67 (s, 1H), 8.58-8.64 (m, 2H), 8.26-8.33 (m, 2H), 8.21-8.26 (m, 1H), 8.16 (ddd, J = 8.6, 4.6, 2.0 Hz, 1H), 8.04-8.12 (m, 2H), 7.42 (dd, J = 11.0, 8.6 Hz, 1H), 4.99 (t, J = 5.6 Hz, 1H), 4.24 (t, J = 4.9 Hz, 2H), 3.84 (q, J = 5.2 Hz, 2H). MS(M+1): 546. Yellow solid. [0169] Compound 1-15 [0170] N-(6-(4-fluoro-3-(2-hydroxyethoxy)phenyl)-1-(3-fluorophenyl) -1H-pyrazolo[3,4- d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide [0171] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.08 (br. s., 1H), 8.65 (s, 1H), 8.37 (d, J = 4.4 Hz, 1H), 8.10-8.32 (m, 6H), 7.63-7.74 (m, 1H), 7.39-7.50 (m, 1H), 7.22-7.32 (m, 1H), 4.99 (t, J = 5.4 Hz, 1H), 4.23 (t, J = 4.9 Hz, 2H), 3.83 (q, J = 5.1 Hz, 2H). MS(M+1): 539. Yellow solid. [0172] Compound 1-16 [0173] N-(6-(4-cyano-3-(methylamino)phenyl)-1-(3-fluorophenyl)-1H-p yrazolo[3,4- d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide [0174] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.12 (s, 1H), 8.70 (s, 1H), 8.40 (d, J = 4.4 Hz, 1H), 8.25-8.30 (m, 2H), 8.18-8.25 (m, 2H), 7.88 (d, J = 1.0 Hz, 1H), 7.77-7.86 (m, 1H), 7.66-7.76 (m, 2H), 7.29 (td, J = 8.6, 2.4 Hz, 1H), 2.94 (s, 4H). MS(M+1): 515. Yellow solid. [0175] Compound 1-17 [0176] N-(6-(4-fluoro-3-methoxyphenyl)-1-(3-fluoro-4-methoxyphenyl) -1H- pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamid e [0177] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.00 (br. s., 1H), 8.58 (s, 1H), 8.35 (d, J = 4.4 Hz, 1H), 8.22-8.27 (m, 2H), 8.09-8.18 (m, 2H), 8.04-8.09 (m, 1H), 7.38-7.47 (m, 2H), 4.00 (s, 3H), 3.93 (s, 3H).MS(M+1): 539. Pale yellow solid. [0178] Compound 1-18 [0179] N-(6-(4-chloro-3-cyanophenyl)-1-(3-fluorophenyl)-1H-pyrazolo [3,4-d]pyrimidin- 4-yl)-5-nitrothiophene-2-carboxamide [0180] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.00 (br. s., 1H), 8.86 (d, J = 2.0 Hz, 1H), 8.70 (dd, J = 8.6, 2.2 Hz, 1H), 8.65 (s, 1H), 8.32 (d, J = 4.4 Hz, 1H), 8.25 (d, J = 4.4 Hz, 1H), 8.18 (dd, J = 8.3, 1.5 Hz, 1H), 8.08 (dt, J = 10.8, 2.4 Hz, 1H), 7.98 (d, J = 8.3 Hz, 1H), 7.67 (td, J = 8.3, 6.8 Hz, 1H), 7.26 (td, J = 8.6, 2.4 Hz, 1H). MS (M+1): 520. Gray powder. [0181] Compound 1-19 [0182] N-(6-(3-cyano-4-fluorophenyl)-1-(3-fluorophenyl)-1H-pyrazolo [3,4-d]pyrimidin- 4-yl)-5-nitrothiophene-2-carboxamide [0183] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.03 (br. s., 1H), 8.89 (dd, J = 6.4, 2.0 Hz, 1H), 8.83 (ddd, J = 8.9, 5.5, 2.2 Hz, 1H), 8.69 (s, 1H), 8.34 (d, J = 4.4 Hz, 1H), 8.26 (d, J = 3.9 Hz, 1H), 8.22 (dd, J = 7.8, 1.5 Hz, 1H), 8.13 (dt, J = 10.8, 2.2 Hz, 1H), 7.79 (t, J = 8.8 Hz, 1H), 7.70 (td, J = 8.3, 6.8 Hz, 1H), 7.28 (td, J = 8.7, 2.2 Hz, 1H). MS(M+1): 504. Yellow solid. [0184] Compound 1-20 [0185] N-(6-(3-cyano-4-(2-hydroxyethoxy)phenyl)-1-(4-fluorophenyl)- 1H-pyrazolo[3,4- d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide [0186] 1 H NMR (400MHz, DMSO-d 6 ): δ 11.97 (br. s., 1H), 8.76 (d, J = 2.0 Hz, 1H), 8.73 (dd, J = 9.0, 2.2 Hz, 1H), 8.63 (s, 1H), 8.35 (d, J = 4.4 Hz, 1H), 8.25-8.31 (m, 3H), 7.44- 7.53 (m, 3H), 5.00 (t, J = 5.1 Hz, 1H), 4.30 (t, J = 4.9 Hz, 2H), 3.81 (q, J = 4.9 Hz, 2H). MS(M+1): 546. Yellow solid. [0187] Compound 1-21 [0188] N-(6-(3-cyano-4-ethoxyphenyl)-1-(3-fluorophenyl)-1H-pyrazolo [3,4-d]pyrimidin- 4-yl)-5-nitrothiophene-2-carboxamide [0189] 1 H NMR (400MHz, DMSO-d 6 ): δ 11.85 (s, 1H), 8.60-8.68 (m, 2H), 8.58 (s, 1H), 8.34 (d, J = 4.4 Hz, 1H), 8.24 (d, J = 4.4 Hz, 1H), 8.15 (dd, J = 8.1, 1.2 Hz, 1H), 8.09 (dt, J = 11.0, 2.3 Hz, 1H), 7.64 (td, J = 8.3, 6.4 Hz, 1H), 7.42 (d, J = 9.3 Hz, 1H), 7.23 (td, J = 8.4, 2.7 Hz, 1H), 4.29 (q, J = 7.2 Hz, 2H), 1.42 (t, J = 6.8 Hz, 3H). MS(M+1): 530. Yellow solid. [0190] Compound 1-22 [0191] N-(6-(4-cyano-3-fluorophenyl)-1-(3-fluorophenyl)-1H-pyrazolo [3,4-d]pyrimidin- 4-yl)-5-nitrothiophene-2-carboxamide [0192] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.07 (br. s., 1H), 8.70 (s, 1H), 8.47 (dd, J = 7.8, 1.5 Hz, 1H), 8.44 (dd, J = 10.5, 1.2 Hz, 1H), 8.34 (d, J = 4.4 Hz, 1H), 8.27 (d, J = 4.4 Hz, 1H), 8.15-8.24 (m, 2H), 8.07-8.15 (m, 1H), 7.70 (td, J = 8.3, 6.4 Hz, 1H), 7.28 (td, J = 8.1, 2.4 Hz, 1H). MS(M+1): 504. Yellow solid. [0193] Compound 1-23 [0194] N-(6-(4-carbamoyl-3-(methylamino)phenyl)-1-(3-fluorophenyl)- 1H-pyrazolo[3,4- d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide [0195] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.02 (br. s., 1H), 8.64 (s, 1H), 8.34-8.41 (m, 1H), 8.28-8.34 (m, 1H), 8.22-8.28 (m, 1H), 8.15-8.22 (m, 1H), 8.09-8.15 (m, 1H), 7.93 (br. s., 1H), 7.77-7.86 (m, 2H), 7.62-7.72 (m, 2H), 7.25 (td, J = 8.7, 2.2 Hz, 2H), 2.96 (d, J = 4.9 Hz, 3H). MS(M+1): 533. Yellow solid. [0196] Compound 1-24 [0197] N-(6-(4-fluoro-3-hydroxyphenyl)-1-(3-fluorophenyl)-1H-pyrazo lo[3,4- d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide [0198] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.05 (br. s., 1H), 10.21 (s, 1H), 8.64 (s, 1H), 8.36 (d, J = 4.4 Hz, 1H), 8.26 (d, J = 4.9 Hz, 1H), 8.22 (ddd, J = 8.3, 2.0, 1.0 Hz, 1H), 8.13-8.19 (m, 2H), 7.98-8.06 (m, 1H), 7.69 (td, J = 8.2, 6.6 Hz, 1H), 7.33-7.40 (m, 1H), 7.22-7.33 (m, 1H). MS(M+1): 495. Yellow solid. [0199] Compound 1-25 [0200] N-(6-(3-cyano-4-methylphenyl)-1-(3-fluorophenyl)-1H-pyrazolo [3,4- d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide [0201] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.01 (br. s., 1H), 8.77 (d, J = 1.5 Hz, 1H), 8.60-8.70 (m, 2H), 8.35 (d, J = 4.4 Hz, 1H), 8.26 (d, J = 4.4 Hz, 1H), 8.21 (dd, J = 8.3, 1.5 Hz, 1H), 8.14 (dt, J = 10.8, 2.2 Hz, 1H), 7.65-7.76 (m, 2H), 7.27 (td, J = 8.7, 2.2 Hz, 1H), 2.59 (s, 3H). MS (M+1): 500. Yellow powder. [0202] Table 2 [0203] Compound 2-1 [0204] N-(6-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-methoxyphen yl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamid e [0205] 1 H NMR (400MHz, DMSO-d 6 ): δ 11.74 (s, 1H), 8.47 (s, 1H), 8.27-8.35 (m, 2H), 8.18-8.26 (m, 2H), 8.01-8.08 (m, 2H), 7.53 (d, J = 8.3 Hz, 1H), 7.06-7.17 (m, 2H), 3.83 (s, 3H). MS(M+1): 553. Yellow solid. [0206] Compound 2-2 [0207] N-(6-(benzo[d][1,3]dioxol-5-yl)-1-(3-cyanophenyl)-1H-pyrazol o[3,4- d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide

[0208] 1 H NMR (400MHz, DMSO-d 6 ): δ 11.94 (br. s., 1H), 8.69-8.75 (m, 2H), 8.64 (s, 1H), 8.36 (d, J = 4.4 Hz, 1H), 8.21 (d, J = 4.9 Hz, 1H), 8.16 (dd, J = 8.3, 2.0 Hz, 1H), 8.00 (d, J = 1.5 Hz, 1H), 7.77-7.88 (m, 2H), 7.08 (d, J = 8.3 Hz, 1H), 6.14 (s, 2H). MS(M+1): 512. Yellow solid. [0209] Compound 2-3 [0210] N-(1-(3-cyanophenyl)-6-(2-(2-hydroxyethyl)benzo[d][1,3]dioxo l-5-yl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamid e [0211] 1 H NMR (400MHz, DMSO-d 6 ): δ 11.99 (br. s., 1H), 8.58-8.66 (m, 1H), 8.54-8.58 (m, 1H), 8.52 (s, 1H), 8.44 (d, J = 4.4 Hz, 1H), 8.21 (d, J = 4.4 Hz, 1H), 8.03 (dd, J = 8.1, 1.7 Hz, 1H), 7.82-7.90 (m, 1H), 7.76-7.82 (m, 2H), 6.99 (d, J = 8.3 Hz, 1H), 6.41 (t, J = 5.1 Hz, 1H), 4.87 (t, J = 4.9 Hz, 1H), 3.61-3.71 (m, 2H), 2.04-2.18 (m, 2H). MS(M+1): 556. Yellow solid. [0212] Table 3 [0213] Compound 3-1 [0214] N-(6-(benzo[d]oxazol-5-yl)-1-(4-methoxyphenyl)-1H-pyrazolo[3 ,4-d]pyrimidin- 4-yl)-5-nitrothiophene-2-carboxamide [0215] 1 H NMR (DMSO-d 6 ) : δ 11.94 (br. s., 1H), 8.91 (d, J = 1.5 Hz, 1H), 8.86 (s, 1H), 8.62-8.68 (m, 1H), 8.59 (s, 1H), 8.39 (d, J = 4.4 Hz, 1H), 8.26 (d, J = 4.4 Hz, 1H), 8.12- 8.18 (m, 2H), 7.94 (d, J = 8.8 Hz, 1H), 7.18-7.26 (m, 2H), 3.87 (s, 3H). MS(M+1):514. Yellow solid. [0216] Compound 3-2 [0217] N-(6-(benzo[d]oxazol-5-yl)-1-(4-fluorophenyl)-1H-pyrazolo[3, 4-d]pyrimidin-4- yl)-5-nitrothiophene-2-carboxamide [0218] 1 H NMR (400MHz, DMSO-d 6 ): δ 11.99 (br. s., 1H), 8.92 (d, J = 1.5 Hz, 1H), 8.86 (s, 1H), 8.62-8.67 (m, 2H), 8.39 (d, J = 4.4 Hz, 1H), 8.28-8.35 (m, 2H), 8.27 (d, J = 4.4 Hz, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.47-7.55 (m, 2H). MS(M+1): 502. Yellow solid. [0219] Compound 3-3 [0220] N-(6-(benzo[d]oxazol-5-yl)-1-(2,4-difluorophenyl)-1H-pyrazol o[3,4-d]pyrimidin- 4-yl)-5-nitrothiophene-2-carboxamide [0221] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.05 (br. s., 1H), 8.81-8.86 (m, 2H), 8.66 (s, 1H), 8.53 (dd, J = 8.8, 1.5 Hz, 1H), 8.38 (d, J = 4.4 Hz, 1H), 8.27 (d, J = 4.4 Hz, 1H), 7.87-7.95 (m, 2H), 7.66-7.74 (m, 1H), 7.37-7.44 (m, 1H). MS(M+1):520. Orange solid. [0222] Compound 3-4 [0223] N-(6-(benzo[d]oxazol-5-yl)-1-(4-cyanophenyl)-1H-pyrazolo[3,4 -d]pyrimidin-4- yl)-5-nitrothiophene-2-carboxamide [0224] 1 H NMR (DMSO-d 6 ) : δ 11.87 (br. s., 1H), 8.89 (d, J = 1.5 Hz, 1H), 8.64 (s, 1H), 8.67 (s, 1H), 8.56-8.63 (m, 3H), 8.37 (d, J = 4.4 Hz, 1H), 8.12 (s, 1H), 7.93-7.99 (m, 2H), 7.78 (d, J = 8.8 Hz, 1H). MS(M+1): 509. Brown solid. [0225] Compound 3-5 [0226] N-(1-(4-cyanophenyl)-6-(2-(2-methoxyethyl)benzo[d]oxazol-5-y l)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamid e [0227] 1 H NMR (DMSO-d 6 ) : δ 11.69 (br. s., 1H), 8.55 (s, 1H), 8.47 (s, 1H), 8.31-8.43 (m, 3H), 8.28 (d, J = 4.4 Hz, 1H), 8.18 (d, J = 4.4 Hz, 1H), 7.93 (d, J = 8.8 Hz, 2H), 7.66 (d, J = 8.3 Hz, 1H), 3.84 (t, J = 6.4 Hz, 2H), 3.20 (t, J = 6.1 Hz, 2H). MS(M+1): 567. Brown solid. [0228] Compound 3-6 [0229] N-(1-(3-cyanophenyl)-6-(2-(methoxymethyl)benzo[d]oxazol-5-yl )-1H- pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamid e [0230] 1 H NMR (400MHz, DMSO-d 6 ): δ 11.97 (br. s., 1H), 8.81 (d, J = 1.0 Hz, 1H), 8.68 (dt, J = 5.9, 2.9 Hz, 1H), 8.61-8.66 (m, 2H), 8.58 (dd, J = 8.6, 1.7 Hz, 1H), 8.37 (d, J = 4.4 Hz, 1H), 8.26 (d, J = 4.9 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.79-7.88 (m, 2H), 4.77 (s, 2H), 3.46 (s, 3H). MS(M+1):553. Khaki solid. [0231] Compound 3-7 [0232] N-(6-(benzo[d]oxazol-5-yl)-1-(3-fluorophenyl)-1H-pyrazolo[3, 4-d]pyrimidin-4- yl)-5-nitrothiophene-2-carboxamide [0233] 1 H NMR (400MHz, DMSO-d 6 ): δ 11.99 (br. s., 1H), 8.84 - 8.93 (m, 2H), 8.61 - 8.68 (m, 2H), 8.37 (d, J = 4.4 Hz, 1H), 8.26 (d, J = 4.4 Hz, 1H), 8.15 - 8.25 (m, 2H), 7.97 (d, J = 8.8 Hz, 1H), 7.70 (td, J = 8.3, 6.8 Hz, 1H), 7.26 (td, J = 8.6, 2.0 Hz, 1H). MS(M+1): 502. Khaki solid. [0234] Compound 3-8 [0235] N-(6-(benzo[d]oxazol-6-yl)-1-(3-methoxyphenyl)-1H-pyrazolo[3 ,4-d]pyrimidin- 4-yl)-5-nitrothiophene-2-carboxamide [0236] 1 H NMR (400MHz, DMSO-d 6 ): δ 11.98 (br. s., 1H), 8.89 (s, 1H), 8.79 (d, J = 1.5 Hz, 1H), 8.57-8.66 (m, 2H), 8.37 (d, J = 4.4 Hz, 1H), 8.26 (d, J = 4.4 Hz, 1H), 7.98 (d, J = 8.3 Hz, 1H), 7.89-7.96 (m, 2H), 7.51-7.59 (m, 1H), 6.96-7.04 (m, 1H), 3.91 (s, 3H). MS(M+1): 514. Yellow solid. [0237] Compound 3-9 [0238] N-(1-(3-fluorophenyl)-6-(2-(methoxymethyl)benzo[d]oxazol-5-y l)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamid e [0239] 1 H NMR (400MHz, DMSO-d 6 ): δ 11.97 (br. s., 1H), 8.83 (d, J = 1.5 Hz, 1H), 8.62 (s, 1H), 8.59 (dd, J = 8.6, 1.7 Hz, 1H), 8.36 (d, J = 4.4 Hz, 1H), 8.13-8.27 (m, 3H), 7.91 (d, J = 8.3 Hz, 1H), 7.68 (td, J = 8.2, 6.6 Hz, 1H), 7.21-7.30 (m, 1H), 4.76 (s, 2H), 3.41- 3.49 (m, 3H).MS(M+1): 546. Yellow solid. [0240] Table 4 [0241] Compound 4-1 [0242] N-(6-(benzo[b]thiophen-5-yl)-1-(4-fluorophenyl)-1H-pyrazolo[ 3,4-d]pyrimidin-4- yl)-5-nitrothiophene-2-carboxamide [0243] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.05 (br. s., 1H), 9.05 (s, 1H), 8.62 (s, 1H), 8.48-8.56 (m, 1H), 8.39 (d, J = 4.4 Hz, 1H), 8.33 (dd, J = 9.0, 4.6 Hz, 2H), 8.26 (d, J = 4.4 Hz, 1H), 8.19 (d, J = 8.8 Hz, 1H), 7.88 (d, J = 5.4 Hz, 1H), 7.64 (d, J = 5.4 Hz, 1H), 7.46-7.54 (m, 2H). MS(M+1): 517. Pale orange solid. [0244] Compound 4-2 [0245] N-(6-(benzo[d]thiazol-5-yl)-1-(3-fluorophenyl)-1H-pyrazolo[3 ,4-d]pyrimidin-4- yl)-5-nitrothiophene-2-carboxamide [0246] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.03 (br. s., 1H), 9.50 (s, 1H), 9.20 (d, J = 1.5 Hz, 1H), 8.65 (s, 1H), 8.62 (dd, J = 8.6, 1.7 Hz, 1H), 8.34-8.41 (m, 2H), 8.22-8.28 (m, 2H), 8.19 (dt, J = 10.9, 2.4 Hz, 1H), 7.70 (td, J = 8.3, 6.8 Hz, 1H), 7.27 (td, J = 8.6, 2.0 Hz, 1H). MS(M+1): 518. Yellow solid. [0247] Compound 4-3 [0248] N-(1-(3-fluorophenyl)-6-(2-methylbenzo[d]thiazol-5-yl)-1H-py razolo[3,4- d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide [0249] 1 H NMR (400MHz, DMSO-d 6 ): δ 11.94 (br. s., 1H), 8.97 (d, J = 1.5 Hz, 1H), 8.60 (s, 1H), 8.50 (dd, J = 8.3, 1.5 Hz, 1H), 8.33 (d, J = 4.4 Hz, 1H), 8.20-8.27 (m, 2H), 8.12- 8.20 (m, 2H), 7.68 (td, J = 8.2, 6.6 Hz, 1H), 7.24 (td, J = 8.7, 2.2 Hz, 1H), 2.84 (s, 3H). MS(M+1): 532. Brown solid. [0250] Compound 4-4 [0251] N-(6-(benzo[d]thiazol-5-yl)-1-(4-fluorophenyl)-1H-pyrazolo[3 ,4-d]pyrimidin-4- yl)-5-nitrothiophene-2-carboxamide [0252] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.01 (br. s., 1H), 9.50 (s, 1H), 9.21 (d, J = 1.5 Hz, 1H), 8.51-8.70 (m, 2H), 8.22-8.43 (m, 5H), 7.44-7.55 (m, 2H). MS(M+1): 518. Yellow solid. [0253] Compound 4-5 [0254] N-(6-(benzo[d]thiazol-5-yl)-1-(thiophen-3-yl)-1H-pyrazolo[3, 4-d]pyrimidin-4- yl)-5-nitrothiophene-2-carboxamide [0255] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.05 (br. s., 1H), 9.51 (s, 1H), 9.28 (d, J = 1.5 Hz, 1H), 8.70-8.75 (m, 1H), 8.61 (s, 1H), 8.30-8.39 (m, 3H), 8.26 (d, J = 4.4 Hz, 1H), 7.97-8.03 (m, 1H), 7.82 (dd, J = 5.1, 3.2 Hz, 1H). MS(M+1): 505.6. Yellow solid. [0256] Compound 4-6 [0257] N-(1-(3-chlorophenyl)-6-(2-methylbenzo[d]thiazol-5-yl)-1H-py razolo[3,4- d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide [0258] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.04 (br. s., 1H), 9.02 (s, 1H), 8.66 (s, 1H), 8.55 (dd, J = 8.3, 1.5 Hz, 1H), 8.41-8.45 (m, 1H), 8.34-8.41 (m, 2H), 8.20-8.29 (m, 2H), 7.70 (t, J = 8.1 Hz, 1H), 7.49 (dd, J = 7.6, 1.7 Hz, 1H), 2.86 (s, 3H). MS(M+1): 548. Black solid. [0259] Compound 4-7 [0260] N-(6-(benzo[d]thiazol-5-yl)-1-(4-methoxyphenyl)-1H-pyrazolo[ 3,4-d]pyrimidin- 4-yl)-5-nitrothiophene-2-carboxamide [0261] 1 H NMR (400MHz, DMSO-d 6 ): δ 11.93 (br. s., 1H), 9.49 (s, 1H), 9.19 (d, J = 0.98 Hz, 1H), 8.60 (dd, J = 1.47, 8.31 Hz, 1H), 8.57 (s, 1H), 8.38 (d, J = 4.40 Hz, 1H), 8.32 (d, J = 8.31 Hz, 1H), 8.24 (d, J = 4.40 Hz, 1H), 8.10-8.16 (m, 2H), 7.16-7.23 (m, 2H), 3.86 (s, 3H). MS(M+1): 530. Orange solid. [0262] Compound 4-8 [0263] N-(6-(benzo[d]thiazol-5-yl)-1-(thiophen-2-yl)-1H-pyrazolo[3, 4-d]pyrimidin-4- yl)-5-nitrothiophene-2-carboxamide [0264] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.09 (br. s., 1H), 9.52 (s, 1H), 9.28 (d, J = 1.5 Hz, 1H), 8.71 (dd, J = 8.3, 1.5 Hz, 1H), 8.65 (s, 1H), 8.35-8.42 (m, 2H), 8.27 (d, J = 4.4 Hz, 1H), 7.88 (dd, J = 3.4, 1.5 Hz, 1H), 7.47 (dd, J = 5.4, 1.5 Hz, 1H), 7.21 (dd, J = 5.6, 3.7 Hz, 1H). MS(M+1): 506. Orange solid. [0265] Compound 4-9 [0266] N-(6-(benzo[d]thiazol-5-yl)-1-(5-methylthiophen-3-yl)-1H-pyr azolo[3,4- d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide [0267] 1 H NMR (400MHz, DMSO-d 6 ) : δ 12.03 (br. s., 1H), 9.51 (s, 1H), 9.28 (d, J = 1.0 Hz, 1H), 8.72 (dd, J = 8.6, 1.2 Hz, 1H), 8.60 (s, 1H), 8.32-8.45 (m, 2H), 8.27 (d, J = 4.4 Hz, 1H), 8.09 (d, J = 1.5 Hz, 1H), 7.67 (s, 1H), 2.58 (s, 3H). MS(M+1): 520. Brown solid. [0268] Compound 4-10 [0269] N-(6-(benzo[d]thiazol-5-yl)-1-phenyl-1H-pyrazolo[3,4-d]pyrim idin-4-yl)-5- nitrothiophene-2-carboxamide [0270] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.04 (s, 1H), 9.51 (s, 1H), 9.24 (d, J = 1.5 Hz, 1H), 8.63-8.72 (m, 2H), 8.42 (d, J = 4.4 Hz, 1H), 8.37 (d, J = 8.8 Hz, 1H), 8.32 (dd, J = 8.8, 1.0 Hz, 2H), 8.28 (d, J = 4.9 Hz, 1H), 7.65-7.71 (m, 2H), 7.43-7.48 (m, 1H). MS(M+1): 500. Brown solid. [0271] Compound 4-11 [0272] N-(6-(benzo[d]thiazol-5-yl)-1-(p-tolyl)-1H-pyrazolo[3,4-d]py rimidin-4-yl)-5- nitrothiophene-2-carboxamide [0273] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.02 (br. s., 1H), 9.50 (s, 1H), 9.22 (d, J = 1.5 Hz, 1H), 8.62-8.67 (m, 2H), 8.33-8.41 (m, 2H), 8.27 (d, J = 4.4 Hz, 1H), 8.13-8.19 (m, 2H), 7.43-7.52 (m, J = 8.3 Hz, 2H), 2.42 (s, 3H). MS(M+1): 514. Yellow solid. [0274] Compound 4-12 [0275] N-(6-(benzo[d]thiazol-5-yl)-1-(m-tolyl)-1H-pyrazolo[3,4-d]py rimidin-4-yl)-5- nitrothiophene-2-carboxamide [0276] 1 H NMR (400MHz, DMSO-d 6 ): δ 11.99 (br. s., 1H), 9.50 (s, 1H), 9.21 (d, J = 1.5 Hz, 1H), 8.60-8.66 (m, 2H), 8.32-8.41 (m, 2H), 8.25 (d, J = 4.4 Hz, 1H), 8.16 (d, J = 7.8 Hz, 1H), 8.08 (s, 1H), 7.54 (t, J = 8.1 Hz, 1H), 7.25 (d, J = 7.3 Hz, 1H), 2.48 (s, 3H). MS(M+1): 514. Yellow solid. [0277] Compound 4-13 [0278] N-(6-(benzo[d]thiazol-5-yl)-1-(3,5-difluorophenyl)-1H-pyrazo lo[3,4-d]pyrimidin- 4-yl)-5-nitrothiophene-2-carboxamide [0279] 1 H NMR (400MHz, DMSO-d 6 ): δ 11.90 (br. s., 1H), 9.46 (s, 1H), 9.08 (d, J = 1.0 Hz, 1H), 8.57 (s, 1H), 8.48 (dd, J = 8.3, 1.5 Hz, 1H), 8.33 (d, J = 4.4 Hz, 1H), 8.28 (d, J = 8.8 Hz, 1H), 8.21 (d, J = 4.4 Hz, 1H), 8.03 (dd, J = 8.8, 2.0 Hz, 2H), 7.17-7.27 (m, 1H). MS(M+1): 536. Brown solid. [0280] Compound 4-14 [0281] N-(6-(benzo[d]thiazol-5-yl)-1-(4-(2-methoxyethoxy)phenyl)-1H -pyrazolo[3,4- d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide [0282] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.04 (br. s., 1H), 9.51 (s, 1H), 9.23 (d, J = 1.5 Hz, 1H), 8.65 (dd, J = 8.6, 1.7 Hz, 1H), 8.62 (s, 1H), 8.36 (d, J = 8.3 Hz, 2H), 8.27 (d, J = 4.4 Hz, 1H), 8.13-8.20 (m, 2H), 7.21-7.28 (m, 2H), 4.18-4.26 (m, 2H), 3.68-3.77 (m, 2H), 3.35 (s, 3H). MS(M+1): 574. Orange solid. [0283] Compound 4-15 [0284] N-(6-(benzo[d]thiazol-5-yl)-1-(3-fluoro-4-methoxyphenyl)-1H- pyrazolo[3,4- d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide [0285] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.01 (br. s., 1H), 9.50 (s, 1H), 9.21 (d, J = 1.0 Hz, 1H), 8.57-8.67 (m, 2H), 8.32-8.42 (m, 2H), 8.26 (d, J = 4.4 Hz, 1H), 8.08-8.17 (m, 2H), 7.41-7.51 (m, 1H), 3.95 (s, 3H). MS(M+1): 548. Brown solid. [0286] Compound 4-16 [0287] N-(6-(benzo[d]thiazol-5-yl)-1-(4-fluoro-3-methoxyphenyl)-1H- pyrazolo[3,4- d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide [0288] 1 H NMR (400MHz, DMSO-d 6 ): δ 11.96 (br. s., 1H), 9.48 (s, 1H), 9.18 (d, J = 1.5 Hz, 1H), 8.57-8.62 (m, 2H), 8.37 (d, J = 4.4 Hz, 1H), 8.31 (d, J = 8.3 Hz, 1H), 8.24 (d, J = 4.4 Hz, 1H), 8.15 (dd, J = 7.8, 2.4 Hz, 1H), 7.86 (ddd, J = 8.9, 3.8, 2.4 Hz, 1H), 7.46 (dd, J = 11.2, 8.8 Hz, 1H), 4.02 (s, 3H). MS(M+1): 548. Brown solid. [0289] Compound 4-17 [0290] N-(6-(benzo[d]thiazol-5-yl)-1-(3-fluoro-4-(2-methoxyethoxy)p henyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamid e [0291] 1 H NMR (400MHz, DMSO-d 6 ): δ 9.51 (s, 1H), 9.21 (d, J = 1.5 Hz, 1H), 8.55-8.69 (m, 2H), 8.37 (d, J = 8.3 Hz, 1H), 8.11-8.27 (m, 5H), 7.44-7.55 (m, 1H), 4.25-4.33 (m, 2H), 3.74 (dd, J = 5.1, 3.7 Hz, 2H), 3.36 (s, 3H). MS(M+1): 592. Orange solid. [0292] Compound 4-18 [0293] N-(6-(benzo[d]thiazol-5-yl)-1-(3-methoxyphenyl)-1H-pyrazolo[ 3,4-d]pyrimidin- 4-yl)-5-nitrothiophene-2-carboxamide [0294] 1 H NMR (400MHz, DMSO-d 6 ): δ 11.99 (br. s., 1H), 9.50 (s, 1H), 9.21 (d, J = 1.5 Hz, 1H), 8.63 (s, 1H), 8.39 (d, J = 4.4 Hz, 1H), 8.35 (d, J = 8.8 Hz, 1H), 8.25 (d, J = 4.4 Hz, 1H), 7.98 (t, J = 2.2 Hz, 1H), 7.92 (dd, J = 8.1, 1.2 Hz, 1H), 7.55-7.63 (m, 2H), 7.00 (ddd, J = 8.3, 2.4, 1.0 Hz, 1H), 3.92 (s, 3H). MS(M+1): 530. Brown solid. [0295] Compound 4-19 [0296] N-(1-(4-fluorophenyl)-6-(2-(2-methoxyethoxy)benzo[d]thiazol- 5-yl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamid e [0297] 1 H NMR (400MHz, DMSO-d 6 ): δ 11.95 (br. s., 1H), 8.80 (d, J = 1.5 Hz, 1H), 8.64 (s, 1H), 8.45 (dd, J = 8.6, 1.7 Hz, 1H), 8.37 (d, J = 4.4 Hz, 1H), 8.22-8.34 (m, 3H), 8.07 (d, J = 8.3 Hz, 1H), 7.44-7.58 (m, 2H), 4.71 (dt, J = 4.2, 2.3 Hz, 2H), 3.77 (dt, J = 4.2, 2.3 Hz, 2H), 3.34 (s, 3H). MS(M+1): 592. Pale yellow solid. [0298] Table 5 [0299] Compound 5-1 [0300] N-(1-(4-fluorophenyl)-6-(1H-pyrrol-1-yl)-1H-pyrazolo[3,4-d]p yrimidin-4-yl)-5- nitrothiophene-2-carboxamide [0301] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.02 (s, 1H), 8.59 (s, 1H), 8.34 (d, J = 4.4 Hz, 1H), 8.20-8.30 (m, 3H), 7.86 (t, J = 2.4 Hz, 2H), 7.43-7.51 (m, 2H), 6.36-6.42 (m, 2H). MS(M+1): 450. Yellow solid [0302] Compound 5-2 [0303] N-(1-(4-fluorophenyl)-6-(thiazol-4-yl)-1H-pyrazolo[3,4-d]pyr imidin-4-yl)-5- nitrothiophene-2-carboxamide [0304] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.28 (br. s., 1H), 9.30 (br. s., 1H), 8.69 (br. s., 1H), 8.62 (br. s., 1H), 8.34 (br. s., 3H), 8.24 (d, J = 3.9 Hz, 1H), 7.44-7.51 (m, 2H). MS(M+1): 468. Pale yellow solid. [0305] Compound 5-3 [0306] Methyl 1-(1-(4-fluorophenyl)-4-(5-nitrothiophene-2-carboxamido)-1H- pyrazolo[3,4-d]pyrimidin-6-yl)-1H-pyrrole-3-carboxylate [0307] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.01 (br. s., 1H), 8.61 (s, 1H), 8.37 (t, J = 2.0 Hz, 1H), 8.31 (d, J = 4.4 Hz, 1H), 8.24 (d, J = 4.4 Hz, 1H), 8.13-8.23 (m, 2H), 7.85 (dd, J = 3.2, 2.2 Hz, 1H), 7.45 (t, J = 8.8 Hz, 2H), 6.70 (dd, J = 3.4, 2.0 Hz, 1H), 3.78 (s, 3H). MS(M+1): 508. Brown solid. [0308] Compound 5-4 [0309] N-(6-(4-chloro-1H-pyrazol-1-yl)-1-(3-fluorophenyl)-1H-pyrazo lo[3,4- d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide [0310] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.24 (br. s., 1H), 8.84 (s, 1H), 8.61 (s, 1H), 8.33 (d, J = 4.4 Hz, 1H), 8.22 (d, J = 4.4 Hz, 1H), 8.16 (dd, J = 8.3, 2.0 Hz, 1H), 8.00- 8.10 (m, 2H), 7.61-7.72 (m, 1H), 7.24 (td, J = 8.4, 2.7 Hz, 1H). MS(M+1): 485. Yellow solid. [0311] Compound 5-5 [0312] N-(6-(4-chloro-1H-pyrazol-1-yl)-1-(3-chlorophenyl)-1H-pyrazo lo[3,4- d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide [0313] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.31 (br. s., 1H), 8.85 (s, 1H), 8.63 (s, 1H), 8.33 (dd, J = 8.3, 1.5 Hz, 1H), 8.29 (t, J = 2.2 Hz, 1H), 8.24-8.28 (m, 1H), 8.20-8.24 (m, 1H), 8.05 (s, 1H), 7.65 (t, J = 8.3 Hz, 1H), 7.42-7.51 (m, 1H). MS(M+1): 501. Yellow solid. [0314] Compound 5-6 [0315] Methyl 1-(1-(4-cyanophenyl)-4-(5-nitrothiophene-2-carboxamido)-1H- pyrazolo[3,4-d]pyrimidin-6-yl)-1H-pyrrole-3-carboxylate [0316] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.09 (br. s., 1H), 8.68 (s, 1H), 8.49-8.56 (m, J = 8.8 Hz, 2H), 8.45 (t, J = 2.0 Hz, 1H), 8.26 (br. s., 1H), 8.14 (d, J = 4.4 Hz, 1H), 7.98- 8.03 (m, J = 9.3 Hz, 2H), 7.90-7.93 (m, 1H), 6.69 (dd, J = 3.2, 1.7 Hz, 1H), 3.79 (s, 3H). MS(M+1): 515. Yellow solid. [0317] Compound 5-7 [0318] N-(6-(4-cyano-1H-pyrazol-1-yl)-1-(3-fluorophenyl)-1H-pyrazol o[3,4- d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide [0319] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.37 (br. s., 1H), 9.47 (s, 1H), 8.65 (s, 1H), 8.46 (s, 1H), 8.32 (d, J = 3.9 Hz, 1H), 8.14-8.25 (m, 2H), 8.05 (dt, J = 10.8, 2.2 Hz, 1H), 7.65 (td, J = 8.3, 6.8 Hz, 1H), 7.19-7.31 (m, 1H). MS(M+1): 476. Yellow solid. [0320] Compound 5-8 [0321] N-(6-(4-cyano-1H-pyrazol-1-yl)-1-(4-fluorophenyl)-1H-pyrazol o[3,4- d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide [0322] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.44 (br. s., 1H), 9.50 (s, 1H), 8.62 (s, 1H), 8.38-8.49 (m, 1H), 8.25-8.29 (m, 2H), 8.19-8.24 (m, 2H), 7.42-7.47 (m, 2H). MS(M+1): 476. Yellow-brown solid. [0323] Compound 5-9 [0324] Methyl 1-(4-(5-nitrothiophene-2-carboxamido)-1-(thiophen-3-yl)-1H- pyrazolo[3,4-d]pyrimidin-6-yl)-1H-pyrrole-3-carboxylate [0325] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.06 (br. s., 1H), 8.64 (s, 1H), 8.49 (t, J = 2.0 Hz, 1H), 8.34 (d, J = 4.4 Hz, 1H), 8.22-8.31 (m, 2H), 8.01 (dd, J = 3.2, 2.2 Hz, 1H), 7.88 (dd, J = 5.1, 1.2 Hz, 1H), 7.79 (dd, J = 5.4, 3.4 Hz, 1H), 6.74 (dd, J = 3.2, 1.7 Hz, 1H), 3.74-3.85 (m, 3H). MS(M+1): 496. Yellow solid. [0326] Compound 5-10 [0327] N-(1-(4-fluorophenyl)-6-(3-(2-methoxyethoxy)-1H-pyrazol-1-yl )-1H- pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamid e [0328] 1 H NMR (DMSO-d 6 , 400 MHz): δ 12.19 (br. s., 1H), 8.60 (d, J = 2.9 Hz, 1H), 8.56 (s, 1H), 8.36 (d, J = 4.4 Hz, 1H), 8.21 - 8.29 (m, 3H), 7.41 - 7.51 (m, 2H), 6.24 (d, J = 2.9 Hz, 1H), 4.25 - 4.44 (m, 2H), 3.59 - 3.76 (m, 2H), 3.32 (s, 4H). MS(M+1): 525. Yellow solid. [0329] Compound 5-11 [0330] N-(6-(4-fluoro-1H-imidazol-1-yl)-1-(4-fluorophenyl)-1H-pyraz olo[3,4- d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide [0331] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.17 (br. s., 1H), 8.65 (s, 1H), 8.42-8.53 (m, 1H), 8.20-8.39 (m, 4H), 7.73 (dd, J = 8.3, 1.5 Hz, 1H), 7.44 (t, J = 9.3 Hz, 2H). MS(M+1): 469. Yellow-brown solid. [0332] Compound 5-12 [0333] Methyl 1-(1-(5-cyanothiophen-2-yl)-4-(5-nitrothiophene-2-carboxamid o)-1H- pyrazolo[3,4-d]pyrimidin-6-yl)-1H-pyrrole-3-carboxylate [0334] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.18 (br. s., 1H), 8.71 (s, 1H), 8.46 (t, J = 2.0 Hz, 1H), 8.22-8.31 (m, 2H), 8.00-8.07 (m, 2H), 7.90 (d, J = 3.9 Hz, 1H), 6.75 (dd, J = 3.2, 1.7 Hz, 1H), 3.81 (s, 3H). MS(M+1): 521. Yellowish brown solid. [0335] Compound 5-13 [0336] N-(1-(3-fluorophenyl)-6-(3-(2-hydroxyethoxy)-1H-pyrazol-1-yl )-1H- pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamid e [0337] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.18 (br. s., 1H), 8.52-8.64 (m, 2H), 8.36 (d, J = 4.4 Hz, 1H), 8.23 (d, J = 4.4 Hz, 1H), 8.08-8.20 (m, 2H), 7.58-7.68 (m, 1H), 7.23 (td, J = 8.4, 2.2 Hz, 1H), 6.24 (d, J = 2.4 Hz, 1H), 4.91 (t, J = 5.4 Hz, 1H), 4.28 (t, J = 5.1 Hz, 2H), 3.76 (q, J = 5.2 Hz, 2H). MS(M+1): 511. Yellow-green solid. [0338] Compound 5-14 [0339] Methyl 1-(1-(3-cyanophenyl)-4-(5-nitrothiophene-2-carboxamido)- 1H- pyrazolo[3,4-d]pyrimidin-6-yl)-1H-pyrrole-3-carboxylate [0340] 1 H NMR (DMSO-d6, 400 MHz): δ 12.10 (br. s., 1H), 8.70 (s, 1H), 8.52-8.65 (m, 2H), 8.43 (t, J = 1.7 Hz, 1H), 8.33 (d, J = 3.9 Hz, 1H), 8.27 (d, J = 4.4 Hz, 1H), 7.80-7.93 (m, 3H), 6.74 (dd, J = 3.2, 1.7 Hz, 1H), 3.79 (s, 3H). MS(M+NH3):531. Milk tea color solid. [0341] Compound 5-15 [0342] Ethyl 1-(1-(4-fluorophenyl)-4-(5-nitrothiophene-2-carboxamido)- 1H- pyrazolo[3,4-d]pyrimidin-6-yl)-1H-pyrrole-3-carboxylate [0343] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.03 (s, 1H), 8.62 (s, 1H), 8.37 (t, J = 2.0 Hz, 1H), 8.33 (d, J = 4.4 Hz, 1H), 8.25 (d, J = 4.4 Hz, 1H), 8.15-8.23 (m, 2H), 7.86 (dd, J = 3.2, 2.2 Hz, 1H), 7.41-7.50 (m, 2H), 6.70 (dd, J = 3.2, 1.7 Hz, 1H), 4.25 (q, J = 6.8 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H). MS(M+1): 522. Yellow-green solid. [0344] Compound 5-16 [0345] N-(1-(4-fluorophenyl)-6-(3-(2-hydroxyethoxy)-1H-pyrazol-1-yl )-1H- pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamid e [0346] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.22 (br. s., 1H), 8.61 (d, J = 2.9 Hz, 1H), 8.55 (s, 1H), 8.34 (d, J = 4.4 Hz, 1H), 8.21-8.29 (m, 3H), 7.41-7.49 (m, 2H), 6.23 (d, J = 2.9 Hz, 1H), 4.90 (t, J = 5.4 Hz, 1H), 4.27 (t, J = 4.9 Hz, 2H), 3.75 (q, J = 5.4 Hz, 2H). MS(M+1): 511. Yellow solid. [0347] Compound 5-17 [0348] 2-hydroxyethyl 1-(1-(3-fluorophenyl)-4-(5-nitrothiophene-2-carboxamido)-1H- pyrazolo[3,4-d]pyrimidin-6-yl)-1H-pyrrole-3-carboxylate [0349] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.14 (br. s., 1H), 8.66 (s, 1H), 8.44 (t, J = 2.0 Hz, 1H), 8.34 (d, J = 4.4 Hz, 1H), 8.26 (d, J = 4.4 Hz, 1H), 8.15 (dd, J = 8.1, 1.2 Hz, 1H), 8.03 (dt, J = 10.8, 2.2 Hz, 1H), 7.87 (dd, J = 3.2, 2.2 Hz, 1H), 7.68 (td, J = 8.3, 6.8 Hz, 1H), 7.27 (td, J = 8.4, 2.2 Hz, 1H), 6.72-6.78 (m, 1H), 4.89 (t, J = 5.4 Hz, 1H), 4.18- 4.28 (m, 2H), 3.69 (q, J = 5.4 Hz, 2H). MS(M+1):538. Pale yellow solid. [0350] Compound 5-18 [0351] 2-((1-(1-(4-fluorophenyl)-4-(5-nitrothiophene-2-carboxamido) -1H-pyrazolo[3,4- d]pyrimidin-6-yl)-1H-pyrazol-3-yl)oxy)ethyl dihydrogen phosphate [0352] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.23 (br. s., 1H), 8.62 (d, J = 2.9 Hz, 1H), 8.56 (s, 1H), 8.39 (d, J = 4.4 Hz, 1H), 8.22-8.30 (m, 3H), 7.42-7.49 (m, 2H), 6.26 (d, J = 2.9 Hz, 1H), 4.40-4.47 (m, 2H), 4.14-4.21 (m, 2H). MS(M+1):591. Pale yellow solid. [0353] Compound 5-19 [0354] Methyl 1-(1-(5-cyanothiophen-3-yl)-4-(5-nitrothiophene-2-carboxamid o) -1H- pyrazolo[3,4-d]pyrimidin-6-yl)-1H-pyrrole-3-carboxylate [0355] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.10 (br. s., 1H), 8.75 (s, 1H), 8.61-8.67 (m, 2H), 8.51 (d, J = 2.0 Hz, 1H), 8.30 (br. s., 1H), 8.24-8.28 (m, 1H), 8.08 (d, J = 2.0 Hz, 1H), 6.73 (d, J = 2.0 Hz, 1H), 3.80 (s, 3H). MS(M+1): 521. Brown solid. [0356] Compound 5-20 [0357] N-(1-(3-fluorophenyl)-6-(3-(4-hydroxybutoxy)-1H-pyrazol-1-yl )-1H- pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamid e [0358] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.21 (br. s., 1H), 8.54-8.62 (m, 2H), 8.32 (d, J = 4.4 Hz, 1H), 8.23 (d, J = 4.4 Hz, 1H), 8.14-8.21 (m, 2H), 7.65 (td, J = 8.3, 6.4 Hz, 1H), 7.19-7.29 (m, 1H), 6.23 (d, J = 2.9 Hz, 1H), 4.46 (t, J = 5.1 Hz, 1H), 4.27 (t, J = 6.6 Hz, 2H), 3.42-3.52 (m, 2H), 1.74-1.87 (m, 2H), 1.52-1.65 (m, 2H). MS(M+1): 539. Pale yellow solid. [0359] Compound 5-21 [0360] N-(6-(3-(3-hydroxypropoxy)-1H-pyrazol-1-yl)-1-(thiophen-3-yl )-1H- pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamid e [0361] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.26 (br. s., 1H), 8.71 (d, J = 2.9 Hz, 1H), 8.53 (s, 1H), 8.35 (br. s., 1H), 8.18-8.28 (m, 2H), 7.92 (dd, J = 5.4, 1.5 Hz, 1H), 7.71-7.88 (m, 1H), 6.24 (d, J = 2.9 Hz, 1H), 4.51-4.66 (m, 1H), 4.34 (t, J = 6.4 Hz, 2H), 3.49-3.66 (m, 2H), 1.91 (t, J = 6.4 Hz, 2H). MS(M+1): 513. Pale yellow solid. [0362] Compound 5-22 [0363] N-(1-(4-fluorophenyl)-6-(3-(4-hydroxybutoxy)-1H-pyrazol-1-yl )-1H- pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamid e [0364] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.22 (br. s., 1H), 8.60 (d, J = 2.9 Hz, 1H), 8.56 (s, 1H), 8.33 (d, J = 4.4 Hz, 1H), 8.19-8.31 (m, 3H), 7.38-7.51 (m, 2H), 6.22 (d, J = 2.9 Hz, 1H), 4.45 (t, J = 5.1 Hz, 1H), 4.26 (t, J = 6.6 Hz, 2H), 3.43-3.51 (m, 2H), 1.73-1.84 (m, 2H), 1.52-1.63 (m, 2H). MS(M+1): 539. Pale yellow solid. [0365] Compound 5-23 [0366] 2-hydroxyethyl 1-(1-(4-cyanophenyl)-4-(5-nitrothiophene-2-carboxamido)-1H- pyrazolo[3,4-d]pyrimidin-6-yl)-1H-pyrrole-3-carboxylate [0367] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.13 (br. s., 1H), 8.67 (s, 1H), 8.44-8.51 (m, 2H), 8.42 (t, J = 2.0 Hz, 1H), 8.32 (d, J = 4.4 Hz, 1H), 8.25 (d, J = 4.4 Hz, 1H), 8.04-8.09 (m, 2H), 7.92 (dd, J = 3.2, 2.2 Hz, 1H), 6.74 (dd, J = 3.2, 1.7 Hz, 1H), 4.88 (t, J = 5.6 Hz, 1H), 4.18-4.27 (m, 2H), 3.69 (q, J = 5.1 Hz, 2H). MS(M+1): 545. Tan solid. [0368] Compound 5-24 [0369] methyl 1-(1-(3-fluorophenyl)-4-(5-nitrothiophene-2-carboxamido)-1H- pyrazolo [3,4-d]pyrimidin-6-yl)-1H-pyrrole-3-carboxylate [0370] 1 H NMR (400MHz, DMSO-d 6 ): δ 11.95 (br. s., 1H), 8.58 (s, 1H), 8.28-8.35 (m, 2H), 8.23 (d, J = 4.4 Hz, 1H), 8.08 (dd, J = 8.1, 1.2 Hz, 1H), 7.96 (dt, J = 10.8, 2.2 Hz, 1H), 7.75-7.81 (m, 1H), 7.63 (td, J = 8.3, 6.4 Hz, 1H), 7.23 (td, J = 8.4, 2.7 Hz, 1H), 6.68 (dd, J = 3.4, 2.0 Hz, 1H), 3.77 (s, 3H). MS(M+1): 508. Light yellow solid. [0371] Compound 5-25 [0372] methyl 1-(1-(5-methylthiophen-3-yl)-4-(5-nitrothiophene-2-carboxami do)-1H- pyrazolo[3,4-d]pyrimidin-6-yl)-1H-pyrrole-3-carboxylate [0373] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.05 (br. s., 1H), 8.59 (s, 1H), 8.48 (t, J = 2.0 Hz, 1H), 8.22-8.32 (m, 2H), 7.96-8.03 (m, 2H), 7.59 (t, J = 1.5 Hz, 1H), 6.73 (dd, J = 3.2, 1.7 Hz, 1H), 3.80 (s, 3H), 2.56 (s, 3H). MS(M+1): 510. Pale yellow solid. [0374] Compound 5-26 [0375] 1-(1-(4-cyanophenyl)-4-(5-nitrothiophene-2-carboxamido)-1H-p yrazolo[3,4- d]pyrimidin-6-yl)-N-methoxy-N-methyl-1H-pyrrole-3-carboxamid e [0376] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.12 (br. s., 1H), 8.66-8.70 (m, 1H), 8.46-8.51 (m, 2H), 8.42 (t, J = 2.0 Hz, 1H), 8.34 (d, J = 4.4 Hz, 1H), 8.26 (d, J = 4.4 Hz, 1H), 8.07- 8.11 (m, 2H), 7.88-7.92 (m, 1H), 6.78 (dd, J = 3.2, 1.7 Hz, 1H), 3.79 (s, 3H), 3.28 (s, 3H). MS(M+1): 544. Brown solid. [0377] Compound 5-27 [0378] N-methoxy-N-methyl-1-(1-(5-methylthiophen-3-yl)-4-(5-nitroth iophene-2- carboxamido)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-1H-pyrrole-3- carboxamide [0379] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.07 (br. s., 1H), 8.59 (s, 1H), 8.46 (t, J = 2.0 Hz, 1H), 8.34 (d, J = 4.4 Hz, 1H), 8.26 (d, J = 4.4 Hz, 1H), 7.96 (dd, J = 3.2, 2.2 Hz, 1H), 7.93 (d, J = 1.5 Hz, 1H), 7.61 (t, J = 1.2 Hz, 1H), 6.78 (dd, J = 3.2, 1.7 Hz, 1H), 3.79 (s, 3H), 3.28 (s, 3H), 2.54-2.59 (m, 3H). MS (M+1): 539. Pale brown solid. [0380] Compound 5-28 [0381] 1-(1-(3-fluorophenyl)-4-(5-nitrothiophene-2-carboxamido)-1H- pyrazolo[3,4- d]pyrimidin-6-yl)-N-methoxy-N-methyl-1H-pyrrole-3-carboxamid e [0382] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.08 (br. s., 1H), 8.63 (s, 1H), 8.41 (t, J = 2.0 Hz, 1H), 8.32 (d, J = 4.4 Hz, 1H), 8.24 (d, J = 4.9 Hz, 1H), 8.05-8.13 (m, 2H), 7.80-7.87 (m, 1H), 7.66 (td, J = 8.2, 6.6 Hz, 1H), 7.22-7.29 (m, 1H), 6.77 (dd, J = 3.2, 1.7 Hz, 1H), 3.79 (s, 3H), 3.27 (s, 3H). MS(M+1): 537. Yellow solid. [0383] Compound 5-29 [0384] 1-(1-(4-fluorophenyl)-4-(5-nitrothiophene-2-carboxamido)-1H- pyrazolo[3,4- d]pyrimidin-6-yl)-N-methoxy-N-methyl-1H-pyrrole-3-carboxamid e [0385] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.07 (s, 1H), 8.63 (s, 1H), 8.41 (t, J = 1.7 Hz, 1H), 8.34 (d, J = 4.4 Hz, 1H), 8.26 (d, J = 4.4 Hz, 1H), 8.17-8.24 (m, 2H), 7.83-7.89 (m, 1H), 7.43-7.52 (m, 2H), 6.77 (dd, J = 3.2, 1.7 Hz, 1H), 3.78 (s, 3H), 3.27 (s, 3H). MS(M+1): 537. Yellow solid. [0386] Compound 5-30 [0387] 2-((1-(1-(4-fluorophenyl)-4-(5-nitrothiophene-2-carboxamido) -1H-pyrazolo[3,4- d]pyrimidin-6-yl)-1H-pyrazol-3-yl)oxy)ethyl acetate [0388] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.23 (br. s., 1H), 8.62 (d, J = 2.4 Hz, 1H), 8.55 (s, 1H), 8.09-8.38 (m, 4H), 7.45 (t, J = 9.0 Hz, 2H), 6.25 (d, J = 2.9 Hz, 1H), 4.42-4.66 (m, 2H), 4.25-4.42 (m, 2H), 2.05 (s, 3H). MS (M+1): 553. Yellow solid powder. [0389] Compound 5-31 [0390] N-(6-(3-acetyl-1H-pyrrol-1-yl)-1-(4-fluorophenyl)-1H-pyrazol o[3,4-d]pyrimidin- 4-yl)-5-nitrothiophene-2-carboxamide [0391] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.13 (br. s., 1H), 8.64 (s, 1H), 8.49 (t, J = 2.0 Hz, 1H), 8.30 (d, J = 4.4 Hz, 1H), 8.20-8.28 (m, 3H), 7.91 (dd, J = 3.4, 2.0 Hz, 1H), 7.43- 7.52 (m, 2H), 6.72 - 6.78 (m, 1H), 2.46 (s, 3H). MS (M+1): 492. Yellow solid powder. [0392] Compound 5-32 [0393] 2-((1-(1-(4-fluorophenyl)-4-(5-nitrothiophene-2-carboxamido) -1H-pyrazolo[3,4- d]pyrimidin-6-yl)-1H-pyrazol-3-yl)oxy)ethyl propionate [0394] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.23 (br. s., 1H), 8.63 (d, J = 2.9 Hz, 1H), 8.55-8.60 (m, 1H), 8.36 (d, J = 4.4 Hz, 1H), 8.22-8.31 (m, 3H), 7.41-7.51 (m, 2H), 6.27 (d, J = 2.9 Hz, 1H), 4.44-4.50 (m, 2H), 4.37-4.43 (m, 2H), 2.36 (q, J = 7.3 Hz, 2H), 1.03 (t, J = 7.6 Hz, 3H). MS (M+1): 567. Pale yellow solid powder. [0395] Compound 5-33 [0396] N-(1-(4-fluorophenyl)-6-(3-propionyl-1H-pyrrol-1-yl)-1H-pyra zolo[3,4- d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide [0397] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.09 (br. s., 1H), 8.64 (s, 1H), 8.47 (t, J = 2.0 Hz, 1H), 8.33 (d, J = 4.4 Hz, 1H), 8.20-8.27 (m, 3H), 7.89 (dd, J = 3.2, 2.2 Hz, 1H), 7.42- 7.51 (m, 2H), 6.76 (dd, J = 3.2, 1.7 Hz, 1H), 2.88 (q, J = 7.3 Hz, 2H), 1.09 (t, J = 7.3 Hz, 3H). MS (M+1): 506. Brown solid. [0398] Compound 5-34 [0399] 2-((1-(1-(4-fluorophenyl)-4-(5-nitrothiophene-2-carboxamido) -1H-pyrazolo[3,4- d]pyrimidin-6-yl)-1H-pyrazol-3-yl)oxy)ethyl L-valinate 2,2,2-trifluoroacetate [0400] 1 H NMR (400MHz, DMSO-d 6 ): δ 8.64 (d, J = 2.9 Hz, 1H), 8.59 (s, 1H), 8.38 (d, J = 4.4 Hz, 1H), 8.18-8.32 (m, 3H), 7.36-7.55 (m, 2H), 6.24 (d, J = 2.9 Hz, 1H), 4.62-4.79 (m, 1H), 4.45-4.60 (m, 3H), 4.01 (d, J = 4.4 Hz, 1H), 2.16 (dq, J = 11.5, 6.9 Hz, 1H), 0.99 (d, J = 6.8 Hz, 3H), 0.95 (d, J = 6.8 Hz, 3H). MS (M+1): 610. Yellow solid powder. [0401] Compound 5-35 [0402] (S)-2-amino-4-(2-((1-(1-(4-fluorophenyl)-4-(5-nitrothiophene -2-carboxamido)- 1H-pyrazolo[3,4-d]pyrimidin-6-yl)-1H-pyrazol-3-yl)oxy)ethoxy )-4-oxobutanoic acid compound with 2,2,2-trifluoroacetic acid (1:1) [0403] 1 H NMR (400MHz, DMSO-d 6 ): δ 8.63 (d, J = 2.9 Hz, 1H), 8.58 (s, 1H), 8.39 (d, J = 4.4 Hz, 1H), 8.21-8.31 (m, 3H), 7.46 (t, J = 9.0 Hz, 2H), 6.27 (d, J = 2.9 Hz, 1H), 4.41- 4.54 (m, 4H), 3.94 (t, J = 5.4 Hz, 1H), 2.93 (dd, J = 17.1, 4.9 Hz, 1H), 2.81 (dd, J = 17.1, 6.8 Hz, 1H). MS (M+1): 626. Yellow solid powder. [0404] Compound 5-36 [0405] N-(6-(3-acetyl-1H-pyrrol-1-yl)-1-(3-fluorophenyl)-1H-pyrazol o[3,4-d]pyrimidin- 4-yl)-5-nitrothiophene-2-carboxamide [0406] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.13 (br. s., 1H), 8.65 (s, 1H), 8.48 (t, J = 2.0 Hz, 1H), 8.34 (d, J = 4.4 Hz, 1H), 8.26 (d, J = 4.4 Hz, 1H), 8.17 (dd, J = 8.3, 1.5 Hz, 1H), 8.04 (dt, J = 10.8, 2.2 Hz, 1H), 7.88 (dd, J = 3.2, 2.2 Hz, 1H), 7.69 (td, J = 8.3, 6.8 Hz, 1H), 7.27 (td, J = 8.4, 2.2 Hz, 1H), 6.76 (dd, J = 3.2, 1.7 Hz, 1H), 2.46 (s, 3H). MS (M+1): 492. Light brown powder. [0407] Table 6 [0408] Compound 6-1 [0409] N-(1-(3-fluorophenyl)-6-(2-oxo-1,2,3,4-tetrahydroquinolin-7- yl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamid e [0410] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.07 (br. s., 1H), 10.41 (s, 1H), 8.62 (s, 1H), 8.37 (d, J = 4.4 Hz, 1H), 8.31 (dd, J = 8.1, 1.2 Hz, 1H), 8.25 (d, J = 4.4 Hz, 1H), 8.08- 8.19 (m, 2H), 8.04 (d, J = 1.5 Hz, 1H), 7.69 (td, J = 8.3, 6.4 Hz, 1H), 7.38 (d, J = 8.3 Hz, 1H), 7.28 (td, J = 8.3, 2.4 Hz, 1H), 2.98 (t, J = 7.6 Hz, 2H), 2.52 (t, J = 7.6 Hz, 2H). MS(M+1): 530. Yellow solid. [0411] Compound 6-2 [0412] N-(1-(4-fluorophenyl)-6-(imidazo[1,2-a]pyridin-6-yl)-1H-pyra zolo[3,4- d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide [0413] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.07 (br. s., 1H), 9.59 (s, 1H), 8.61 (s, 1H), 8.36 (d, J = 4.4 Hz, 1H), 8.23-8.33 (m, 4H), 8.17 (s, 1H), 7.72 (d, J = 9.3 Hz, 1H), 7.68 (d, J = 1.5 Hz, 1H), 7.43-7.52 (m, 2H). MS(M+1): 501. Yellow solid. [0414] Compound 6-3 [0415] N-(6-(benzo[d]oxazol-6-yl)-1-(4-fluorophenyl)-1H-pyrazolo[3, 4-d]pyrimidin-4- yl)-5-nitrothiophene-2-carboxamide [0416] 1 H NMR (400MHz, DMSO-d 6 ): δ 12.00 (br. s., 1H), 8.90 (s, 1H), 8.81 (d, J = 1.0 Hz, 1H), 8.57-8.68 (m, 2H), 8.23-8.42 (m, 4H), 7.97 (d, J = 8.3 Hz, 1H), 7.39-7.58 (m, 2H). MS(M+1): 502. Yellow solid. [0417] Shown in Tables 7 are in vitro activities of exemplary compounds of formula (I). The results indicate that the compounds of the present invention indeed have efficacy for inhibiting the growth of various tumor cells. [0418] Table 7 [0419] 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. [0420] Further, from the above description, one skilled in the art can easily ascertain the essential characteristics of the present invention, 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.




 
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