ANTITUMOR EFFECT POTENTIATOR COMPRISING PYRROLOPYRIMIDINE COMPOUND

Abstract

Disclosed is an antitumor effect potentiator for one or more other compounds having an antitumor effect, the antitumor effect potentiator comprising a novel pyrrolopyrimidine compound.

Claims

1. An antitumor effect potentiator for one or more other compounds having an antitumor effect, the antitumor effect potentiator comprising a compound represented by Formula (A) below or a salt thereof: ##STR00309## wherein: is a single bond or a double bond; X is O, CH.sub.2, or CH; Y is NH or O; R.sub.1 is hydrogen, fluorine, a hydroxy group, a cyano group, or an amino group; R.sub.2 is hydrogen, fluorine, a hydroxy group, a cyano group, or an amino group; R.sub.3 is a vinylene group, an ethynylene group, a C6-C14 arylene group, or a monocyclic or bicyclic heteroarylene group having at least one heteroatom selected from the group consisting of N, S, and O; R.sub.4 is a bond, a methylene group, or a C3-C7 cycloalkylidene group; R.sub.5 is a C3-C7 saturated cycloalkyl group that may have one or more R.sub.6, a C6-C10 unsaturated cycloalkyl group that may have one or more R.sub.6, or a monocyclic or bicyclic unsaturated heterocycloalkyl group that has at least one heteroatom selected from the group consisting of N, S, and O, and that may have one or more R.sub.6; R.sub.6 is halogen, a hydroxy group, a cyano group, a C1-C6 alkyl group that may be substituted with one or more phenoxy groups, a carbamoyl group, a C1-C6 alkoxycarbonyl group, a monocyclic or bicyclic unsaturated heterocycloalkyl group having at least one heteroatom selected from the group consisting of N, S, and O, a monocyclic or bicyclic saturated heterocycloalkyl group that has at least one heteroatom selected from the group consisting of N, S, and O, and that may be substituted with one or more of halogen, hydroxy group, carboxyl group, or C1-C6 alkyl group, an amino group, a mono- or di-(C1-C4 alkyl) amino group that may be substituted with one or more hydroxy groups or phenyl groups, a C1-C6 alkoxy group that may be substituted with one or more of halogen, C3-C7 saturated cycloalkyl group, or monocyclic or bicyclic unsaturated heterocycloalkyl group having at least one heteroatom selected from the group consisting of N, S, and O, a benzyloxy group that may be substituted with one or more carbamoyl groups, a C1-C6 alkylthio group, a C1-C6 alkylsulfonyl group, or an aminosulfonyl group, when a plurality of R.sub.6 are present, the plurality of R.sub.6 may be the same or different.

2. The antitumor effect potentiator according to claim 1, wherein in Formula (A), R1 is hydrogen, fluorine, or a hydroxy group; R2 is hydrogen, fluorine, or a hydroxy group; and R3 is an ethynylene group, or a monocyclic or bicyclic heteroarylene group having 1 to 4 of at least one kind of heteroatom selected from the group consisting of N, S, and O.

3. The antitumor effect potentiator according to claim 1, wherein in Formula (A), R1 is a hydroxy group; R2 is hydrogen or a hydroxy group; R3 is an ethynylene group, or a monocyclic heteroarylene group having 2 of at least one kind of heteroatom selected from the group consisting of N, S, and O; R5 is a C3-C7 saturated cycloalkyl group that may have one or more R.sub.6, a C6-C10 unsaturated cycloalkyl group that may have one or more R.sub.6, or a monocyclic or bicyclic unsaturated heterocycloalkyl group that has at least one heteroatom selected from the group consisting of N, S, and O, and that may have one or more R.sub.6; and R.sub.6 is halogen; a hydroxy group; a cyano group; a C1-C6 alkyl group that may be substituted with one or more phenoxy groups; a carbamoyl group; a C1-C6 alkoxycarbonyl group; a monocyclic or bicyclic unsaturated heterocycloalkyl group having at least one heteroatom selected from the group consisting of N, S, and O; a monocyclic or bicyclic saturated heterocycloalkyl group that has at least one heteroatom selected from the group consisting of N, S, and O, and that may be substituted with one or more of halogen, hydroxy group, carboxyl group, or C1-C6 alkyl group; an amino group; a mono- or di-(C1-C4 alkyl) amino group that may be substituted with one or more hydroxy groups or phenyl groups; a C1-C6 alkoxy group that may be substituted with one or more of halogen, C3-C7 saturated cycloalkyl group, or monocyclic or bicyclic unsaturated heterocycloalkyl group having at least one heteroatom selected from the group consisting of N, S, and O; a benzyloxy group that may be substituted with one or more carbamoyl groups; a C1-C4 alkylthio group; a C1-C4 alkylsulfonyl group; or an aminosulfonyl group (when a plurality of R.sub.6 are present, the plurality of R.sub.6 may be the same or different).

4. The antitumor effect potentiator according to claim 1, wherein, in Formula (A), R.sub.1 is a hydroxy group; R.sub.2 is hydrogen or a hydroxy group; R.sub.3 is an ethynylene group, or a monocyclic heteroarylene group having 2 of at least one kind of heteroatom selected from the group consisting of N, S, and O; R.sub.5 is a C3-C7 saturated cycloalkyl group that may have one or more R.sub.6, a C6-C10 unsaturated cycloalkyl group that may have one or more R.sub.6, or a monocyclic or bicyclic unsaturated heterocycloalkyl group that has at least one heteroatom selected from the group consisting of N, S, and O, and that may have one or more R.sub.6; and R.sub.6 is fluorine; chlorine; a hydroxy group; a cyano group; a C1-C6 alkyl group that may be substituted with one or more phenoxy groups; a carbamoyl group; a C1-C6 alkoxycarbonyl group; a pyridinyl group that may have at least one member selected from the group consisting of halogen, hydroxy group and C1-C4 alkyl group as a substituent; an azetidinyl group; a hydroxyazetidinyl group; a thiomorpholinyl group; a dioxidothiomorpholinyl group; a methylpiperazinyl group; a hydroxypiperidinyl group; an oxopiperidinyl group; a piperidinyl group; a hydroxypyrrolidinyl group; an oxopyrrolidinyl group; a pyrrolidinyl group; a carboxylpyrrolidinyl group; a fluoropyrrolidinyl group; a morpholinyl group; a 9-oxa-3-azabicyclo[3.3.1]nonan-3-yl group; a 3-oxa-8-azabicyclo[3.2.1]octan-8-yl group; an amino group; a methylamino group; an ethylamino group; an isopropylamino group; a hydroxyethylamino group; a dimethylamino group; a phenylmethylamino group; a C1-C6 alkoxy group that may be substituted with one or more of halogen, C3-C7 saturated cycloalkyl group, or monocyclic or bicyclic unsaturated heterocycloalkyl group having at least one heteroatom selected from the group consisting of N, S, and O; a benzyloxy group that may be substituted with one or more carbamoyl groups; a C1-C4 alkylthio group; a C1-C4 alkylsulfonyl group; or an aminosulfonyl group (when a plurality of R.sub.6 are present, the plurality of R.sub.6 may be the same or different).

5. The antitumor effect potentiator according to claim 1, wherein, in Formula (A), R.sup.1 is a hydroxy group; R.sub.2 is a hydroxy group; R.sub.3 is an ethynylene group; R.sub.4 is a bond; R.sub.5 is a C6-C10 unsaturated cycloalkyl group that may have one or more R.sub.6; or a monocyclic or bicyclic unsaturated heterocycloalkyl group that has at least one heteroatom selected from the group consisting of N, S, and O, and that may have one or more R.sub.6; and R.sub.6 is fluorine; chlorine; a hydroxy group; a cyano group; a methyl group; a 3-fluoropyrrolidinyl group; a morpholinyl group; a thiomorpholinyl group; a 3-hydroxyazetidinyl group; an azetidinyl group; an amino group; a N-methylamino group; a C1-C6 alkoxy group that may be substituted with one or more of either halogen or C3-C7 saturated cycloalkyl group; or a C1-C4 alkylthio group (when a plurality of R.sub.6 are present, the plurality of R.sub.6 may be the same or different).

6. The antitumor effect potentiator according to claim 1, wherein in Formula (A), Y is NH; R.sub.1 is a hydroxy group; R.sub.2 is a hydroxy group; R.sub.3 is an ethynylene group; R.sub.4 is a bond; R.sub.5 is a phenyl group or a naphthyl group that may have one or more R.sub.6; or a monocyclic or bicyclic unsaturated heterocycloalkyl group that has at least one heteroatom selected from the group consisting of N, S, and O, and that may have one or more R.sub.6; R.sub.6 is fluorine; a methyl group; 3-fluoropyrrolidinyl; 3-hydroxyazetidinyl; azetidinyl; an amino group; a N-methylamino group; a C1-C6 alkoxy group that may have one or more cyclopropyl groups; or a C1-C4 alkylthio group (when a plurality of R.sub.6 are present, the plurality of R.sub.6 may be the same or different).

7. The antitumor effect potentiator according to claim 1, wherein the compound represented by Formula (A) or a salt thereof is at least one member selected from the group consisting of: 4-amino-5-[2-(2,6-difluorophenyl)ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine; 4-amino-5-[2-(4-amino-2,6-difluoro-phenyl)ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine; 4-amino-5-[2-[2,6-difluoro-4-(methylamino)phenyl]ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine; 4-amino-5-[2-[2,6-difluoro-4-[(3R)-3-fluoropyrrolidin-1-yl]phenyl]ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine; 4-amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-ethoxy-4,6-difluoro-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine; 4-amino-5-[2-[2,6-difluoro-4-(3-hydroxyazetidin-1-yl)phenyl]ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine; 4-amino-5-[2-[4-(azetidin-1-yl)-2,6-difluoro-phenyl]ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine; 4-amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-ethoxy-6-fluoro-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine; 4-amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-fluoro-6-propoxy-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine; 8-[2-[4-amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]-7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine; 4-amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-ethylsulfanyl-6-fluoro-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine; 4-amino-5-[2-[2-(cyclopropylmethoxy)-6-fluoro-phenyl]ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine; 4-amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]-5-[2-(2-fluoro-6-methylsulfanyl-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine; 8-[2-[4-amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]-7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine; 4-amino-7-[(1R,4R,5S)-4,5-dihydroxy-3-[(sulfamoylamino)methyl]cyclopent-2-en-1-yl]-5-[2-(2-ethoxy-6-fluoro-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine; and 4-amino-7-[(1R,4R,5S)-4,5-dihydroxy-3-5 [(sulfamoylamino)methyl]cyclopent-2-en-1-yl]-5-[2-(2-fluoro-6-methylsulfanyl-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine; and salts of these compounds.

8. The antitumor effect potentiator according to claim 1, wherein the one or more other compounds having an antitumor effect are one or more members selected from the group consisting of kinase inhibitors, apoptosis inducers, nuclear receptor modulators, immunomodulators, nuclear export signal inhibitors, proteasome modulators, DNA-damaging agents, antimetabolites, platinum-based antitumor agents, microtubule inhibitors, alkylating agents, and anthracycline-based antitumor agents.

9. The antitumor effect potentiator according to claim 1, wherein the one or more other compounds having an antitumor effect are one or more members selected from the group consisting of bortezomib, carfilzomib, ixazomib, alectinib, crizotinib, afatinib, erlotinib, gefitinib, osimertinib, lapatinib, ARRY380, dasatinib, imatinib, quizartinib, gilteritinib, sunitinib, regorafenib, lenvatinib, pazopanib, crenolanib, masitinib, ponatinib, ruxolitinib, everolimus, rapamycin, AZD5363, MK2206, idelalisib, duvelisib, volasertib, olaparib, prednisolone, dexamethasone, lenalidomide, pomalidomide, thalidomide, KPT-330, ibrutinib, ABT-199, panobinostat, vorinostat, fluorouracil, gemcitabine, cytarabine, 6-mercaptopurine, pemetrexed, trifluridine, cisplatin, carboplatin, oxaliplatin, eribulin, paclitaxel, trabectedin, ifosfamide, dacarbazine, doxorubicin, pixantrone, rituximab, azacitidine, and GDC-0152.

10. An antitumor agent comprising a combination of the compound represented by Formula (A) or a salt thereof according to claim 1, and one or more other compounds having an antitumor effect.

11. The antitumor agent according to claim 10, wherein the one or more other compounds having an antitumor effect are one or more members selected from the group consisting of kinase inhibitors, apoptosis inducers, nuclear receptor modulators, immunomodulators, nuclear export signal inhibitors, proteasome modulators, DNA-damaging agents, antimetabolites, platinum-based antitumor agents, microtubule inhibitors, alkylating agents, and anthracycline-based antitumor agents.

12. The antitumor agent according to claim 10, wherein the one or more other compounds having an antitumor effect are one or more members selected from the group consisting of bortezomib, carfilzomib, ixazomib, alectinib, crizotinib, afatinib, erlotinib, gefitinib, osimertinib, lapatinib, ARRY380, dasatinib, imatinib, quizartinib, gilteritinib, sunitinib, regorafenib, lenvatinib, pazopanib, crenolanib, masitinib, ponatinib, ruxolitinib, everolimus, rapamycin, AZD5363, MK2206, idelalisib, duvelisib, volasertib, olaparib, prednisolone, dexamethasone, lenalidomide, pomalidomide, thalidomide, KPT-330, ibrutinib, ABT-199, panobinostat, vorinostat, fluorouracil, gemcitabine, cytarabine, 6-mercaptopurine, pemetrexed, trifluridine, cisplatin, carboplatin, oxaliplatin, eribulin, paclitaxel, trabectedin, ifosfamide, dacarbazine, doxorubicin, pixantrone, rituximab, azacitidine, and GDC-0152.

13. Use of the compound represented by Formula (A) or a salt thereof according to claim 1 for potentiating the antitumor effect of one or more other compounds having an antitumor effect.

14. Use of the compound represented by Formula (A) or a salt thereof according to claim 1 for producing an antitumor effect potentiator for one or more other compounds having an antitumor effect.

15. Use of the compound represented by Formula (A) or a salt thereof according to claim 1 for producing an antitumor agent comprising a combination of the compound or a salt thereof (A) and one or more other compounds having an antitumor effect.

16. The use according to claim 13, wherein the one or more other compounds having an antitumor effect are one or more members selected from the group consisting of kinase inhibitors, apoptosis inducers, nuclear receptor modulators, immunomodulators, nuclear export signal inhibitors, proteasome modulators, DNA-damaging agents, antimetabolites, platinum-based antitumor agents, microtubule inhibitors, alkylating agents, and anthracycline-based antitumor agents.

17. The use according to claim 15, wherein the one or more other compounds having an antitumor effect are one or more members selected from the group consisting of bortezomib, carfilzomib, ixazomib, alectinib, crizotinib, afatinib, erlotinib, gefitinib, osimertinib, lapatinib, ARRY380, dasatinib, imatinib, quizartinib, gilteritinib, sunitinib, regorafenib, lenvatinib, pazopanib, crenolanib, masitinib, ponatinib, ruxolitinib, everolimus, rapamycin, AZD5363, MK2206, idelalisib, duvelisib, volasertib, olaparib, prednisolone, dexamethasone, lenalidomide, pomalidomide, thalidomide, KPT-330, ibrutinib, ABT-199, panobinostat, vorinostat, fluorouracil, gemcitabine, cytarabine, 6-mercaptopurine, pemetrexed, trifluridine, cisplatin, carboplatin, oxaliplatin, eribulin, paclitaxel, trabectedin, ifosfamide, dacarbazine, doxorubicin, pixantrone, rituximab, azacitidine, and GDC-0152.

18. A product as a combined preparation for use simultaneously, sequentially, or at one or more intervals upon prevention and/or treatment of a tumor, the product comprising the compound represented by Formula (A) or a salt thereof according to claim 1 and one or more other compounds having an antitumor effect.

19. The compound represented by Formula (A) or a salt thereof according to claim 1 for potentiating the antitumor effect of one or more other compounds having an antitumor effect.

20. A pharmaceutical composition comprising the compound represented by Formula (A) or a salt thereof according to claim 1 and a pharmaceutical carrier, the pharmaceutical composition being for potentiating the antitumor effect of one or more other compounds having an antitumor effect.

21. An antitumor composition comprising the compound represented by Formula (A) or a salt thereof according to claim 1, and one or more other compounds having an antitumor effect.

22. A method for treating a tumor, comprising administering to a patient the compound represented by Formula (A) or a salt thereof according to claim 1, and one or more other compounds having an antitumor effect, in combination.

23. A method for potentiating the antitumor effect of one or more other compounds having an antitumor effect, the method comprising administering to a patient the compound represented by Formula (A) or a salt thereof according to claim 1, and the one or more other compounds having an antitumor effect, in combination.

24. A combination of the compound represented by Formula (A) or a salt thereof according to claim 1, and one or more other compounds having an antitumor effect, for tumor treatment.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0053] FIG. 1 is a graph showing tumor volume measurement values of the control group, the group administered with the reference example compound, the group administered with bortezomib, and the group administered with the combination.

[0054] FIG. 2 is a graph showing tumor volume measurement values of the control group, the group administered with the reference example compound, the group administered with gilteritinib, and the group administered with the combination.

[0055] FIG. 3 is a graph showing tumor volume measurement values of the control group, the group administered with the reference example compound, the group administered with doxorubicin, and the group administered with the combination.

[0056] FIG. 4 is a graph showing tumor volume measurement values of the control group, the group administered with the reference example compound, the group administered with rituximab, and the group administered with the combination.

[0057] FIG. 5 is a graph showing tumor volume measurement values of the control group, the group administered with the reference example compound, the group administered with rituximab, and the group administered with the combination.

[0058] FIG. 6 is a graph showing tumor volume measurement values of the control group, the group administered with the reference example compound, the group administered with azacytidine, and the group administered with the combination.

DESCRIPTION OF EMBODIMENTS

[0059] The pyrrolopyrimidine compound represented by Formula (A) above has an action of potentiating the antitumor effect of one or more other compounds having an antitumor effect.

[0060] An embodiment of the present invention provides an antitumor effect potentiator for one or more other compounds having an antitumor effect, the antitumor effect potentiator comprising the compound represented by Formula (A) or a salt thereof.

[0061] The forms of other compounds having an antitumor effect are not limited as long as they are compounds that are different from the compound represented by Formula (A), and have an antitumor effect. Examples include low-molecular compounds or salts thereof, antibodies, proteins, nucleic acids (e.g., aptamers, antisense molecules, and siRNA), and the like.

[0062] The mechanism of action of other compounds having an antitumor effect that can be used in the present invention is not particularly limited. Usable compounds include one or more antitumor agents selected from the group consisting of kinase inhibitors, apoptosis inducers, nuclear receptor modulators, immunomodulators, nuclear export signal inhibitors, proteasome modulators, DNA-damaging agents, antimetabolites, platinum-based antitumor agents (platinum complexes), microtubule inhibitors, alkylating agents, and anthracycline-based antitumor agents. The other compounds having an antitumor effect also include salts thereof.

[0063] Examples of kinase inhibitors include tyrosine kinase inhibitors and serine-threonine kinase inhibitors.

[0064] Examples of tyrosine kinase inhibitors include receptor tyrosine kinase inhibitors and non-receptor tyrosine kinase inhibitors; receptor tyrosine kinase inhibitors are preferable.

[0065] Examples of receptor tyrosine kinase inhibitors include ALK inhibitors, EGFR family inhibitors, FLT3 inhibitors, VEGFR inhibitors, c-kit inhibitors, multikinase inhibitors that inhibit multiple receptor tyrosine kinases, and the like.

[0066] Examples of ALK inhibitors include alectinib, crizotinib, and the like.

[0067] Examples of EGFR family inhibitors include EGFR inhibitors and HER2 inhibitors.

[0068] Examples of EGFR inhibitors include afatinib, erlotinib, gefitinib, osimertinib (which is also referred to as AZD9291), and the like.

[0069] Examples of HER2 inhibitors include lapatinib, ARRY380, and the like.

[0070] Examples of FLT3 inhibitors include quizartinib, gilteritinib, ASP2215, crenolanib, and the like.

[0071] Examples of VEGFR inhibitors include lenvatinib, pazopanib, sorafenib, sunitinib, regorafenib, and the like.

[0072] Examples of c-kit inhibitors include masitinib, and the like.

[0073] Examples of non-receptor tyrosine kinase inhibitors include BCR-ABL inhibitors, BTK inhibitors, and Janus kinase inhibitors (which are also referred to as JAK kinase inhibitors).

[0074] Examples of BCR-ABL inhibitors include dasatinib, imatinib, ponatinib, and the like.

[0075] Examples of BTK inhibitors include ibrutinib and the like.

[0076] Examples of Janus kinase inhibitors include ruxolitinib and the like.

[0077] Examples of serine-threonine kinase inhibitors include PI3K inhibitors, Akt inhibitors, mTOR inhibitors, and PLK inhibitors.

[0078] Examples of PI3K inhibitors include duvelisib, idelalisib, and the like.

[0079] Examples of AKT inhibitors include AZD5363, MK2206, and the like.

[0080] Examples of mTOR inhibitors include everolimus, rapamycin, and the like.

[0081] Examples of PLK inhibitors include volasertib and the like.

[0082] Examples of apoptosis inducers include BCL-2 inhibitors, IAP antagonists, and the like.

[0083] Examples of BCL-2 inhibitors include ABT-199, ABT-737, and the like.

[0084] Examples of IAP antagonists include GDC-0152 and the like.

[0085] Examples of nuclear receptor modulators include HDAC inhibitors and steroids.

[0086] Examples of HDAC inhibitors include panobinostat, vorinostat (trade name: Zolinda, SAHA) and the like.

[0087] Examples of steroids include dexamethasone, prednisolone, and the like.

[0088] Examples of immunomodulators include lenalidomide, pomalidomide, thalidomide, rituximab, and the like.

[0089] Examples of nuclear export signal inhibitors include Exportin-1 inhibitors.

[0090] Examples of Exportin-1 inhibitors include KPT-330 and the like.

[0091] Examples of proteasome modulators include bortezomib, carfilzomib, ixazomib, and the like.

[0092] Examples of DNA-damaging agents include PARP inhibitors. Specific examples include olaparib and the like.

[0093] Examples of antimetabolites include fluorouracil, tegafur, a combination drug of tegafur and uracil, a combination drug of tegafur, gimeracil, and oteracil potassium, Furtulon, capecitabine, gemcitabine, cytarabine, 6-mercaptopurine, methotrexate, pemetrexed, fludarabine, trifluridine, a combination drug of trifluridine and tipiracil hydrochloride, azacitidine, and the like.

[0094] Examples of platinum-based antitumor agents include cisplatin, carboplatin, oxaliplatin, nedaplatin, and the like.

[0095] Examples of microtubule inhibitors include vinblastine, vincristine, vinorelbine, eribulin, paclitaxel, docetaxel, albumin-bound paclitaxel, and the like.

[0096] Examples of alkylating agents include trabectedin, ifosfamide, bendamustine, cyclophosphamide, dacarbazine, and the like.

[0097] Examples of anthracycline-based antitumor agents include daunorubicin, doxorubicin, pixantrone, and the like.

[0098] In one preferred embodiment, the one or more other compounds having an antitumor effect are one or more members selected from the group consisting of bortezomib, carfilzomib, ixazomib, alectinib, crizotinib, afatinib, erlotinib, gefitinib, osimertinib, lapatinib, ARRY380, dasatinib, imatinib, quizartinib, gilteritinib, sunitinib, regorafenib, lenvatinib, pazopanib, crenolanib, masitinib, ponatinib, ruxolitinib, everolimus, rapamycin, AZD5363, MK2206, idelalisib, duvelisib, volasertib, olaparib, prednisolone, dexamethasone, lenalidomide, pomalidomide, thalidomide, KPT-330, ibrutinib, ABT-199, panobinostat, vorinostat, fluorouracil, gemcitabine, cytarabine, 6-mercaptopurine, pemetrexed, trifluridine, cisplatin, carboplatin, oxaliplatin, eribulin, paclitaxel, trabectedin, ifosfamide, dacarbazine, doxorubicin, pixantrone, rituximab, azacitidine, and GDC-0152.

[0099] Of these, in order to obtain potentiation action that is equal to or greater than an slight synergism, bortezomib, carfilzomib, alectinib, crizotinib, afatinib, erlotinib, gefitinib, lapatinib, ARRY380, imatinib, quizartinib, lenvatinib, pazopanib, masitinib, ponatinib, ruxolitinib, everolimus, rapamycin, AZD5363, MK2206, idelalisib, duvelisib, olaparib, prednisolone, dexamethasone, lenalidomide, pomalidomide, thalidomide, KPT-330, ibrutinib, ABT-199, fluorouracil, gemcitabine, cytarabine, 6-mercaptopurine, pemetrexed, cisplatin, carboplatin, oxaliplatin, ifosfamide, doxorubicin, pixantrone, rituximab, azacitidine, and GDC-0152 are more preferable. In order to obtain potentiation action that is equal to or greater than a moderate synergism, bortezomib, carfilzomib, alectinib, afatinib, erlotinib, gefitinib, lapatinib, ARRY380, imatinib, quizartinib, lenvatinib, masitinib, ponatinib, ruxolitinib, everolimus, rapamycin, AZD5363, MK2206, idelalisib, duvelisib, olaparib, prednisolone, dexamethasone, lenalidomide, pomalidomide, thalidomide, KPT-330, ibrutinib, ABT-199, fluorouracil, gemcitabine, cytarabine, 6-mercaptopurine, pemetrexed, cisplatin, oxaliplatin, ifosfamide, doxorubicin, pixantrone, rituximab, azacitidine, and GDC-0152 are more preferable. In order to obtain potentiation action that is equal to or greater than a synergism, bortezomib, carfilzomib, alectinib, afatinib, erlotinib, gefitinib, lapatinib, ARRY380, imatinib, quizartinib, lenvatinib, masitinib, ponatinib, everolimus, rapamycin, AZD5363, MK2206, idelalisib, duvelisib, olaparib, prednisolone, dexamethasone, thalidomide, ABT-199, fluorouracil, gemcitabine, cytarabine, oxaliplatin, ifosfamide, rituximab, azacitidine, and GDC-0152 are further preferable. In order to obtain potentiation action that is equal to or greater than a strong synergism, lapatinib is particularly preferable.

[0100] Additive slight synergism moderate synergism synergism strong synergism and very strong synergism as used herein are known criteria commonly used in determining the presence or absence of the synergistic effect of a combined use (Pharmacol Rev., 2006; 58(3):621-81, BMC Complement Altern Med., 2013; 13:212, Anticancer Res, 2005; 25(3B):1909-17). More specifically, although it is not particularly limited, the presence or absence of the synergistic effect can be determined according to the combination index (CI) value, as described later in Example 1.

[0101] The other compounds having an antitumor effect of the present invention can be individually produced according to known methods, or may be commercially available products.

[0102] Each group shown in the aforementioned Formula (A) is specifically as follows.

[0103] In Formula (A), the C6-C14 arylene group represented by R.sub.3 is a monocyclic or polycyclic bivalent aromatic hydrocarbon group having 6 to 14 carbon atoms. More specifically, examples of the C6-C14 arylene group include phenylene, naphthylene, and tetrahydronaphthylene. Phenylene and naphthylene are preferable.

[0104] In Formula (A), the monocyclic or bicyclic heteroarylene group having at least one heteroatom selected from the group consisting of N, S, and O represented by R.sub.3 is a monocyclic or bicyclic heteroarylene group having 1 to 3 of at least one kind of heteroatom selected from the group consisting of N, S, and O. Specific examples include thiazolylene, pyrazolylene, imidazolylene, thienylene, furylene, pyrrolylene, oxazolylene, isoxazolylene, isothiazolylene, thiadiazolylene, triazolylene, tetrazolylene, pyridylene, pyrazylene, pyrimidinylene, pyridazinylene, indolylene, isoindolylene, indazolylene, triazolopyridilene, benzimidazolylene, benzoxazolylene, benzothiazolylene, benzothienylene, benzofuranylene, purinylene, quinolylene, isoquinolylene, quinazolinylene, quinoxalylene, methylenedioxyphenylene, ethylenedioxyphenylene, dihydrobenzofuranylene, benzoxazinylene, dihydrobenzoxazinylene, chromanylene, thiochromanylene, 1,1-dioxythiochromanylene, dihydrobenzothienylene, and 1,1-dioxydihydrobenzothienylene. Preferable examples include a monocyclic heteroarylene group having 1 to 3 of at least one kind of heteroatom selected from the group consisting of N, S, and O. More preferable examples include a monocyclic 5-membered heteroarylene group having 1 or 2 of at least one kind of heteroatom selected from the group consisting of N, S, and O. Particularly preferable examples include thiazolylene, pyrazolylene, imidazolylene, thienylene, and oxazolylene.

[0105] In Formula (A), the C3-C7 cycloalkylidene group is a monocyclic saturated alkylidene group having 3 to 7 carbon atoms. Specific examples include the following.

Cyclopropylidene group

##STR00002##

cyclobutylidene group

##STR00003##

cyclopentylidene group

##STR00004##

cyclohexylidene group

##STR00005##

and cycloheptylidene group

##STR00006##

[0106] Preferable examples include a cyclopropylidene group.

[0107] In the present specification, the cycloalkyl group refers to a saturated or unsaturated monovalent cyclic hydrocarbon group. Unless otherwise specified, the term cycloalkyl encompasses monocyclic cycloalkyl, and polycyclic cycloalkyl such as bicyclic or tricyclic cycloalkyl.

[0108] In the present specification, the heterocycloalkyl group refers to a saturated or unsaturated monovalent heterocyclic group. Unless otherwise specified, the term heterocycloalkyl encompasses monocyclic heterocycloalkyl, and polycyclic heterocycloalkyl such as bicyclic or tricyclic heterocycloalkyl.

[0109] In Formula (A), the C3-C7 saturated cycloalkyl group of the C3-C7 saturated cycloalkyl group that may have one or more R.sub.6 represented by R.sub.5 refers to a cyclic saturated hydrocarbon group having 3 to 7 carbon atoms. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Preferable examples include cyclohexyl.

[0110] In Formula (A), the C6-C10 unsaturated cycloalkyl group of the C6-C10 unsaturated cycloalkyl group that may have one or more R.sub.6 represented by R.sub.5 is a monocyclic or bicyclic unsaturated hydrocarbon group having 6 to 10 carbon atoms. Specific examples include phenyl, naphthyl, tetrahydronaphthyl, and 2,3-dihydroindenyl. Preferable examples include phenyl, naphthyl, and 2,3-dihydroindenyl.

[0111] In Formula (A), specific examples of the monocyclic or bicyclic unsaturated heterocycloalkyl group that has at least one heteroatom selected from the group consisting of N, S, and O of the monocyclic or bicyclic unsaturated heterocycloalkyl group that has at least one heteroatom selected from the group consisting of N, S, and O, and that may have one or more R.sub.6 represented by R.sub.5 include hexamethyleneimino, imidazolyl, thienyl, furyl, pyrrolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrazyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indazolyl, methylenedioxy phenyl, ethylenedioxyphenyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, purinyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, 1H-pyrazolo[4,3-b]pyridin-5-yl, 2,3-dihydro-1,4-benzoxazino, 1,1-dioxo-3,4-dihydro-2H-thiochromen-8-yl, 2,3-dihydrobenzothiophen-7-yl, and 1,1-dioxo-2,3-dihydrobenzothiophen-7-yl. Preferable examples include a monocyclic or bicyclic 5- to 10-membered unsaturated heterocycloalkyl group having 1 to 3 of at least one kind of heteroatom selected from the group consisting of N, S, and O. More preferable examples include thienyl, pyridyl, pyrazyl, quinolyl, isoquinolyl, 1H-pyrazolo[4,3-b]pyridin-5-yl, 2,3-dihydro-1,4-benzoxazino, 1,1-dioxo-3,4-dihydro-2H-thiochromen-8-yl, 2,3-dihydrobenzothiophen-7-yl, and 1,1-dioxo-2,3-dihydrobenzothiophen-7-yl.

[0112] In Formula (A), specific examples of the halogen represented by R.sub.6 include fluorine, chlorine, bromine, and iodine. Preferable examples include fluorine and chlorine.

[0113] In Formula (A), the C1-C6 alkyl group of the C1-C6 alkyl group that may be substituted with one or more phenoxy groups represented by R.sub.6 refers to a linear or branched alkyl group having 1 to 6 carbon atoms. Specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl. Methyl is preferable.

[0114] In Formula (A), the C1-C6 alkoxy group of the C1-C6 alkoxy group that may be substituted with one or more of halogen, C3-C7 saturated cycloalkyl group, or monocyclic or bicyclic unsaturated heterocycloalkyl group having at least one heteroatom selected from the group consisting of N, S, and O represented by R.sub.6 refers to a linear or branched alkoxy group having 1 to 6 carbon atoms. Specific examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy. Methoxy, ethoxy, n-propoxy, and isopropoxy are preferable.

[0115] In Formula (A), the halogen of the C1-C6 alkoxy group that may be substituted with one or more of halogen, C3-C7 saturated cycloalkyl group, or monocyclic or bicyclic unsaturated heterocycloalkyl group having at least one heteroatom selected from the group consisting of N, S, and O represented by R.sub.6 refers to the halogen listed above, and is preferably fluorine. The number of halogens as substituents is 1 to 3, preferably 2 or 3.

[0116] In Formula (A), the C3-C7 saturated cycloalkyl group of the C1-C6 alkoxy group that may be substituted with one or more of halogen, C3-C7 saturated cycloalkyl group, or monocyclic or bicyclic unsaturated heterocycloalkyl group having at least one heteroatom selected from the group consisting of N, S, and O represented by R.sub.6 refers to a saturated cycloalkyl group having 3 to 7 carbon atoms. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Cyclopropyl is preferable. The number of C3-C7 saturated cycloalkyl groups as substituents is preferably 1.

[0117] In Formula (A), the monocyclic or bicyclic unsaturated heterocycloalkyl group having at least one heteroatom selected from the group consisting of N, S, and O of the C1-C6 alkoxy group that may be substituted with one or more of halogen, C3-C7 saturated cycloalkyl group, or monocyclic or bicyclic unsaturated heterocycloalkyl group having at least one heteroatom selected from the group consisting of N, S, and O represented by R.sub.6 refers to the unsaturated heterocycloalkyl group described above. Preferable examples include a monocyclic unsaturated heterocycloalkyl group having 1 to 3 of at least one kind of heteroatom selected from the group consisting of N, S, and O. More preferable examples include a monocyclic 5- or 6-membered unsaturated heterocycloalkyl group having 1 or 2 of at least one kind of heteroatom selected from the group consisting of N, S, and O. Particularly preferable examples include pyrazolyl, triazolyl, and pyridyl. The number of unsaturated heterocycloalkyl groups as substituents is preferably 1.

[0118] In Formula (A), preferable examples of the C1-C6 alkoxy group that may be substituted with one or more of halogen, C3-C7 saturated cycloalkyl group, or monocyclic or bicyclic unsaturated heterocycloalkyl group having at least one heteroatom selected from the group consisting of N, S, and O represented by R.sub.6 include methoxy, difluoromethoxy, trifluoromethoxy, cyclopropylmethoxy, 3-pyridylmethoxy, pyrazol-1-ylmethoxy, ethoxy, 2,2,2-trifluoroethoxy, n-propoxy, and isopropoxy.

[0119] In Formula (A), preferable examples of the benzyloxy group that may be substituted with one or more carbamoyl groups represented by R.sub.6 include benzyloxy and 3-carbamoyl benzyloxy.

[0120] In Formula (A), the mono- or di-(C1-C4 alkyl) amino group of the mono- or di-(C1-C4 alkyl) amino group that may be substituted with one or more hydroxy groups or phenyl groups represented by R.sub.6 refers to an amino group monosubstituted or disubstituted with a C1-C4 alkyl group among the above C1-C6 alkyl groups. Specific examples include methylamino, ethylamino, diethylamino, methylethylamino, isopropylamino, butylmethylamino, and dimethylamino. Preferably examples include methylamino, ethylamino, dimethylamino, and isopropylamino.

[0121] In Formula (A), the mono- or di-(C1-C4 alkyl) amino group that may be substituted with one or more hydroxy groups or phenyl groups represented by R.sub.6 is preferably methylamino, ethylamino, isopropylamino, hydroxyethylamino, dimethylamino, or phenylmethylamino (benzylamino).

[0122] In Formula (A), the C1-C6 alkoxycarbonyl group represented by R.sub.6 refers to a carbonyl group substituted with the above alkoxy group. Specific examples include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, 1-methylpropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, 2-methyl-butoxycarbonyl, neopentyloxycarbonyl, and pentan-2-yloxycarbonyl. Methoxycarbonyl is preferable.

[0123] In Formula (A), the monocyclic or bicyclic unsaturated heterocycloalkyl group having at least one heteroatom selected from the group consisting of N, S, and O represented by R.sub.6 refers to the unsaturated heterocycloalkyl group described above, preferably a monocyclic 5- or 6-membered unsaturated heterocycloalkyl group having 1 or 2 of at least one kind of heteroatom selected from the group consisting of N, S, and O, and more preferably pyridyl.

[0124] In Formula (A), specific examples of the monocyclic or bicyclic saturated heterocycloalkyl group that has at least one heteroatom selected from the group consisting of N, S, and O of the monocyclic or bicyclic saturated heterocycloalkyl group that has at least one heteroatom selected from the group consisting of N, S, and O, and that may be substituted with one or more of halogen, hydroxy group, carboxyl group, or C1-C6 alkyl group represented by R.sub.6 include azetidinyl, pyrrolidinyl, piperidinyl, 2-oxo-1-pyrrolidinyl, 4-oxo-1-piperidinyl, piperazinyl, hexamethyleneimino, morpholino, thiomorpholino, 1,1-dioxo-thiomorpholino, homopiperazinyl, tetrahydrofuranyl, tetrahydropyranyl, 9-oxa-3-azabicyclo[3.3.1]nonan-3-yl, and 3-oxa-8-azabicyclo[3.2.1]octan-8-yl. Preferable examples include a monocyclic or bicyclic 5- to 10-membered saturated heterocycloalkyl group having 1 to 4 of at least one kind of heteroatom selected from the group consisting of N, S, and O. More preferable examples include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 2-oxo-1-pyrrolidinyl, 4-oxo-1-piperidinyl, morpholino, thiomorpholino, 1,1-dioxo-thiomorpholino, 9-oxa-3-azabicyclo[3.3.1]nonan-3-yl, and 3-oxa-8-azabicyclo[3.2.1]octan-8-yl.

[0125] In Formula (A), the halogen of the monocyclic or bicyclic saturated heterocycloalkyl group that has at least one heteroatom selected from the group consisting of N, S, and O, and that may be substituted with one or more of halogen, hydroxy group, carboxyl group, or C1-C6 alkyl group represented by R.sub.6 refers to the halogen listed above, preferably fluorine, chlorine, etc., and more preferably fluorine.

[0126] In Formula (A), examples of the C1-C6 alkyl group of the monocyclic or bicyclic saturated heterocycloalkyl group that has at least one heteroatom selected from the group consisting of N, S, and O, and that may be substituted with one or more of halogen, hydroxy group, carboxyl group, or C1-C6 alkyl group represented by R.sub.6 include, among the above alkyl groups, an alkyl group having 1 to 6 carbon atoms, preferably a methyl group.

[0127] In Formula (A), preferable examples of the monocyclic or bicyclic saturated heterocycloalkyl group that has at least one heteroatom selected from the group consisting of N, S, and O, and that may be substituted with one or more of halogen, hydroxy group, carboxyl group, or C1-C6 alkyl group represented by R.sub.6 include azetidinyl, 3-hydroxyazetidin-1-yl, pyrrolidinyl, 3-fluoropyrrolidin-1-yl, 3-hydroxypyrrolidin-1-yl, 3-carboxy-1-pyrrolidin-1-yl, piperidinyl, 4-oxo-1-piperidinyl, 3-hydroxy-1-piperidinyl, piperazinyl, 4-methylpiperazin-1-yl, 4-oxo-1-piperidinyl, morpholino, thiomorpholino, 1,1-dioxo-thiomorpholino, 9-oxa-3-azabicyclo[3.3.1]nonan-3-yl, and 3-oxa-8-azabicyclo[3.2.1]octan-8-yl.

[0128] In Formula (A), the C1-C6 alkylthio group represented by R.sub.6 refers to a thio group having the above C1-C6 alkyl group, preferably a C1-C4 alkylthio group, more preferably a methylthio group or an ethylthio group.

[0129] In Formula (A), the C1-C6 alkylsulfonyl group represented by R.sub.6 refers to a sulfonyl group having the above C1-C6 alkyl group, preferably a C1-C4 alkylsulfonyl group, more preferably a methylsulfonyl group or an ethylsulfonyl group.

[0130] Y in Formula (A) is NH or O, preferably NH.

[0131] R.sub.1 in Formula (A) is hydrogen, fluorine, a hydroxy group, a cyano group or an amino group, preferably hydrogen, fluorine or a hydroxy group, further preferably a hydroxy group.

[0132] R.sub.2 in Formula (A) is hydrogen, fluorine, a hydroxy group, a cyano group or an amino group, preferably hydrogen, fluorine, or a hydroxy group, further preferably hydrogen or a hydroxy group, particularly preferably a hydroxy group.

[0133] R.sub.3 in Formula (A) is preferably an ethynylene group, or a monocyclic heteroarylene group having 2 of at least one kind of heteroatom selected from the group consisting of N, S, and O, more preferably an ethynylene group.

[0134] R.sub.4 in Formula (A) is preferably a bond.

[0135] R.sub.5 in Formula (A) is a C3-C7 saturated cycloalkyl group that may have one or more R.sub.6, a C6-C10 unsaturated cycloalkyl group that may have one or more R.sub.6, or a monocyclic or bicyclic unsaturated heterocycloalkyl group that has at least one heteroatom selected from the group consisting of N, S, and O, and that may have one or more R.sub.6. Preferably, R.sub.5 is a phenyl group or a naphthyl group that may be substituted with one or more R.sub.6, or a monocyclic or bicyclic unsaturated heterocycloalkyl group that has at least one heteroatom selected from the group consisting of N, S, and O, and that may have one or more R.sub.6. More preferably, R.sub.5 is a unsaturated heterocycloalkyl group or a phenyl group that may be substituted with one or more R.sub.6, further preferably a phenyl group, thienyl group, pyridyl group, pyrazyl group, quinolyl group, isoquinolyl group, 1H-pyrazolo[4,3-b]pyridin-5-yl group, 2,3-dihydro-1,4-benzoxazino group, 1,1-dioxo-3,4-dihydro-2H-thiochromen-8-yl group, 2,3-dihydrobenzothiophen-7-yl group, or 1,1-dioxo-2,3-dihydrobenzothiophen-7-yl group that may be substituted with one or more R.sub.6.

[0136] When R.sub.5 is an unsaturated heterocycloalkyl group, R.sub.5 is preferably a 2,3-dihydro-1,4-benzoxazinyl group, a 3,4-dihydro-2H-thiochromen-8-yl group, a 2,3-dihydrobenzothiophen-7-yl group or the like, more preferably a 2,3-dihydro-1,4-benzoxazinyl group. The unsaturated heterocycloalkyl groups listed above may be substituted with one or more R.sub.6.

[0137] When R.sub.5 has R.sub.6, the number of R.sub.6 is, for example, 1 to 5, preferably 1 to 3.

[0138] When R.sub.5 has one or more R.sub.6, R.sub.6 is any of:

(i-1) halogen,
(i-2) hydroxy group,
(i-3) cyano group,
(i-4) C1-C6 alkyl group that may be substituted with one or more phenoxy groups,
(i-5) carbamoyl group,
(i-6) C1-C6 alkoxycarbonyl group,
(i-7) monocyclic or bicyclic unsaturated heterocycloalkyl group having at least one heteroatom selected from the group consisting of N, S, and O,
(i-8) monocyclic or bicyclic saturated heterocycloalkyl group that has at least one heteroatom selected from the group consisting of N, S, and O, and that may be substituted with one or more of halogen, hydroxy group, carboxyl group, or C1-C6 alkyl group,
(i-9) amino group,
(i-10) mono- or di-(C1-C4 alkyl) amino group that may be substituted with one or more hydroxy groups or phenyl groups,
(i-11) C1-6 alkoxy group that may be substituted with one or more of halogen, C3-C7 saturated cycloalkyl group, or monocyclic or bicyclic unsaturated heterocycloalkyl group having at least one heteroatom selected from the group consisting of N, S, and O,
(i-12) benzyloxy group that may be substituted with one or more carbamoyl groups,
(i-13) C1-C6 alkylthio group,
(i-14) C1-C6 alkylsulfonyl group, or
(i-15) aminosulfonyl group.

[0139] When R.sub.5 has one or more R.sub.6, R.sub.6 in Formula (A) is more preferably any of:

(ii-1) halogen,
(ii-2) hydroxy group,
(ii-3) cyano group,
(ii-4) C1-C6 alkyl group that may be substituted with one or more phenoxy groups,
(ii-5) carbamoyl group,
(ii-6) C1-C6 alkoxycarbonyl group,
(ii-7) monocyclic 5- or 6-membered unsaturated heterocycloalkyl group having 1 or 2 of at least one kind of heteroatom selected from the group consisting of N, S, and O,
(ii-8) monocyclic or bicyclic 5- to 10-membered saturated heterocycloalkyl group that has 1 to 4 of at least one kind of heteroatom selected from the group consisting of N, S, and O, and that may be substituted with one or more of halogen, hydroxy group, carboxyl group, or C1-C6 alkyl group,
(ii-9) amino group,
(ii-10) mono- or di-(C1-C4 alkyl) amino group that may be substituted with one or more hydroxy groups or phenyl groups,
(ii-1) C1-6 alkoxy group that may be substituted with one or more of halogen, C3-C7 saturated cycloalkyl group, or monocyclic or bicyclic unsaturated heterocycloalkyl group having at least one heteroatom selected from the group consisting of N, S, and O,
(ii-12) benzyloxy group that may be substituted with one or more carbamoyl groups,
(ii-13) C1-C4 alkylthio group,
(ii-14) C1-C4 alkylsulfonyl group, or
(ii-15) aminosulfonyl group.

[0140] When R.sub.5 has one or more R.sub.6, R.sub.6 in Formula (A) is more preferably any of:

(iii-1) fluorine, chlorine
(iii-2) hydroxy group,
(iii-3) cyano group,
(iii-4) C1-C6 alkyl group that may be substituted with one or more phenoxy groups,
(iii-5) carbamoyl group,
(iii-6) C1-C6 alkoxycarbonyl group,
(iii-7) 3- to 7-membered saturated heterocycloalkyl group, in particular, 5- to 7-membered saturated heterocycloalkyl group,
(iii-8) azetidinyl group, hydroxyazetidinyl group, thiomorpholinyl group, dioxidothiomorpholinyl group, methylpiperazinyl group, hydroxypiperidinyl group, oxopiperidinyl group, piperidinyl group, hydroxypyrrolidinyl group, oxopyrrolidinyl group, pyrrolidinyl group, carboxylpyrrolidinyl group, fluoropyrrolidinyl group, morpholinyl group, 9-oxa-3-azabicyclo[3.3.1]nonan-3-yl group, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl group,
(iii-9) amino group,
(iii-10) methylamino group, ethylamino group, isopropylamino group, hydroxyethylamino group, dimethylamino group, phenylmethylamino group,
(iii-11) C1-C6 alkoxy group that may be substituted with one or more of halogen, C3-C7 saturated cycloalkyl group, or monocyclic or bicyclic unsaturated heterocycloalkyl group having at least one heteroatom selected from the group consisting of N, S, and O,
(iii-12) benzyloxy group that may be substituted with one or more carbamoyl groups,
(iii-13) C1-C4 alkylthio group,
(iii-14) C1-C4 alkylsulfonyl group, or
(iii-15) aminosulfonyl group.

[0141] When R.sub.5 has one or more R.sub.6, R.sub.6 in Formula (A) is more preferably any of:

(iv-1) fluorine, chlorine
(iv-2) hydroxy group,
(iv-3) cyano group,
(iv-4) methyl group,
(iv-7) 3-fluoropyrrolidinyl group, morpholinyl group, thiomorpholinyl group, 3-hydroxyazetidinyl group, azetidinyl group,
(iv-8) azetidinyl group, pyrrolidinyl group, piperidinyl group, piperazinyl group, 2-oxo-1-pyrrolidinyl group, 4-oxo-1-piperidinyl group, morpholino group, thiomorpholino group, 1,1-dioxo-thiomorpholino group, 9-oxa-3-azabicyclo[3,3,1]nonan-3-yl group, and 3-oxa-8-azabicyclo[3,2,1]octan-8-yl group,
(iv-9) amino group,
(iv-10) methylamino group,
(iv-11) C1-C6 alkoxy group that may be substituted with one or more of either halogen or C3-C7 saturated cycloalkyl group, or
(iv-13) C1-C4 alkylthio group.

[0142] When R.sub.5 has one or more R.sub.6, R.sub.6 in Formula (A) is more preferably any of:

(v-1) fluorine,
(v-4) methyl group,
(v-7) saturated heterocycloalkyl group selected from the group consisting of 3-fluoropyrrolidinyl, 3-hydroxyazetidinyl, and azetidinyl,
(v-9) amino group,
(v-10) methylamino group,
(v-11) C1-C6 alkoxy group that may have one or more cyclopropyl groups, or
(v-13) C1-C4 alkylthio group.

[0143] When a plurality of R.sub.6 are present, the plurality of R.sub.6 may be the same or different.

[0144] The compound represented by Formula (A) is preferably a compound having high enzyme inhibitory activity against NAE that can generally be tested by a known method, more preferably, a compound such that the concentration (IC.sub.50) of the compound by which 50% of the enzyme can be inhibited is 0.03 M or less, further preferably a compound having an IC.sub.50 of 0.01 M or less, particularly preferably a compound having an IC.sub.50 of 0.003 M or less.

[0145] The compound represented by Formula (A) is preferably a compound having high tumor growth inhibitory activity that can generally be tested by a known method, more preferably a compound such that the concentration (IC.sub.50) of the compound by which 50% of tumor growth can be inhibited is 0.01 M or less, particularly preferably a compound having an IC.sub.50 of 0.003 M or less.

[0146] Further preferable examples of the compound include a compound wherein in Formula (A),

R.sub.1 is hydrogen, fluorine, or a hydroxy group;
R.sub.2 is hydrogen, fluorine, or a hydroxy group; and
R.sub.3 is an ethynylene group, or a monocyclic or bicyclic heteroarylene group having 1 to 4 of at least one kind of heteroatom selected from the group consisting of N, S, and O.

[0147] Further preferable examples of the compound include a compound wherein in Formula (A),

R.sub.1 is a hydroxy group;
R.sub.2 is hydrogen or a hydroxy group;
R.sub.3 is an ethynylene group, or a monocyclic heteroarylene group having 2 of at least one kind of heteroatom selected from the group consisting of N, S, and O;
R.sub.5 is a C3-C7 saturated cycloalkyl group that may have one or more R.sub.6; a C6-C10 unsaturated cycloalkyl group that may have one or more R.sub.6; or a monocyclic or bicyclic unsaturated heterocycloalkyl group that has at least one heteroatom selected from the group consisting of N, S, and O, and that may be substituted with one or more R.sub.6;

R.SUB.6 .is

[0148] halogen,
a hydroxy group,
a cyano group,
a C1-C6 alkyl group that may be substituted with one or more phenoxy groups,
a carbamoyl group,
a C1-C6 alkoxycarbonyl group,
a monocyclic or bicyclic unsaturated heterocycloalkyl group having at least one heteroatom selected from the group consisting of N, S, and O,
a monocyclic or bicyclic saturated heterocycloalkyl group that has at least one heteroatom selected from the group consisting of N, S, and O, and that may be substituted with one or more of halogen, hydroxy group, carboxyl group, or C1-C6 alkyl group,
an amino group,
a mono- or di-(C1-C4 alkyl) amino group that may be substituted with one or more hydroxy groups or phenyl groups,
a C1-6 alkoxy group that may be substituted with one or more of halogen, C3-C7 saturated cycloalkyl group, or monocyclic or bicyclic unsaturated heterocycloalkyl group having at least one heteroatom selected from the group consisting of N, S, and O, a benzyloxy group that may be substituted with one or more carbamoyl groups,
a C1-C4 alkylthio group,
a C1-C4 alkylsulfonyl group, or
an aminosulfonyl group
(when a plurality of R.sub.6 are present, the plurality of R.sub.6 may be the same or different).

[0149] Further preferable examples of the compound include a compound wherein, in Formula (A), R.sub.1 is a hydroxy group;

R.sub.2 is hydrogen or a hydroxy group;
R.sub.3 is an ethynylene group, or a monocyclic heteroarylene group having 2 of at least one kind of heteroatom selected from the group consisting of N, S, and O;
R.sub.5 is a C3-C7 saturated cycloalkyl group that may have one or more R.sub.6; a C6-C10 unsaturated cycloalkyl group that may have one or more R.sub.6; or a monocyclic or bicyclic unsaturated heterocycloalkyl group that has at least one heteroatom selected from the group consisting of N, S, and O, and that may have one or more R.sub.6;
R.sub.6 is fluorine,
chlorine,
a hydroxy group,
a cyano group,
a C1-C6 alkyl group that may be substituted with one or more phenoxy groups,
a carbamoyl group,
a C1-C6 alkoxycarbonyl group,
a pyridinyl group that may have at least one substituent selected from the group consisting of halogen, hydroxy group, and C1-C4 alkyl group,
a saturated heterocycloalkyl group selected from the group consisting of azetidinyl, hydroxyazetidinyl, thiomorpholinyl, dioxidothiomorpholinyl, methylpiperazinyl, hydroxypiperidinyl, oxopiperidinyl, piperidinyl, hydroxypyrrolidinyl, oxopyrrolidinyl, pyrrolidinyl, carboxylpyrrolidinyl, fluoropyrrolidinyl and morpholinyl,
an amino group,
a methylamino group,
an ethylamino group,
an isopropylamino group,
a hydroxyethylamino group,
a dimethylamino group,
a phenylmethylamino group,
a 9-oxa-3-azabicyclo[3.3.1]nonan-3-yl group,
a 3-oxa-8-azabicyclo[3.2.1]octan-8-yl group,
a C1-C6 alkoxy group that may be substituted with one or more of halogen, C3-C7 saturated cycloalkyl group, or monocyclic or bicyclic unsaturated heterocycloalkyl group having at least one heteroatom selected from the group consisting of N, S, and O, a benzyloxy group that may be substituted with one or more carbamoyl groups,
a C1-C4 alkylthio group,
a C1-C4 alkylsulfonyl group, or
an aminosulfonyl group
(when a plurality of R.sub.6 are present, the plurality of R.sub.6 may be the same or different).

[0150] Further preferable examples of the compound include a compound wherein in Formula (A),

R.sub.1 is a hydroxy group;
R.sub.2 is a hydroxy group;
R.sub.3 is an ethynylene group;
R.sub.4 is a bond;
R.sub.5 is a C6-C10 unsaturated cycloalkyl group that may have one or more R.sub.6, or
a monocyclic or bicyclic unsaturated heterocycloalkyl group that has at least one heteroatom selected from the group consisting of N, S, and O, and that may have one or more R.sub.6; and

R.SUB.6 .is

[0151] fluorine,
chlorine,
a hydroxy group,
a cyano group,
a methyl group,
a 3-fluoropyrrolidinyl group,
a morpholinyl group,
a thiomorpholinyl group,
a 3-hydroxyazetidinyl group,
an azetidinyl group,
an amino group,
a methylamino group,
a C1-C6 alkoxy group that may be substituted with one or more of either halogen or C3-C7 saturated cycloalkyl group, or
a C1-C4 alkylthio group
(when a plurality of R.sub.6 are present, the plurality of R.sub.6 may be the same or different).

[0152] Further preferable examples of the compound include a compound wherein, in Formula (A), Y is NH;

R.sub.1 is a hydroxy group;
R.sub.2 is a hydroxy group;
R.sub.3 is an ethynylene group;
R.sub.4 is a bond;
R.sub.5 is a phenyl group or a naphthyl group that may have one or more R.sub.6, or
a monocyclic or bicyclic unsaturated heterocycloalkyl group that has at least one heteroatom selected from the group consisting of N, S, and O, and that may have one or more R.sub.6; and R.sub.6 is
fluorine,
a methyl group,
3-fluoropyrrolidinyl,
3-hydroxyazetidinyl,
azetidinyl,
an amino group,
a methylamino group,
a C1-C6 alkoxy group that may have one or more cyclopropyl groups, or
a C1-C4 alkylthio group
(when a plurality of R.sub.6 are present, the plurality of R.sub.6 may be the same or different).

[0153] Specifically, preferable examples of the compound include: 4-amino-5-[2-(2,6-difluorophenyl)ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine; 4-amino-5-[2-(4-amino-2,6-difluoro-phenyl)ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine; 4-amino-5-[2-[2,6-difluoro-4-(methylamino)phenyl]ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine; 4-amino-5-[2-[2,6-difluoro-4-[(3R)-3-fluoropyrrolidin-1-yl]phenyl]ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine; 4-[4-[2-[4-amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]-3-ethoxy-5-fluoro-phenyl]morpholine; 4-amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-ethoxy-4,6-difluoro-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine; 4-[4-[2-[4-amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]-3,5-difluoro-phenyl]thiomorpholine; 4-amino-5-[2-[2,6-difluoro-4-(3-hydroxyazetidin-1-yl)phenyl]ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine; 4-amino-5-[2-[4-(azetidin-1-yl)-2,6-difluoro-phenyl]ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine; 4-amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-fluoro-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine; 4-amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-propoxy-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine; 4-amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-[2-(2,2,2-trifluoroethoxy)phenyl]ethynyl]pyrrolo[2,3-d]pyrimidine; 8-[2-[4-amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]-7-fluoro-4-methyl-2,3-dihydro-1, benzoxazine; 4-amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-ethylsulfanyl-6-fluoro-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine; 4-amino-5-[2-[2-(cyclopropylmethoxy)-6-fluoro-phenyl]ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine; 4-amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]-5-[2-(2-ethoxy-6-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine; 4-amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]-5-[2-(2-fluoro-6-methylsulfanyl-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine; 8-[2-[4-amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]-7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine; 4-amino-7-[(1R,4R,5S)-4,5-dihydroxy-3-[(sulfamoylamino)methyl]cyclopent-2-en-1-yl]-5-[2-(2-ethoxy-6-fluoro-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine; 4-amino-7-[(1R,4R,5S)-4,5-dihydroxy-3-[(sulfamoylamino)methyl]cyclopent-2-en-1-yl]-5-[2-(2-fluoro-6-methylsulfanyl-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine; [(2R,3S,4R,5R)-5-[4-amino-5-[2-(2,6-difluorophenyl)ethynyl]pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2-yl]methylsulfamate; and salts of these compounds,

further preferably, 4-amino-5-[2-(2,6-difluorophenyl)ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine; 4-amino-5-[2-(4-amino-2,6-difluoro-phenyl)ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine; 4-amino-5-[2-[2,6-difluoro-4-(methylamino)phenyl]ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine; 4-amino-5-[2-[2,6-difluoro-4-[(3R)-3-fluoropyrrolidin-1-yl]phenyl]ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine; 4-amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-ethoxy-4,6-difluoro-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine; 4-amino-5-[2-[2,6-difluoro-4-(3-hydroxyazetidin-1-yl)phenyl]ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine; 4-amino-5-[2-[4-(azetidin-1-yl)-2,6-difluoro-phenyl]ethynyl]-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]pyrrolo[2,3-d]pyrimidine; 4-amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-ethoxy-6-fluoro-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine; 4-amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-fluoro-6-propoxy-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine; 8-[2-[4-amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]-7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine; 4-amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-ethylsulfanyl-6-fluoro-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine; 4-amino-5-[2-[2-(cyclopropylmethoxy)-6-fluoro-phenyl]ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine; 4-amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]-5-[2-(2-fluoro-6-methylsulfanyl-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine; 8-[2-[4-amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]-7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine; 4-amino-7-[(1R,4R,5S)-4,5-dihydroxy-3-[(sulfamoylamino)methyl]cyclopent-2-en-1-yl]-5-[2-(2-ethoxy-6-fluoro-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine; 4-amino-7-[(1R,4R,5S)-4,5-dihydroxy-3-[(sulfamoylamino)methyl]cyclopent-2-en-1-yl]-5-[2-(2-fluoro-6-methylsulfanyl-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine; and salts of these compounds.

[0154] The method for producing the compound of the present invention is described below.

[0155] The compounds of the present invention may be produced, for example, through the production methods below, or the methods described in the Reference Examples. However, the method for producing the compounds of the present invention is not limited to these reaction examples.

Production Method A

[0156] ##STR00007##

[0157] In the formula, Z.sup.1 and Z.sup.2 are the same or different, and each represents hydrogen, fluorine, a hydroxy group, an amino group, a cyano group, or a protector thereof.

P.sub.1 is a protecting group of an amino group.
R.sub.3 represents a vinylene group, an ethynylene group, a C6-C14 arylene group, or a monocyclic or bicyclic heteroarylene group having at least one heteroatom selected from the group consisting of N, S, and O.
R.sub.4 represents a single bond, a methylene group, or a C3-C7 cycloalkylidene.
R.sub.5 is a C3-C7 saturated cycloalkyl group that may be substituted with one or more R.sub.6;
a C6-C10 unsaturated cycloalkyl group that may be substituted with one or more R.sub.6; or
a monocyclic or bicyclic unsaturated heterocycloalkyl group that has at least one heteroatom selected from the group consisting of N, S, and O, and that may be substituted with one or more R.sub.6.

R.SUB.6 .is

[0158] halogen;
a hydroxy group;
a cyano group;
a C1-C6 alkyl group that may be substituted with one or more phenoxy groups;
a carbamoyl group, a C1-C6 alkoxycarbonyl group;
a C4-C7 unsaturated cycloalkyl group that may be substituted with one or more of halogen, hydroxy group, C1-C4 alkyl group, or carbamoyl group;
a monocyclic or bicyclic unsaturated heterocycloalkyl group having at least one heteroatom selected from the group consisting of N, S, and O;
a monocyclic or bicyclic saturated heterocycloalkyl group that has at least one heteroatom selected from the group consisting of N, S, and O, and that may be substituted with one or more of halogen, hydroxy group, oxo group, carboxyl group, dioxide group, or C1-C6 alkyl group;
an amino group;
a mono- or di-(C1-C4 alkyl) amino group that may be substituted with one or more hydroxy groups or phenyl groups;
a C1-C6 alkoxy group that may be substituted with one or more of halogen, C3-C7 saturated cycloalkyl group, or monocyclic or bicyclic unsaturated heterocycloalkyl group having at least one heteroatom selected from the group consisting of N, S, and O;
a benzyloxy group that may be substituted with one or more carbamoyl groups;
a C1-C4 alkylthio group;
a C1-C4 alkylsulfonyl group; or
an aminosulfonyl group.

[0159] When a plurality of R.sub.6 are present, the plurality of R.sub.6 may be the same or different.

##STR00008##

[0160] represents O, CH.sub.2 or CH.

Step 1

[0161] This step produces Compound (2) using a compound represented by Formula (1) (in this specification, the compound represented by Formula (1) may be simply referred to as Compound (1); similarly, compounds represented by Formulas (2) to (30) may be simply referred to as Compounds (2) to (30) as a raw material, through a Mitsunobu reaction using a nitrogen nucleophile, and a subsequent deprotection reaction.

[0162] In Compound (1), when Z.sup.1 and/or Z.sup.2 represents a protector of a hydroxy group, examples of the protector include dimethyl acetal group, benzylidene acetal group, benzoyl group, and tert-butyldimethylsilyloxy group. Z.sup.1 and Z.sup.2 may form the structure below, or the like,

##STR00009##

[0163] (wherein Ra are the same or different, and each represents hydrogen, methyl, ethyl, phenyl, cyclohexyl or cyclopentyl)

together with the carbon atoms bound thereto. Examples of nitrogen nucleophiles include phthalimide. When phthalimide is used as a nitrogen nucleophile, the amount of phthalimide used is generally 1 to 10 moles, preferably 1 to 5 moles, per mole of Compound (1).

[0164] The Mitsunobu reaction can generally be performed by a known method, such as, for example, the method described in Synthesis, p. 1 (1981); or a similar method.

[0165] Examples of azodicarboxylic acid esters used for the Mitsunobu reaction include diethyl azodicarboxylate and diisopropyl azodicarboxylate. Such an azodicarboxylic acid ester can be generally used in an amount of 1 to 10 moles, and preferably 1 to 5 moles, per mole of Compound (1).

[0166] Examples of phosphine compounds used in the Mitsunobu reaction include triphenylphosphine and tributylphosphine, and the amount of phosphine compound used is generally 1 to 10 moles, preferably 1 to 5 moles, per mole of Compound (1).

[0167] Examples of the solvent include tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methylpyrrolidin-2-one. These solvents may be used alone, or in a mixture. The reaction time generally ranges from 0.1 to 100 hours, preferably 0.1 to 24 hours. The reaction temperature generally ranges from 0 C. to the boiling temperature of the solvent, preferably 0 C. to 100 C. The removal of the protecting group of a nitrogen nucleophile can generally be performed by a known method, such as the method described in Protective Groups in Organic Synthesis, T. W. Greene, John Wiley & Sons (1981); or a similar method.

[0168] The removal of the phthalimide group can be performed by using an isolated phthalimide intermediate or by directly using the Mitsunobu reaction solution, with hydrazine, hydroxylamine, methylamine, ethylamine, n-butylamine, etc., as a deprotection reagent. The amount of the deprotection reagent is typically an equimolar to excessive molar amount per mole of Compound (1).

[0169] Examples of the solvent include alcohol solvents (ethanol, methanol, etc.), acetonitrile, dichloromethane, chloroform, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidin-2-one. These solvents may be used alone, or in a mixture. The reaction time generally ranges from 0.1 to 100 hours, preferably 0.1 to 24 hours. The reaction temperature generally ranges from 0 C. to the boiling temperature of the solvent, preferably 0 C. to 100 C.

Step 2

[0170] This step produces Compound (3) by reacting a sulfamoyl-introducing reagent with Compound (2).

[0171] The sulfamoyl-introducing reagent can be obtained from commercial suppliers, or can be produced through a known method using, for example, sulfamoyl chloride, 1-aza-4-azoniabicyclo [2.2.2]octane-4-ylsulphonyl(tert-butoxycarbonyl)azanide or the like. The amount of the sulfamoyl-introducing reagent used is generally 1 to 10 moles, preferably 1 to 5 moles, per mole of Compound (2).

[0172] Examples of the protecting group of an amino group include C1-C6 alkyl group, tert-butoxycarbonyl group, benzyloxycarbonyl group, acetyl group, and propionyl group.

[0173] Examples of bases include triethylamine, diisopropylethylamine, pyridine, imidazole, and DBU. When a base is used, the amount of the base is generally 1 to 30 moles, preferably 1 to 10 moles, per mole of Compound (2).

[0174] Examples of the solvent include acetonitrile, dichloromethane, chloroform, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, toluene, N,N-dimethyl formamide, N,N-dimethylacetamide, and N-methylpyrrolidin-2-one. These solvents may be used alone, or in a mixture. The reaction time generally ranges from 0.1 to 100 hours, preferably 0.1 to 24 hours. The reaction temperature generally ranges from 0 C. to the boiling temperature of the solvent, and preferably from 0 C. to 100 C.

Step 3

[0175] Using Compound (3) as a raw material, this step produces Compound (4) through a coupling reaction (Sonogashira coupling, Suzuki-Miyaura coupling, etc.). This step may be performed through multiple steps as necessary, and may suitably be combined with a protection reaction, a deprotection reaction.

[0176] For example, among various Compounds (4), a compound in which R.sub.3 has an alkynylene group may be obtained through a coupling (Sonogashira) reaction, using Compound (3) and a compound: HCCR.sub.4R.sub.5 (wherein R.sub.4 and R.sub.5 are as defined above)

[0177] In this case, the compound: HCCR.sub.4R.sub.5 (wherein R.sub.4 and R.sub.5 are as defined above) can be obtained from commercial suppliers, or can be produced through a known method. The amount of this compound is generally 1 to 10 moles, preferably 1 to 3 moles, per mole of Compound (3).

[0178] This step can generally be performed by a known method, for example, the method disclosed in Chemical Reviews, Vol. 107, p. 874 (2007). For example, this step can be performed in the presence of a transition metal catalyst and a base in a solvent that does not adversely affect the reaction.

[0179] Examples of transition metal catalysts usable in this step include palladium catalysts (e.g., palladium acetate, tris(dibenzylideneacetone)dipalladium, 1,1-bis(diphenylphosphino) ferrocene-palladium(II) dichloride-dichloromethane complex, etc.). As necessary, a ligand (e.g., triphenylphosphine, tri-tert-butylphosphine, etc.) is added, and a copper reagent (e.g., copper iodide, copper acetate, etc.) is used as a cocatalyst. The amount of the transition metal catalyst varies depending on the type of catalyst. For example, the amount of the transition metal catalyst used is generally 0.0001 to 1 mole, preferably 0.01 to 0.5 moles, per mole of Compound (4). The amount of the ligand used is generally 0.0001 to 4 moles, preferably 0.01 to 2 moles, per mole of Compound (4). The amount of the cocatalyst used is generally 0.0001 to 4 moles, preferably 0.001 to 2 moles, per mole of Compound (4).

[0180] Further, a base may be added during the above reaction as necessary. Examples of bases include organic bases such as triethylamine, diisopropylethylamine, pyridine, lutidine, collidine, 4-dimethylaminopyridine, potassium tert-butyrate, sodium tert-butyrate, sodium methoxide, sodium ethoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, and butyl lithium; and inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, and sodium hydride. Among these, organic bases such as triethylamine and diisopropylethylamine are preferable. The amount of the base used is generally 0.1 to 50 moles, and preferably 1 to 20 moles, per mole of Compound (4).

[0181] The reaction solvent is not particularly limited, and any solvent that does not adversely affect the reaction can be used. Examples of the solvent include hydrocarbons (e.g., benzene, toluene, xylene, etc.), nitriles (e.g., acetonitrile etc.), ethers (e.g., dimethoxyethane, tetrahydrofuran, 1,4-dioxane, etc.), alcohols (e.g., methanol, ethanol, etc.), aprotic polar solvents (e.g., dimethylformamide, dimethylsulfoxide, hexamethyl phosphoramide, etc.), water, and mixtures thereof. The reaction time generally ranges from 0.1 to 100 hours, preferably 0.5 to 24 hours. The reaction temperature generally ranges from 0 C. to the boiling temperature of the solvent, preferably 0 to 150 C.

[0182] Further, this step may also be performed through Suzuki-Miyaura coupling using Compound (3) and an organic boron compound (boric-acid compound, boric-acid ester, etc.) having a substituent R.sub.3R.sub.4R.sub.5 (wherein R.sub.3, R.sub.4, and R.sub.5 are as defined above)

[0183] In this method, the organic boron compound can be obtained from commercial suppliers, or can be produced through a known method. The amount of the organic boron compound used is generally 1 to 10 moles, preferably 1 to 3 moles, per mole of Compound (3).

[0184] In this method, the Suzuki-Miyaura coupling can generally be performed by a known method, such as the method described in Chemical Reviews, Vol. 95, p. 2457 (1995); or a similar method.

[0185] Examples of reaction catalysts used for the Suzuki-Miyaura coupling include tetrakis triphenylphosphine palladium (0), bis (triphenylphosphine)palladium(II) dichloride, and 1,1-bis (diphenyl phosphino)ferrocene-palladium(II) dichloride-dichloromethane complex. The amount of the reaction catalyst used depends on the type of the catalyst. The amount of the catalyst used is generally 0.0001 to 1 mole, preferably 0.01 to 0.5 moles, per mole of Compound (3).

[0186] Examples of the solvent include hydrocarbons (e.g., benzene, toluene, xylene, etc.), nitriles (e.g., acetonitrile etc.), ethers (e.g., dimethoxyethane, tetrahydrofuran, 1,4-dioxane, etc.), alcohols (e.g., methanol, ethanol, etc.), aprotic polar solvents (e.g., dimethylformamide, dimethylsulfoxide, etc.), and water. These solvents may be used alone, or in a mixture. The reaction time generally ranges from 0.1 to 100 hours, preferably 0.1 to 24 hours. The reaction temperature generally ranges from 0 C. to the boiling temperature of the solvent, preferably 0 C. to 100 C.

Step 4

[0187] This step produces Compound (5) by deprotecting the protected amino group of Compound (4). The deprotection can generally be performed by a known method, such as the method described in Protective Groups in Organic Synthesis, T. W. Greene, John Wiley & Sons (1981); or a similar method. An example of the protecting group is tert-butyloxycarbonyl. When a tert-butyloxycarbonyl group is used as a protecting group, the deprotection is preferably performed under acidic conditions. Examples of acids that can be used include hydrochloric acid, acetic acid, trifluoroacetic acid, sulfuric acid, methanesulfonic acid, tosic acid, and the like. The amount of the acid used is preferably 1 to 100 moles per mole of Compound (4).

[0188] Any solvent that does not adversely affect the reaction may be used for the reaction. Examples of the solvent include alcohols (e.g., methanol etc.), hydrocarbons (e.g., benzene, toluene, xylene, etc.), halogenated hydrocarbons (e.g., methylene chloride, chloroform, 1,2-dichloroethane, etc.), nitriles (e.g., acetonitrile etc.), ethers (e.g., dimethoxyethane, tetrahydrofuran, etc.), aprotic polar solvents (e.g., N,N-dimethylformamide, dimethylsulfoxide, hexamethyl phosphoramide, etc.), and mixtures thereof. The reaction time generally ranges from 0.1 to 100 hours, preferably 0.5 to 24 hours. The reaction temperature generally ranges from 0 to 120 C., preferably 0 to 90 C.

[0189] Compound (1) used as a raw material in Production Method A can be obtained from commercial suppliers, or can be produced through a known method. For example, Compound (7) in which Z.sup.1 and Z.sup.2 in Formula (1) represent a specific protector of a hydroxy group may be produced through Production Method B below.

Production Method B

[0190] ##STR00010##

[0191] wherein Ra are the same or different, and each represents hydrogen, methyl, ethyl, phenyl, cyclohexyl, or cyclopentyl.

Step 5

[0192] This step produces Compound (7) by protecting two hydroxy groups among the hydroxy groups of Compound (6). Examples of the protection reagent include dialkoxy alkane and the like. The amount of the protection reagent used is generally 1 to 100 moles, preferably 1 to 10 moles, per mole of Compound (6).

[0193] The protection can generally be performed by a known method, such as the method described in Protective Groups in Organic Synthesis, T. W. Greene, John Wiley & Sons (1981); or a similar method.

[0194] Examples of the reaction catalyst include p-toluenesulfonic acid, methanesulfonic acid, pyridinium p-toluenesulfonates, perchloric acid, and sulfuric acid. When a reaction catalyst is used, the amount of the reaction catalyst depends on the type of the catalyst. For example, the amount of the reaction catalyst is generally 0.0001 to 1 mole, preferably 0.01 to 0.5 moles, per mole of Compound (6).

[0195] Examples of the solvent include acetonitrile, dichloromethane, chloroform, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidin-2-one. These solvents may be used alone, or in a mixture. The reaction time generally ranges from 0.1 to 100 hours, preferably 0.1 to 24 hours. The reaction temperature generally ranges from 0 C. to the boiling temperature of the solvent, preferably 0 C. to 100 C.

[0196] Further, Compound (15) in which Z.sup.1 and Z.sup.2 in Formula (1) represent a specific protector of a hydroxy group may be produced through Production Method C below.

Production Method C

[0197] ##STR00011## ##STR00012##

[0198] wherein P.sub.2 is a protecting group of a hydroxy group. Ra is as defined above.

Step 6

[0199] This step produces Compound (9) by protecting two hydroxy groups among the hydroxy groups of Compound (8). The protection reaction may be performed in the same manner as in Step 5.

Step 7

[0200] This step produces an isomer mixture of Compound (10), which is a pyrrolopyrimidine compound, by reacting an isomer mixture of Compound (9) and 2-(4,6-dichloro pyrimidin-5-yl)acetaldehyde in the presence of a base.

[0201] The amount of the 2-(4,6-dichloro pyrimidin-5-yl)acetaldehyde is generally 1 to 10 moles, preferably 1 to 3 moles, per mole of Compound (9).

[0202] The reaction can generally be performed by a known method, for example, the method disclosed in Tetrahedron Letters, 26 (16), 2001-2 (1985); or a similar method.

[0203] Examples of bases include triethylamine, diisopropylethylamine, pyridine, lutidine, collidine, and DBU. When a base is used, the amount of the base is generally 1 to 100 moles, preferably 1 to 20 moles, per mole of Compound (9).

[0204] Examples of the solvent include ethanol, 2-propanol, 2-butanol, acetonitrile, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidin-2-one. These solvents may be used alone, or in a mixture. The reaction time generally ranges from 0.1 to 100 hours, preferably 0.1 to 24 hours. The reaction temperature generally ranges from 0 C. to the boiling temperature of the solvent, preferably 0 C. to 100 C.

Step 8

[0205] This step converts the isomer mixture of Compound (10) into Compound (11) consisting of only one of the isomers, in the presence of an acid catalyst.

[0206] Examples of acids include p-toluenesulfonic acid, methanesulfonic acid, pyridinium p-toluene sulfonate, perchloric acid, and sulfuric acid. The amount of the acid is generally 0.001 to 10 moles, preferably 0.01 to 2 moles, per mole of Compound (10)

[0207] Examples of the solvent include acetone, 2-butanone, acetonitrile, dichloromethane, chloroform, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidin-2-one. These solvents may be used alone, or in a mixture. The reaction time generally ranges from 0.1 to 100 hours, preferably 1 to 48 hours. The reaction temperature generally ranges from 0 C. to the boiling temperature of the solvent, preferably 0 C. to 100 C.

Step 9

[0208] This step protects the hydroxy group of Compound (11) using Compound P.sub.2Cl (wherein P.sub.2 is a protecting group of a hydroxy group).

[0209] The reaction can generally be performed by a known method, such as the method described in Protective Groups in Organic Synthesis, T. W. Greene, John Wiley & Sons (1981); or a similar method.

[0210] The protecting group of a hydroxy group represented by P.sub.2 in Compound P.sub.2Cl is not particularly limited insofar as it has a protecting function. Examples include lower alkyl groups such as methyl, ethyl, propyl, isopropyl, and tert-butyl; lower alkylsilyl groups such as trimethylsilyl and tert-butyldimethylsilyl; lower alkoxymethyl groups such as methoxymethyl and 2-methoxyethoxymethyl; tetrahydropyranyl; trimethylsilylethoxymethyl; aralkyl groups such as benzyl, p-methoxybenzyl, 2,3-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, and trityl; and acyl groups such as formyl, acetyl, and trifluoroacetyl. In particular, methyl, methoxymethyl, tetrahydropyranyl, trimethylsilylethoxymethyl, tert-butyldimethylsilyl, and acetyl are preferable.

[0211] The compound can be obtained from commercial suppliers, or can be produced through a known method. The amount of the compound is generally 1 to 20 moles, preferably 1 to 5 moles, per mole of Compound (11).

[0212] Examples of the base include triethylamine, diisopropylethylamine, pyridine, lutidine, collidine, and DBU. The amount of the base is generally 1 to 20 moles, preferably 1 to 5 moles, per mole of Compound (11).

[0213] Examples of the solvent include acetonitrile, dichloromethane, chloroform, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidin-2-one. These solvents may be used alone, or in a mixture. The reaction time generally ranges from 0.1 to 100 hours, preferably 0.1 to 24 hours. The reaction temperature generally ranges from 0 C. to the boiling temperature of the solvent, preferably 0 C. to 100 C.

Step 10

[0214] This step produces Compound (13) by reacting Compound (12) with iodosuccinimide, thereby introducing an iodine atom.

[0215] The iodination may be performed according to the method disclosed in WO2006/102079, or a similar method. The amount of the iodosuccinimide is generally 1 to 20 moles, preferably 1 to 5 moles, per mole of Compound (12).

[0216] Examples of the solvent include acetone, acetonitrile, ethyl acetate, dichloromethane, chloroform, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidin-2-one. These solvents may be used alone, or in a mixture. The reaction time generally ranges from 0.1 to 100 hours, preferably 0.1 to 24 hours. The reaction temperature generally ranges from 0 C. to the boiling temperature of the solvent, preferably 0 C. to 100 C.

Step 11

[0217] This step produces Compound (14) by deprotecting the protected hydroxy group of Compound (13).

[0218] The deprotection can generally be performed by a known method, such as the method described in Protective Groups in Organic Synthesis, T. W. Greene, John Wiley & Sons (1981); or a similar method.

[0219] When a tert-butyldimethylsilyl group is used as a protecting group, tetrabutylammonium fluoride, for example, is used as a deprotection reagent. The amount of the reagent is preferably 1 to 10 moles, per mole of Compound (13).

[0220] Any solvent that does not adversely affect the reaction may be used for the reaction. Examples of the solvent include ethers (e.g., 1,2-dimethoxyethane, tetrahydrofuran, etc.), aprotic polar solvents (e.g., N,N-dimethylformamide, dimethylsulfoxide, hexamethyl phosphoryl amide, etc.), and mixtures thereof. The reaction time generally ranges from 0.1 to 100 hours, preferably 0.5 to 24 hours. The reaction temperature generally ranges from 0 to 80 C., preferably 0 to 50 C.

Step 12

[0221] This step produces Compound (15) by reacting Compound (14) with ammonia.

[0222] The amount of the ammonia used in this step is typically an equimolar to excessive molar amount per mole of Compound (14)

[0223] The reaction solvent is not particularly limited, and any solvent that does not adversely affect the reaction can be used. Examples of the solvent include water, methanol, ethanol, isopropanol, tert-butyl alcohol, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, N,N-dimethylformamide, N-methylpyrrolidin-2-one, dimethylsulfoxide, and mixtures thereof.

[0224] The reaction temperature is generally 0 C. to 200 C., preferably from room temperature to 150 C. The reaction time is generally 5 minutes to 7 days, preferably 30 minutes to 72 hours.

Production Method D

[0225] Further, Compound (19), which is a compound in which Z.sup.1 in Formula (1) is a hydroxy group, Z.sup.2 is hydrogen, and X is CH.sub.2, may be produced through Production Method D below.

##STR00013##

Step 13

[0226] This step reacts Compound (16) with 2-(4,6-dichloro pyrimidin-5-yl)acetaldehyde. This reaction may be performed in the same manner as in Step 7.

Step 14

[0227] This step reacts the reaction product obtained in Step 13 with iodosuccinimide, thereby introducing an iodine atom. This reaction may be performed in the same manner as in Step 10.

Step 15

[0228] This step produces Compound (19) by reacting the reaction product obtained in Step 14 with ammonia. This reaction may be performed in the same manner as in Step 12.

[0229] Further, Compound (20), which is a compound in which Z.sup.1 in Formula (1) is a hydroxy group, Z.sup.2 is hydrogen, and X is O, is a publicly known compound.

##STR00014##

Production Method E

[0230] Further, among Compounds (A), Compound (27) in which R.sub.1 and R.sub.2 are hydroxy groups, and

##STR00015##

is CH may be produced through Production Method E below.

##STR00016## ##STR00017##

[0231] wherein R.sub.3, R.sub.4, and R.sub.5 are as defined above.

Step 16

[0232] This step produces Compound (22) by reducing the carboxyl group of Compound (21). This step is performed in the presence of a reducing agent. In this step, the amount of the reducing agent is 1 to 20 moles, preferably 1 to 5 moles, per mole of Compound (21). Examples of the reducing agent include sodium borohydride, lithium aluminum hydride, borane reagent (e.g., diborane), and diisobutylaluminum hydride.

[0233] Examples of the solvent include methanol, ethanol, diethylether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, and toluene. These solvents may be used alone, or in a mixture. The reaction time generally ranges from 0.1 to 100 hours, preferably 0.1 to 24 hours. The reaction temperature generally ranges from 0 C. to the boiling temperature of the solvent, preferably 0 C. to 100 C.

Step 17

[0234] This step produces Compound (23) through a Mitsunobu reaction using Compound (22) as a raw material, and 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine as a nucleophilic agent.

[0235] This reaction may be performed in the same manner as in Step 1.

Step 18

[0236] This step produces Compound (24) by reacting Compound (23) with ammonia. This reaction may be performed in the same manner as in Step 12.

Step 19

[0237] This step produces Compound (25) by deprotecting the protected hydroxy group of Compound (24). This reaction may be performed in the same manner as in Step 11.

Step 20

[0238] This step produces Compound (26) through a Mitsunobu reaction using Compound (25) as a raw material, and tert-butyl sulfamoyl carbamate as a nucleophilic agent.

[0239] This reaction may be performed in the same manner as in Step 1.

Step 21

[0240] This step produces Compound (27) using Compound (26) as a raw material, by deprotecting the protected amino group after a coupling reaction (Sonogashira coupling, Suzuki-Miyaura coupling, etc.). This reaction may be performed in the same manner as in Step 3 and Step 4.

Production Method F

[0241] Further, among Compounds (A), Compound (29) in which R.sub.1 and R.sub.2 are the same or different, and each represent hydrogen, fluorine, a hydroxy group, an amino group, a cyano group, or a protector thereof may be produced through Production Method F below.

##STR00018##

[0242] wherein X, R.sub.3, R.sub.4, R.sub.5, Z.sup.1, and Z.sup.2 are as defined above.

Step 22

[0243] This step produces Compound (28) through a coupling reaction (Sonogashira coupling, Suzuki-Miyaura coupling, etc.) using Compound (1) as a raw material. This reaction may be performed in the same manner as in Step 3.

Step 23

[0244] This step produces Compound (29) by reacting Compound (28) with a sulfamoyl-introducing reagent.

[0245] This reaction may be performed in the same manner as in Step 2. This step may be performed through multiple steps as necessary, and may suitably be combined with a deprotection reaction.

Production Method G

[0246] Further, among Compounds (A), Compound (32) may be produced through Production Method G below.

##STR00019##

[0247] wherein P.sub.1, Z.sup.1, and Z.sup.2 are as defined above. Rb is the same as R.sub.6 above. Rc represents a substituted or unsubstituted alkyl group.

Step 24

[0248] This step produces Compound (31) by oxidizing Compound (30). This step is performed in the presence of an oxidant. The amount of the oxidant used in this step is generally 1 to 20 moles, preferably 1 to 5 moles, per mole of Compound (30). Examples of the oxidant include oxone, m-chloroperbenzoic acid, hydrogen peroxide, and potassium permanganate.

[0249] Examples of the solvent include water, acetone, 2-butanone, acetonitrile, ethyl acetate, dichloromethane, chloroform, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidin-2-one. These solvents may be used alone, or in a mixture. The reaction time generally ranges from 0.1 to 100 hours, preferably 0.1 to 24 hours. The reaction temperature generally ranges from 0 C. to the boiling temperature of the solvent, preferably 0 C. to 100 C.

Step 25

[0250] This step produces Compound (32) by deprotecting the protected amino group of Compound (31). This reaction may be performed in the same manner as in Step 4.

[0251] The compounds thus-obtained through Production Methods A to G can be subjected to the subsequent step after or without isolation and purification by known separation and purification means, such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation, and chromatography.

[0252] When the compound represented by Formula (A) or other compounds having an antitumor effect have isomers such as optical isomers, stereoisomers, regioisomers, and rotational isomers, any of the isomers and mixtures thereof is included within the scope of the compounds of the present invention. For example, when the compounds of the present invention have optical isomers, the optical isomer separated from a racemic mixture is also included within the scope of the compounds of the present invention. Each of such isomers can be obtained as a single compound by known synthesis and separation means (e.g., concentration, solvent extraction, column chromatography, recrystallization, etc.).

[0253] The compound represented by Formula (A) or other compounds having an antitumor effect can be easily isolated and purified by usual isolation and purification means. Examples of such means include solvent extraction, recrystallization, preparative reversed-phase high-performance liquid chromatography, column chromatography, preparative thin-layer chromatography, and the like.

[0254] The compound represented by Formula (A) or other compounds having an antitumor effect may be in the form of crystals. Single crystals and polymorphic mixtures are included within the scope of the compounds of the present invention. Such crystals can be produced by crystallization according to a crystallization method known per se in the art. The compounds of the present invention may be solvates (e.g., hydrates) or non-solvates. Any of such forms are included within the scope of the compounds of the present invention. Compounds labeled with an isotope (e.g., .sup.3H, .sup.14C, .sup.35S, .sup.125I) are also included within the scope of the compounds of the present invention.

[0255] A prodrug of the compound represented by Formula (A) or prodrugs of other compounds having an antitumor effect refer to a compound that can be converted to the compound through a reaction with an enzyme, gastric acid, or the like, under physiological conditions in vivo, i.e., a compound that can be converted to the compound by enzymatic oxidation, reduction, hydrolysis, or the like; or a compound that can be converted to the compound by hydrolysis with gastric acid or the like. Further, the prodrugs of the compounds may be compounds that can be converted to the compounds under physiological conditions, such as those described in Iyakuhin no Kaihatsu [Development of Pharmaceuticals], Vol. 7, Molecular Design, published in 1990 by Hirokawa Shoten Co., pp. 163-198.

[0256] The salt of the compound represented by Formula (A) or the salts of other compounds having an antitumor effect refer to a common salt used in the field of organic chemistry. Examples of such salts include base addition salts to a carboxyl group when the compound has a carboxyl group, and acid addition salts to an amino or basic heterocycloalkyl group when the compound has an amino or basic heterocycloalkyl group. The salt of the compound represented by Formula (A) or the salts of other compounds having an antitumor effect include pharmaceutically acceptable salts of the compound.

[0257] Examples of base addition salts include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; ammonium salts; and organic amine salts such as trimethylamine salts, triethylamine salts, dicyclohexylamine salts, ethanolamine salts, diethanolamine salts, triethanolamine salts, procaine salts, and N,N-dibenzylethylenediamine salts.

[0258] Examples of acid addition salts include inorganic acid salts such as hydrochlorides, sulfates, nitrates, phosphates, and perchlorates; organic acid salts such as acetates, formates, maleates, fumarates, tartrates, citrates, ascorbates, and trifluoroacetates; and sulfonates such as methanesulfonates, isethionates, benzenesulfonates, and p-toluenesulfonates. The acid addition salts are preferably hydrochlorides.

[0259] The compound represented by Formula (A) is useful as an antitumor effect potentiator of or one or more other compounds having an antitumor effect. The compound represented by Formula (A) or one or more other compounds having an antitumor effect are also useful as an antitumor agent comprising the compound represented by Formula (A) and the one or more other compounds having an antitumor effect in combination. The type of malignant tumor to be treated is not particularly limited. Further, the organ from which the tumor is developed is not particularly limited. Examples include head and neck cancers, esophagus cancer, gastric cancer, colon cancer, rectum cancer, liver cancer, gallbladder cancer, cholangiocarcinoma, biliary tract cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer, endometrial cancer, renal cancer, bladder cancer, prostate cancer, testicular tumor, osteosarcoma, soft-tissue sarcoma, multiple myeloma, skin cancer, brain tumor, and mesothelioma. Preferably, the target cancer is colon cancer, rectum cancer, pancreatic cancer, lung cancer, prostate cancer, breast cancer, osteosarcoma, soft-tissue sarcoma, or skin cancer.

[0260] Further, examples of hematopoietic tumors include bone marrow tumors (e.g., lymphocytic leukemia, myelogenous leukemia, acute leukemia, chronic leukemia, and the like), and lymphoid tumors.

[0261] Examples of bone marrow tumors include myeloproliferative neoplasm (MPN), acute myelogenous leukemia (AML), related precursor neoplasm, acute lymphocytic leukemia, chronic myelogenous leukemia (CML), and myelodysplastic syndrome (MDS). Preferable examples include acute leukemia. Particularly preferable examples include acute myelogenous leukemia.

[0262] Examples of lymphoid tumors include precursor lymphoid tumor, mature B-cell tumor, mature T-cell tumor and NK-cell tumor, and Hodgkin's lymphoma. Preferable examples include precursor lymphoid tumors, mature B-cell tumor, mature T-cell tumor and NK-cell tumor. Lymphoid tumors that are not regarded as Hodgkin's lymphoma may be collectively referred to as non-Hodgkin's lymphoma.

[0263] Examples of precursor lymphoid tumors include B-lymphoblastic leukemia/lymphoma, T-lymphoblastic leukemia/lymphoma (ALL), blastic NK-cell lymphoma, and like blastic lymphoma. T-lymphoblastic leukemia/lymphoma is preferable.

[0264] Examples of mature B-cell tumor include chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), B-cell prolymphocytic leukemia (B-PLL), splenic marginal zone lymphoma (SMZL), hairy cell leukemia (HCL), Waldenstrom's macroglobulinemia (WM), plasma cell tumor, MALT lymphoma, follicular lymphoma, mantle cell lymphoma (MCL), B-cell lymphoma (diffuse large B-cell lymphoma (DLBCL), and Burkitt's lymphoma). Plasma cell tumor and B-cell lymphoma are preferable.

[0265] Preferable examples of plasma cell tumor include multiple myeloma.

[0266] Examples of mature T-cell tumor and NK-cell tumor include T-cell prolymphocytic leukemia (T-PLL), aggressive NK-cell leukemia/lymphoma, adult T-cell leukemia/lymphoma, and peripheral T-cell lymphoma not otherwise specified (PTCL-NOS).

[0267] Examples of Hodgkin's lymphoma include nodular lymphocyte-predominant Hodgkin's lymphoma, classical Hodgkin's lymphoma, nodular sclerosis classical Hodgkin's lymphoma, and mixed cellularity classical Hodgkin's lymphoma.

[0268] FAB classification has been hitherto known for use in the diagnosis and classification of hematopoietic tumors. In recent years, WHO classification has also been used. The compound represented by Formula (A) or one or more other compounds having an antitumor effect are useful for the various hematopoietic tumors classified by both FAB classification and WHO classification.

[0269] When the compound represented by Formula (A) or one or more other compounds having an antitumor effect are used as a pharmaceutical preparation, a pharmaceutical carrier can be added, if required, thereby forming a suitable dosage form according to prevention and treatment purposes. Examples of dosage forms include oral preparations, injections, suppositories, ointments, patches, eye drops, and the like. Of these, injections (intravenous injections etc.) are preferable. Such dosage forms can be formed by methods conventionally known to persons skilled in the art. Further, the compound represented by Formula (A) or one or more other compounds having an antitumor effect may be formulated as a single composition, or two or more compositions.

[0270] As the pharmaceutical carrier, various conventional organic or inorganic carrier materials used as preparation materials may be blended as an excipient, binder, disintegrant, lubricant, or coating agent in solid preparations; or as a solvent, solubilizing agent, suspending agent, isotonizing agent, pH adjuster, pH buffer, or soothing agent in liquid preparations. Moreover, pharmaceutical preparation additives, such as antiseptics, antioxidants, colorants, sweetening agents, flavoring agents, and stabilizers, may also be used, if required.

[0271] When liquid preparations for oral administration are prepared, a sweetening agent, a buffer, a stabilizer, a flavoring agent, and the like, may be added to the compounds of the present invention; and the resulting mixtures may be formulated into oral liquid preparations, syrups, elixirs, etc., according to an ordinary method.

[0272] When suppositories are prepared, pharmaceutically acceptable carriers known in the art, such as polyethylene glycol, lanolin, cacao butter, and fatty acid triglyceride; and as necessary, surfactants such as Tween 80, may be added to the compounds of the present invention, and the resulting mixtures may be formulated into suppositories according to an ordinary method.

[0273] When ointments are prepared, a commonly used base, stabilizer, wetting agent, preservative, and the like, may be blended into the compounds of the present invention, as necessary; and the obtained mixtures may be mixed and formulated into ointments according to an ordinary method.

[0274] Examples of bases include liquid paraffin, white petrolatum, white beeswax, octyl dodecyl alcohol, paraffin, and the like.

[0275] Examples of excipients include lactose, sucrose, D-mannitol, starch, crystalline cellulose, calcium silicate, and the like.

[0276] Examples of binders include hydroxypropyl cellulose, methyl cellulose, polyvinylpyrrolidone, candy powder, hypromellose, and the like.

[0277] Examples of disintegrators include sodium starch glycolate, carmellose calcium, croscarmellose sodium, crospovidon, low-substituted hydroxy propyl cellulose, partially pregelatinized starch, and the like.

[0278] Examples of lubricants include talc, magnesium stearate, sucrose fatty acid ester, stearic acid, sodium stearyl fumarate, and the like.

[0279] Examples of coating agents include ethyl cellulose, aminoalkyl methacrylate copolymer RS, hypromellose, sucrose, and the like.

[0280] Examples of solvents include water, propylene glycol, physiological saline, and the like.

[0281] Examples of solubilizing agents include polyethylene glycol, ethanol, -cyclodextrin, macrogol 400, polysorbate 80, and the like.

[0282] Examples of suspending agents include carrageenan, crystalline cellulose/carmellose sodium, polyoxyethylene hydrogenated castor oil, and the like.

[0283] Examples of isotonizing agents include sodium chloride, glycerin, potassium chloride, and the like.

[0284] Examples of pH adjusters and pH buffers include sodium citrate, hydrochloric acid, lactic acid, phosphoric acid, sodium dihydrogen phosphate, and the like.

[0285] Examples of soothing agents include procaine hydrochloride, lidocaine, and the like.

[0286] Examples of antiseptics include ethyl parahydroxybenzoate, cresol, benzalkonium chloride, and the like.

[0287] Examples of antioxidants include sodium sulfite, ascorbic acid, natural vitamin E, and the like.

[0288] Examples of coloring agents include titanium oxide, iron sesquioxide, Food Blue No. 1, copper chlorophyll, and the like.

[0289] Examples of sweetening agents and flavoring agents include aspartame, saccharins, sucralose, 1-menthol, mint flavor, and the like.

[0290] Examples of stabilizers include sodium pyrosulfite, edetate sodium, erythorbic acid, magnesium oxide, dibutylhydroxytoluene, and the like.

[0291] Examples of preservatives include methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, and the like.

[0292] When a patch is prepared, the above-described ointment, cream, gel, paste, or the like, may be applied to an ordinary substrate according to an ordinary method.

[0293] As the substrate, woven fabrics or non-woven fabrics comprising cotton, staple fibers, or chemical fibers; and films or foam sheets of soft vinyl chloride, polyethylene, polyurethane, etc., are suitable.

[0294] The amount of the compound represented by Formula (A) or one or more other compounds having an antitumor effect to be incorporated in each of such dosage unit forms depends on the condition of the patient to whom the compound or one or more other compounds are administered, the dosage form, etc. In general, in the case of an oral agent, an injection, and a suppository, the amount of the compound of the present invention is preferably 10 mg/m.sup.2 to 1000 mg/m.sup.2 per dosage unit form.

[0295] The daily dose of the medicine in such a dosage form depends on the condition, body weight, age, gender, etc., of the patient, and cannot be generalized. For example, the daily dose of the compound for an adult (body weight: 50 kg) may be 13.9 to 1500 mg, and preferably 50 to 1000 mg; and is preferably administered in one dose, or in two to three divided doses, per day.

[0296] The amount of one or more other compounds having an antitumor effect to be incorporated in each of such dosage unit forms is suitably determined according to the type of antitumor agent used, the condition of a patient, the dosage form, etc. The daily dose of the medicine in such a dosage form as described above is also suitably determined.

[0297] When the compound represented by Formula (A) and one or more other compounds having an antitumor effect are formulated into two or more separate compositions, the method for administering the compositions is not particularly limited; and they may be administered simultaneously, sequentially, or at one or more intervals as long as the potentiation action of the present invention is attained. The order of administration of the compositions is also not particularly limited. An antitumor agent comprising the compound represented by Formula (A) may be administered before, simultaneously with, or after administration of antitumor agent(s) comprising one or more other compounds having an antitumor effect.

[0298] Another embodiment provides an antitumor agent comprising a combination of the compound represented by Formula (A) and one or more other compounds having an antitumor effect.

[0299] The terms combination and combined use used in the present specification mean that the compound represented by Formula (A) and one or more other compounds having an antitumor effect can be administered simultaneously as a single composition or two separate compositions, or that the compound represented by Formula (A) and one or more other compounds having an antitumor effect can be administered sequentially or at one or more intervals as two separate compositions, as long as the potentiation action of the present invention is attained. The compound represented by Formula (A) may be administered before, simultaneously with, or after administration of one or more other compounds having an antitumor effect.

[0300] Another embodiment provides use of the compound represented by Formula (A) or a salt thereof for potentiating the antitumor effect of antitumor agent(s) containing one or more other compounds having an antitumor effect.

[0301] Another embodiment provides use of the compound represented by Formula (A) or a salt thereof for producing an antitumor effect potentiator for antitumor agent(s) containing one or more other compounds having an antitumor effect.

[0302] Another embodiment provides use of the compound represented by Formula (A) or a salt thereof for producing an antitumor agent comprising a combination of the compound or a salt thereof and one or more other compounds having an antitumor effect.

[0303] Another embodiment provides a pharmaceutical composition for preventing and/or treating a tumor, the composition comprising the compound represented by Formula (A) or a salt thereof, and one or more other compounds having an antitumor effect.

[0304] Another embodiment provides an antitumor effect potentiating method for one or more other antitumor agents, comprising administering to a patient the compound represented by Formula (A) or a salt thereof in an amount effective for prevention and/or treatment of a tumor.

[0305] Another embodiment provides a method for preventing and/or treating a tumor, comprising administering to a patient a combination of the compound represented by Formula (A) or a salt thereof and one or more other compounds having an antitumor effect in an amount effective for prevention and/or treatment of a tumor.

[0306] Another embodiment provide a product as a combined preparation for use simultaneously, sequentially, or at one or more intervals upon prevention and/or treatment of a tumor, the product comprising the compound represented by Formula (A) or a salt thereof and one or more other compounds having an antitumor effect.

EXAMPLES

[0307] The following describes the present invention in more detail with reference to Reference Examples, Test Examples, and Examples. However, the scope of the present invention is not limited to these Examples.

[0308] Commercially available reagents were used in the Examples, unless otherwise specified.

[0309] For silica gel column chromatography, Purif-Pack (registered trademark) SI produced by Moritex Corp., KP-Sil (registered trademark) Silica prepacked column produced by Biotage, or HP-Sil (registered trademark) Silica prepacked column produced by Biotage was used.

[0310] For basic silica gel column chromatography, Purif-Pack (registered trademark) NH produced by Moritex Corp or KP-NH (registered trademark) prepacked column produced by Biotage was used.

[0311] For preparative thin-layer chromatography, Kieselgel 60F 254, Art. 5744 produced by Merck or NH.sub.2 Silica Gel 60F254 Plate produced by Wako was used.

[0312] NMR spectra were measured by using AL400 (400 MHz; produced by JEOL), Mercury 400 (400 MHz; produced by Agilent Technologies, Inc.) model spectrometer, or Inova 400 (400 MHz; produced by Agilent Technologies, Inc.) model spectrometer equipped with an OMNMR probe (produced by Protasis). The measurement was carried out using tetramethylsilane as an internal standard when tetramethylsilane was contained in a deuterated solvent; otherwise, an NMR solvent was used as an internal standard. All the values are shown by ppm.

[0313] The microwave reaction was performed using Discover S-class produced by CEM Corporation, or Initiator produced by Biotage.

[0314] LCMS spectra were measured using an Acquity SQD (quadrupole) produced by Waters Corporation under the following conditions.

Column: YMC-Triart C18, 2.050 mm, 1.9 m (produced by YMC)
MS detection: ESI positive
UV detection: 254 and 210 nm
Column flow rate: 0.5 mL/min
Mobile phase: Water/acetonitrile (0.1% formic acid)
Injection volume: 1 L

TABLE-US-00001 TABLE 1 Gradient Time (min) Water (%) Acetonitrile (%) 0 95 5 0.1 95 5 2.1 5 95 3.0 STOP

[0315] Preparative reversed-phase HPLC purification was performed using a preparative separation system available from Waters Corporation under the following conditions.

Column: Connected YMC-Actus Triart C18, 2050 mm, 5 m (produced by YMC) and YMC-Actus Triart C18, 2010 mm, 5 m (produced by YMC)
UV detection: 254 nm
MS detection: ESI positive
Column flow rate: 25 mL/min
Mobile phase: Water/acetonitrile (0.1% formic acid)
Injection volume: 0.1 to 0.5 mL

Abbreviations

s: Singlet

d: Doublet

t: Triplet

q: Quartet

m: Multiplet

brs: Broad Singlet

brm: Broad Multiplet

dd: Double Doublet

dt: Double Triplet

dq: Double Quartet

ddd: Double Double Doublet

[0316] DMSO-D.sub.6: Deuterated dimethyl sulfoxide
CDCl.sub.3: Deuterated chloroform
CD.sub.3OD: Deuterated methanol
PdCl.sub.2 (dppf) CH.sub.2Cl.sub.2: 1,1-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex
n-butyllithium: normal butyl lithium

Reference Example 1

4-Amino-5-[2-(2,6-difluorophenyl)ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of [(3aR,4R,6R,6aR)-4-(4-amino-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol

[0317] (2R,3R,4S,5R)-2-(4-Amino-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (15 g, 34.8 mmol) was suspended at room temperature in acetone (120 mL) and 2,2-dimethoxypropane (24.4 mL). Thereafter, boron trifluoride diethyl etherate (27.8 mL, 6.3 eq) was added thereto dropwise in an ice bath with stirring so as to keep the internal temperature at 10 C. or lower. The obtained mixture was stirred for 75 minutes in an ice bath, and a 5 M aqueous sodium hydroxide solution (60 mL) was then slowly added thereto dropwise so as to keep the internal temperature at 15 C. or lower. After acetone was distilled off under reduced pressure, chloroform and water were added thereto, followed by stirring for about 5 minutes. The reaction solution was filtered through a celite bed to remove the generated insoluble matter. Thereafter, the aqueous layer was separated and extracted twice with chloroform. All of the organic layers were combined, washed with water and saturated saline, and dried over sodium sulfate, followed by distilling off the solvent. The brown oil residue was suspended in hexane (50 mL), and stirred for 2 hours. The formed solid was then collected by filtration, followed by drying, thereby obtaining the title compound (10.7 g, 71%) as a light-brown solid.

[0318] .sup.1H-NMR (CDCl.sub.3) : 8.23 (1H, s), 7.12 (1H, s), 6.40 (1H, d, J=11.5 Hz), 5.76-5.74 (2H, brs), 5.69 (1H, d, J=5.1 Hz), 5.24-5.22 (1H, m), 5.10-5.08 (1H, m), 4.49 (1H, s), 3.97-3.94 (1H, m), 3.78 (1H, t, J=11.5 Hz), 1.63 (3H, s), 1.36 (3H, s). LCMS (ESI) m/z 433 [M+H].sup.+

Step 2: Synthesis of 7-((3aR,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0319] [(3aR,4R,6R,6aR)-4-(4-Amino-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol (3.2 g, 7.4 mmol) and phthalimide (2.18 g, 14.8 mmol) were dissolved in tetrahydrofuran (30 mL), and triphenylphosphine (2.9 g, 11.1 mmol) was added thereto with stirring under ice-cooling. After triphenylphosphine was dissolved, diisopropyl azodicarboxylate (2.2 mL, 11.1 mmol) was added thereto dropwise with stirring under ice-cooling. After the reaction solution was stirred for 1.5 h under ice-cooling, the reaction solution was distilled off under reduced pressure, and ethanol (30 mL), water (9 mL), and hydrazine monohydrate (1.2 mL, 24.7 mmol) were added at room temperature to the residue. After being stirred under reflux overnight, the reaction solution was distilled off under reduced pressure. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. Then, the aqueous layer was separated and extracted with ethyl acetate. All of the organic layers were combined and dried over sodium sulfate, followed by distilling off the solvent. The residue was then purified by basic silica gel column chromatography (developing solvent: methanol/chloroform), thereby obtaining the title compound (3.23 g, quantitative) as a yellow solid.

[0320] .sup.1H-NMR (CDCl.sub.3) : 8.28 (1H, s), 7.19 (1H, s), 6.13 (1H, d, J=3.2 Hz), 5.65-5.63 (2H, brs), 5.23 (1H, dd, J=6.7, 3.2 Hz), 4.93 (1H, dd, J=6.7, 4.0 Hz), 4.18-4.14 (1H, m), 3.04 (1H, dd, J=13.4, 4.3 Hz), 2.93 (1H, dd, J=13.4, 5.9 Hz), 1.61 (3H, s), 1.37 (3H, s). LCMS (ESI) m/z 432 [M+H].sup.+

Step 3: Synthesis of tert-butyl N-(((3aR,4R,6R,6aR)-6-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)sulfamoyl carbamate

[0321] 7-((3aR,4R,6R,6aR)-6-(Aminomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (3.23 g) was dissolved in chloroform (40 mL), and 1-aza-4-azoniabicyclo[2.2.2]octan-4-ylsulfonyl(tert-butoxycarbonyl)azanido: 1,4-diazabicyclo[2.2.2]octane monohydrochloride (Reference: Organic Letters, 2012, 10, 2626-2629) (6.2 g, 14.1 mmol) was added thereto at room temperature. After the reaction solution was stirred for 2 hours at room temperature, the precipitate was filtered off and washed with chloroform. After the filtrate was concentrated, the residue was purified by silica gel column chromatography (developing solvent: chloroform/methanol), thereby obtaining the title compound (4.0 g, 88%) as a milky-white solid.

[0322] .sup.1H-NMR (CDCl.sub.3) : 9.27-9.25 (1H, brs), 8.50 (1H, s), 7.08 (1H, s), 6.04-6.02 (2H, brs), 5.65 (1H, d, J=4.7 Hz), 5.28 (1H, dd, J=6.3, 4.7 Hz), 5.07 (1H, dd, J=6.3, 2.2 Hz), 4.50 (1H, d, J=2.2 Hz), 3.63-3.49 (2H, m), 1.61 (3H, s), 1.44 (9H, s), 1.35 (3H, s). LCMS (ESI) m/z 611 [M+H].sup.+

Step 4: Synthesis of Reference Example Compound 1

[0323] tert-Butyl N-(((3aR,4R,6R,6aR)-6-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)sulfamoyl carbamate (20 mg, 0.033 mmol), 2-ethynyl-1,3-difluorobenzene (9.0 mg, 0.066 mmol), bis(triphenylphosphine)palladium (II) dichloride (3 mg, 0.0043 mmol), copper iodide (1 mg, 0.0053 mmol), and diisopropylethylamine (0.011 mL, 0.066 mmol) were suspended in tetrahydrofuran (0.20 mL). After the reaction solution was stirred at 70 C. for 2 hours, a mixed solution (0.60 mL) of trifluoroacetic acid/water=4/1 was added thereto at room temperature, followed by stirring at room temperature overnight. After the solvent was distilled off, the residue was purified by basic silica gel column chromatography (developing solvent: methanol/chloroform), thereby obtaining the title compound (14 mg, 91%) as a yellow powder.

[0324] .sup.1H-NMR (CD.sub.3OD) : 8.25 (1H, s), 7.68 (1H, s), 7.45-7.37 (1H, m), 7.10-7.04 (2H, m), 5.86 (1H, d, J=7.3 Hz), 4.86-4.81 (1H, m), 4.31-4.29 (1H, m), 4.27-4.25 (1H, m), 3.40-3.35 (2H, m). LCMS (ESI) m/z 481 [M+H].sup.+

Step 5: Synthesis of 4-amino-5-[2-(2,6-difluorophenyl)ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine hydrochloride

[0325] tert-Butyl N-(((3aR,4R,6R,6aR)-6-(4-amino-5-((2,6-difluorophenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl) sulfamoyl carbamate (8.05 g, 12.9 mmol) was dissolved in acetonitrile (120 mL), and concentrated hydrochloric acid (10.8 mL, 129 mmol) was added thereto at room temperature. After the mixture was stirred at room temperature for 6 hours, acetonitrile (80 mL) was added thereto, followed by stirring at room temperature overnight. The precipitate was collected by filtration and washed with acetonitrile (80 mL), followed by drying, thereby obtaining the title compound hydrochloride (5.93 g, 88%) as a white solid.

[0326] .sup.1H-NMR (DMSO-D.sub.6) : 8.42 (1H, s), 8.25 (1H, s), 7.55 (1H, tt, J=8.1, 7.7 Hz), 7.28 (2H, dd, J=8.4, 8.1 Hz), 7.02 (1H, brs), 6.61 (1H, brs), 6.03 (1H, d, J=6.6 Hz), 4.48 (1H, dd, J=6.6, 5.1 Hz), 4.12-4.10 (1H, m), 4.06-4.03 (1H, m), 3.22 (1H, dd, J=13.9, 5.5 Hz), 3.12 (1H, dd, J=13.2, 5.5 Hz). LCMS (ESI) m/z 481 [M+H].sup.+.

Reference Example 2

4-[4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]-2-(o-tolyl)thiazole

[0327] tert-Butyl N-(((3aR,4R,6R,6aR)-6-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl) sulfamoyl carbamate (300 mg, 0.491 mmol), 1,1-bis(diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex (40.1 mg, 0.049 mmol), and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(o-tolyl)thiazole (295 mg, 0.982 mmol) were suspended in a 2 M aqueous sodium carbonate solution (1.23 mL) and dimethoxyethane (5 mL), followed by stirring at 70 C. for 17 hours. The reaction solution was partitioned between ethyl acetate and water, and the organic layer was washed with water and concentrated. The residue was dissolved in acetonitrile (1 mL), trifluoroacetic acid (0.5 mL), and water (0.1 mL), followed by stirring at room temperature overnight. After the reaction liquid was concentrated, the residue was purified by basic silica gel column chromatography (developing solvent: methanol/chloroform), thereby obtaining the target product (110 mg, 43%) as a yellowish white solid.

[0328] .sup.1H-NMR (DMSO-D.sub.6) : 8.10 (1H, s), 8.08 (1H, s), 8.06 (1H, s), 7.70 (1H, d, J=7.3 Hz), 7.46-7.35 (3H, m), 6.60 (2H, s), 5.97 (1H, d, J=6.6 Hz), 5.40 (1H, d, J=6.6 Hz), 5.20 (1H, d, J=4.8 Hz), 4.60 (1H, dt, J=6.6, 5.5 Hz), 4.14-4.11 (1H, m), 4.08-4.04 (1H, m), 2.53 (3H, s). LCMS (ESI) m/z 518 [M+H].sup.+.

Reference Example 3

4-Amino-5-[2-(4-benzyloxyphenyl)ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine

[0329] The title compound was obtained as in step 4 of Reference Example 1, except that 1-(benzyloxy)-4-ethynylbenzene was used in place of 2-ethynyl-1,3-difluorobenzene.

[0330] .sup.1H-NMR (CDCl.sub.3) : 8.29 (1H, s), 7.44-7.27 (8H, m), 6.96 (2H, d, J=8.8 Hz), 5.69 (1H, d, J=6.8 Hz), 5.10 (2H, s), 4.87-4.84 (1H, m), 4.36-4.33 (2H, m), 3.46-3.40 (4H, m). LCMS (ESI) m/z 551 [M+H].sup.+.

Reference Example 4

4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-[5-(2-pyridyl)-2-thienyl]ethynyl]pyrrolo[2,3-d]pyrimidine

[0331] The title compound was obtained as in step 4 of Reference Example 1, except that 2-(5-ethynylthiophen-2-yl)pyridine was used in place of 2-ethynyl-1,3-difluorobenzene.

[0332] .sup.1H-NMR (CD.sub.3OD) : 8.49 (1H, d, J=5.1 Hz), 8.25 (1H, s), 7.84-7.82 (2H, m), 7.64 (1H, s), 7.64 (1H, d, J=4.1 Hz), 7.35 (1H, d, J=4.1 Hz), 7.30-7.27 (1H, m), 5.87 (1H, d, J=6.8 Hz), 4.87-4.84 (1H, m), 4.32-4.30 (1H, m), 4.28-4.25 (1H, m), 3.39-3.30 (2H, m). LCMS (ESI) m/z 528 [M+H].sup.+.

Reference Example 5

4-[4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]-2-(2-methoxyphenyl)thiazole

[0333] The title compound was obtained as in Reference Example 2, except that 2-(2-methoxyphenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole was used in place of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(o-tolyl)thiazole.

[0334] .sup.1H-NMR (CD.sub.3OD) : 8.20 (1H, s), 8.17 (1H, dd, J=7.7, 1.8 Hz), 7.88 (1H, s), 7.84 (1H, s), 7.49 (1H, dt, J=1.1, 8.8 Hz), 7.24 (1H, d, J=8.8 Hz), 7.15 (1H, t, J=7.7 Hz), 5.98 (1H, d, J=6.6 Hz), 4.84-4.80 (1H, m), 4.36 (1H, dd, J=5.5, 2.9 Hz), 4.29-4.26 (1H, m), 4.08 (3H, s), 3.47-3.37 (2H, m). LCMS (ESI) m/z 534 [M+H].sup.+.

Reference Example 6

4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(1-naphthyl)ethynyl]pyrrolo[2,3-d]pyrimidine

[0335] The title compound was obtained as in step 4 of Reference Example 1, except that 1-ethynylnaphthalene was used in place of 2-ethynyl-1,3-difluorobenzene.

[0336] .sup.1H-NMR (CD.sub.3OD) : 8.36 (1H, d, J=8.0 Hz), 8.26 (1H, s), 7.93-7.90 (2H, m), 7.77 (1H, d, J=7.6 Hz), 7.73 (1H, s), 7.64-7.47 (3H, m), 5.90 (1H, d, J=6.8 Hz), 4.87-4.84 (1H, m), 4.34-4.32 (1H, m), 4.30-4.25 (1H, m), 3.39-3.30 (2H, m). LCMS (ESI) m/z 495 [M+H].sup.+.

Reference Example 7

4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-(3-phenylprop-1-ynyl)pyrrolo[2,3-d]pyrimidine

[0337] The title compound was obtained as in step 4 of Reference Example 1, except that prop-2-yn-1-yl benzene was used in place of 2-ethynyl-1,3-difluorobenzene.

[0338] .sup.1H-NMR (CD.sub.3OD) : 8.18 (1H, s), 7.43 (1H, s), 7.40 (2H, d, J=7.6 Hz), 7.33 (2H, dd, J=7.6, 7.3 Hz), 7.24 (1H, t, J=7.3 Hz), 5.80 (1H, d, J=6.8 Hz), 4.87-4.80 (1H, m), 4.30-4.25 (1H, m), 4.24-4.20 (1H, m), 3.88 (2H, s), 3.39-3.30 (2H, m). LCMS (ESI) m/z 459 [M+H].sup.+.

Reference Example 8

4-[2-[4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]quinoline

[0339] The title compound was obtained as in step 4 of Reference Example 1, except that 4-ethynylquinoline was used in place of 2-ethynyl-1,3-difluorobenzene.

[0340] .sup.1H-NMR (CD.sub.3OD) : 8.83 (1H, d, J=4.4 Hz), 8.40 (1H, d, J=9.5 Hz), 8.28 (1H, s), 8.06 (1H, d, J=8.0 Hz), 7.91 (1H, s), 7.84 (1H, dd, J=8.8, 8.0 Hz), 7.76-7.73 (2H, m), 5.93 (1H, d, J=6.6 Hz), 4.87-4.80 (1H, m), 4.35-4.30 (1H, m), 4.29-4.26 (1H, m), 3.40-3.30 (2H, m). LCMS (ESI) m/z 496 [M+H].sup.+.

Reference Example 9

4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-[4-(phenoxymethyl)phenyl]ethynyl]pyrrolo[2,3-d]pyrimidine

[0341] The title compound was obtained as in step 4 of Reference Example 1, except that 1-ethynyl-4-(phenoxymethyl)benzene was used in place of 2-ethynyl-1,3-difluorobenzene.

[0342] .sup.1H-NMR (CD.sub.3OD) : 8.25 (1H, s), 7.61 (1H, s), 7.57 (2H, d, J=8.3 Hz), 7.49 (2H, d, J=8.3 Hz), 7.28 (2H, dd, J=8.0, 7.8 Hz), 7.00 (2H, d, J=7.8 Hz), 6.94 (1H, t, J=8.0 Hz), 5.86 (1H, d, J=6.8 Hz), 5.12 (2H, s), 4.85-4.75 (1H, m), 4.35-4.30 (1H, m), 4.28-4.25 (1H, m), 3.40-3.30 (2H, m). LCMS (ESI) m/z 551 [M+H].sup.+.

Reference Example 10

4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(1-phenylcyclopropyl)ethynyl]pyrrolo[2,3-d]pyrimidine

[0343] The title compound was obtained as in step 4 of Reference Example 1, except that (1-ethynylcyclopropyl)benzene was used in place of 2-ethynyl-1,3-difluorobenzene.

[0344] .sup.1H-NMR (CD.sub.3OD) : 8.21 (1H, s), 7.46 (1H, s), 7.43-7.40 (2H, m), 7.32 (2H, d, J=8.0 Hz), 7.23-7.19 (1H, m), 5.82 (1H, d, J=6.8 Hz), 4.82-4.79 (1H, m), 4.30-4.28 (1H, m), 4.25-4.21 (1H, m), 3.37-3.34 (2H, m), 1.54-1.50 (2H, m), 1.40-1.37 (2H, m). LCMS (ESI) m/z 485 [M+H].sup.+.

Reference Example 11

1-[2-[4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]isoquinoline

[0345] The title compound was obtained as in step 4 of Reference Example 1, except that 1-ethynylisoquinoline was used in place of 2-ethynyl-1,3-difluorobenzene.

[0346] .sup.1H-NMR (DMSO-D.sub.6) : 8.56 (1H, d, J=8.0 Hz), 8.45 (1H, d, J=8.0 Hz), 8.23 (1H, s), 8.19 (1H, s), 8.07 (1H, d, J=8.0 Hz), 7.90 (1H, d, J=8.0 Hz), 7.88-7.78 (2H, m), 7.38-7.34 (1H, brs), 6.64 (2H, s), 5.99 (1H, d, J=6.8 Hz), 5.48-5.46 (1H, brs), 5.29-5.25 (1H, brs), 4.63-4.59 (1H, m), 4.15-4.11 (1H, m), 4.10-4.06 (1H, m), 3.25-3.21 (1H, m), 3.18-3.12 (1H, m). LCMS (ESI) m/z 496 [M+H].sup.+.

Reference Example 12

4-[4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]-2-phenyl-oxazol

[0347] The title compound was obtained as in Reference Example 2, except that 2-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazol was used in place of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(o-tolyl)thiazole.

[0348] .sup.1H-NMR (CD.sub.3OD) : 8.28 (1H, s), 8.07-8.00 (2H, m), 7.93 (1H, s), 7.51-7.49 (3H, m), 7.48 (1H, s), 6.05 (1H, d, J=6.3 Hz), 4.77-4.71 (2H, m), 4.33 (1H, dd, J=5.4, 3.2 Hz), 4.26-4.22 (1H, m), 3.45-3.35 (2H, m). LCMS (ESI) m/z 488 [M+H].sup.+.

Reference Example 13

5-[2-[4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]quinoline

[0349] The title compound was obtained as in step 4 of Reference Example 1, except that 5-ethynylquinoline was used in place of 2-ethynyl-1,3-difluorobenzene.

[0350] .sup.1H-NMR (CD.sub.3OD) : 8.91 (1H, dd, J=4.4, 1.7 Hz), 8.84-8.78 (1H, m), 8.26 (1H, s), 8.04 (1H, d, J=8.5 Hz), 7.89 (1H, dd, J=7.9, 1.1 Hz), 7.81 (1H, s), 7.80-7.76 (1H, m), 7.67 (1H, dd, J=8.5, 4.4 Hz), 5.92 (1H, d, J=6.8 Hz), 4.87-4.82 (1H, m), 4.35-4.33 (1H, m), 4.29-4.26 (1H, m), 3.45-3.36 (2H, m). LCMS (ESI) m/z 496 [M+H].sup.+.

Reference Example 14

4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-[2-(trifluoromethoxy)phenyl]ethynyl]pyrrolo[2,3-d]pyrimidine

[0351] The title compound was obtained as in step 4 of Reference Example 1, except that 1-ethynyl-2-(trifluoromethoxy)benzene was used in place of 2-ethynyl-1,3-difluorobenzene.

[0352] .sup.1H-NMR (CD.sub.3OD) : 8.26 (1H, s), 7.68-7.62 (1H, m), 7.65 (1H, s), 7.50-7.46 (1H, m), 7.42-7.38 (2H, m), 5.86 (1H, d, J=7.1 Hz), 4.86-4.81 (1H, m), 4.31-4.29 (1H, m), 4.27-4.25 (1H, m), 3.40-3.35 (2H, m). LCMS (ESI) m/z 529 [M+H].sup.+.

Reference Example 15

4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-methoxy-1-naphthyl)ethynyl]pyrrolo[2,3-d]pyrimidine

[0353] The title compound was obtained as in step 4 of Reference Example 1, except that 1-ethynyl-2-methoxynaphthalene was used in place of 2-ethynyl-1,3-difluorobenzene.

[0354] .sup.1H-NMR (CD.sub.3OD) : 8.23 (1H, s), 7.89-7.80 (2H, m), 7.66-7.57 (1H, m), 7.64 (1H, s), 7.58-7.54 (1H, m), 7.42-7.36 (2H, m), 5.90 (1H, d, J=8.0 Hz), 4.83-4.81 (1H, m), 4.37-4.33 (1H, m), 4.27-4.25 (1H, m), 4.06 (3H, s), 3.40-3.35 (2H, m). LCMS (ESI) m/z 525 [M+H].sup.+.

Reference Example 16

4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2,6-dimethoxyphenyl)ethynyl]pyrrolo[2,3-d]pyrimidine

[0355] The title compound was obtained as in step 4 of Reference Example 1, except that 2-ethynyl-1,3-dimethoxybenzene was used in place of 2-ethynyl-1,3-difluorobenzene.

[0356] .sup.1H-NMR (CD.sub.3OD) : 8.22 (1H, s), 7.50 (1H, s), 7.28 (1H, t, J=8.5 Hz), 6.69 (2H, d, J=8.5 Hz), 5.86 (1H, d, J=6.8 Hz), 4.83-4.81 (1H, m), 4.32-4.30 (1H, m), 4.27-4.25 (1H, m), 3.91 (6H, s), 3.40-3.35 (2H, m). LCMS (ESI) m/z 505 [M+H].sup.+.

Reference Example 17

8-[2-[4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]quinoline

[0357] The title compound was obtained as in step 4 of Reference Example 1, except that 8-ethynylquinoline was used in place of 2-ethynyl-1,3-difluorobenzene.

[0358] .sup.1H-NMR (CD.sub.3OD) : 8.99 (1H, dd, 4.1, 1.7 Hz), 8.33 (1H, dd, 8.5, 1.7 Hz), 8.22 (1H, s), 7.91 (1H, s), 7.90-7.82 (2H, m), 7.58-7.52 (2H, m), 5.86 (1H, d, J=6.8 Hz), 4.87-4.85 (1H, m), 4.32-4.30 (1H, m), 4.27-4.25 (1H, m), 3.40-3.35 (2H, m). LCMS (ESI) m/z 496 [M+H].sup.+.

Reference Example 18

4-Amino-5-[2-[2-(difluoromethoxy)phenyl]ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine

[0359] The title compound was obtained as in step 4 of Reference Example 1, except that 1-(difluoromethoxy)-2-ethynylbenzene was used in place of 2-ethynyl-1,3-difluorobenzene.

[0360] .sup.1H-NMR (CD.sub.3OD) : 8.24 (1H, s), 7.62 (1H, s), 7.58 (1H, d, J=7.8, 1.7 Hz), 7.43-7.39 (1H, m), 7.28-7.23 (2H, m), 7.01 (1H, t, J=7.2 Hz), 5.86 (1H, d, J=6.8 Hz), 4.87-4.85 (1H, m), 4.32-4.30 (1H, m), 4.27-4.25 (1H, m), 3.40-3.35 (2H, m). LCMS (ESI) m/z 511 [M+H].sup.+.

Reference Example 19

4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(1H-pyrazolo[4,3-b]pyridin-5-yl)ethynyl]pyrrolo[2,3-d]pyrimidine

[0361] The title compound was obtained as in step 4 of Reference Example 1, except that 5-ethynyl-1H-pyrazolo[4,3-b]pyridine was used in place of 2-ethynyl-1,3-difluorobenzene.

[0362] .sup.1H-NMR (CD.sub.3OD) : 8.25 (1H, s), 8.23 (1H, s), 8.06 (1H, d, J=8.8 Hz), 7.75 (1H, s), 7.64 (1H, d, J=8.8 Hz), 5.89 (1H, d, J=6.8 Hz), 4.87-4.85 (1H, m), 4.34-4.30 (1H, m), 4.27-4.25 (1H, m), 3.40-3.35 (2H, m). LCMS (ESI) m/z 486 [M+H].sup.+.

Reference Example 20

4-Amino-5-[2-(4-amino-2-fluoro-phenyl)ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine

[0363] The title compound was obtained as in step 4 of Reference Example 1, except that 4-ethynyl-3-fluoroaniline was used in place of 2-ethynyl-1,3-difluorobenzene.

[0364] .sup.1H-NMR (CD.sub.3OD) : 8.22 (1H, s), 7.48 (1H, s), 7.21-7.17 (1H, m), 6.46-6.41 (2H, m), 5.84 (1H, d, J=6.8 Hz), 4.87-4.85 (1H, m), 4.32-4.28 (1H, m), 4.27-4.24 (1H, m), 3.40-3.35 (2H, m). LCMS (ESI) m/z 478 [M+H].sup.+.

Reference Example 21

4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-(2-indan-1-ylethynyl)pyrrolo[2,3-d]pyrimidine

[0365] The title compound was obtained as in step 4 of Reference Example 1, except that 1-ethynyl-2,3-dihydro-1H-indene was used in place of 2-ethynyl-1,3-difluorobenzene.

[0366] .sup.1H-NMR (CD.sub.3OD) : 8.19 (1H, s), 7.42 (1H, s), 7.42-7.38 (1H, m), 7.26-7.18 (3H, m), 5.81 (1H, d, J=7.1 Hz), 4.84-4.79 (1H, m), 4.30-4.18 (3H, m), 3.40-3.35 (2H, m), 3.04-2.91 (2H, m), 2.62-2.54 (1H, m), 2.19-2.11 (1H, m). LCMS (ESI) m/z 485 [M+H].sup.+.

Reference Example 22

4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-methylsulfonylphenyl)ethynyl]pyrrolo[2,3-d]pyrimidine

[0367] The title compound was obtained as in step 4 of Reference Example 1, except that 1-ethynyl-2-(methylsulfonyl)benzene was used in place of 2-ethynyl-1,3-difluorobenzene.

[0368] .sup.1H-NMR (CD.sub.3OD) : 8.24 (1H, s), 8.07 (1H, dd, J=7.7, 1.3 Hz), 7.79 (1H, dd, J=7.7, 1.3 Hz), 7.77 (1H, s), 7.75-7.70 (1H, m), 7.62-7.57 (1H, m), 5.89 (1H, d, J=6.8 Hz), 4.85-4.81 (1H, m), 4.33-4.29 (1H, m), 4.28-4.24 (1H, m), 3.40-3.35 (2H, m), 3.30 (3H, s). LCMS (ESI) m/z 523 [M+H].sup.+.

Reference Example 23

4-[4-[2-[4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]-3,5-difluoro-phenyl]morpholine

Step 1: Synthesis of 4-(4-ethynyl-3,5-difluorophenyl)morpholine

[0369] 2-Ethynyl-1,3,5-trifluorobenzene (52 mg, 0.33 mmol) and cesium carbonate (163 mg, 0.50 mmol) were dissolved in N,N-dimethylformamide (0.50 mL). Morpholine (0.044 mL, 0.50 mmol) was added thereto at room temperature, followed by stirring at 80 C. overnight. After the resulting mixture was air-cooled to room temperature, ethyl acetate (2.0 mL) and a saturated aqueous ammonium chloride solution (1.0 mL) were sequentially added thereto, and the mixture was partitioned into an aqueous layer and an organic layer. The organic layer was then sequentially washed with water and saturated saline, and dried over anhydrous sodium sulfate, followed by distilling off the solvent. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/hexane), thereby obtaining 4-(4-ethynyl-3,5-difluorophenyl)morpholine (40 mg, 54%) as a white solid.

[0370] .sup.1H-NMR (CDCl.sub.3) : 6.37 (2H, d, J=10.7 Hz), 3.83 (4H, dd, J=5.7, 4.2 Hz), 3.40 (1H, s), 3.19 (4H, dd, J=5.7, 4.2 Hz). LCMS (ESI) m/z 224 [M+H].sup.+

Step 2: Synthesis of Reference Example Compound 23

[0371] The title compound was obtained as in step 4 of Reference Example 1, except that 4-(4-ethynyl-3,5-difluorophenyl)morpholine was used in place of 2-ethynyl-1,3-difluorobenzene.

[0372] .sup.1H-NMR (CD.sub.3OD) : 8.23 (1H, s), 7.56 (1H, s), 6.63 (2H, d, J=11.5 Hz), 5.85 (1H, d, J=7.1 Hz), 4.85-4.79 (1H, m), 4.30 (1H, dd, J=5.6, 2.4 Hz), 4.27-4.23 (1H, m), 3.80 (4H, t, J=4.9 Hz), 3.42-3.32 (2H, m), 3.27-3.22 (4H, m). LCMS (ESI) m/z 566 [M+H].sup.+.

Reference Example 24

4-Amino-5-[2-(4-amino-2,6-difluoro-phenyl)ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine

[0373] The title compound was obtained as in step 4 of Reference Example 1, except that 4-ethynyl-3,5-difluoroaniline was used in place of 2-ethynyl-1,3-difluorobenzene.

[0374] .sup.1H-NMR (CD.sub.3OD) : 8.23 (1H, s), 7.52 (1H, s), 6.26 (2H, d, J=10.2 Hz), 5.85 (1H, d, J=6.8 Hz), 4.85-4.81 (1H, m), 4.33-4.29 (1H, m), 4.26-4.23 (1H, m), 3.40-3.34 (2H, m). LCMS (ESI) m/z 496 [M+H].sup.+.

Reference Example 25

4-Amino-5-[2-[2,6-difluoro-4-(methylamino)phenyl]ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of 4-ethynyl-3,5-difluoro-N-methylaniline

[0375] The title compound was obtained as in step 1 of Reference Example 23, except that methylamine was used in place of morpholine.

[0376] .sup.1H-NMR (CDCl.sub.3) : 6.11 (2H, d, J=10.6 Hz), 4.22-4.14 (1H, brm), 3.39 (1H, s), 2.84 (3H, s). LRMS (ESI) m/z 168 [M+H].sup.+

Step 2: Synthesis of Reference Example Compound 25

[0377] The title compound was obtained as in step 4 of Reference Example 1, except that 4-ethynyl-3,5-difluoro-N-methylaniline was used in place of 2-ethynyl-1,3-difluorobenzene.

[0378] .sup.1H-NMR (CD.sub.3OD) : 8.24 (1H, s), 8.18 (1H, brs), 8.03 (1H, dd, J=7.7, 1.1 Hz), 7.53 (1H, s), 7.48 (1H, t, J=7.7 Hz), 6.22 (2H, d, J=11.0 Hz), 5.86 (1H, d, J=7.0 Hz), 4.86-4.81 (1H, m), 4.32 (1H, dd, J=5.5, 2.2 Hz), 4.27-4.25 (1H, m), 3.43-3.34 (2H, m), 2.79 (3H, s). LCMS (ESI) m/z 510 [M+H].sup.+.

Reference Example 26

4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-[4-(ethylamino)-2,6-difluoro-phenyl]ethynyl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of N-ethyl-4-ethynyl-3,5-difluoroaniline

[0379] The title compound was obtained as in step 1 of Reference Example 23, except that ethylamine was used in place of morpholine.

[0380] .sup.1H-NMR (CDCl.sub.3) : 6.10 (2H, d, J=10.3 Hz), 4.07-4.00 (1H, brm), 3.38 (1H, s), 3.18-3.11 (2H, m), 1.27 (5H, t, J=7.3 Hz). LRMS (ESI) m/z 182 [M+H].sup.+

Step 2: Synthesis of Reference Example Compound 26

[0381] The title compound was obtained as in step 4 of Reference Example 1, except that N-ethyl-4-ethynyl-3,5-difluoroaniline was used in place of 2-ethynyl-1,3-difluorobenzene.

[0382] .sup.1H-NMR (CD.sub.3OD) : 8.24 (1H, s), 8.07-8.00 (1H, m), 7.59-7.45 (1H, m), 7.57 (1H, s), 6.23 (2H, d, J=11.0 Hz), 5.89 (1H, d, J=7.0 Hz), 4.80 (1H, dd, J=7.0, 5.5 Hz), 4.32 (1H, dd, J=5.5, 2.6 Hz), 4.26 (1H, ddd, J=4.0, 3.7, 2.6 Hz), 3.41 (1H, dd, J=13.2, 3.7 Hz), 3.36 (1H, dd, J=13.2, 4.0 Hz), 3.13 (2H, q, J=7.3 Hz), 1.25 (3H, t, J=7.3 Hz). LCMS (ESI) m/z 524 [M+H].sup.+

Reference Example 27

4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-[3-(isopropylamino)phenyl]ethynyl]pyrrolo[2,3-d]pyrimidine

[0383] The title compound was obtained as in step 4 of Reference Example 1, except that 3-ethynyl-N-isopropylaniline was used in place of 2-ethynyl-1,3-difluorobenzene.

[0384] .sup.1H-NMR (CD.sub.3OD) : 8.24 (1H, s), 7.55 (1H, s), 7.11 (1H, t, J=8.3 Hz), 6.79-6.76 (2H, m), 6.67-6.65 (1H, m), 5.86 (1H, d, J=6.8 Hz), 4.84-4.79 (1H, m), 4.31 (1H, dd, J=5.6, 2.4 Hz), 4.25 (1H, q, J=3.2 Hz), 3.67-3.54 (1H, m), 3.39-3.35 (2H, m), 1.20 (6H, d, J=6.3 Hz). LCMS (ESI) m/z 502 [M+H].sup.+.

Reference Example 28

4-Amino-5-[2-(5-amino-2-fluoro-phenyl)ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine

[0385] The title compound was obtained as in step 4 of Reference Example 1, except that 3-ethynyl-4-fluoroaniline was used in place of 2-ethynyl-1,3-difluorobenzene.

[0386] .sup.1H-NMR (DMSO-D.sub.6) : 8.18 (1H, s), 7.90 (1H, s), 7.38-7.33 (1H, m), 6.99 (1H, t, J=9.3 Hz), 6.70 (1H, dd, J=6.1, 2.9 Hz), 6.62-6.56 (3H, m), 5.92 (1H, d, J=7.1 Hz), 5.40 (1H, d, J=6.3 Hz), 5.23 (1H, d, J=4.4 Hz), 5.16 (2H, s), 4.57 (1H, dd, J=12.1, 6.7 Hz), 4.12-4.08 (1H, m), 4.07-4.03 (1H, m), 3.24-3.08 (2H, m). LCMS (ESI) m/z 478 [M+H].sup.+.

Reference Example 29

4-Amino-5-[2-[2,6-difluoro-4-[(3R)-3-fluoropyrrolidin-1-yl]phenyl]ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of (3R)-1-(4-ethynyl-3,5-difluorophenyl)-3-fluoropyrrolidine

[0387] The title compound was obtained as in step 1 of Reference Example 23, except that (R)-3-fluoropyrrolidine was used in place of morpholine.

[0388] .sup.1H-NMR (CDCl.sub.3) : 6.07 (2H, d, J=10.3 Hz), 5.38 (1H, d, J=52.8 Hz), 3.59-3.38 (5H, m), 2.47-2.36 (1H, m), 2.27-2.06 (1H, m). LCMS (ESI) m/z 226 [M+H].sup.+

Step 2: Synthesis of Reference Example Compound 29

[0389] The title compound was obtained as in step 4 of Reference Example 1, except that (3R)-1-(4-ethynyl-3,5-difluorophenyl)-3-fluoropyrrolidine was used in place of 2-ethynyl-1,3-difluorobenzene.

[0390] .sup.1H-NMR (DMSO-D.sub.6) : 8.16 (1H, s), 7.84 (1H, s), 7.35-7.30 (1H, m), 6.58 (2H, s), 6.42 (2H, d, J=11.2 Hz), 5.91 (1H, d, J=7.1 Hz), 5.45 (1H, d, J=52.7 Hz), 5.37 (1H, d, J=6.3 Hz), 5.20 (1H, d, J=4.4 Hz), 4.56 (1H, dd, J=12.1, 6.7 Hz), 4.11-4.07 (1H, m), 4.06-4.01 (1H, m), 3.61-3.45 (3H, m), 3.41-3.33 (1H, m), 3.24-3.16 (1H, m), 3.14-3.06 (1H, m), 2.30-2.10 (2H, m). LCMS (ESI) m/z 568 [M+H].sup.+.

Reference Example 30

4-Amino-5-[2-[2,6-difluoro-4-[(3R)-3-hydroxypyrrolidin-1-yl]phenyl]ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of (3R)-1-(4-ethynyl-3,5-difluorophenyl)-pyrrolidin-3-ol

[0391] The title compound was obtained as in step 1 of Reference Example 23, except that (R)-pyrrolidin-3-ol was used in place of morpholine.

[0392] .sup.1H-NMR (CDCl.sub.3) : 6.02 (2H, d, J=10.5 Hz), 4.63-4.60 (1H, m), 3.50-3.43 (2H, m), 3.40-3.38 (1H, m), 3.33 (1H, dt, J=3.3, 9.0 Hz), 3.22 (1H, d, J=10.7 Hz), 2.22-2.11 (1H, m), 2.11-2.06 (1H, m). LCMS (ESI) m/z 224 [M+H].sup.+

Step 2: Synthesis of Reference Example Compound 30

[0393] The title compound was obtained as in step 4 of Reference Example 1, except that (3R)-1-(4-ethynyl-3,5-difluorophenyl)-pyrrolidin-3-ol was used in place of 2-ethynyl-1,3-difluorobenzene.

[0394] .sup.1H-NMR (DMSO-D.sub.6) : 8.17 (1H, s), 7.85 (1H, s), 7.36 (1H, dd, J=7.7, 4.8 Hz), 6.60 (2H, s), 6.35 (2H, d, J=11.0 Hz), 5.91 (1H, d, J=7.0 Hz), 5.39 (1H, d, J=6.2 Hz), 5.23 (1H, d, J=4.4 Hz), 5.06 (1H, d, J=3.7 Hz), 4.60-4.55 (1H, m), 4.42-4.37 (1H, m), 4.11-4.07 (1H, m), 4.06-4.02 (1H, m), 3.45-3.37 (2H, m), 3.24-3.18 (1H, m), 3.16-3.09 (2H, m), 2.07-1.99 (1H, m), 1.94-1.86 (1H, m). LCMS (ESI) m/z 566.3 [M+H].sup.+.

Reference Example 31

4-Amino-5-[3-(2,6-difluorophenyl)prop-1-ynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine

[0395] The title compound was obtained as in step 4 of Reference Example 1, except that 1,3-difluoro-2-(prop-2-yn-1-yl)benzene was used in place of 2-ethynyl-1,3-difluorobenzene.

[0396] .sup.1H-NMR (CD.sub.3OD) : 8.20 (1H, s), 7.40 (1H, s), 7.36-7.30 (1H, m), 7.04-6.99 (2H, m), 5.79 (1H, d, J=6.8 Hz), 4.80-4.69 (1H, m), 4.28-4.25 (1H, m), 4.22-4.20 (1H, m), 3.88 (2H, s), 3.39-3.32 (2H, m). LCMS (ESI) m/z 495 [M+H].sup.+.

Reference Example 32

4-Amino-5-[2-[2,6-difluoro-4-(2-hydroxyethylamino)phenyl]ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine

[0397] 2-((4-Ethynyl-3,5-difluorophenyl)amino)ethanol was obtained as in step 1 of Reference Example 23, except that 2-aminoethanol was used in place of morpholine, and the title compound was then obtained as in step 4 of Reference Example 1, except that the thus-obtained 2-((4-ethynyl-3,5-difluorophenyl)amino)ethanol was used in place of 2-ethynyl-1,3-difluorobenzene.

[0398] .sup.1H-NMR (DMSO-D.sub.6) : 8.20 (1H, s), 7.91 (1H, s), 7.38 (1H, s), 7.03 (2H, t, J=9.5 Hz), 6.61 (2H, brs), 5.93 (1H, d, J=6.6 Hz), 5.47-5.36 (1H, m), 5.34-5.18 (1H, m), 4.60 (1H, t, J=10.0 Hz), 4.13-4.08 (1H, m), 4.08-4.04 (1H, m), 3.26-3.19 (1H, m), 3.16-3.08 (1H, m), 2.55 (2H, s). LCMS (ESI) m/z 540.3 [M+H].sup.+.

Reference Example 33

4-Amino-5-[2-[2,6-difluoro-4-(2-oxopyrrolidin-1-yl)phenyl]ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of 1-(4-ethynyl-3,5-difluorophenyl)pyrrolidin-2-one

[0399] The title compound was obtained as in step 1 of Reference Example 23, except that pyrrolidin-2-one was used in place of morpholine.

[0400] .sup.1H-NMR (CDCl.sub.3) : 7.35 (2H, d, J=10.0 Hz), 3.82 (2H, t, J=7.2 Hz), 3.47 (1H, s), 2.65 (2H, t, J=8.2 Hz), 2.23-2.15 (2H, m). LCMS (ESI) m/z 222 [M+H].sup.+

Step 2: Synthesis of Reference Example Compound 33

[0401] The title compound was obtained as in step 4 of Reference Example 1, except that 1-(4-ethynyl-3,5-difluorophenyl)pyrrolidin-2-one was used in place of 2-ethynyl-1,3-difluorobenzene.

[0402] .sup.1H-NMR (DMSO-D.sub.6) : 8.18 (1H, s), 7.97 (1H, s), 7.64 (2H, d, J=10.5 Hz), 7.33-7.30 (1H, brs), 6.58 (2H, s), 5.92 (1H, d, J=7.3 Hz), 5.38 (1H, d, J=6.8 Hz), 5.21 (1H, d, J=4.1 Hz), 4.60-4.54 (1H, m), 4.08-4.07 (1H, m), 4.05-4.02 (1H, m), 3.84 (2H, t, J=7.2 Hz), 3.27-3.18 (1H, m), 3.15-3.08 (1H, m), 2.56 (2H, t, J=8.2 Hz), 2.10-2.02 (2H, m). LCMS (ESI) m/z 564 [M+H].sup.+.

Reference Example 34

4-[4-[2-[4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]-3-ethoxy-5-fluoro-phenyl]morpholine

Step 1: Synthesis of 4-(3-ethoxy-4-ethynyl-5-fluorophenyl)morpholine

[0403] 4-(4-ethynyl-3,5-difluorophenyl)morpholine (100 mg, 0.448 mmol) was dissolved in ethanol (3 mL). Sodium ethoxide (a 21 wt % ethanol solution, 0.168 mL, 0.448 mmol) was added thereto, followed by stirring for 0.5 hours in a sealed container at 160 C. After the resulting mixture was air-cooled to room temperature, ethyl acetate (5.0 mL) and a saturated ammonium chloride solution (2.0 mL) were sequentially added thereto, and the mixture was partitioned into an aqueous layer and an organic layer. The organic layer was then sequentially washed with water and saturated saline, and dried over anhydrous sodium sulfate, followed by distilling off the solvent. The residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate), thereby obtaining 4-(3-ethoxy-4-ethynyl-5-fluorophenyl)morpholine (60 mg, 54%) as a green solid.

[0404] .sup.1H-NMR (CDCl.sub.3) : 6.20 (1H, dd, J=12.1, 2.2 Hz), 6.13 (1H, s), 4.12-4.07 (2H, m), 3.85-3.82 (4H, m), 3.41 (1H, s), 3.20-3.15 (4H, m), 1.46 (3H, t, J=7.1 Hz). LCMS (ESI) m/z 250 [M+H].sup.+

Step 2: Synthesis of Reference Example Compound 34

[0405] The title compound was obtained as in Reference Example 1, except that 4-(3-ethoxy-4-ethynyl-5-fluorophenyl)morpholine was used in place of 2-ethynyl-1,3-difluorobenzene.

[0406] .sup.1H-NMR (DMSO-D.sub.6) : 8.17 (1H, s), 7.77 (1H, s), 7.41-7.36 (1H, m), 6.60 (2H, s), 6.48 (1H, d, J=13.6 Hz), 6.42 (1H, s), 5.90 (1H, d, J=7.0 Hz), 5.37 (1H, d, J=6.6 Hz), 5.21 (1H, d, J=4.4 Hz), 4.60-4.55 (1H, m), 4.20 (2H, q, J=7.0 Hz), 4.12-4.07 (1H, m), 4.06-4.02 (1H, m), 3.74-3.69 (4H, m), 3.27-3.05 (6H, m), 1.36 (3H, t, J=7.0 Hz). LCMS (ESI) m/z 592 [M+H].sup.+.

Reference Example 35

4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-ethoxy-4,6-difluoro-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of 1-ethoxy-2-ethynyl-3,5-difluorobenzene

[0407] The title compound was obtained as in step 1 of Reference Example 34, except that 2-ethynyl-1,3,5-trifluorobenzene was used in place of 4-(4-ethynyl-3,5-difluorophenyl)morpholine.

[0408] .sup.1H-NMR (CDCl.sub.3) : 6.48-6.39 (2H, m), 4.09 (2H, q, J=7.0 Hz), 3.45 (1H, s), 1.47 (3H, t, J=7.0 Hz).

Step 2: Synthesis of Reference Example Compound 35

[0409] The title compound was obtained as in Reference Example 1, except that 1-ethoxy-2-ethynyl-3,5-difluorobenzene was used in place of 2-ethynyl-1,3-difluorobenzene.

[0410] .sup.1H-NMR (DMSO-D.sub.6) : 8.18 (1H, s), 7.90 (1H, s), 7.36 (1H, s), 7.02-6.97 (2H, m), 6.61-6.58 (2H, m), 5.92 (1H, d, J=7.1 Hz), 5.41-5.36 (1H, m), 5.24-5.21 (1H, m), 4.61-4.55 (1H, m), 4.24 (2H, q, J=7.0 Hz), 4.11-4.08 (1H, m), 4.07-4.03 (1H, m), 3.25-3.07 (2H, m), 1.38 (3H, t, J=7.0 Hz). LCMS (ESI) m/z 525 [M+H].sup.+.

Reference Example 36

4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[3-(2-fluorophenyl)prop-1-ynyl]pyrrolo[2,3-d]pyrimidine

[0411] The title compound was obtained as in Reference Example 1, except that 1-fluoro-2-(prop-2-yn-1-yl)benzene was used in place of 2-ethynyl-1,3-difluorobenzene.

[0412] .sup.1H-NMR (CD.sub.3OD) : 8.20 (1H, s), 7.54 (1H, t, J=8.0 Hz), 7.45 (1H, s), 7.33-7.25 (1H, m), 7.20-7.16 (1H, m), 7.13-7.08 (1H, m), 5.82 (1H, d, J=6.8 Hz), 4.80-4.77 (1H, m), 4.30-4.28 (1H, m), 4.24-4.23 (1H, m), 3.90 (2H, s), 3.40-3.31 (2H, m). LCMS (ESI) m/z 477 [M+H].sup.+.

Reference Example 37

4-[4-[2-[4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]-3,5-difluoro-phenyl]thiomorpholine

Step 1: Synthesis of 4-(4-ethynyl-3,5-difluorophenyl)thiomorpholine

[0413] The title compound was obtained as in step 1 of Reference Example 23, except that thiomorpholine was used in place of morpholine.

[0414] .sup.1H-NMR (CDCl.sub.3) : 6.32 (2H, d, J=11.0 Hz), 3.69-3.66 (4H, m), 3.38 (1H, s), 2.69-2.66 (4H, m). LCMS (ESI) m/z 240 [M+H].sup.+

Step 2: Synthesis of Reference Example Compound 37

[0415] The title compound was obtained as in Reference Example 1, except that 4-(4-ethynyl-3,5-difluorophenyl)thiomorpholine was used in place of 2-ethynyl-1,3-difluorobenzene.

[0416] .sup.1H-NMR (DMSO-D.sub.6) : 8.18 (1H, s), 7.87 (1H, s), 7.36-7.32 (1H, m), 6.78 (2H, d, J=12.1 Hz), 6.59 (2H, s), 5.92 (1H, d, J=7.0 Hz), 5.46-5.32 (1H, m), 5.30-5.16 (1H, m), 4.59-4.55 (1H, m), 4.11-4.07 (1H, m), 4.06-4.02 (1H, m), 3.78-3.72 (4H, m), 3.24-3.06 (2H, m), 2.63-2.58 (4H, m). LCMS (ESI) m/z 582 [M+H].sup.+.

Reference Example 38

4-Amino-5-[2-[2,6-difluoro-4-(3-hydroxy-1-piperidyl)phenyl]ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of 1-(4-ethynyl-3,5-difluorophenyl)piperidin-3-ol

[0417] The title compound was obtained as in step 1 of Reference Example 23, except that piperidin-3-ol was used in place of morpholine.

[0418] .sup.1H-NMR (CDCl.sub.3) : 6.39 (2H, dt, J=17.2, 3.2 Hz), 3.91-3.83 (1H, m), 3.49 (1H, dd, J=12.7, 3.4 Hz), 3.38 (1H, s), 3.31-3.28 (1H, m), 3.12-3.00 (2H, m), 1.98-1.82 (3H, m), 1.68-1.56 (2H, m). LCMS (ESI) m/z 238 [M+H].sup.+

Step 2: Synthesis of Reference Example Compound 38

[0419] The title compound was obtained as in Reference Example 1, except that 1-(4-ethynyl-3,5-difluorophenyl)piperidin-3-ol was used in place of 2-ethynyl-1,3-difluorobenzene.

[0420] .sup.1H-NMR (DMSO-D.sub.6) : 8.20 (1H, s), 7.86 (1H, s), 7.36-7.32 (1H, m), 6.72 (2H, d, J=12.1 Hz), 6.59 (2H, s), 5.92 (1H, d, J=7.0 Hz), 5.38 (1H, d, J=6.2 Hz), 5.22 (1H, d, J=3.3 Hz), 4.88-4.83 (1H, m), 4.60-4.54 (1H, m), 4.11-4.08 (1H, m), 4.06-4.03 (1H, m), 3.68-3.51 (3H, m), 3.25-3.17 (1H, m), 3.15-3.07 (1H, m), 3.01-2.94 (1H, m), 2.84 (1H, dd, J=12.6, 8.6 Hz), 1.89-1.83 (1H, m), 1.75-1.69 (1H, m), 1.48-1.34 (2H, m). LCMS (ESI) m/z 580 [M+H].sup.+.

Reference Example 39

4-Amino-5-[2-[2,6-difluoro-4-(3-hydroxyazetidin-1-yl)phenyl]ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of 1-(4-ethynyl-3,5-difluorophenyl)azetidin-3-ol

[0421] The title compound was obtained as in step 1 of Reference Example 23, except that azetidin-3-ol was used in place of morpholine.

[0422] .sup.1H-NMR (CDCl.sub.3) : 5.90 (2H, dq, J=19.2, 3.4 Hz), 4.83-4.76 (1H, m), 4.17 (2H, dd, J=8.4, 7.0 Hz), 3.75 (2H, dd, J=8.4, 4.2 Hz), 3.38 (1H, s), 2.21 (1H, d, J=6.2 Hz). LCMS (ESI) m/z 210 [M+H].sup.+

Step 2: Synthesis of Reference Example Compound 39

[0423] The title compound was obtained as in Reference Example 1, except that 1-(4-ethynyl-3,5-difluorophenyl)azetidin-3-ol was used in place of 2-ethynyl-1,3-difluorobenzene.

[0424] .sup.1H-NMR (DMSO-D.sub.6) : 8.17 (1H, s), 7.85 (1H, s), 7.37-7.32 (1H, m), 6.59 (2H, s), 6.24 (2H, d, J=9.9 Hz), 5.91 (1H, d, J=7.0 Hz), 5.75 (1H, d, J=6.6 Hz), 5.38 (1H, d, J=6.6 Hz), 5.22 (1H, d, J=4.4 Hz), 4.60-4.54 (2H, m), 4.16-4.07 (3H, m), 4.06-4.02 (1H, m), 3.64 (2H, dd, J=8.6, 4.6 Hz), 3.25-3.17 (1H, m), 3.14-3.05 (1H, m). LCMS (ESI) m/z 552 [M+H].sup.+.

Reference Example 40

4-Amino-5-[2-[2,6-difluoro-4-[(3R)-3-hydroxy-1-piperidyl]phenyl]ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of (3R)-1-(4-ethynyl-3,5-difluorophenyl)piperidin-3-ol

[0425] The title compound was obtained as in step 1 of Reference Example 23, except that (R)-piperidin-3-ol was used in place of morpholine.

[0426] .sup.1H-NMR (CDCl.sub.3) : 6.39 (2H, d, J=11.0 Hz), 3.91-3.84 (1H, m), 3.49 (1H, dd, J=12.5, 3.3 Hz), 3.38 (1H, s), 3.33-3.27 (1H, m), 3.12-3.01 (2H, m), 1.98-1.85 (2H, m), 1.80 (1H, d, J=6.2 Hz), 1.69-1.60 (1H, m). LCMS (ESI) m/z 238 [M+H].sup.+

Step 2: Synthesis of Reference Example Compound 40

[0427] The title compound was obtained as in Reference Example 1, except that (3R)-1-(4-ethynyl-3,5-difluorophenyl)piperidin-3-ol was used in place of 2-ethynyl-1,3-difluorobenzene.

[0428] .sup.1H-NMR (DMSO-D.sub.6) : 8.17 (1H, s), 7.86 (1H, s), 7.36-7.32 (1H, m), 6.72 (2H, d, J=12.1 Hz), 6.59 (2H, s), 5.92 (1H, d, J=7.0 Hz), 5.38 (1H, d, J=6.6 Hz), 5.22 (1H, d, J=4.4 Hz), 4.86 (1H, d, J=4.4 Hz), 4.57 (1H, dd, J=12.3, 6.8 Hz), 4.11-4.08 (1H, m), 4.06-4.03 (1H, m), 3.68-3.50 (3H, m), 3.23-3.18 (1H, m), 3.15-3.07 (1H, m), 3.01-2.94 (1H, m), 2.84 (1H, dd, J=12.6, 8.6 Hz), 1.89-1.83 (1H, m), 1.75-1.69 (1H, m), 1.47-1.37 (2H, m). LCMS (ESI) m/z 580 [M+H].sup.+.

Reference Example 41

1-[4-[2-[4-amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]-3,5-difluoro-phenyl]pyrrolidine-3-carboxylic Acid

Step 1: Synthesis of 1-(4-ethynyl-3,5-difluorophenyl)pyrrolidine-3-carboxylic Acid

[0429] The title compound was obtained as in step 1 of Reference Example 23, except that pyrrolidine-3-carboxylic acid was used in place of morpholine.

[0430] .sup.1H-NMR (CDCl.sub.3) : 6.06 (2H, d, J=10.3 Hz), 3.61-3.52 (2H, m), 3.46-3.25 (4H, m), 2.38-2.33 (2H, m). LCMS (ESI) m/z 252 [M+H].sup.+

Step 2: Synthesis of Reference Example Compound 41

[0431] The title compound was obtained as in step 4 of Reference Example 1, except that 1-(4-ethynyl-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid was used in place of 2-ethynyl-1,3-difluorobenzene.

[0432] .sup.1H-NMR (DMSO-D.sub.6) : 12.59 (1H, s), 8.17 (1H, s), 7.85 (1H, s), 7.36-7.32 (1H, m), 6.59 (2H, s), 6.39 (2H, d, J=11.0 Hz), 5.91 (1H, d, J=7.0 Hz), 5.38 (1H, d, J=6.2 Hz), 5.22 (1H, d, J=4.4 Hz), 4.59-4.55 (1H, m), 4.12-4.08 (1H, m), 4.06-4.02 (1H, m), 3.54-3.42 (2H, m), 3.24-3.07 (5H, m), 2.27-2.11 (2H, m). LCMS (ESI) m/z 594 [M+H].sup.+.

Reference Example 42

4-Amino-5-[2-[2,6-difluoro-4-(4-oxo-1-piperidyl)phenyl]ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of 1-(4-ethynyl-3,5-difluorophenyl)piperidin-4-one

[0433] The title compound was obtained as in step 1 of Reference Example 23, except that piperidin-4-one was used in place of morpholine.

[0434] .sup.1H-NMR (CDCl.sub.3) : 6.40 (2H, d, J=11.0 Hz), 3.66 (4H, t, J=6.0 Hz), 3.41 (1H, s), 2.57 (4H, t, J=6.0 Hz). LCMS (ESI) m/z 236 [M+H].sup.+

Step 2: Synthesis of Reference Example Compound 42

[0435] The title compound was obtained as in step 4 of Reference Example 1, except that 1-(4-ethynyl-3,5-difluorophenyl)piperidin-4-one was used in place of 2-ethynyl-1,3-difluorobenzene.

[0436] .sup.1H-NMR (DMSO-D.sub.6) : 8.18 (1H, s), 7.88 (1H, s), 7.37-7.32 (1H, m), 6.86 (2H, d, J=11.7 Hz), 6.60 (2H, s), 5.92 (1H, d, J=7.0 Hz), 5.40 (1H, d, J=6.2 Hz), 5.24 (1H, d, J=4.0 Hz), 4.60-4.55 (1H, m), 4.11-4.08 (1H, m), 4.06-4.03 (1H, m), 3.73 (4H, t, J=5.9 Hz), 3.25-3.18 (1H, m), 3.14-3.07 (1H, m), 2.44 (4H, t, J=5.9 Hz). LCMS (ESI) m/z 578 [M+H].sup.+.

Reference Example 43

4-amino-5-[2-[4-(azetidin-1-yl)-2,6-difluoro-phenyl]ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of 1-(4-ethynyl-3,5-difluorophenyl)azetidine

[0437] The title compound was obtained as in step 1 of Reference Example 23, except that azetidine was used in place of morpholine.

[0438] .sup.1H-NMR (CDCl.sub.3) : 5.86 (2H, d, J=9.5 Hz), 3.93-3.89 (4H, m), 3.37 (1H, s), 2.45-2.37 (2H, m). LCMS (ESI) m/z 194 [M+H].sup.+

Step 2: Synthesis of Reference Example Compound 43

[0439] The title compound was obtained as in step 4 of Reference Example 1, except that 1-(4-ethynyl-3,5-difluorophenyl)azetidine was used in place of 2-ethynyl-1,3-difluorobenzene.

[0440] .sup.1H-NMR (DMSO-D.sub.6) : 8.17 (1H, s), 7.85 (1H, s), 7.36-7.33 (1H, m), 6.60 (2H, s), 6.20 (2H, d, J=9.9 Hz), 5.91 (1H, d, J=7.0 Hz), 5.38 (1H, d, J=6.6 Hz), 5.22 (1H, d, J=4.4 Hz), 4.57 (1H, q, J=6.2 Hz), 4.11-4.07 (1H, m), 4.05-4.03 (1H, m), 3.91 (4H, t, J=7.3 Hz), 3.25-3.17 (1H, m), 3.14-3.07 (1H, m), 2.37-2.30 (2H, m). LCMS (ESI) m/z 536 [M+H].sup.+.

Reference Example 44

4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-pyridyl)ethynyl]pyrrolo[2,3-d]pyrimidine

[0441] The title compound was obtained as in step 4 of Reference Example 1, except that 2-ethynylpyridine was used in place of 2-ethynyl-1,3-difluorobenzene.

[0442] .sup.1H-NMR (DMSO-D.sub.6) : 8.12 (1H, s), 7.90 (1H, s), 7.78 (1H, t, J=7.6 Hz), 7.60 (1H, d, J=7.6 Hz), 7.33 (1H, dd, J=7.6, 5.1 Hz), 7.28 (1H, dd, J=7.6, 5.1 Hz), 6.53 (2H, s), 5.86 (1H, d, J=7.0 Hz), 4.52 (1H, dd, J=7.0, 5.7 Hz), 4.04 (1H, dd, J=5.1, 2.5 Hz), 4.01-3.97 (1H, brm), 3.18-3.02 (2H, m). LCMS (ESI) m/z 446 [M+H].sup.+.

Reference Example 45

4-Amino-5-[2-(2-chlorophenyl)ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine

[0443] The title compound was obtained as in step 4 of Reference Example 1, except that 1-chloro-2-ethynylbenzene was used in place of 2-ethynyl-1,3-difluorobenzene.

[0444] .sup.1H-NMR (DMSO-D.sub.6) : 8.12 (1H, s), 7.88 (1H, s), 7.63-7.52 (1H, m), 7.54-7.53 (1H, m), 7.38-7.32 (2H, m), 7.27 (1H, dd, J=7.6, 5.1 Hz), 6.53 (2H, s), 5.86 (1H, d, J=7.0 Hz), 4.51 (1H, dd, J=7.0, 5.1 Hz), 4.03 (1H, dd, J=5.1, 2.5 Hz), 4.00-3.97 (1H, brm), 3.19-3.02 (2H, m). LCMS (ESI) m/z 479 [M+H].sup.+.

Reference Example 46

4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-fluorophenyl)ethynyl]pyrrolo[2,3-d]pyrimidine

[0445] The title compound was obtained as in step 4 of Reference Example 1, except that 1-ethynyl-2-fluorobenzene was used in place of 2-ethynyl-1,3-difluorobenzene.

[0446] .sup.1H-NMR (DMSO-D.sub.6) : 8.11 (1H, s), 7.86 (1H, s), 7.58 (1H, t, J=7.6 Hz), 7.43-7.37 (1H, m), 7.30-7.26 (2H, m), 7.21 (1H, t, J=7.6 Hz), 6.52 (2H, s), 5.86 (1H, d, J=7.0 Hz), 4.51 (1H, dd, J=7.0, 5.1 Hz), 4.03 (1H, t, J=2.5 Hz), 4.00-3.97 (1H, m), 3.17-3.02 (2H, m). LCMS (ESI) m/z 463 [M+H].sup.+.

Reference Example 47

4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-methoxyphenyl)ethynyl]pyrrolo[2,3-d]pyrimidine

[0447] The title compound was obtained as in step 4 of Reference Example 1, except that 1-ethynyl-2-methoxybenzene was used in place of 2-ethynyl-1,3-difluorobenzene.

[0448] .sup.1H-NMR (DMSO-D.sub.6) : 8.10 (1H, s), 7.73 (1H, s), 7.36-7.29 (3H, m), 7.04 (1H, d, J=8.2 Hz), 6.92 (1H, t, J=7.6 Hz), 6.53 (2H, s), 5.84 (1H, d, J=7.0 Hz), 4.50 (1H, dd, J=7.0, 5.1 Hz), 4.03 (1H, dd, J=5.1, 2.5 Hz), 3.84-3.84 (1H, brm), 4.00 (3H, s), 3.21-3.01 (2H, m). LCMS (ESI) m/z 475 [M+H].sup.+.

Reference Example 48

4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(4-dimethylaminophenyl)ethynyl]pyrrolo[2,3-d]pyrimidine

[0449] The title compound was obtained as in step 4 of Reference Example 1, except that 4-ethynyl-N,N-dimethylaniline was used in place of 2-ethynyl-1,3-difluorobenzene.

[0450] .sup.1H-NMR (DMSO-D.sub.6) : 8.10 (1H, s), 7.73 (1H, s), 7.36-7.29 (3H, m), 7.04 (1H, d, J=8.2 Hz), 6.92 (1H, t, J=7.6 Hz), 6.53 (2H, s), 5.84 (1H, d, J=7.0 Hz), 4.50 (1H, dd, J=7.0, 5.1 Hz), 4.03 (1H, dd, J=5.1, 2.5 Hz), 3.84-3.84 (1H, brm), 4.00 (3H, s), 3.21-3.01 (2H, m). LCMS (ESI) m/z 475 [M+H].sup.+.

Reference Example 49

4-Amino-5-[2-(2-cyanophenyl)ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine

[0451] The title compound was obtained as in step 4 of Reference Example 1, except that 2-ethynylbenzonitrile was used in place of 2-ethynyl-1,3-difluorobenzene.

[0452] .sup.1H-NMR (DMSO-D.sub.6) : 8.12 (1H, s), 7.93 (1H, s), 7.87 (1H, d, J=7.5 Hz), 7.74-7.68 (2H, m), 7.52 (1H, dt, J=1.4, 7.5 Hz), 7.29 (1H, m), 6.53 (2H, s), 5.87 (1H, d, J=6.8 Hz), 5.40 (1H, brs), 5.23 (1H, brs), 4.53 (1H, t, J=5.5 Hz), 4.04 (2H, dd, J=5.5, 2.7 Hz), 4.01-3.98 (2H, brm), 3.19-3.03 (2H, m). LCMS (ESI) m/z 470 [M+H].sup.+.

Reference Example 50

4-Amino-5-(3-cyclohexylprop]-1-ynyl)-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine

[0453] The title compound was obtained as in step 4 of Reference Example 1, except that prop-2-yn-1-yl cyclohexane was used in place of 2-ethynyl-1,3-difluorobenzene.

[0454] .sup.1H-NMR (DMSO-D.sub.6) : 8.05 (1H, s), 7.56 (1H, s), 7.27 (1H, dd, J=7.5, 4.1 Hz), 6.51 (2H, s), 5.79 (1H, d, J=6.8 Hz), 4.46 (1H, dd, J=6.8, 5.5 Hz), 4.01 (1H, dd, J=5.5, 2.1 Hz), 3.97-3.94 (1H, brm), 3.17-2.99 (2H, m), 2.32 (2H, d, J=6.2 Hz), 1.76-1.72 (2H, brm), 1.65-1.60 (2H, brm), 1.58-1.54 (1H, brm), 1.49-1.41 (1H, brm), 1.23-0.93 (5H, m). LCMS (ESI) m/z 465 [M+H].sup.+.

Reference Example 51

4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-fluoro-6-methoxy-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of 2-ethynyl-1-fluoro-3-methoxybenzene

[0455] 2-Fluoro-6-methoxybenzaldehyde (2.0 g, 13 mmol) was dissolved in methanol (20 mL). Then, potassium carbonate (3.6 g, 26 mmol) was added thereto at room temperature, and dimethyl(1-diazo-2-oxopropyl)phosphonate (2.3 mL, 16 mmol) was added thereto under ice-cooling, followed by stirring under ice-cooling for 1 hour and at room temperature for another 1 hour. The reaction solution was partitioned with the addition of ethyl acetate, a saturated aqueous sodium hydrogen carbonate solution, and water, and the organic layer was washed with saturated saline. After being dried over sodium sulfate, the resulting product was filtered and concentrated, and the residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/hexane), thereby obtaining 2-ethynyl-1-fluoro-3-methoxybenzene (1.6 g, 11 mmol, 81%) as a reddish brown solid.

[0456] .sup.1H-NMR (CDCl.sub.3) : 7.31-7.22 (1H, m), 6.76-6.65 (2H, m), 3.92 (3H, s), 3.53 (1H, s).

Step 2: Synthesis of Reference Example Compound 51

[0457] The title compound was obtained as in step 4 of Reference Example 1, except that 2-ethynyl-1-fluoro-3-methoxybenzene was used in place of 2-ethynyl-1,3-difluorobenzene.

[0458] .sup.1H-NMR (CD.sub.3OD) : 8.23 (1H, s), 7.57 (1H, s), 7.37-7.30 (1H, m), 6.90 (1H, d, J=8.5 Hz), 6.82-6.78 (1H, m), 5.86 (1H, d, J=6.8 Hz), 4.87-4.85 (1H, m), 4.32-4.27 (1H, m), 4.26-4.24 (1H, m), 3.97 (3H, s), 3.40-3.35 (2H, m). LCMS (ESI) m/z 493 [M+H].sup.+.

Reference Example 52

4-Amino-5-[2-(5-benzyloxy-2-pyridyl)ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of 5-(benzyloxy)-2-ethynylpyridine

[0459] The title compound was obtained as in step 1 of Reference Example 51, except that 5-(benzyloxy)picolinaldehyde was used in place of 2-fluoro-6-methoxybenzaldehyde.

[0460] .sup.1H-NMR (CDCl.sub.3) : 8.36 (1H, d, J=2.9 Hz), 7.44-7.34 (5H, m), 7.20 (2H, dd, 8.8, 2.9 Hz), 5.13 (2H, s), 3.07 (1H, s). LCMS (ESI) m/z 210 [M+H].sup.+

Step 2: Synthesis of Reference Example Compound 52

[0461] The title compound was obtained as in step 4 of Reference Example 1, except that 5-(benzyloxy)-2-ethynylpyridine was used in place of 2-ethynyl-1,3-difluorobenzene.

[0462] .sup.1H-NMR (CD.sub.3OD) : 8.29 (1H, d, J=2.9 Hz), 8.22 (1H, s), 7.65 (1H, s), 7.56 (1H, d, J=8.0 Hz), 7.50-7.30 (6H, m), 5.86 (1H, d, J=6.8 Hz), 5.20 (2H, s), 4.85-4.75 (1H, m), 4.35-4.20 (2H, m), 3.40-3.30 (2H, m). LCMS (ESI) m/z 552 [M+H].sup.+.

Reference Example 53

4-Amino-5-[2-(4-benzyloxy-2-methoxy-phenyl)ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of 4-(benzyloxy)-1-ethynyl-2-methoxybenzene

[0463] The title compound was obtained as in step 1 of Reference Example 51, except that 4-(benzyloxy)-2-methoxybenzaldehyde was used in place of 2-fluoro-6-methoxybenzaldehyde.

[0464] .sup.1H-NMR (CDCl.sub.3) : 7.48-7.32 (6H, m), 6.50-6.55 (2H, m), 5.07 (2H, s), 3.87 (3H, s), 3.24 (1H, s). LCMS (ESI) m/z 239 [M+H].sup.+

Step 2: Synthesis of Reference Example Compound 53

[0465] The title compound was obtained as in step 4 of Reference Example 1, except that 4-(benzyloxy)-1-ethynyl-2-methoxybenzene was used in place of 2-ethynyl-1,3-difluorobenzene.

[0466] .sup.1H-NMR (DMSO-D.sub.6) : 8.16 (1H, s), 7.74 (1H, s), 7.46-7.32 (7H, m), 6.78-6.76 (1H, brs), 6.67 (1H, d, J=8.0 Hz), 6.63-6.59 (2H, brs), 5.90 (1H, d, J=6.3 Hz), 5.39 (1H, d, J=6.1 Hz), 5.23 (1H, d, J=4.1 Hz), 5.16 (2H, s), 4.61-4.55 (1H, m), 4.12-4.08 (1H, m), 4.06-4.04 (1H, m), 3.89 (3H, s), 3.26-3.15 (1H, m), 3.15-3.03 (1H, m). LCMS (ESI) m/z 581 [M+H].sup.+.

Reference Example 54

4-Amino-5-[2-(2,6-difluoro-4-hydroxy-phenyl)ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of 4-ethynyl-3,5-difluorophenol

[0467] The title compound was obtained as in step 1 of Reference Example 51, except that 2,6-difluoro-4-hydroxybenzaldehyde was used in place of 2-fluoro-6-methoxybenzaldehyde.

[0468] .sup.1H-NMR (CDCl.sub.3) : 6.43 (2H, d, J=8.0 Hz), 5.60-5.40 (1H, brs.), 3.42 (1H, s).

Step 2: Synthesis of Reference Example Compound 54

[0469] The title compound was obtained as in step 4 of Reference Example 1, except that 4-ethynyl-3,5-difluorophenol was used in place of 2-ethynyl-1,3-difluorobenzene.

[0470] .sup.1H-NMR (CD.sub.3OD) : 8.23 (1H, s), 7.58 (1H, s), 6.48 (2H, d, J=9.5 Hz), 5.86 (1H, d, J=6.8 Hz), 4.85-4.81 (1H, m), 4.33-4.29 (1H, m), 4.26-4.23 (1H, m), 3.40-3.34 (2H, m). LCMS (ESI) m/z 497 [M+H].sup.+.

Reference Example 55

4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-ethoxy-6-fluoro-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of 2-ethoxy-6-fluorobenzaldehyde

[0471] 2-Fluoro-6-hydroxybenzaldehyde (50 g, 360 mmol) was dissolved in N,N-dimethylformamide (500 mL), and potassium carbonate (74 g, 540 mmol) and iodoethane (86 mL, 1.1 mol) were added thereto at room temperature, followed by stirring at room temperature overnight. The reaction solution was partitioned with the addition of ethyl acetate and water, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over sodium sulfate, followed by filtration and concentration. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/hexane), thereby obtaining 2-ethoxy-6-fluorobenzaldehyde (59 g, 98%) as a white solid.

[0472] .sup.1H-NMR (CDCl.sub.3) : 10.47 (1H, s), 7.50-7.41 (1H, m), 6.77-6.67 (2H, m), 4.16 (2H, q, J=6.8 Hz), 1.48 (3H, t, J=6.8 Hz). LCMS (ESI) m/z 169 [M+H].sup.+

Step 2: Synthesis of 1-ethoxy-2-ethynyl-3-fluorobenzene

[0473] The title compound was obtained as in step 1 of Reference Example 51, except that 2-ethoxy-6-fluorobenzaldehyde was used in place of 2-fluoro-6-methoxybenzaldehyde.

[0474] .sup.1H-NMR (CDCl.sub.3) : 7.28-7.20 (1H, m), 6.74-6.63 (2H, m), 4.13 (2H, q, J=7.1 Hz), 3.50 (1H, s), 1.47 (3H, t, J=7.1 Hz).

Step 3: Synthesis of Reference Example Compound 55

[0475] The title compound was obtained as in step 4 of Reference Example 1, except that 1-ethoxy-2-ethynyl-3-fluorobenzene was used in place of 2-ethynyl-1,3-difluorobenzene.

[0476] .sup.1H-NMR (CD.sub.3OD) : 8.24 (1H, s), 7.58 (1H, s), 7.34-7.28 (1H, m), 6.88 (1H, d, J=8.0 Hz), 6.82-6.74 (1H, m), 5.86 (1H, d, J=7.0 Hz), 4.85-4.81 (1H, m), 4.33-4.29 (1H, m), 4.27-4.21 (3H, m), 3.40-3.34 (2H, m), 1.47 (3H, t, J=7.0 Hz). LCMS (ESI) m/z 507 [M+H].sup.+.

Step 4: Synthesis of 4-amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-ethoxy-6-fluoro-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine hydrochloride

[0477] The title compound hydrochloride was obtained as in step 5 of Reference Example 1.

[0478] .sup.1H-NMR (DMSO-D.sub.6) : 8.38 (1H, s), 8.13 (1H, s), 7.44-7.38 (1H, m), 7.01-6.91 (3H, m), 6.80-6.40 (1H, brs), 6.01 (1H, d, J=6.8 Hz), 4.51-4.48 (1H, m), 4.24 (2H, q, J=7.0 Hz), 4.11-4.09 (1H, m), 4.06-4.02 (1H, m), 3.24-3.19 (1H, m), 3.14-3.09 (1H, m), 1.38 (3H, t, J=7.0 Hz). LCMS (ESI) m/z 507 [M+H]+

Reference Example 56

4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-fluoro-6-isopropoxy-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of 2-fluoro-6-isopropoxybenzaldehyde

[0479] The title compound was obtained as in step 1 of Reference Example 55, except that 2-iodopropane was used in place of iodoethane.

[0480] .sup.1H-NMR (CDCl.sub.3) : 10.44 (1H, s), 7.44 (1H, dt, J=6.3, 8.5 Hz), 6.77 (1H, d, J=8.5 Hz), 6.68 (1H, dd, J=10.2, 8.5 Hz), 4.72-4.62 (1H, m), 1.41 (6H, d, J=6.1 Hz).

Step 2: Synthesis of 2-ethynyl-1-fluoro-3-isopropoxybenzene

[0481] The title compound was obtained as in step 1 of Reference Example 51, except that 2-fluoro-6-isopropoxybenzaldehyde was used in place of 2-fluoro-6-methoxybenzaldehyde.

[0482] .sup.1H-NMR (CDCl.sub.3) : 7.22 (1H, dt, J=6.6, 8.4 Hz), 6.71-6.65 (2H, m), 4.64-4.56 (1H, m), 3.47 (1H, s), 1.39 (6H, d, J=6.2 Hz).

Step 3: Synthesis of Reference Example Compound 56

[0483] The title compound was obtained as in step 4 of Reference Example 1, except that 2-ethynyl-1-fluoro-3-isopropoxybenzene was used in place of 2-ethynyl-1,3-difluorobenzene.

[0484] .sup.1H-NMR (CD.sub.3OD) : 8.24 (1H, s), 7.57 (1H, s), 7.32-7.26 (1H, m), 6.89 (1H, d, J=9.0 Hz), 6.78-6.73 (1H, m), 5.87 (1H, d, J=6.8 Hz), 4.85-4.81 (1H, m), 4.79-4.71 (1H, m), 4.33-4.31 (1H, m), 4.27-4.24 (1H, m), 3.42-3.33 (2H, m), 1.41 (6H, d, J=5.9 Hz). LCMS (ESI) m/z 521 [M+H].sup.+.

Reference Example 57

4-Amino-5-[2-(4-cyano-2,6-difluoro-phenyl)ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of 4-ethynyl-3,5-difluorobenzonitrile

[0485] The title compound was obtained as in step 1 of Reference Example 51, except that 3,5-difluoro-4-formylbenzonitrile was used in place of 2-fluoro-6-methoxybenzaldehyde.

[0486] .sup.1H-NMR (CDCl.sub.3) : 7.25 (2H, d, J=8.0 Hz), 3.73 (1H, s).

Step 2: Synthesis of Reference Example Compound 57

[0487] The title compound was obtained as in step 4 of Reference Example 1, except that 4-ethynyl-3,5-difluorobenzonitrile was used in place of 2-ethynyl-1,3-difluorobenzene.

[0488] .sup.1H-NMR (CD.sub.3OD) : 8.26 (1H, s), 7.78 (1H, s), 7.58 (2H, d, J=7.1 Hz), 5.88 (1H, d, J=6.8 Hz), 4.85-4.78 (1H, m), 4.33-4.30 (1H, m), 4.27-4.24 (1H, m), 3.42-3.33 (2H, m). LCMS (ESI) m/z 506 [M+H].sup.+.

Reference Example 58

Methyl 4-[2-[4-amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]-3,5-difluoro-benzoate

Step 1: Synthesis of methyl 4-ethynyl-3,5-difluorobenzimidate

[0489] 3,5-Difluoro-4-formylbenzonitrile (200 mg, 1.2 mmol) was dissolved in methanol (3 mL). Then, potassium carbonate (331 mg, 24 mmol) was added thereto at room temperature, and dimethyl(1-diazo-2-oxopropyl)phosphonate (0.22 mL, 1.4 mmol) was added thereto under ice-cooling, followed by stirring under ice-cooling for 30 minutes and at room temperature for additional 2 hours and 30 minutes. The reaction solution was partitioned with the addition of ethyl acetate, a saturated aqueous sodium hydrogen carbonate solution, and water, and the organic layer was washed with saturated saline. After being dried over sodium sulfate, the resulting product was filtered and concentrated, and the residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/hexane), thereby obtaining methyl 4-ethynyl-3,5-difluorobenzimidate (172 mg).

[0490] LCMS (ESI) m/z 196 [M+H].sup.+

Step 2: Synthesis of Reference Example Compound 58

[0491] The title compound was obtained as in step 4 of Reference Example 1, except that methyl 4-ethynyl-3,5-difluorobenzimidate was used in place of 2-ethynyl-1,3-difluorobenzene.

[0492] .sup.1H-NMR (CD.sub.3OD) : 8.27 (1H, s), 7.76 (1H, s), 7.69 (2H, d, J=7.8 Hz), 5.88 (1H, d, J=6.6 Hz), 4.85-4.78 (1H, m), 4.33-4.31 (1H, m), 4.27-4.24 (1H, m), 3.94 (3H, s), 3.42-3.33 (2H, m). LCMS (ESI) m/z 539 [M+H].sup.+.

Reference Example 59

4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-fluoro-6-methylsulfanyl-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of (2-ethynyl-3-fluorophenyl)(methyl)sulfane

[0493] The title compound was obtained as in step 1 of Reference Example 51, except that 2-fluoro-6-(methylthio)benzaldehyde was used in place of 2-fluoro-6-methoxybenzaldehyde.

[0494] .sup.1H-NMR (CDCl.sub.3) : 7.32-7.25 (1H, m), 6.94 (1H, d, J=8.1 Hz), 6.89-6.64 (1H, m), 3.70 (1H, s), 2.51 (3H, s).

Step 2: Synthesis of Reference Example Compound 59

[0495] The title compound was obtained as in step 4 of Reference Example 1, except that (2-ethynyl-3-fluorophenyl)(methyl)sulfane was used in place of 2-ethynyl-1,3-difluorobenzene.

[0496] .sup.1H-NMR (CD.sub.3OD) : 8.24 (1H, s), 7.65 (1H, s), 7.37-7.31 (1H, m), 7.11 (1H, d, J=8.0 Hz), 6.99-6.94 (1H, m), 5.88 (1H, d, J=6.8 Hz), 4.85-4.78 (1H, m), 4.33-4.31 (1H, m), 4.27-4.24 (1H, m), 3.42-3.33 (2H, m), 2.56 (3H, s). LCMS (ESI) m/z 509 [M+H].sup.+.

Reference Example 60

4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-fluoro-6-propoxy-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of 2-fluoro-6-propoxybenzaldehyde

[0497] The title compound was obtained as in step 1 of Reference Example 55, except that 1-iodopropane was used in place of iodoethane.

[0498] .sup.1H-NMR (CDCl.sub.3) : 10.48 (1H, s), 7.46 (1H, dt, J=6.3, 8.5 Hz), 6.76 (1H, d, J=8.5 Hz), 6.71 (1H, dd, J=10.4, 8.5 Hz), 4.04 (2H, t, J=6.3 Hz), 1.93-1.83 (2H, m), 1.56 (1H, s), 1.07 (3H, t, J=7.3 Hz). LCMS (ESI) m/z 183 [M+H].sup.+

Step 2: Synthesis of 2-ethynyl-1-fluoro-3-propoxybenzene

[0499] The title compound was obtained as in step 1 of Reference Example 51, except that 2-fluoro-6-propoxybenzaldehyde was used in place of 2-fluoro-6-methoxybenzaldehyde.

[0500] .sup.1H-NMR (CDCl.sub.3) : 7.27-7.20 (1H, m), 6.72-6.63 (2H, m), 4.01 (2H, t, J=6.5 Hz), 3.49 (1H, s), 1.81-1.91 (2H, m), 1.07 (3H, t, J=8.0 Hz).

Step 3: Synthesis of Reference Example Compound 60

[0501] The title compound was obtained as in step 4 of Reference Example 1, except that 2-ethynyl-1-fluoro-3-propoxybenzene was used in place of 2-ethynyl-1,3-difluorobenzene.

[0502] .sup.1H-NMR (CD.sub.3OD) : 8.24 (1H, s), 7.57 (1H, s), 7.34-7.28 (1H, m), 6.88 (1H, d, J=8.0 Hz), 6.80-6.74 (1H, m), 5.86 (1H, d, J=6.8 Hz), 4.85-4.78 (1H, m), 4.33-4.31 (1H, m), 4.27-4.24 (1H, m), 4.13 (2H, t, J=6.7 Hz), 3.42-3.33 (2H, m), 1.92-1.82 (2H, m), 1.07 (3H, t, 7.4 Hz). LCMS (ESI) m/z 521 [M+H].sup.+.

Reference Example 61

4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-[2-fluoro-6-(2,2,2-trifluoroethoxy)phenyl]ethynyl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of 2-fluoro-6-(2,2,2-trifluoroethoxy)benzaldehyde

[0503] The title compound was obtained as in step 1 of Reference Example 55, except that 1,1,1-trifluoro-2-iodoethane was used in place of iodoethane.

[0504] .sup.1H-NMR (CDCl.sub.3) : 10.45 (1H, s), 7.53 (1H, dt, J=6.1, 8.6 Hz), 6.89 (1H, dd, J=9.8, 8.6 Hz), 6.77 (1H, d, J=8.6 Hz), 4.48 (2H, q, J=8.0 Hz). LCMS (ESI) m/z 223 [M+H].sup.+

Step 2: Synthesis of 2-ethynyl-1-fluoro-3-(2,2,2-trifluoroethoxy)benzene

[0505] The title compound was obtained as in step 1 of Reference Example 51, except that 2-fluoro-6-(2,2,2-trifluoroethoxy)benzaldehyde was used in place of 2-fluoro-6-methoxybenzaldehyde.

[0506] .sup.1H-NMR (CDCl.sub.3) : 7.32-7.24 (1H, m), 6.88-6.81 (1H, m), 6.72 (1H, d, J=8.0 Hz), 4.45 (2H, q, J=8.0 Hz), 3.53 (1H, s).

Step 3: Synthesis of Reference Example Compound 61

[0507] The title compound was obtained as in step 4 of Reference Example 1, except that 2-ethynyl-1-fluoro-3-(2,2,2-trifluoroethoxy)benzene was used in place of 2-ethynyl-1,3-difluorobenzene.

[0508] .sup.1H-NMR (CD.sub.3OD) : 8.24 (1H, s), 7.60 (1H, s), 7.39-7.33 (1H, m), 6.98 (1H, d, J=8.5 Hz), 6.93-6.89 (1H, m), 5.86 (1H, d, J=7.1 Hz), 4.84-4.82 (1H, m), 4.76 (2H, q, J=8.4 Hz), 4.33-4.29 (1H, m), 4.27-4.25 (1H, m), 3.40-3.37 (2H, m). LCMS (ESI) m/z 561 [M+H].sup.+.

Reference Example 62

4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-ethoxy-6-methoxy-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of 2-ethoxy-6-methoxybenzaldehyde

[0509] The title compound was obtained as in step 1 of Reference Example 55, except that 2-hydroxy-6-methoxybenzaldehyde was used in place of 2-fluoro-6-hydroxybenzaldehyde.

[0510] .sup.1H-NMR (CDCl.sub.3) : 10.53 (1H, s), 7.42 (1H, t, J=8.5 Hz), 6.56 (2H, d, J=8.5 Hz), 4.15-4.08 (2H, q, J=7.0 Hz), 3.90 (3H, s), 1.46 (3H, t, J=7.0 Hz). LCMS (ESI) m/z 181 [M+H].sup.+

Step 2: Synthesis of 1-ethoxy-2-ethynyl-3-methoxybenzene

[0511] The title compound was obtained as in step 1 of Reference Example 51, except that 2-ethoxy-6-methoxybenzaldehyde was used in place of 2-fluoro-6-methoxybenzaldehyde.

[0512] .sup.1H-NMR (CDCl.sub.3) : 7.23 (1H, t, J=8.4 Hz), 6.55-6.50 (2H, m), 4.12 (2H, q, J=7.0 Hz), 3.90 (3H, s), 3.53 (1H, s), 1.46 (3H, t, J=7.0 Hz). LCMS (ESI) m/z 177 [M+H].sup.+

Step 3: Synthesis of Reference Example Compound 62

[0513] The title compound was obtained as in step 4 of Reference Example 1, except that 1-ethoxy-2-ethynyl-3-methoxybenzene was used in place of 2-ethynyl-1,3-difluorobenzene.

[0514] .sup.1H-NMR (CD.sub.3OD) : 8.22 (1H, s), 7.48 (1H, s), 7.27-7.23 (1H, m), 6.67-6.64 (2H, m), 5.85 (1H, d, J=6.5 Hz), 4.88-4.80 (1H, m), 4.32-4.30 (1H, m), 4.26-4.23 (1H, m), 4.18 (2H, q, J=7.0 Hz), 3.91 (3H, s), 3.42-3.31 (2H, m), 1.45 (3H, t, J=7.0 Hz). LCMS (ESI) m/z 519 [M+H].sup.+.

Reference Example 63

8-[2-[4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2.3-d]pyrimidin-5-yl]ethynyl]-7-methoxyquinoline

Step 1: Synthesis of 8-ethynyl-7-methoxyquinoline

[0515] The title compound was obtained as in step 1 of Reference Example 51, except that 7-methoxyquinoline-8-carbaldehyde was used in place of 2-fluoro-6-methoxybenzaldehyde.

[0516] .sup.1H-NMR (CDCl.sub.3) : 9.03 (1H, dd, J=4.2, 1.8 Hz), 8.12 (1H, dd, J=8.3, 1.8 Hz), 7.83 (1H, d, J=9.2 Hz), 7.35 (1H, d, J=9.2 Hz), 7.33 (1H, dd, J=8.3, 4.2 Hz), 4.10 (3H, s), 3.87 (1H, s). LCMS (ESI) m/z 184 [M+H].sup.+

Step 2: Synthesis of Reference Example Compound 63

[0517] The title compound was obtained as in step 4 of Reference Example 1, except that 8-ethynyl-7-methoxyquinoline was used in place of 2-ethynyl-1,3-difluorobenzene.

[0518] .sup.1H-NMR (CD.sub.3OD) : 8.92 (1H, dd, J=4.3, 1.7 Hz), 8.29 (1H, dd, J=8.3, 1.7 Hz), 8.22 (1H, s), 7.92 (1H, d, J=9.0 Hz), 7.59 (1H, s), 7.54 (1H, d, J=9.0 Hz), 7.43 (1H, dd, J=8.3, 4.3 Hz), 5.89 (1H, d, J=6.8 Hz), 4.61-4.59 (1H, m), 4.33 (1H, dd, J=5.4, 2.7 Hz), 4.29-4.26 (1H, m), 4.11 (3H, s), 3.44-3.34 (2H, m). LCMS (ESI) m/z 526 [M+H].sup.+.

Reference Example 64

8-[2-[4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]-7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine

Step 1: Synthesis of 7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine

[0519] 7-Fluoro-2,3-dihydro-1,4-benzoxazine (1.50 g, 9.79 mmol) was dissolved in N,N-dimethylformamide (15 mL), and potassium carbonate (2.98 g, 21.5 mmol) and methyl iodide (1.67 g, 11.8 mmol) were added thereto at room temperature. After the resulting mixture was stirred at room temperature for 3 days, water (60 mL) and ethyl acetate (60 mL) were sequentially added thereto to partition the mixture into an aqueous layer and an organic layer, followed by separation of each layer. The aqueous layer was extracted with ethyl acetate (60 mL), and the obtained organic layers were combined. The combined organic layer was sequentially washed with water (60 mL) and saturated saline (60 mL), and dried over anhydrous sodium sulfate, followed by distilling off the solvent. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/hexane), thereby obtaining 7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine (1.09 g) as a light-yellow oil.

[0520] .sup.1H-NMR (CDCl.sub.3) : 6.58-6.51 (3H, m), 4.31 (2H, t, J=4.4 Hz), 3.20 (2H, t, J=4.4 Hz), 2.84 (3H, s). LCMS (ESI) m/z 168.1 [M+H].sup.+

Step 2: Synthesis of 7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine-8-carbaldehyde

[0521] 7-Fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine (1.07 g, 6.40 mmol) was dissolved in tetrahydrofuran (17.1 mL), and n-butyllithium (a 1.6 M hexane solution, 4.83 mL) was added thereto dropwise with stirring at 78 C. After the mixture was stirred at 78 C. for 3 hours, N,N-dimethylformamide (702 mg, 9.60 mmol) was added thereto dropwise, and the temperature was increased to 0 C. A saturated aqueous ammonium chloride solution (40 mL) and ethyl acetate (40 mL) were sequentially added thereto, followed by separation of each layer. The aqueous layer was extracted twice with ethyl acetate (40 mL), and the obtained organic layers were combined. The combined organic layer was sequentially washed with a saturated aqueous ammonium chloride solution (100 mL), water (100 mL), and saturated saline (100 mL), and dried over anhydrous sodium sulfate, followed by distilling off the solvent. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/hexane), thereby obtaining 7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine-8-carbaldehyde (1.13 g) as a bright yellow solid.

[0522] .sup.1H-NMR (CDCl.sub.3) : 10.38 (1H, d, J=2.2 Hz), 6.78-6.73 (1H, m), 6.62-6.57 (1H, m), 4.45-4.42 (2H, m), 3.28-3.25 (2H, m), 2.87 (3H, d, J=1.8 Hz). LCMS (ESI) m/z 196.2 [M+H].sup.+

Step 3: Synthesis of 8-ethynyl-7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine

[0523] The title compound was obtained as in step 1 of Reference Example 51, except that 7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine-8-carbaldehyde was used in place of 2-fluoro-6-methoxybenzaldehyde.

[0524] .sup.1H-NMR (CDCl.sub.3) : 6.59-6.56 (2H, m), 4.43 (2H, t, J=4.4 Hz), 3.49 (1H, s), 3.22 (2H, t, J=4.4 Hz), 2.84 (3H, s). LCMS (ESI) m/z 192.4 [M+H].sup.+

Step 4: Synthesis of Reference Example Compound 64

[0525] The title compound was obtained as in step 4 of Reference Example 1, except that 8-ethynyl-7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine was used in place of 2-ethynyl-1,3-difluorobenzene.

[0526] .sup.1H-NMR (DMSO-D.sub.6) : 8.17 (1H, s), 7.88 (1H, s), 7.38 (1H, dd, J=7.3, 4.8 Hz), 6.78-6.69 (2H, m), 6.60 (2H, s), 5.91 (1H, d, J=7.3 Hz), 5.40 (1H, s), 5.24 (1H, s), 4.58 (1H, t, J=6.2 Hz), 4.43 (2H, t, J=4.2 Hz), 4.12-4.07 (1H, m), 4.07-4.02 (1H, m), 3.26 (2H, t, J=4.2 Hz), 3.23-3.16 (1H, m), 3.15-3.07 (1H, m), 2.82 (3H, s). LCMS (ESI) m/z 534.3 [M+H].sup.+.

Step 5: Synthesis of 8-[2-[4-amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]-7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine hydrochloride

[0527] The title compound hydrochloride was obtained as in step 5 of Reference Example 1.

[0528] .sup.1H-NMR (DMSO-D.sub.6) : 8.47 (1H, s), 8.23 (1H, s), 6.82-6.76 (2H, m), 6.06 (1H, d, J=6.8 Hz), 4.49-4.45 (3H, m), 4.12 (1H, dd, J=5.2, 2.8 Hz), 4.05 (1H, dt, J=5.6, 2.8 Hz), 3.28 (2H, t, J=4.4 Hz), 3.23 (1H, dd, J=14.0, 6.0 Hz), 3.13 (1H, dd, J=14.0, 6.0 Hz), 2.84 (3H, s). LCMS (ESI) m/z 534.3 [M+H].sup.+

Reference Example 65

4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2,4-dimethoxy-3-pyridyl)ethynyl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of 3-ethynyl-2,4-dimethoxypyridine

[0529] The title compound was obtained as in step 1 of Reference Example 51, except that 2,4-dimethoxynicotinaldehyde was used in place of 2-fluoro-6-methoxybenzaldehyde.

[0530] .sup.1H-NMR (CDCl.sub.3) : 8.05 (1H, d, J=6.1 Hz), 6.54 (1H, d, J=6.1 Hz), 4.02 (3H, s), 3.95 (3H, s), 3.58 (1H, s). LCMS (ESI) m/z 164 [M+H].sup.+

Step 2: Synthesis of Reference Example Compound 65

[0531] The title compound was obtained as in step 4 of Reference Example 1, except that 3-ethynyl-2,4-dimethoxypyridine was used in place of 2-ethynyl-1,3-difluorobenzene.

[0532] .sup.1H-NMR (DMSO-D.sub.6) : 8.18 (1H, s), 8.08 (1H, d, J=6.1 Hz), 7.85 (1H, d, J=2.0 Hz), 7.35 (1H, s), 6.89 (1H, d, J=6.1 Hz), 6.59 (2H, s), 5.91 (1H, d, J=7.1 Hz), 4.58 (1H, t, J=5.7 Hz), 4.11-4.08 (1H, m), 4.06-4.03 (1H, m), 3.95 (6H, d, J=2.7 Hz), 3.35 (2H, s), 3.22-3.10 (2H, m). LCMS (ESI) m/z 506 [M+H].sup.+.

Reference Example 66

4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-ethylsulfanyl-6-fluoro-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of 2-(ethylthio)-6-fluorobenzaldehyde

[0533] Ethyl (3-fluorophenyl)sulfane (2.0 g, 12.8 mmol) was dissolved in tetrahydrofuran (30 mL), and n-butyllithium (a 2.69 M hexane solution, 5.71 mL) was added thereto dropwise while being stirred with cooling at 78 C. After the resulting mixture was stirred at 78 C. for 30 minute, N,N-dimethylformamide (2.95 mL, 38.4 mmol) was added thereto, followed by stirring for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction liquid, followed by extraction with ethyl acetate. After the solvent was distilled off, the residue was purified by column chromatography (developing solvent: hexane/ethyl acetate), thereby obtaining 2-(ethylthio)-6-fluorobenzaldehyde (430 mg, 18%) as a light-yellow solid.

[0534] .sup.1H-NMR (CDCl.sub.3) : 10.52 (1H, s), 7.51-7.46 (1H, m), 7.13 (1H, d, J=8.8 Hz), 6.91 (1H, t, J=8.8 Hz), 2.99 (2H, q, J=7.3 Hz), 1.42 (3H, t, J=7.3 Hz).

Step 2: Synthesis of ethyl(2-ethynyl-3-fluorophenyl)sulfane

[0535] The title compound was obtained as in step 1 of Reference Example 51, except that 2-(ethylthio)-6-fluorobenzaldehyde was used in place of 2-fluoro-6-methoxybenzaldehyde.

[0536] .sup.1H-NMR (CDCl.sub.3) : 7.30-7.24 (1H, m), 7.03 (1H, d, J=8.1 Hz), 6.89 (1H, dd, J=8.8, 8.1 Hz), 3.71 (1H, s), 3.03 (2H, q, J=7.3 Hz), 1.40 (3H, t, J=7.3 Hz).

Step 3: Synthesis of Reference Example Compound 66

[0537] The title compound was obtained as in step 4 of Reference Example 1, except that ethyl (2-ethynyl-3-fluorophenyl)sulfane was used in place of 2-ethynyl-1,3-difluorobenzene.

[0538] .sup.1H-NMR (DMSO-D.sub.6) : 8.16 (1H, s), 7.95 (1H, s), 7.91 (1H, d, J=7.0 Hz), 7.46 (1H, t, J=7.7 Hz), 7.41-7.32 (2H, m), 7.22 (1H, d, J=8.1 Hz), 7.12 (1H, t, J=8.8 Hz), 6.57 (2H, s), 5.91 (1H, d, J=7.0 Hz), 5.37 (1H, brs), 5.21 (1H, brs), 4.57 (1H, brs), 4.09-4.06 (1H, brm), 4.04-4.01 (1H, brm), 3.23-3.05 (2H, m), 1.28 (3H, t, J=7.0 Hz). LCMS (ESI) m/z 523 [M+H].sup.+.

Reference Example 67

4-Amino-5-[2-[2,6-difluoro-4-(triazol-2-ylmethoxy)phenyl]ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of 4-((2H-1,2,3-triazol-2-yl)methoxy)-2,6-difluorobenzaldehyde

[0539] The title compound was obtained as in step 1 of Reference Example 55, except that 2,6-difluoro-4-hydroxybenzaldehyde was used in place of 2-fluoro-6-hydroxybenzaldehyde, and that 2-(chloromethyl)triazole was used in place of iodoethane.

[0540] .sup.1H-NMR (CDCl.sub.3) : 10.21 (1H, s), 7.76 (2H, s), 6.88 (2H, d, J=10.0 Hz), 6.30 (2H, s). LCMS (ESI) m/z 240 [M+H].sup.+

Step 2: Synthesis of 2-((4-ethynyl-3,5-difluorophenoxy)methyl)-2H-1,2,3-triazole

[0541] The title compound was obtained as in step 1 of Reference Example 51, except that 4-((2H-1,2,3-triazol-2-yl)methoxy)-2,6-difluorobenzaldehyde was used in place of 2-fluoro-6-methoxybenzaldehyde.

[0542] .sup.1H-NMR (CDCl.sub.3) : 7.74 (2H, s), 7.26 (2H, s), 6.82 (1H, d, J=8.5 Hz), 6.24 (1H, s), 3.43 (1H, s). LCMS (ESI) m/z 236 [M+H].sup.+

Step 3: Synthesis of Reference Example Compound 67

[0543] The title compound was obtained as in step 4 of Reference Example 1, except that 2-((4-ethynyl-3,5-difluorophenoxy)methyl)-2H-1,2,3-triazole was used in place of 2-ethynyl-1,3-difluorobenzene.

[0544] .sup.1H-NMR (DMSO-D.sub.6) : 8.17 (1H, s), 7.99 (2H, s), 7.96 (1H, s), 7.36-7.31 (1H, brs), 7.19 (2H, d, J=9.5 Hz), 6.61-6.57 (2H, s), 6.52 (2H, s), 5.91 (1H, d, J=7.1 Hz), 5.40 (1H, d, J=6.6 Hz), 5.23 (1H, d, J=4.1 Hz), 4.59-4.54 (1H, m), 4.10-4.06 (1H, m), 4.05-4.02 (1H, m), 3.22-3.16 (1H, m), 3.10-3.06 (1H, m). LCMS (ESI) m/z 578 [M+H].sup.+.

Reference Example 68

4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-[2-(ethylamino)-6-fluoro-phenyl]ethynyl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of 2-(ethylamino)-6-fluorobenzaldehyde

[0545] The title compound was obtained as in step 1 of Reference Example 23, except that 2,6-difluorobenzaldehyde and ethylamine were used in place of 2-ethynyl-1,3,5-trifluorobenzene and morpholine.

[0546] .sup.1H-NMR (CDCl.sub.3) : 10.28 (1H, s), 8.66 (1H, brs), 7.35-7.29 (1H, m), 6.45 (1H, d, J=8.1 Hz), 6.27 (1H, dd, J=11.4, 8.1 Hz), 3.32-3.25 (2H, m), 1.33 (3H, t, J=7.3 Hz). LRMS (ESI) m/z 168 [M+H].sup.+

Step 2: Synthesis of N-ethyl-2-ethynyl-3-fluoroaniline

[0547] The title compound was obtained as in step 1 of Reference Example 51, except that 2-(ethylamino)-6-fluorobenzaldehyde was used in place of 2-fluoro-6-methoxybenzaldehyde.

[0548] .sup.1H-NMR (CDCl.sub.3) : 7.13 (1H, dd, J=14.7, 7.7 Hz), 6.38-6.34 (2H, m), 4.62-4.56 (1H, brm), 3.62 (1H, s), 3.21 (2H, dq, J=7.3, 6.6 Hz), 1.29 (3H, t, J=7.3 Hz). LRMS (ESI) m/z 164 [M+H].sup.+

Step 3: Synthesis of Reference Example Compound 68

[0549] The title compound was obtained as in step 4 of Reference Example 1, except that N-ethyl-2-ethynyl-3-fluoroaniline was used in place of 2-ethynyl-1,3-difluorobenzene.

[0550] .sup.1H-NMR (CD.sub.3OD) : 8.22 (1H, s), 7.55 (1H, s), 7.26 (1H, ddd, J=8.4, 8.4, 7.0 Hz), 6.82 (1H, d, J=8.4 Hz), 6.74 (1H, t, J=8.4 Hz), 5.87 (1H, d, J=6.6 Hz), 4.79 (1H, t, J=6.6 Hz), 4.30 (1H, dd, J=5.5, 2.6 Hz), 4.23-4.17 (2H, m), 4.19 (1H, q, J=7.0 Hz), 3.56-3.54 (2H, m), 1.46 (3H, t, J=7.0 Hz). LCMS (ESI) m/z 506 [M+H].sup.+.

Reference Example 69

4-Amino-5-[2-(2,4-difluoro-3-pyridyl)ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of 3-ethynyl-2,4-difluoropyridine

[0551] The title compound was obtained as in step 1 of Reference Example 51, except that 2,4-difluoronicotinaldehyde was used in place of 2-fluoro-6-methoxybenzaldehyde.

[0552] .sup.1H-NMR (ACETONE-D.sub.6) : 8.38 (1H, dd, J=8.2, 5.7 Hz), 7.44-7.40 (1H, m), 4.46 (1H, s). LCMS (ESI) m/z 140 [M+H].sup.+

Step 2: Synthesis of Reference Example Compound 69

[0553] The title compound was obtained as in step 4 of Reference Example 1, except that 3-ethynyl-2,4-difluoropyridine was used in place of 2-ethynyl-1,3-difluorobenzene.

[0554] .sup.1H-NMR (CD.sub.3OD) : 8.25 (1H, s), 8.18 (1H, dd, J=8.2, 5.8 Hz), 7.73 (1H, s), 7.27 (1H, dd, J=8.2, 5.8 Hz), 5.87 (1H, d, J=6.6 Hz), 4.82 (1H, d, J=5.9 Hz), 4.32 (1H, dd, J=5.5, 2.6 Hz), 4.26 (1H, q, J=3.1 Hz), 3.43-3.33 (2H, m). LCMS (ESI) m/z 482 [M+H].sup.+.

Reference Example 70

4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-ethylsulfonyl-6-fluoro-4-pyrrolidin-1-yl-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of 2,6-difluoro-4-(pyrrolidin-1-yl)benzaldehyde

[0555] The title compound was obtained as in step 1 of Reference Example 23, except that 2,4,6-trifluorobenzaldehyde and pyrrolidine were used in place of 2-ethynyl-1,3,5-trifluorobenzene and morpholine.

[0556] .sup.1H-NMR (CDCl.sub.3) : 10.04 (1H, s), 6.01 (2H, d, J=12.8 Hz), 3.35-3.32 (4H, m), 2.07-2.03 (4H, m). LCMS (ESI) m/z 212 [M+H].sup.+

Step 2: Synthesis of 2-(ethylthio)-6-fluoro-4-(pyrrolidin-1-yl)benzaldehyde

[0557] 2,6-Difluoro-4-(pyrrolidin-1-yl)benzaldehyde (3.7 g, 18 mmol) was dissolved in N,N-dimethylformamide (37 mL), and sodium ethanethiolate (1.6 g, 18 mmol) was added thereto, followed by stirring at room temperature for 30 minutes. Ethyl acetate, water, and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride aqueous solution, and dried over sodium sulfate, followed by distilling off the solvent. The residue was purified by silica gel column chromatography (developing solvent: chloroform), thereby obtaining 2-(ethylthio)-6-fluoro-4-(pyrrolidin-1-yl)benzaldehyde (4.4 g) as a white solid.

[0558] .sup.1H-NMR (CDCl.sub.3) : 10.18 (1H, s), 6.10 (1H, d, J=2.0 Hz), 5.98 (1H, dd, J=14.3, 2.0 Hz), 3.39-3.35 (4H, m), 2.91 (2H, q, J=7.3 Hz), 2.07-2.04 (4H, m), 1.41 (3H, t, J=7.3 Hz). LCMS (ESI) m/z 254 [M+H].sup.+

Step 3: Synthesis of 2-(ethylsulfonyl)-6-fluoro-4-(pyrrolidin-1-yl)benzaldehyde

[0559] 2-(Ethylthio)-6-fluoro-4-(pyrrolidin-1-yl)benzaldehyde (79 mg, 0.31 mmol) was dissolved in dichloromethane (1.6 mL), and 3-chloroperbenzoic acid (110 mg, 0.65 mmol) was added thereto in an ice bath, followed by stirring for 2 hours in an ice bath. 3-chloroperbenzoic acid (56 mg, 0.32 mmol) was added to the resulting mixture in an ice bath, followed by stirring for 1 hour in an ice bath. Thereafter, 3-chloroperbenzoic acid (10 mg, 0.058 mmol) was further added thereto in an ice bath, followed by stirring for 30 minutes in an ice bath. Chloroform, water, and a saturated aqueous sodium hydrogen carbonate solution were added in an ice bath to the reaction solution, and the aqueous layer was extracted with chloroform. The organic layer was washed with a saturated sodium chloride aqueous solution, and dried over sodium sulfate, followed by distilling off the solvent. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/hexane), thereby obtaining 2-(ethylsulfonyl)-6-fluoro-4-(pyrrolidin-1-yl)benzaldehyde (54 mg, 0.19 mmol, 62%) as a yellow solid.

[0560] .sup.1H-NMR (CDCl.sub.3) : 10.28 (1H, s), 7.19 (1H, d, J=2.6 Hz), 6.33 (1H, dd, J=13.9, 2.6 Hz), 3.62 (2H, q, J=7.5 Hz), 3.50-3.40 (4H, m), 2.11-2.08 (4H, m), 1.31 (3H, t, J=7.5 Hz). LCMS (ESI) m/z 286 [M+H].sup.+

Step 4: Synthesis of 1-(3-(ethylsulfonyl)-4-ethynyl-5-fluorophenyl)pyrrolidine

[0561] The title compound was obtained as in step 1 of Reference Example 51, except that 2-(ethylsulfonyl)-6-fluoro-4-(pyrrolidin-1-yl)benzaldehyde was used in place of 2-fluoro-6-methoxybenzaldehyde.

[0562] .sup.1H-NMR (CDCl.sub.3) : 7.01 (1H, d, J=2.3 Hz), 6.38 (1H, dd, J=11.9, 2.3 Hz), 3.63 (1H, s), 3.49 (2H, q, J=7.4 Hz), 3.36-3.32 (4H, m), 2.07-2.04 (4H, m), 1.27 (3H, t, J=7.4 Hz). LCMS (ESI) m/z 282 [M+H].sup.+

Step 5: Synthesis of Reference Example Compound 70

[0563] The title compound was obtained as in step 4 of Reference Example 1, except that 1-(3-(ethylsulfonyl)-4-ethynyl-5-fluorophenyl)pyrrolidine was used in place of 2-ethynyl-1,3-difluorobenzene.

[0564] .sup.1H-NMR (CD.sub.3OD) : 8.22 (1H, s), 7.61 (1H, s), 7.01 (1H, d, J=2.3 Hz), 6.66 (1H, dd, J=12.4, 2.3 Hz), 5.86 (1H, d, J=7.1 Hz), 4.85-4.81 (1H, m), 4.32-4.30 (1H, m), 4.27-4.24 (1H, m), 3.49 (2H, q, J=7.3 Hz), 3.40-3.36 (4H, m), 3.31-3.30 (2H, m), 2.10-2.07 (4H, m), 1.25 (3H, t, J=7.3 Hz). LCMS (ESI) m/z 624 [M+H].sup.+.

Reference Example 71

4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(3-fluoro-5-methoxy-4-pyridyl)ethynyl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of 4-ethynyl-3-fluoro-5-methoxypyridine

[0565] The title compound was obtained as in step 1 of Reference Example 51, except that 3-fluoro-5-methoxyisonicotinaldehyde was used in place of 2-fluoro-6-methoxybenzaldehyde.

[0566] .sup.1H-NMR (CDCl.sub.3) : 8.21-8.17 (2H, m), 4.03 (3H, s), 3.69 (1H, s). LCMS (ESI) m/z 152 [M+H].sup.+

Step 2: Synthesis of Reference Example Compound 71

[0567] The title compound was obtained as in step 4 of Reference Example 1, except that 4-ethynyl-3-fluoro-5-methoxypyridine was used in place of 2-ethynyl-1,3-difluorobenzene.

[0568] .sup.1H-NMR (DMSO-D.sub.6) : 8.38 (1H, d, J=7.8 Hz), 8.37 (1H, s), 8.20 (1H, s), 8.05 (1H, s), 7.32-7.29 (1H, brs), 6.58 (2H, s), 5.93 (1H, d, J=6.8 Hz), 5.41-5.38 (1H, brs), 5.23-5.21 (1H, brs), 4.59-4.57 (1H, m), 4.08-4.04 (2H, m), 4.07 (3H, s), 3.22-3.18 (1H, m), 3.12-3.08 (1H, m). LCMS (ESI) m/z 494 [M+H].sup.+.

Reference Example 72

4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-[2-ethylsulfonyl-6-fluoro-4-[(3R)-3-hydroxypyrrolidin-1-yl]phenyl]ethynyl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of 2,6-difluoro-4-[(3R)-3-hydroxypyrrolidin-1-yl]benzaldehyde

[0569] The title compound was obtained as in step 1 of Reference Example 23, except that 2,4,6-trifluorobenzaldehyde and (R)-pyrrolidin-3-ol were used in place of 2-ethynyl-1,3,5-trifluorobenzene and morpholine.

[0570] .sup.1H-NMR (CDCl.sub.3) : 10.05 (1H, s), 6.03 (2H, d, J=12.4 Hz), 4.70-4.66 (1H, m), 3.60-3.53 (2H, m), 3.48-3.42 (1H, m), 3.36-3.31 (1H, m), 2.21-2.12 (2H, m), 1.79 (1H, d, J=3.9 Hz). LCMS (ESI) m/z 228 [M+H].sup.+

Step 2: Synthesis of 2-ethylsulfanyl-6-fluoro-4-[(3R)-3-hydroxypyrrolidin-1-yl]benzaldehyde

[0571] The title compound was obtained as in step 2 of Reference Example 70, except that 2,6-difluoro-4-[(3R)-3-hydroxypyrrolidin-1-yl]benzaldehyde was used in place of 2,6-difluoro-4-(pyrrolidin-1-yl)benzaldehyde.

[0572] .sup.1H-NMR (CDCl.sub.3) : 10.19 (1H, s), 6.11 (1H, d, J=2.2 Hz), 6.00 (1H, dd, J=14.1, 2.2 Hz), 4.69-4.66 (1H, m), 3.63-3.57 (2H, m), 3.50-3.45 (1H, m), 3.41-3.35 (1H, m), 2.91 (2H, q, J=7.4 Hz), 2.21-2.14 (2H, m), 1.77 (1H, d, J=4.1 Hz), 1.41 (3H, t, J=7.4 Hz). LCMS (ESI) m/z 270 [M+H].sup.+

Step 3: Synthesis of 2-ethylsulfonyl-6-fluoro-4-[(3R)-3-hydroxypyrrolidin-1-yl]benzaldehyde

[0573] The title compound was obtained as in step 3 of Reference Example 70, except that 2-ethylsulfanyl-6-fluoro-4-[(3R)-3-hydroxypyrrolidin-1-yl]benzaldehyde was used in place of 2-(ethylthio)-6-fluoro-4-(pyrrolidin-1-yl)benzaldehyde.

[0574] .sup.1H-NMR (CDCl.sub.3) : 10.30 (1H, s), 7.20 (1H, d, J=2.4 Hz), 6.36 (1H, dd, J=14.0, 2.4 Hz), 4.73-4.71 (1H, m), 3.67-3.42 (4H, m), 3.46-3.42 (1H, m), 3.35-3.32 (1H, m), 2.21-2.17 (2H, m), 1.76 (1H, d, J=3.4 Hz), 1.32 (3H, t, J=7.6 Hz). LCMS (ESI) m/z 302 [M+H].sup.+

Step 4: Synthesis of (3R)-1-(3-(ethylsulfonyl)-4-ethynyl-5-fluorophenyl) pyrrolidin-3-ol

[0575] The title compound was obtained as in step 1 of Reference Example 51, except that 2-ethylsulfonyl-6-fluoro-4-[(3R)-3-hydroxypyrrolidin-1-yl]benzaldehyde was used in place of 2-fluoro-6-methoxybenzaldehyde.

[0576] .sup.1H-NMR (CDCl.sub.3) : 7.03 (1H, d, J=2.4 Hz), 6.41 (1H, dd, J=11.7, 2.4 Hz), 4.69-4.67 (1H, m), 3.65 (1H, s), 3.61-3.43 (5H, m), 3.35 (1H, d, J=11.0 Hz), 2.23-2.12 (2H, m), 1.69 (1H, d, J=3.7 Hz), 1.27 (3H, t, J=7.4 Hz). LCMS (ESI) m/z 298 [M+H].sup.+

Step 5: Synthesis of Reference Example Compound 72

[0577] The title compound was obtained as in step 4 of Reference Example 1, except that (3R)-1-(3-(ethylsulfonyl)-4-ethynyl-5-fluorophenyl)pyrrolidin-3-ol was used in place of 2-ethynyl-1,3-difluorobenzene.

[0578] .sup.1H-NMR (CD.sub.3OD) : 8.23 (1H, s), 7.62 (1H, s), 7.01 (1H, d, J=2.3 Hz), 6.67 (1H, dd, J=12.2, 2.3 Hz), 5.87 (1H, d, J=7.1 Hz), 4.85-4.79 (1H, m), 4.58-4.54 (1H, m), 4.32-4.30 (1H, m), 4.26-4.24 (1H, m), 3.58-3.43 (6H, m), 3.42-3.33 (2H, m), 2.22-2.14 (1H, m), 2.12-2.05 (1H, m), 1.25 (3H, t, J=7.4 Hz). LCMS (ESI) m/z 640 [M+H].sup.+.

Reference Example 73

4-Amino-5-[2-(2-chloro-6-fluoro-phenyl)ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of 1-chloro-2-ethynyl-3-fluorobenzene

[0579] The title compound was obtained as in step 1 of Reference Example 51, except that 2-chloro-6-fluorobenzaldehyde was used in place of 2-fluoro-6-methoxybenzaldehyde.

[0580] .sup.1H-NMR (CDCl.sub.3) : 7.29-7.21 (2H, m), 7.05-7.00 (1H, m), 3.61 (1H, s).

Step 2: Synthesis of Reference Example Compound 73

[0581] The title compound was obtained as in step 4 of Reference Example 1, except that 1-chloro-2-ethynyl-3-fluorobenzene was used in place of 2-ethynyl-1,3-difluorobenzene.

[0582] .sup.1H-NMR (CD.sub.3OD) : 8.23 (1H, s), 7.67 (1H, s), 7.37-7.30 (2H, m), 7.18-7.13 (1H, m), 5.87 (1H, d, J=7.1 Hz), 4.85-4.82 (1H, m), 4.33-4.31 (1H, m), 4.27-4.25 (1H, m), 3.43-3.34 (2H, m). LCMS (ESI) m/z 497 [M+H].sup.+.

Reference Example 74

4-[4-[2-[4-amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]-3,5-difluoro-phenyl]-1,1-dioxo-1,4-thiazinane

Step 1: Synthesis of 4-(4-ethynyl-3,5-difluorophenyl)thiomorpholine-1,1-dioxide

[0583] The title compound was obtained as in step 3 of Reference Example 70, except that 4-(4-ethynyl-3,5-difluorophenyl)thiomorpholine was used in place of 2-(ethylthio)-6-fluoro-4-(pyrrolidin-1-yl)benzaldehyde.

[0584] .sup.1H-NMR (CDCl.sub.3) : 6.40 (2H, d, J=10.2 Hz), 3.92-3.88 (4H, m), 3.42 (1H, s), 3.11-3.06 (4H, m). LCMS (ESI) m/z 272 [M+H].sup.+

Step 2: Synthesis of Reference Example Compound 74

[0585] The title compound was obtained as in step 4 of Reference Example 1, except that 4-(4-ethynyl-3,5-difluorophenyl)thiomorpholine-1,1-dioxide was used in place of 2-ethynyl-1,3-difluorobenzene.

[0586] .sup.1H-NMR (DMSO-D.sub.6) : 8.18 (1H, s), 7.90 (1H, s), 7.36-7.32 (1H, m), 6.95 (2H, d, J=11.4 Hz), 6.60 (2H, s), 5.92 (1H, d, J=7.0 Hz), 5.39 (1H, d, J=6.2 Hz), 5.24-5.22 (1H, m), 4.60-4.55 (1H, m), 4.12-4.08 (1H, m), 4.06-4.03 (1H, m), 3.95-3.89 (4H, m), 3.25-3.17 (1H, m), 3.17-3.09 (5H, m). LCMS (ESI) m/z 614 [M+H].sup.+.

Reference Example 75

4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-[2-ethylsulfonyl-6-fluoro-4-[(3R)-3-fluoropyrrolidin-1-yl]phenyl]ethynyl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of 2,6-difluoro-4-[(3R)-fluoropyrrolidin-1-yl]benzaldehyde

[0587] The title compound was obtained as in step 1 of Reference Example 23, except that 2,4,6-trifluorobenzaldehyde and (R)-3-fluoropyrrolidine were used in place of 2-ethynyl-1,3,5-trifluorobenzene and morpholine.

[0588] .sup.1H-NMR (CDCl.sub.3) : 10.07 (1H, s), 6.04 (2H, d, J=12.5 Hz), 5.47-5.32 (1H, m), 3.64-3.51 (4H, m), 2.50-2.41 (1H, m), 2.28-2.08 (1H, m). LCMS (ESI) m/z 230 [M+H].sup.+

Step 2: Synthesis of 2-(ethylthio)-6-fluoro-4-[(3R)-3-fluoropyrrolidin-1-yl]benzaldehyde

[0589] The title compound was obtained as in step 2 of Reference Example 70, except that 2,6-difluoro-4-[(3R)-fluoropyrrolidin-1-yl]benzaldehyde was used in place of 2,6-difluoro-4-(pyrrolidin-1-yl)benzaldehyde.

[0590] .sup.1H-NMR (CDCl.sub.3) : 10.21 (1H, s), 6.11 (1H, d, J=1.8 Hz), 6.01 (1H, dd, J=13.9, 1.8 Hz), 5.47-5.33 (1H, m), 3.70-3.52 (4H, m), 2.92 (2H, q, J=7.3 Hz), 2.49-2.40 (1H, m), 2.28-2.09 (1H, m), 1.41 (3H, t, J=7.3 Hz). LCMS (ESI) m/z 272 [M+H].sup.+

Step 3: Synthesis of 2-(ethylsulfonyl)-6-fluoro-4-[(3R)-3-fluoropyrrolidin-1-yl]benzaldehyde

[0591] The title compound was obtained as in step 3 of Reference Example 70, except that 2-(ethylthio)-6-fluoro-4-[(3R)-3-fluoropyrrolidin-1-yl]benzaldehyde was used in place of 2-(ethylthio)-6-fluoro-4-(pyrrolidin-1-yl)benzaldehyde.

[0592] .sup.1H-NMR (CDCl.sub.3) : 10.31 (1H, s), 7.21 (1H, d, J=2.3 Hz), 6.38 (1H, dd, J=13.7, 2.3 Hz), 5.51-5.35 (1H, m), 3.74-3.60 (6H, m), 2.53-2.45 (1H, m), 2.29-2.14 (1H, m), 1.32 (3H, t, J=7.3 Hz). LCMS (ESI) m/z 304 [M+H].sup.+

Step 4: Synthesis of (3R)-1-(3-ethylsulfonyl-4-ethynyl-5-fluoro-phenyl)-3-fluoro-pyrrolidine

[0593] The title compound was obtained as in step 1 of Reference Example 51, except that 2-(ethylsulfonyl)-6-fluoro-4-[(3R)-3-fluoropyrrolidin-1-yl]benzaldehyde was used in place of 2-fluoro-6-methoxybenzaldehyde.

[0594] .sup.1H-NMR (CDCl.sub.3) : 7.03 (1H, d, J=2.4 Hz), 6.42 (1H, dd, J=11.7, 2.4 Hz), 5.47-5.33 (1H, m), 3.66-3.64 (2H, m), 3.61-3.46 (5H, m), 2.49-2.40 (1H, m), 2.29-2.11 (1H, m), 1.27 (3H, t, J=7.5 Hz). LCMS (ESI) m/z 300 [M+H].sup.+

Step 5: Synthesis of Reference Example Compound 75

[0595] The title compound was obtained as in step 4 of Reference Example 1, except that (3R)-1-(3-ethylsulfonyl-4-ethynyl-5-fluoro-phenyl)-3-fluoro-pyrrolidine was used in place of 2-ethynyl-1,3-difluorobenzene.

[0596] .sup.1H-NMR (CD.sub.3OD) : 8.20 (1H, s), 7.60 (1H, s), 6.99 (1H, d, J=2.6 Hz), 6.66 (1H, dd, J=12, 2.6 Hz), 5.86 (1H, d, J=7.0 Hz), 5.47-5.34 (1H, m), 4.81-4.78 (1H, m), 4.31-4.29 (1H, m), 4.25-4.23 (1H, m), 3.70-3.44 (6H, m), 3.41-3.32 (2H, m), 2.42-2.15 (2H, m), 1.24 (3H, t, J=7.3 Hz). LCMS (ESI) m/z 642 [M+H].sup.+.

Reference Example 76

4-Amino-5-[2-(5-benzyloxypyrimidin-2-yl)ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of 5-(benzyloxy)-2-bromopyrimidine

[0597] 2-Bromopyrimidin-5-ol (200 mg, 1.1 mmol) was dissolved in a liquid mixture of tetrahydrofuran (1 mL) and N,N-dimethylformamide (1 mL). Then, potassium carbonate (170 mg, 1.3 mmol) and benzyl bromide (0.15 mL, 1.3 mmol) were added thereto at room temperature, followed by stirring at room temperature for 6 hours. The reaction solution was partitioned with ethyl acetate and water, and the organic layer was washed with water and saturated saline. The resulting product was dried over sodium sulfate, followed by filtration and concentration, and the residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/hexane), thereby obtaining 5-(benzyloxy)-2-bromopyrimidine (200 mg, 0.75 mmol, 66%) as a white powder.

[0598] .sup.1H-NMR (CDCl.sub.3) : 8.31 (2H, s), 7.45-7.36 (5H, m), 5.15 (2H, s). LCMS (ESI) m/z 265 [M+H].sup.+

Step 2: Synthesis of 5-(benzyloxy)-2-((triisopropylsilyl)ethynyl)pyrimidine

[0599] 5-(Benzyloxy)-2-bromopyrimidine (200 mg, 0.75 mmol), ethynyltriisopropylsilane (0.34 mL, 1.5 mmol), bis(triphenylphosphine)palladium (II) dichloride (53 mg, 0.075 mmol), copper iodide (14 mg, 0.075 mmol), and diisopropylethylamine (0.26 mL, 1.5 mmol) were suspended in tetrahydrofuran (2 mL). The reaction solution was stirred at 70 C. for 1 hour and 30 minutes, and filtered through a celite bed, followed by distilling off the solvent. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/hexane), thereby obtaining 5-(benzyloxy)-2-((triisopropylsilyl)ethynyl)pyrimidine (120 mg, 0.32 mmol, 43%) as a yellow oil.

[0600] .sup.1H-NMR (CDCl.sub.3) : 8.42 (2H, s), 7.43-7.36 (5H, m), 5.18 (2H, s), 1.17-1.13 (21H, m). LCMS (ESI) m/z 367 [M+H].sup.+

Step 3: Synthesis of 5-(benzyloxy)-2-ethynylpyrimidine

[0601] 5-(Benzyloxy)-2-((triisopropylsilyl)ethynyl)pyrimidine (120 mg, 0.32 mmol) was dissolved in tetrahydrofuran (1 mL), and a tetrabutylammonium fluoride solution (1 M tetrahydrofuran solution, 0.38 mL, 0.38 mmol) was added thereto at room temperature, followed by stirring at room temperature for 30 minutes.

[0602] After the solvent was distilled off, the residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/hexane), thereby obtaining 5-(benzyloxy)-2-ethynylpyrimidine (45 mg, 0.21 mmol, 67%) as a yellow powder.

[0603] .sup.1H-NMR (CDCl.sub.3) : 8.43 (2H, s), 7.44-7.38 (5H, m), 5.19 (2H, s), 3.04 (1H, s). LCMS (ESI) m/z 211 [M+H].sup.+

Step 4: Synthesis of Reference Example Compound 76

[0604] The title compound was obtained as in step 4 of Reference Example 1, except that 5-(benzyloxy)-2-ethynylpyrimidine was used in place of 2-ethynyl-1,3-difluorobenzene.

[0605] .sup.1H-NMR (CD.sub.3OD) : 8.57 (2H, s), 8.26 (1H, s), 7.75 (1H, s), 7.49-7.33 (5H, m), 5.87 (1H, d, J=6.8 Hz), 5.30 (2H, s), 4.84-4.79 (1H, m), 4.32-4.27 (1H, m), 4.26-4.24 (1H, m), 3.40-3.35 (2H, m). LCMS (ESI) m/z 553 [M+H].sup.+.

Reference Example 77

4-Amino-5-[2-(4-benzyloxy-2-fluoro-phenyl)ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of ((4-(benzyloxy)-2-fluorophenyl)ethynyl)trimethylsilane

[0606] The title compound was obtained as in step 2 of Reference Example 76, except that 4-(benzyloxy)-2-fluoro-1-iodobenzene and ethynyltrimethylsilane were used in place of 5-(benzyloxy)-2-bromopyrimidine and ethynyltriisopropylsilane.

[0607] .sup.1H-NMR (CDCl.sub.3) : 7.43-7.33 (6H, m), 6.77 (1H, dd, J=10.4, 2.8 Hz), 6.70-6.67 (1H, m), 5.04 (2H, s), 0.25 (9H, s).

Step 2: Synthesis of 4-(benzyloxy)-1-ethynyl-2-fluorobenzene

[0608] The title compound was obtained as in step 3 of Reference Example 76, except that 4((4-(benzyloxy)-2-fluorophenyl)ethynyl)trimethylsilane was used in place of 5-(benzyloxy)-2-((triisopropylsilyl)ethynyl)pyrimidine.

[0609] .sup.1H-NMR (CDCl.sub.3) : 7.43-7.29 (6H, m), 6.66-6.79 (2H, m), 5.04 (2H, s), 3.25 (1H, s).

Step 3: Synthesis of Reference Example Compound 77

[0610] The title compound was obtained as in step 4 of Reference Example 1, except that 4-(benzyloxy)-1-ethynyl-2-fluorobenzene was used in place of 2-ethynyl-1,3-difluorobenzene.

[0611] .sup.1H-NMR (CD.sub.3OD) : 8.22 (1H, s), 7.56 (1H, s), 7.40-7.26 (6H, m), 6.87-6.84 (2H, m), 5.85 (1H, d, J=6.8 Hz), 5.12 (2H, s), 4.83-4.81 (1H, m), 4.33-4.29 (1H, m), 4.27-4.25 (1H, m), 3.40-3.35 (2H, m). LCMS (ESI) m/z 569 [M+H].sup.+.

Reference Example 78

4-Amino-5-[2-[4-(benzylamino)phenyl]ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of N-benzyl-4-((triisopropylsilyl)ethynyl)aniline

[0612] The title compound was obtained as in step 2 of Reference Example 76, except that N-benzyl-4-iodoaniline and ethynyltriisopropylsilane were used in place of 5-(benzyloxy)-2-bromopyrimidine and ethynyltriisopropylsilane.

[0613] .sup.1H-NMR (CDCl.sub.3) : 7.37-7.25 (7H, m), 6.53 (2H, d, J=8.8 Hz), 4.34 (2H, s), 1.12-1.05 (21H, m). LCMS (ESI) m/z 364 [M+H].sup.+

Step 2: Synthesis of N-benzyl-4-ethynylaniline

[0614] The title compound was obtained as in step 3 of Reference Example 76, except that N-benzyl-4-((triisopropylsilyl)ethynyl)aniline was used in place of 5-(benzyloxy)-2-((triisopropylsilyl)ethynyl)pyrimidine.

[0615] .sup.1H-NMR (CDCl.sub.3) : 7.39-7.25 (7H, m), 6.55 (2H, d, J=8.0 Hz), 4.35 (2H, s), 4.28-4.19 (1H, brs), 2.96 (1H, s). LCMS (ESI) m/z 208 [M+H].sup.+

Step 3: Synthesis of Reference Example Compound 78

[0616] The title compound was obtained as in step 4 of Reference Example 1, except that N-benzyl-4-ethynylaniline was used in place of 2-ethynyl-1,3-difluorobenzene.

[0617] .sup.1H-NMR (CD.sub.3OD) : 8.25 (1H, s), 7.60 (1H, s), 7.36-7.20 (7H, m), 6.60 (2H, d, J=8.8 Hz), 5.93 (1H, d, J=6.6 Hz), 4.73-4.70 (1H, m), 4.35 (2H, s), 4.31-4.29 (1H, m), 4.25-4.22 (1H, m), 3.40-3.35 (2H, m). LCMS (ESI) m/z 550 [M+H].sup.+.

Reference Example 79

2-[2-[4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]-3-fluorobenzamide

Step 1: Synthesis of 3-fluoro-2-((trimethylsilyl)ethynyl)benzamide

[0618] The title compound was obtained as in step 2 of Reference Example 76, except that 3-fluoro-2-iodobenzamide and ethynyltrimethylsilane were used in place of 5-(benzyloxy)-2-bromopyrimidine and ethynyltriisopropylsilane.

[0619] .sup.1H-NMR (CDCl.sub.3) : 7.96 (1H, d, J=7.8 Hz), 7.83-7.55 (1H, brs), 7.45-7.40 (1H, m), 7.28-7.22 (1H, m), 6.19-5.72 (1H, brs), 0.31 (9H, s). LCMS (ESI) m/z 236 [M+H].sup.+

Step 2: Synthesis of 2-ethynyl-3-fluorobenzamide

[0620] The title compound was obtained as in step 3 of Reference Example 76, except that 3-fluoro-2-((trimethylsilyl)ethynyl)benzamide was used in place of 5-(benzyloxy)-2-((triisopropylsilyl)ethynyl)pyrimidine.

[0621] .sup.1H-NMR (CDCl.sub.3) : 7.89-7.86 (1H, m), 7.46 (1H, dt, J=5.4, 8.0 Hz), 7.30-7.21 (2H, m), 6.29-5.45 (1H, brs), 3.77 (1H, s). LCMS (ESI) m/z 164 [M+H].sup.+

Step 3: Synthesis of Reference Example Compound 79

[0622] The title compound was obtained as in step 4 of Reference Example 1, except that 2-ethynyl-3-fluorobenzamide was used in place of 2-ethynyl-1,3-difluorobenzene.

[0623] .sup.1H-NMR (CD.sub.3OD) : 8.23 (1H, s), 7.66 (1H, s), 7.47-7.41 (2H, m), 7.35-7.30 (1H, m), 5.87 (1H, d, J=6.8 Hz), 4.82-4.75 (1H, m), 4.32-4.29 (1H, m), 4.26-4.24 (1H, m), 3.40-3.35 (2H, m). LCMS (ESI) m/z 506 [M+H].sup.+.

Reference Example 80

4-Amino-5-[2-(3,5-difluoro-2-methoxy-4-pyridyl)ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of 4-ethynyl-3,5-difluoro-2-methoxypyridine

[0624] 2,3,5-Trifluoro-4-iodopyridine (500 mg, 1.93 mmol) was dissolved in methanol (3 mL), and sodium methoxide (a 5 M methanol solution, 1.15 mL) was added thereto at room temperature, followed by stirring at room temperature overnight. The reaction solution was partitioned between ethyl acetate and water, and the organic layer was separated and sequentially washed with water and saturated brine. The solvent was distilled off, and the residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/hexane), thereby obtaining the target product (376 mg) as an oil mixture of 4-ethynyl-3,5-difluoro-2-methoxypyridine and 4-ethynyl-3-fluoro-2,5-dimethoxypyridine.

[0625] The synthesis was performed as in steps 2 and 3 of Reference Example 76 by using the obtained mixture, followed by separation and purification by silica gel column chromatography (developing solvent: ethyl acetate/hexane) to give the title compound.

[0626] .sup.1H-NMR (CDCl.sub.3) : 7.87 (1H, s), 4.02 (3H, s), 3.73 (1H, s)

Step 2: Synthesis of Reference Example Compound 80

[0627] The title compound was obtained as in step 4 of Reference Example 1, except that 4-ethynyl-3,5-difluoro-2-methoxypyridine was used in place of 2-ethynyl-1,3-difluorobenzene.

[0628] .sup.1H-NMR (DMSO-D.sub.6) : 8.20 (1H, s), 8.19 (1H, s), 8.14 (1H, s), 7.32-7.29 (1H, m), 6.59 (2H, s), 5.94 (1H, d, J=6.6 Hz), 5.41 (1H, d, J=6.6 Hz), 5.24 (1H, d, J=4.4 Hz), 4.58 (1H, ddd, J=7.3, 6.2, 4.4 Hz), 4.11-4.04 (2H, m), 3.96 (3H, s). LCMS (ESI) m/z 512 [M+H].sup.+.

Reference Example 81

4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(3-fluoro-2,5-dimethoxy-4-pyridyl)ethynyl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of 4-ethynyl-3-fluoro-2,5-dimethoxypyridine

[0629] In accordance with step 1 of Reference Example 80, the title compound was obtained.

[0630] .sup.1H-NMR (CDCl.sub.3) : 7.76 (1H, s), 4.01 (3H, s), 3.97 (3H, s), 3.66 (1H, s).

Step 2: Synthesis of Reference Example Compound 81

[0631] The title compound was obtained as in step 4 of Reference Example 1, except that 4-ethynyl-3-fluoro-2,5-dimethoxypyridine was used in place of 2-ethynyl-1,3-difluorobenzene.

[0632] .sup.1H-NMR (CD.sub.3OD) : 8.26 (1H, s), 7.83 (1H, s), 7.75 (1H, s), 5.89 (1H, d, J=6.6 Hz), 4.85-4.82 (3H, m), 4.34-4.32 (1H, m), 4.29-4.26 (1H, m), 4.04 (3H, s), 3.99 (3H, s), 3.70-3.67 (1H, m), 3.58-3.56 (1H, m), 3.42 (1H, dd, J=12.5, 4.4 Hz), 3.37 (1H, dd, J=12.5, 3.7 Hz). LCMS (ESI) m/z 524 [M+H].sup.+.

Reference Example 82

4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-ethylsulfanylphenyl)ethynyl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of 1-ethylsulfanyl-2-ethynyl-benzene

[0633] The title compound was obtained as in step 2 and step 3 of Reference Example 76, except that 1-bromo-2-ethylsulfanyl-benzene was used in place of 5-(benzyloxy)-2-bromopyrimidine.

[0634] .sup.1H-NMR (CDCl.sub.3) : 7.49 (1H, dd, J=7.5, 1.3 Hz), 7.33-7.25 (2H, m), 7.12 (1H, dt, J=1.5, 7.3 Hz), 3.47 (1H, s), 3.01 (2H, q, J=7.5 Hz), 1.37 (3H, dd, J=9.5, 5.1 Hz).

Step 2: Synthesis of Reference Example Compound 82

[0635] The title compound was obtained as in step 4 of Reference Example 1, except that 1-ethylsulfanyl-2-ethynyl-benzene was used in place of 2-ethynyl-1,3-difluorobenzene.

[0636] .sup.1H-NMR (DMSO-D.sub.6) : 8.18 (1H, s), 7.91 (1H, s), 7.52 (1H, dd, J=7.7, 1.1 Hz), 7.44-7.36 (3H, m), 7.23 (1H, dt, J=1.5, 7.3 Hz), 6.61 (2H, s), 5.93 (1H, d, J=7.0 Hz), 5.41 (1H, d, J=6.6 Hz), 5.25 (1H, d, J=4.4 Hz), 4.59 (1H, q, J=6.2 Hz), 4.12-4.03 (2H, m), 3.23-3.19 (1H, m), 3.13 (1H, dd, J=8.1, 5.1 Hz), 3.05 (2H, q, J=7.5 Hz), 1.29 (3H, t, J=7.3 Hz). LCMS (ESI) m/z 505.3 [M+H].sup.+.

Reference Example 83

4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(1,1-dioxo-3,4-dihydro-2H-thiochromen-8-yl)ethynyl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of triisopropyl(thiochroman-8-ylethynyl)silane

[0637] The title compound was obtained as in step 2 of Reference Example 76, except that 8-iodothiochroman was used in place of 5-(benzyloxy)-2-bromopyrimidine.

[0638] .sup.1H-NMR (CDCl.sub.3) : 7.27-7.25 (1H, m), 6.97-6.93 (1H, m), 6.89 (1H, t, J=7.6 Hz), 3.07-3.04 (2H, m), 2.80 (2H, t, J=6.1 Hz), 2.12-2.06 (2H, m), 1.26-1.04 (21H, m).

Step 2: Synthesis of 8-ethynyl thiochroman

[0639] The title compound was obtained as in step 3 of Reference Example 76, except that triisopropyl(thiochroman-8-ylethynyl)silane was used in place of 5-(benzyloxy)-2-((triisopropylsilyl)ethynyl)pyrimidine.

[0640] .sup.1H-NMR (CDCl.sub.3) : 7.31-7.26 (1H, m), 7.02-6.98 (1H, m), 6.92 (1H, t, J=7.6 Hz), 3.45 (1H, s), 3.09-3.06 (2H, m), 2.82 (2H, t, J=6.1 Hz), 2.13-2.07 (2H, m).

Step 3: Synthesis of 8-ethynyl thiochroman 1,1-dioxide

[0641] 1,4-Dioxane (1 mL) and water (0.50 mL) were added to 8-ethynyl thiochroman (59 mg, 0.34 mmol). Then, oxone (420 mg, 0.68 mmol) was added thereto under ice-cooling, and the resulting mixture was allowed to warm to room temperature with stirring overnight. The reaction solution was partitioned at room temperature with the addition of ethyl acetate, a saturated aqueous sodium hydrogen carbonate solution, and water, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated saline, and dried over sodium sulfate, followed by filtration and concentration. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/hexane), thereby obtaining the title compound (51 mg, 0.25 mmol, 73%) as a white solid.

[0642] .sup.1H-NMR (CDCl.sub.3) : 7.55 (1H, d, J=7.8 Hz), 7.38 (1H, t, J=7.8 Hz), 7.21 (1H, dd, J=7.8, 1.0 Hz), 3.59 (1H, s), 3.44-3.41 (2H, m), 3.01 (2H, t, J=6.2 Hz), 2.48-2.42 (2H, m). LCMS (ESI) m/z 207 [M+H].sup.+

Step 4: Synthesis of Reference Example Compound 83

[0643] The title compound was obtained as in step 4 of Reference Example 1, except that 8-ethynyl thiochroman 1,1-dioxide was used in place of 2-ethynyl-1,3-difluorobenzene.

[0644] .sup.1H-NMR (CD.sub.3OD) : 8.22 (1H, s), 7.69 (1H, s), 7.57 (1H, d, J=7.6 Hz), 7.48 (1H, t, J=7.6 Hz), 7.30 (1H, d, J=7.6 Hz), 5.87 (1H, d, J=6.8 Hz), 4.83-4.79 (1H, m), 4.32-4.30 (1H, m), 4.27-4.25 (1H, m), 3.54-3.51 (2H, m), 3.43-3.33 (2H, m), 3.07 (2H, t, J=6.0 Hz), 2.43-2.38 (2H, m). LCMS (ESI) m/z 549 [M+H].sup.+.

Reference Example 84

2-[2-[4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]-3-fluoro-benzenesulfonamide

Step 1: Synthesis of 3-fluoro-2-((trimethylsilyl)ethynyl)benzenesulfonamide

[0645] The title compound was obtained as in step 2 of Reference Example 76, except that 3-fluoro-2-iodobenzenesulfonamide and ethynyltrimethylsilane were used in place of 5-(benzyloxy)-2-bromopyrimidine and ethynyltriisopropylsilane.

[0646] .sup.1H-NMR (CDCl.sub.3) : 7.85 (1H, d, J=7.8 Hz), 7.45-7.41 (1H, m), 7.31-7.27 (1H, m), 5.24 (2H, s), 0.33 (9H, s). LCMS (ESI) m/z 272 [M+H].sup.+

Step 2: Synthesis of 2-ethynyl-3-fluorobenzenesulfonamide

[0647] The title compound was obtained as in step 3 of Reference Example 76, except that 3-fluoro-2-((trimethylsilyl)ethynyl)benzenesulfonamide was used in place of 5-(benzyloxy)-2-((triisopropylsilyl)ethynyl)pyrimidine.

[0648] .sup.1H-NMR (CDCl.sub.3) : 7.88 (1H, d, J=7.8 Hz), 7.52-7.47 (1H, m), 7.37-7.31 (1H, m), 5.21 (2H, s), 3.90 (1H, s). LCMS (ESI) m/z 200 [M+H].sup.+

Step 3: Synthesis of Reference Example Compound 84

[0649] The title compound was obtained as in step 4 of Reference Example 1, except that 2-ethynyl-3-fluorobenzenesulfonamide was used in place of 2-ethynyl-1,3-difluorobenzene.

[0650] .sup.1H-NMR (CD3OD) : 8.30 (1H, s), 7.85 (1H, d, J=7.8 Hz), 7.74 (1H, s), 7.54-7.49 (1H, m), 7.46-7.41 (1H, m), 5.88 (1H, d, J=6.8 Hz), 4.84-4.81 (1H, m), 4.33-4.30 (1H, m), 4.27-4.25 (1H, m), 3.43-3.33 (2H, m). LCMS (ESI) m/z 542 [M+H].sup.+.

Reference Example 85

4-Amino-5-[2-(2-cyano-6-fluoro-phenyl)ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of 3-fluoro-2-((trimethylsilyl)ethynyl)benzonitrile

[0651] The title compound was obtained as in step 2 of Reference Example 76, except that 3-fluoro-2-iodobenzonitrile and ethynyltrimethylsilane were used in place of 5-(benzyloxy)-2-bromopyrimidine and ethynyltriisopropylsilane.

[0652] .sup.1H-NMR (CDCl.sub.3) : 7.46-7.44 (1H, m), 7.41-7.35 (1H, m), 7.33-7.29 (1H, m), 0.31 (9H, s). LCMS (ESI) m/z 218 [M+H].sup.+

Step 2: Synthesis of 2-ethynyl-3-fluorobenzonitrile

[0653] The title compound was obtained as in step 3 of Reference Example 76, except that 3-fluoro-2-((trimethylsilyl)ethynyl)benzonitrile was used in place of 5-(benzyloxy)-2-((triisopropylsilyl)ethynyl)pyrimidine.

[0654] .sup.1H-NMR (CDCl.sub.3) : 7.51 (1H, dd, J=7.7, 1.5 Hz), 7.49-7.44 (1H, m), 7.39-7.35 (1H, m), 3.72 (1H, s).

Step 3: Synthesis of Reference Example Compound 85

[0655] The title compound was obtained as in step 4 of Reference Example 1, except that 2-ethynyl-3-fluorobenzonitrile was used in place of 2-ethynyl-1,3-difluorobenzene.

[0656] .sup.1H-NMR (CD.sub.3OD) : 8.27 (1H, s), 7.79 (1H, s), 7.66-7.64 (1H, m), 7.57-7.53 (2H, m), 5.88 (1H, d, J=6.8 Hz), 4.84-4.80 (1H, m), 4.33-4.31 (1H, m), 4.28-4.26 (1H, m), 3.45-3.35 (2H, m). LCMS (ESI) m/z 488 [M+H].sup.+.

Reference Example 86

4-Amino-5-[2-[2-(cyclopropylmethoxy)-6-fluoro-phenyl]ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of 1-(cyclopropylmethoxy)-3-fluoro-2-iodobenzene

[0657] 3-Fluoro-2-iodophenol (200 mg, 0.84 mmol) was dissolved in tetrahydrofuran (2 mL). Then, cyclopropylmethanol (0.14 mL, 1.7 mmol) and triphenylphosphine (440 mg, 1.7 mmol) were added thereto at room temperature, and diisopropyl azodicarboxylate (0.33 ml, 1.7 mmol) was added thereto in an ice bath, followed by stirring for 2 hours in an ice bath. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/hexane), thereby obtaining 1-(cyclopropylmethoxy)-3-fluoro-2-iodobenzene (192 mg) as a yellow oil.

[0658] .sup.1H-NMR (CDCl.sub.3) : 7.26-7.19 (1H, m), 6.72-6.67 (1H, m), 6.57 (1H, d, J=8.3 Hz), 3.91 (2H, d, J=6.6 Hz), 1.33-1.28 (1H, m), 0.68-0.63 (2H, m), 0.44-0.41 (2H, m).

Step 2: Synthesis of ((2-(cyclopropylmethoxy)-6-fluorophenyl)ethynyl)trimethylsilane

[0659] The title compound was obtained as in step 2 of Reference Example 76, except that 1-(cyclopropylmethoxy)-3-fluoro-2-iodobenzene and ethynyltrimethylsilane were used in place of 5-(benzyloxy)-2-bromopyrimidine and ethynyltriisopropylsilane.

[0660] .sup.1H-NMR (CDCl.sub.3) : 7.17 (1H, dt, J=6.6, 8.4 Hz), 6.69-6.64 (1H, m), 6.61 (1H, d, J=8.5 Hz), 3.91 (2H, d, J=6.3 Hz), 1.31-1.24 (1H, m), 0.64-0.60 (2H, m), 0.45-0.41 (2H, m), 0.28 (9H, s).

Step 3: Synthesis of 1-(cyclopropylmethoxy)-2-ethynyl-3-fluorobenzene

[0661] The title compound was obtained as in step 3 of Reference Example 76, except that ((2-(cyclopropylmethoxy)-6-fluorophenyl)ethynyl)trimethylsilane was used in place of 5-(benzyloxy)-2-((triisopropylsilyl)ethynyl)pyrimidine.

[0662] .sup.1H-NMR (CDCl.sub.3) : 7.24 (1H, dt, J=6.6, 8.4 Hz), 6.72 (1H, t, J=8.4 Hz), 6.67 (1H, J=8.4 Hz), 3.93 (2H, d, J=6.6 Hz), 3.52 (1H, s), 1.36-1.30 (1H, m), 0.68-0.63 (2H, m), 0.43-0.39 (2H, m).

Step 4: Synthesis of Reference Example Compound 86

[0663] The title compound was obtained as in step 4 of Reference Example 1, except that 1-(cyclopropylmethoxy)-2-ethynyl-3-fluorobenzene was used in place of 2-ethynyl-1,3-difluorobenzene.

[0664] .sup.1H-NMR (CD.sub.3OD) : 8.25 (1H, s), 7.59 (1H, s), 7.33-7.27 (1H, m), 6.88 (1H, d, J=8.5 Hz), 6.79 (1H, t, J=8.5 Hz), 5.88 (1H, d, J=7.0 Hz), 4.86-4.83 (1H, m), 4.34-4.32 (1H, m), 4.28-4.26 (1H, m), 4.01 (2H, d, J=7.0 Hz), 3.44-3.34 (2H, m), 1.40-1.32 (1H, m), 0.73-0.68 (2H, m), 0.43 (2H, m). LCMS (ESI) m/z 533 [M+H].sup.+.

Reference Example 87

4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-[4-(3-pyridylmethoxy)phenyl]ethynyl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of tert-butyl N-(((3aR,4R,6R,6aR)-6-(4-amino-5-((trimethylsilyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)sulfamoyl carbamate

[0665] tert-Butyl N-(((3aR,4R,6R,6aR)-6-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)sulfamoyl carbamate (500 mg, 0.82 mmol), ethynyltrimethylsilane (240 mg, 2.5 mmol), bis(triphenylphosphine)palladium (II) dichloride (58 mg, 0.082 mmol), copper iodide (16 mg, 0.082 mmol), and diisopropylethylamine (0.28 mL, 1.6 mmol) were suspended in tetrahydrofuran (5 mL). The reaction solution was stirred at 70 C. overnight and filtered through a celite bed, followed by distilling off the solvent. The residue was purified by silica gel column chromatography (developing solvent: methanol/chloroform), thereby obtaining the title compound (339 mg, 0.58 mmol, 71%) as a yellow amorphous substance.

[0666] .sup.1H-NMR (CDCl.sub.3) : 9.41 (1H, brs), 8.50 (1H, s), 7.16 (1H, s), 5.98 (2H, brs), 5.63 (1H, d, J=4.6 Hz), 5.25-5.21 (1H, m), 5.07-5.03 (1H, m), 4.51-4.49 (1H, m), 3.59-3.50 (2H, m), 1.59 (3H, s), 1.43 (9H, s), 1.34 (3H, s), 0.26 (9H, s). LCMS (ESI) m/z 581 [M+H].sup.+

Step 2: Synthesis of tert-butyl N-(((3aR,4R,6R,6aR)-6-(4-amino-5-ethynyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl) sulfamoyl carbamate

[0667] tert-Butyl N-(((3aR,4R,6R,6aR)-6-(4-amino-5-((trimethylsilyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)sulfamoyl carbamate (339 mg, 0.58 mmol) was dissolved in tetrahydrofuran (6.8 mL), and a tetrabutylammonium fluoride solution (a 1 M tetrahydrofuran solution, 0.70 mL, 0.70 mmol) was added thereto at room temperature, followed by stirring at room temperature for 25 minutes. After the solvent was distilled off, the residue was purified by silica gel column chromatography (developing solvent: methanol/chloroform), thereby obtaining the title compound (260 mg, 0.51 mmol, 88%) as a yellow powder.

[0668] .sup.1H-NMR (CDCl.sub.3) : 9.25 (1H, brs), 8.51 (1H, s), 7.20 (1H, s), 6.11 (2H, brs), 5.65 (1H, d, J=4.6 Hz), 5.29-5.25 (1H, m), 5.10-5.06 (1H, m), 4.52-4.49 (1H, m), 3.66-3.53 (2H, m), 3.25 (1H, s), 1.61 (3H, s), 1.44 (9H, s), 1.35 (3H, s). LCMS (ESI) m/z 509 [M+H].sup.+

Step 3: Synthesis of Reference Example Compound 87

[0669] tert-Butyl N-(((3aR,4R,6R,6aR)-6-(4-amino-5-ethynyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)sulfamoyl carbamate (20 mg, 0.039 mmol), 3-((4-iodophenoxy)methyl)pyridine (24 mg, 0.079 mmol), bis(triphenylphosphine)palladium (II) dichloride (3 mg, 0.0043 mmol), copper iodide (1 mg, 0.0053 mmol), and diisopropylethylamine (0.013 mL, 0.079 mmol) were suspended in tetrahydrofuran (0.30 mL). The reaction solution was stirred at 70 C. overnight, and a mixed solution (0.60 mL) of trifluoroacetic acid/water=4/1 was added thereto at room temperature, followed by stirring at room temperature overnight. After the solvent was distilled off, the residue was purified by basic silica gel column chromatography (developing solvent: methanol/chloroform), thereby obtaining the title compound (2.1 mg, 0.0039 mmol, 10%) as a yellow powder.

[0670] .sup.1H-NMR (CD.sub.3OD) : 8.65-8.60 (1H, m), 8.55-8.50 (1H, m), 8.24 (1H, s), 7.95-7.90 (1H, m), 7.50-7.40 (4H, m), 7.05-7.00 (2H, brs), 5.84-5.82 (1H, brs), 5.19 (2H, s), 4.80-4.70 (1H, m), 4.35-4.20 (2H, m), 3.40-3.30 (2H, m). LCMS (ESI) m/z 552 [M+H].sup.+.

Reference Example 88

4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(3-fluoro-2-pyridyl)ethynyl]pyrrolo[2,3-d]pyrimidine

[0671] The title compound was obtained as in step 3 of Reference Example 87, except that 3-fluoro-2-iodopyridine was used in place of 3-((4-iodophenoxy)methyl)pyridine.

[0672] .sup.1H-NMR (CD.sub.3OD) : 8.43-8.39 (1H, m), 8.26 (1H, s), 7.78 (1H, s), 7.78-7.71 (1H, m), 7.50-7.46 (1H, m), 5.88 (1H, d, J=7.1 Hz), 4.90-4.60 (1H, m), 4.33-4.31 (1H, m), 4.28-4.25 (1H, m), 3.40-3.31 (2H, m). LCMS (ESI) m/z 464 [M+H].sup.+.

Reference Example 89

4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-methylsulfanylphenyl)ethynyl]pyrrolo[2,3-d]pyrimidine

[0673] The title compound was obtained as in step 3 of Reference Example 87, except that (2-iodophenyl)(methyl)sulfane was used in place of 3-((4-iodophenoxy)methyl)pyridine.

[0674] .sup.1H-NMR (CD.sub.3OD) : 8.24 (1H, s), 7.62 (1H, s), 7.48-7.46 (1H, m), 7.37-7.34 (2H, m), 7.22-7.16 (1H, m), 5.86 (1H, d, J=8.0 Hz), 4.83-4.81 (1H, m), 4.33-4.29 (1H, m), 4.27-4.25 (1H, m), 3.40-3.35 (2H, m), 2.55 (3H, s). LCMS (ESI) m/z 491 [M+H].sup.+.

Reference Example 90

2-[2-[4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]benzenesulfonamide

[0675] The title compound was obtained as in step 3 of Reference Example 87, except that 2-iodobenzenesulfonamide was used in place of 3-((4-iodophenoxy)methyl)pyridine.

[0676] .sup.1H-NMR (CD.sub.3OD) : 8.23 (1H, s), 8.02 (1H, dd, J=8.0, 4.0 Hz), 7.74 (1H, dd, J=7.8, 4.0 Hz), 7.71 (1H, s), 7.85-7.56 (1H, m), 7.53-7.49 (1H, m), 5.87 (1H, d, J=6.8 Hz), 4.83-4.81 (1H, m), 4.33-4.29 (1H, m), 4.27-4.25 (1H, m), 3.40-3.35 (2H, m). LCMS (ESI) m/z 524 [M+H].sup.+.

Reference Example 91

3-[[4-[2-[4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]phenoxy]methyl]benzamide

[0677] The title compound was obtained as in step 3 of Reference Example 87, except that 3-((4-iodophenoxy)methyl)benzamide was used in place of 3-((4-iodophenoxy)methyl)pyridine.

[0678] .sup.1H-NMR (CD.sub.3OD) : 8.23 (1H, s), 7.98 (1H, s), 7.84 (1H, d, J=8.1 Hz), 7.65 (1H, d, J=8.0 Hz), 7.54 (1H, s), 7.54-7.49 (1H, m), 7.48 (2H, d, J=8.0 Hz), 7.05 (2H, d, J=8.0 Hz), 5.85 (1H, d, J=7.1 Hz), 5.19 (2H, s), 4.83-4.81 (1H, m), 4.33-4.29 (1H, m), 4.27-4.25 (1H, m), 3.40-3.35 (2H, m). LCMS (ESI) m/z 594 [M+H].sup.+.

Reference Example 92

4-[2-[4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]isoquinoline

[0679] The title compound was obtained as in step 3 of Reference Example 87, except that 4-iodoisoquinoline was used in place of 3-((4-iodophenoxy)methyl)pyridine.

[0680] .sup.1H-NMR (CD.sub.3OD) : 9.20 (1H, s), 8.69 (1H, s), 8.34 (1H, d, J=8.3 Hz), 8.26 (1H, s), 8.16 (1H, d, J=8.3 Hz), 7.95-7.90 (1H, m), 7.81 (1H, s), 7.80-7.74 (1H, m), 5.92 (1H, d, J=6.8 Hz), 4.87-4.81 (1H, m), 4.36-4.33 (1H, m), 4.29-4.25 (1H, m), 3.43-3.39 (2H, m). LCMS (ESI) m/z 496 [M+H].sup.+.

Reference Example 93

4-Amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]-5-[2-(1-naphthyl)ethynyl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of ((3aR,4R,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol and (4aR,6R,7S,7aR)-6-amino-2,2-dimethylhexahydrocyclopenta[d][1,3]dioxin-7-ol

[0681] (1R,2S,3R,5R)-3-Amino-5-(hydroxymethyl)cyclopentane-1,2-diol hydrochloride (40 g, 218 mmol) was dissolved at room temperature in methanol (400 mL) and 2,2-dimethoxypropane (54 mL, 436 mmol), and methanesulfonic acid (14 mL, 218 mmol) was added thereto dropwise in an ice bath with stirring so as to keep the internal temperature at 7 C. or lower. After the mixture was stirred in an ice bath for 5 minutes and at room temperature overnight, triethylamine (122 mL, 872 mmol) was added thereto dropwise in an ice bath so as to keep the internal temperature at 10 C. or lower. After the mixture was stirred in an ice bath for 5 minutes and at room temperature for 30 minutes, the solvent was distilled off under reduced pressure, thereby obtaining the title compound as a crude isomeric mixture (102 g). LCMS (ESI) m/z 188 [M+H].sup.+

Step 2: Synthesis of ((3aR,4R,6R,6aS)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol and (4aR,6R,7S,7aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethylhexahydrocyclopenta[d][1,3]dioxin-7-ol

[0682] The crude isomeric mixture (102 g) of ((3aR,4R,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol and (4aR,6R,7S,7aR)-6-amino-2,2-dimethylhexahydrocyclopenta[d][1,3]dioxin-7-ol obtained in step 1 of Reference Example 93, and 2-(4,6-dichloropyrimidin-5-yl)acetaldehyde (46 g, 240 mmol) was suspended in 2-butanol (400 mL). Then, triethylamine (61 mL, 436 mmol) was added thereto at room temperature, and the reaction solution was stirred at 80 C. overnight. After the reaction solvent was distilled off under reduced pressure, the residue was partitioned with the addition of ethyl acetate and an aqueous sodium hydrogen carbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline, and dried over sodium sulfate, followed by distilling off the solvent, thereby obtaining the title compound as a crude isomeric mixture (72 g). LCMS (ESI) m/z 324 [M+H].sup.+

Step 3: Synthesis of ((3aR,4R,6R,6aS)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol

[0683] The crude isomeric mixture (72 g) of ((3aR,4R,6R,6aS)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol and (4aR,6R,7S,7aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethylhexahydrocyclopenta[d][1,3]dioxin-7-ol, obtained in step 2 of Reference Example 93, was suspended in acetone (720 mL), and methanesulfonic acid (14.2 mL, 218 mmol) was added thereto in an ice bath. After the reaction solution was stirred in an ice bath for 40 minutes and at room temperature overnight, triethylamine (122 mL, 872 mmol) was added thereto dropwise in an ice bath so as to keep the internal temperature at 10 C. or lower. After the mixture was stirred in an ice bath for 10 minutes and at room temperature for 30 minutes, the solvent was distilled off under reduced pressure. The residue was partitioned with the addition of ethyl acetate and a sodium bicarbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline, and dried over sodium sulfate. The solvent was distilled off, thereby giving a crude product of the title compound (77 g) as a brown oil.

[0684] .sup.1H-NMR (CDCl.sub.3) : 8.63 (1H, s), 7.33 (1H, d, J=3.7 Hz), 6.63 (1H, d, J=3.7 Hz), 5.03-4.95 (2H, m), 4.73-4.70 (1H, m), 3.90-3.86 (1H, m), 3.83-378 (1H, m), 2.52-2.43 (2H, m), 2.38-2.32 (1H, m), 2.18-2.16 (1H, m), 1.60 (3H, s), 1.32 (3H, s). LCMS (ESI) m/z 324 [M+H].sup.+

Step 4: Synthesis of 7-((3aS,4R,6R,6aR)-6-(((tert-butyldimethylsilyl)oxy)methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine

[0685] The crude product (77 g), i.e., ((3aR,4R,6R,6aS)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol, obtained in step 3 of Reference Example 93 was dissolved in N,N-dimethylformamide (770 mL). Then, imidazole (37 g, 545 mmol) was added thereto at room temperature, and tert-butyldimethylchlorosilicane (58 g, 382 mmol) was added in a water bath (25 C.), followed by stirring for 40 minutes in a water bath (29 C.). The reaction solution was partitioned with the addition of ethyl acetate (800 mL) and water (800 mL) in an ice bath, and the organic layer was washed with water (400 mL). After the aqueous layer (about 300 mL) was removed, saturated saline (100 mL) was added to the organic layer and washed, followed by further washing with saturated saline (400 mL). After the resulting product was dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/hexane), thereby obtaining the title compound (79 g, four steps: 83%) as a yellow oil.

[0686] .sup.1H-NMR (CDCl.sub.3) : 8.62 (1H, s), 7.31 (1H, d, J=3.7 Hz), 6.63 (1H, d, J=3.7 Hz), 5.09-5.04 (1H, m), 4.88 (1H, t, J=6.3 Hz), 4.67-4.64 (1H, m), 3.82-3.74 (2H, m), 2.39-2.37 (3H, m), 1.59 (3H, s), 1.31 (3H, s), 0.93 (9H, s), 0.087 (3H, s), 0.074 (3H, s). LCMS (ESI) m/z 438 [M+H].sup.+

Step 5: Synthesis of 7-((3aS,4R,6R,6aR)-6-(((tert-butyldimethylsilyl)oxy)methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine

[0687] 7-((3aS,4R,6R,6aR)-6-(((tert-Butyldimethylsilyl)oxy)methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (79 g, 180 mmol) was dissolved in N,N-dimethylformamide (790 mL), and N-iodosuccinimide (45 g, 198 mmol) was added thereto at room temperature, followed by stirring at 50 C. for 11 hours and at room temperature for 12 hours. Ethyl acetate (600 mL), a saturated sodium hydrogen sulphite solution (300 mL), and water (600 mL) were added in an ice bath to the reaction solution, followed by stirring at room temperature for 10 minutes. After partition, the organic layer was sequentially washed with a liquid mixture of water (600 mL) and saturated saline (100 mL), and saturated saline (500 mL). After the resulting product was dried over sodium sulfate, the solvent was distilled off under reduced pressure, thereby giving a crude product of the title compound (95 g) as a brown oil.

[0688] .sup.1H-NMR (CDCl.sub.3) : 8.61 (1H, s), 7.46 (1H, s), 5.08-5.04 (1H, m), 4.85 (1H, t, J=6.3 Hz), 4.64-4.62 (1H, m), 3.81-3.73 (2H, m), 2.42-2.32 (3H, m), 1.58 (3H, s), 1.30 (3H, s), 0.94 (9H, s), 0.095 (3H, s), 0.082 (3H, s). LCMS (ESI) m/z 564 [M+H].sup.+

Step 6: Synthesis of ((3aR,4R,6R,6aS)-6-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol

[0689] The crude product (95 g), i.e., 7-((3aS,4R,6R,6aR)-6-(((tert-butyldimethylsilyl)oxy)methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine, obtained in step 5 of Reference Example 93 was dissolved in tetrahydrofuran (950 mL), and a tetrabutylammonium fluoride solution (1 M tetrahydrofuran solution, 180 mL) was added thereto at room temperature, followed by stirring at room temperature for 1 hour. The resulting mixture was partitioned in an ice bath with the addition of ethyl acetate (500 mL), water (500 mL), and a saturated sodium bicarbonate solution (300 mL), and the aqueous layer was extracted with ethyl acetate (500 mL). The organic layer was washed with saturated saline (500 mL), and dried over sodium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/hexane), thereby obtaining the title compound (70 g, two steps: 86%) as a light-green amorphous substance.

[0690] .sup.1H-NMR (CDCl.sub.3) : 8.62 (1H, s), 7.48 (1H, s), 5.05-4.99 (1H, m), 4.91 (1H, t, J=6.5 Hz), 4.71-4.68 (1H, m), 3.89-3.85 (1H, m), 3.82-3.78 (1H, m), 2.50-2.45 (2H, m), 2.31-2.27 (1H, m), 1.90-1.88 (1H, m), 1.59 (3H, s), 1.31 (3H, s). LCMS (ESI) m/z 450 [M+H].sup.+

Step 7: Synthesis of ((3aR,4R,6R,6aS)-6-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol

[0691] ((3aR,4R,6R,6aS)-6-(4-Chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol (70 g) was dissolved in 1,4-dioxane (350 mL), and 28% aqueous ammonia (350 mL) was added thereto at room temperature, followed by stirring at 100 C. overnight in a pressure-resistant container. After the solvent was distilled off under reduced pressure, the resulting product was suspended in water (700 mL), followed by stirring at room temperature overnight. The precipitate was collected by filtration and washed with water (420 mL), followed by drying to give the title compound (67 g, 99%) as a light-brown powder.

[0692] .sup.1H-NMR (CDCl.sub.3) : 8.26 (1H, s), 7.12 (1H, s), 5.69-5.67 (2H, brs), 4.94 (1H, t, J=6.2 Hz), 4.90-4.84 (1H, m), 4.72-4.70 (1H, m), 3.89-3.85 (1H, m), 3.81-3.77 (1H, m), 3.06-3.04 (1H, brs), 2.58-2.46 (2H, m), 2.35-2.27 (1H, m), 1.59 (3H, s), 1.33 (3H, s) LCMS (ESI) m/z 431 [M+H].sup.+.

Step 8: Synthesis of 7-((3aS,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0693] ((3aR,4R,6R,6aS)-6-(4-Amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol (51 g, 118 mmol) and phthalimide (35 g, 236 mmol) were dissolved in tetrahydrofuran (1000 mL). Then, triphenylphosphine (93 g, 354 mmol) was added thereto with stirring under ice-cooling. After triphenylphosphine was dissolved, diisopropyl azodicarboxylate (70 mL, 354 mmol) was added thereto dropwise with stirring under ice-cooling. After the reaction solution was stirred for 30 minutes under ice-cooling, the resulting product was stirred at room temperature for 90 minutes, and the reaction solution was distilled off under reduced pressure. Ethanol (750 mL), hydrazine monohydrate (25 mL, 519 mmol), and water (150 mL) were added to the residue, followed by stirring at 80 C. overnight. After the solvent was distilled off under reduced pressure, the resulting product was partitioned with the addition of chloroform, water, and a saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was then separated and extracted with chloroform. All of the organic layers were combined and dried over sodium sulfate, followed by distilling off the solvent. The residue was purified by basic silica gel column chromatography (developing solvent: methanol/chloroform), thereby obtaining the title compound (52 g, 89 wt %) as a yellow amorphous substance.

[0694] .sup.1H-NMR (CDCl.sub.3) : 8.27 (1H, s), 7.13 (1H, s), 5.62-5.60 (2H, brs), 4.96-4.90 (2H, m), 4.56 (1H, t, J=6.0 Hz), 2.90 (2H, d, J=6.6 Hz), 2.46-2.40 (1H, m), 2.27-2.21 (1H, m), 2.17-2.08 (1H, m), 1.58 (3H, s), 1.32 (3H, s). LCMS (ESI) m/z 430 [M+H].sup.+.

Step 9: Synthesis of tert-butyl N-(((3aR,4R,6R,6aS)-6-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl) sulfamoyl carbamate

[0695] 7-((3aS,4R,6R,6aR)-6-(Aminomethyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (51.5 g, 89 wt %, ca. 107 mmol) obtained in step 8 of Reference Example 93 was dissolved in acetonitrile (515 mL). Then, 1-aza-4-azoniabicyclo[2.2.2]octan-4-ylsulfonyl(tert-butoxycarbonyl)azanido: 1,4-diazabicyclo[2.2.2]octane monohydrochloride (Reference: Organic Letters, 2012, 10, 2626-2629) (70.5 g, 160 mmol) was added thereto at room temperature. After the reaction solution was stirred at room temperature for 30 minutes, water (1030 mL) and a saturated aqueous ammonium chloride solution (258 mL) were added to the reaction solution, followed by stirring at room temperature for 5 hours. The precipitate was collected by filtration and washed with water (1545 mL), followed by drying to give the title compound (57.1 g, 88%) as a yellowish white powder.

[0696] .sup.1H-NMR (CDCl.sub.3) : 8.33 (1H, s), 7.05 (1H, s), 6.62-6.60 (1H, brs), 5.73-5.71 (2H, brs), 4.99 (1H, t, J=5.9 Hz), 4.78-4.72 (1H, m), 4.64-4.62 (1H, m), 3.36-3.32 (1H, m), 3.24-3.25 (1H, m), 2.57-2.46 (2H, m), 2.38-2.32 (1H, m), 1.56 (3H, s), 1.48 (9H, s), 1.29 (3H, s). LCMS (ESI) m/z 609 [M+H].sup.+.

Step 10: Synthesis of Reference Example Compound 93

[0697] tert-Butyl N-(((3aR,4R,6R,6aS)-6-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl) sulfamoyl carbamate (20 mg, 0.033 mmol), 1-ethynylnaphthalene (10 mg, 0.066 mmol), bis(triphenylphosphine)palladium (II) dichloride (3 mg, 0.0043 mmol), copper iodide (1 mg, 0.0053 mmol), and diisopropylethylamine (0.011 mL, 0.066 mmol) were suspended in tetrahydrofuran (0.30 mL). After the reaction solution was stirred at 70 C. for 1 hour, a mixed solution (0.60 mL) of trifluoroacetic acid/water=4/1 was added thereto at room temperature, followed by stirring at room temperature overnight. After the solvent was distilled off, the residue was purified by silica gel column chromatography (developing solvent: methanol/chloroform), thereby obtaining the title compound (8.2 mg, 50%) as a yellow powder.

[0698] .sup.1H-NMR (CD.sub.3OD) : 8.36 (1H, d, J=8.5 Hz), 8.17 (1H, s), 7.93-7.89 (2H, m), 7.78-7.75 (1H, m), 7.74 (1H, s), 7.64-7.47 (3H, m), 5.02-4.95 (1H, m), 4.47-4.44 (1H, m), 4.05-4.03 (1H, m), 3.30-3.16 (2H, m), 2.52-2.44 (1H, m), 2.37-2.28 (1H, m), 1.90-1.82 (1H, m). LCMS (ESI) m/z 493 [M+H].sup.+.

Reference Example 94

4-Amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]-5-[2-(2,6-dimethoxyphenyl)ethynyl]pyrrolo[2,3-d]pyrimidine

[0699] The title compound was obtained as in step 10 of Reference Example 93, except that 2-ethynyl-1,3-dimethoxybenzene was used in place of 1-ethynylnaphthalene.

[0700] .sup.1H-NMR (CD.sub.3OD) : 8.12 (1H, s), 7.52 (1H, s), 7.27 (1H, t, J=8.5 Hz), 6.68 (2H, d, J=8.5 Hz), 4.95-4.86 (1H, m), 4.40-4.35 (1H, m), 4.05-3.95 (1H, m), 3.91 (6H, s), 3.30-3.13 (2H, m), 2.50-2.40 (1H, m), 2.34-2.28 (1H, m), 1.85-1.73 (1H, m). LCMS (ESI) m/z 503 [M+H].sup.+.

Reference Example 95

4-Amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]-5-[2-(2-fluoro-6-methoxy-phenyl) ethynyl]pyrrolo[2,3-d]pyrimidine

[0701] The title compound was obtained as in step 10 of Reference Example 93, except that 2-ethynyl-1-fluoro-3-methoxybenzene was used in place of 1-ethynylnaphthalene.

[0702] .sup.1H-NMR (CD.sub.3OD) : 8.13 (1H, s), 7.59 (1H, s), 7.34-7.28 (1H, m), 6.88 (1H, d, J=8.5 Hz), 6.78-6.74 (1H, m), 4.97-4.86 (1H, m), 4.43-4.39 (1H, m), 4.03-4.00 (1H, m), 3.96 (3H, s), 3.30-3.23 (1H, m), 3.22-3.14 (1H, m), 2.50-2.40 (1H, m), 2.34-2.28 (1H, m), 1.85-1.73 (1H, m). LCMS (ESI) m/z 491 [M+H].sup.+.

Reference Example 96

8-[2-[4-Amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]quinoline

[0703] The title compound was obtained as in step 10 of Reference Example 93, except that 8-ethynylquinoline was used in place of 1-ethynylnaphthalene.

[0704] .sup.1H-NMR (CD.sub.3OD) : 9.04-9.02 (1H, m), 8.40-8.35 (1H, m), 8.16 (1H, s), 7.94-7.85 (2H, m), 7.63 (1H, s), 7.61-7.57 (2H, m), 5.00-4.91 (1H, m), 4.46-4.42 (1H, m), 4.05-4.00 (1H, m), 3.30-3.14 (2H, m), 2.50-2.38 (1H, m), 2.34-2.28 (1H, m), 1.87-1.81 (1H, m). LCMS (ESI) m/z 494 [M+H].sup.+.

Reference Example 97

4-Amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]-5-[2-(2-ethoxy-6-fluoro-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine

Step 1: The Title Compound was Obtained as in Step 10 of Reference Example 93, Except that 1-ethoxy-2-ethynyl-3-fluorobenzene was Used in Place of 1-ethynylnaphthalene

[0705] .sup.1H-NMR (CD.sub.3OD) : 8.14 (1H, s), 7.60 (1H, s), 7.32-7.26 (1H, m), 6.86 (1H, d, J=8.5 Hz), 6.79-6.74 (1H, m), 5.00-4.91 (1H, m), 4.45-4.42 (1H, m), 4.23 (2H, q, J=7.1 Hz), 4.05-4.00 (1H, m), 3.30-3.24 (1H, m), 3.21-3.15 (1H, m), 2.50-2.40 (1H, m), 2.34-2.28 (1H, m), 1.87-1.81 (1H, m), 1.47 (3H, t, J=7.1 Hz). LCMS (ESI) m/z 505 [M+H].sup.+.

Step 2: Synthesis of 4-amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]-5-[2-(2-ethoxy-6-fluoro-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine hydrochloride

[0706] The title compound hydrochloride was obtained in accordance with step 5 of Reference Example 1.

[0707] .sup.1H-NMR (CD.sub.3OD) : 8.32 (1H, s), 7.95 (1H, s), 7.38-7.34 (1H, m), 6.93 (1H, d, J=8.5 Hz), 6.84-6.80 (1H, m), 5.13-5.09 (1H, m), 4.41-4.37 (1H, m), 4.27 (2H, q, J=7.0 Hz), 4.02-4.00 (1H, m), 3.28-3.23 (1H, m), 3.19-3.13 (1H, m), 2.47-2.42 (1H, m), 2.32-2.80 (1H, m), 1.87-1.79 (1H, m), 1.48 (3H, t, J=7.0 Hz). LCMS (ESI) m/z 505 [M+H].sup.+

Reference Example 98

4-Amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]-5-[2-(2-fluoro-6-methylsulfanyl-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine

[0708] The title compound was obtained as in step 10 of Reference Example 93, except that 2-ethynyl-1-fluoro-3-methylsulfanyl-benzene was used in place of 1-ethynylnaphthalene.

[0709] .sup.1H-NMR (CD.sub.3OD) : 8.15 (1H, s), 7.67 (1H, s), 7.35-7.30 (1H, m), 7.10 (1H, d, J=7.8 Hz), 6.98-6.92 (1H, m), 5.00-4.91 (1H, m), 4.45-4.40 (1H, m), 4.05-4.00 (1H, m), 3.30-3.24 (1H, m), 3.21-3.15 (1H, m), 2.56 (3H, s), 2.50-2.41 (1H, m), 2.34-2.28 (1H, m), 1.87-1.78 (1H, m). LCMS (ESI) m/z 507 [M+H].sup.+.

Reference Example 99

4-Amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]-5-[2-(2-ethylsulfanyl-6-fluoro-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine

[0710] The title compound was obtained as in step 10 of Reference Example 93, except that 1-ethylsulfanyl-2-ethynyl-3-fluoro-benzene was used in place of 1-ethynylnaphthalene.

[0711] .sup.1H-NMR (DMSO-D.sub.6) : 8.15 (1H, s), 7.93 (1H, s), 7.42-7.36 (1H, m), 7.23 (1H, d, J=8.8 Hz), 7.13 (1H, t, J=8.8 Hz), 6.65 (1H, dd, J=6.6, 5.9 Hz), 6.53 (2H, brs), 4.90 (1H, ddd, J=10.3, 9.9, 8.4 Hz), 4.71 (1H, brs), 4.24 (1H, dd, J=8.8, 5.5 Hz), 3.79 (1H, dd, J=5.5, 3.7 Hz), 3.10-3.05 (1H, m), 3.09 (2H, q, J=7.3 Hz), 2.96-2.89 (1H, m), 2.22 (1H, dt, J=13.2, 8.1 Hz), 2.15-2.06 (1H, m), 1.61-1.53 (1H, m), 1.30 (3H, t, J=7.3 Hz). LCMS (ESI) m/z 521 [M+H].sup.+.

Reference Example 100

4-Amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]-5-[2-(2-ethoxy-6-methoxy-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine

[0712] The title compound was obtained as in step 10 of Reference Example 93, except that 1-ethoxy-2-ethynyl-3-methoxybenzene was used in place of 1-ethynylnaphthalene.

[0713] .sup.1H-NMR (DMSO-D.sub.6) : 8.12 (1H, s), 7.72 (1H, s), 7.27 (1H, t, J=8.4 Hz), 6.72-6.65 (3H, m), 6.53 (2H, s), 4.92-4.85 (2H, m), 4.68 (1H, d, J=4.4 Hz), 4.25-4.20 (1H, m), 4.16 (2H, q, J=7.0 Hz), 3.87 (3H, s), 3.82-3.78 (1H, m), 3.12-3.06 (1H, m), 2.96-2.90 (1H, m), 2.23-2.18 (1H, m), 2.15-2.07 (1H, m), 1.61-1.53 (1H, m), 1.37 (3H, t, J=7.0 Hz). LCMS (ESI) m/z 517.3 [M+H].sup.+.

Reference Example 101

4-[4-[2-[4-amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]-3,5-difluoro-phenyl]morpholine

[0714] The title compound was obtained as in step 10 of Reference Example 93, except that 4-(4-ethynyl-3,5-difluorophenyl)morpholine was used in place of 1-ethynylnaphthalene.

[0715] .sup.1H-NMR (CD.sub.3OD) : 8.14 (1H, s), 7.59 (1H, s), 6.63 (2H, d, J=11.5 Hz), 4.97-4.93 (1H, m), 4.41 (1H, dd, J=8.4, 5.7 Hz), 4.01 (1H, dd, J=5.7, 3.8 Hz), 3.80 (4H, t, J=4.9 Hz), 3.27-3.11 (6H, m), 2.48-2.40 (1H, m), 2.35-2.25 (1H, m), 1.84-1.76 (1H, m). LCMS (ESI) m/z 564 [M+H].sup.+.

Reference Example 102

4-Amino-5-[2-[2,6-difluoro-4-(1-piperidyl)phenyl]ethynyl]-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of 1-(4-ethynyl-3,5-difluorophenyl)piperidine

[0716] The title compound was obtained as in step 1 of Reference Example 23, except that piperidine was used in place of morpholine.

[0717] .sup.1H-NMR (CDCl.sub.3) : 6.34 (2H, d, J=11.4 Hz), 3.37 (1H, s), 3.26-3.20 (4H, m), 1.68-1.60 (6H, m). LCMS (ESI) m/z 222 [M+H].sup.+

Step 2: Synthesis of Reference Example Compound 102

[0718] The title compound was obtained as in step 10 of Reference Example 93, except that 1-(4-ethynyl-3,5-difluorophenyl)piperidine was used in place of 1-ethynylnaphthalene.

[0719] .sup.1H-NMR (CD.sub.3OD) : 8.13 (1H, s), 7.57 (1H, s), 6.54 (2H, d, J=11.7 Hz), 4.98-4.91 (1H, m), 4.40 (1H, dd, J=8.4, 5.6 Hz), 4.01 (1H, dd, J=5.6, 3.8 Hz), 3.31-3.30 (4H, m), 3.28-3.14 (2H, m), 2.48-2.39 (1H, m), 2.35-2.26 (1H, m), 1.85-1.75 (1H, m), 1.70-1.63 (6H, m). LCMS (ESI) m/z 562 [M+H].sup.+.

Reference Example 103

4-Amino-5-[2-[2,6-difluoro-4-(4-methylpiperazin-1-yl)phenyl]ethynyl]-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of 1-(4-ethynyl-3,5-difluorophenyl)-4-methylpiperazine

[0720] The title compound was obtained as in step 1 of Reference Example 23, except that 4-methylpiperazine was used in place of morpholine.

[0721] .sup.1H-NMR (CDCl.sub.3) : 6.36 (2H, d, J=11.0 Hz), 3.39 (1H, s), 3.27-3.23 (4H, m), 2.54-2.50 (4H, m), 2.34 (3H, s). LCMS (ESI) m/z 237 [M+H].sup.+

Step 2: Synthesis of Reference Example Compound 103

[0722] The title compound was obtained as in step 10 of Reference Example 93, except that 1-(4-ethynyl-3,5-difluorophenyl)-4-methylpiperazine was used in place of 1-ethynylnaphthalene.

[0723] .sup.1H-NMR (CD.sub.3OD) : 8.23 (1H, s), 7.76 (1H, s), 6.76 (2H, d, J=10.6 Hz), 5.06-4.97 (1H, m), 4.40 (1H, dd, J=8.6, 5.6 Hz), 4.01 (1H, dd, J=5.6, 3.7 Hz), 3.49-3.11 (10H, m), 2.97 (3H, s), 2.48-2.40 (1H, m), 2.34-2.26 (1H, m), 1.87-1.77 (1H, m). LCMS (ESI) m/z 577 [M+H].sup.+.

Reference Example 104

4-Amino-5-[2-[2,6-difluoro-4-(pyrazol-1-ylmethoxy)phenyl]ethynyl]-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of 4-((1H-pyrazol-1-yl)methoxy)-2,6-difluorobenzaldehyde

[0724] The title compound was obtained as in step 1 of Reference Example 55, except that 2,6-difluoro-4-hydroxybenzaldehyde and 1-(chloromethyl)pyrazole hydrochloride were used in place of 2-fluoro-6-hydroxybenzaldehyde and iodoethane.

[0725] .sup.1H-NMR (CDCl.sub.3) : 10.20 (1H, s), 7.65-7.62 (2H, m), 6.81 (2H, d, J=10.0 Hz), 6.39 (1H, t, J=2.1 Hz), 6.05 (2H, s). LCMS (ESI) m/z 239 [M+H].sup.+

Step 2: Synthesis of 1-((4-ethynyl-3,5-difluorophenoxy)methyl)-1H-pyrazole

[0726] The title compound was obtained as in step 1 of Reference Example 51, except that 4-((1H-pyrazol-1-yl)methoxy)-2,6-difluorobenzaldehyde was used in place of 2-fluoro-6-methoxybenzaldehyde.

[0727] .sup.1H-NMR (CDCl.sub.3) : 7.64-7.60 (2H, m), 6.73 (2H, d, J=8.8 Hz), 6.37 (1H, t, J=2.2 Hz), 5.99 (2H, s), 3.42 (1H, s). LCMS (ESI) m/z 235 [M+H].sup.+

Step 3: Synthesis of Reference Example Compound 104

[0728] The title compound was obtained as in step 10 of Reference Example 93, except that 1-((4-ethynyl-3,5-difluorophenoxy)methyl)-1H-pyrazole was used in place of 1-ethynylnaphthalene.

[0729] .sup.1H-NMR (DMSO-D.sub.6) : 8.14 (1H, s), 8.04 (1H, d, J=2.0 Hz), 7.91 (1H, s), 7.61 (1H, d, J=1.5 Hz), 7.15 (2H, d, J=9.5 Hz), 6.64 (1H, t, J=6.3 Hz), 6.51 (2H, s), 6.37-6.36 (1H, m), 6.18 (2H, s), 4.91-4.86 (2H, m), 4.69-4.66 (1H, brs), 4.23-4.19 (1H, m), 3.80-3.77 (1H, brs), 3.09-3.04 (1H, m), 2.95-2.88 (1H, m), 2.26-2.18 (1H, m), 2.14-2.10 (1H, m), 1.59-1.51 (1H, m). LCMS (ESI) m/z 575 [M+H].sup.+.

Reference Example 105

4-Amino-5-[2-(2,6-difluoro-4-pyrrolidin-1-yl-phenyl)ethynyl]-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of 1-(4-ethynyl-3,5-difluorophenyl)pyrrolidine

[0730] The title compound was obtained as in step 1 of Reference Example 23, except that pyrrolidine was used in place of morpholine.

[0731] .sup.1H-NMR (CDCl.sub.3) : 6.02 (2H, d, J=10.6 Hz), 3.38 (1H, s), 3.28-3.22 (4H, m), 2.04-2.00 (4H, m). LCMS (ESI) m/z 208 [M+H].sup.+

Step 2: Synthesis of Reference Example Compound 105

[0732] The title compound was obtained as in step 10 of Reference Example 93, except that 1-(4-ethynyl-3,5-difluorophenyl)pyrrolidine was used in place of 1-ethynylnaphthalene.

[0733] .sup.1H-NMR (CD.sub.3OD) : 8.13 (1H, s), 7.54 (1H, s), 6.21 (2H, d, J=11.0 Hz), 4.40 (1H, dd, J=8.6, 5.7 Hz), 4.00 (1H, t, J=4.6 Hz), 3.67-3.62 (1H, m), 3.29-3.05 (6H, m), 2.48-2.39 (1H, m), 2.35-2.25 (1H, m), 2.08-2.02 (4H, m), 1.85-1.75 (1H, m). LCMS (ESI) m/z 548 [M+H].sup.+.

Reference Example 106

4-Amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]-5-[2-[2-ethoxy-6-fluoro-4-(1-piperidyl)phenyl]ethynyl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of 1-(3-ethoxy-4-ethynyl-5-fluorophenyl)piperidine

[0734] The title compound was obtained as in step 1 of Reference Example 34, except that 1-(4-ethynyl-3,5-difluorophenyl)piperidine was used in place of 4-(4-ethynyl-3,5-difluorophenyl)morpholine.

[0735] .sup.1H-NMR (CDCl.sub.3) : 6.24 (1H, dd, J=12.8, 2.2 Hz), 6.18-6.16 (1H, m), 4.12 (2H, q, J=7.0 Hz), 3.42 (1H, s), 3.27-3.22 (4H, m), 1.73-1.60 (6H, m), 1.48 (3H, t, J=7.0 Hz). LCMS (ESI) m/z 248 [M+H].sup.+

Step 2: Synthesis of Reference Example Compound 106

[0736] The title compound was obtained as in step 10 of Reference Example 93, except that 1-(3-ethoxy-4-ethynyl-5-fluorophenyl)piperidine was used in place of 1-ethynylnaphthalene.

[0737] .sup.1H-NMR (CD.sub.3OD) : 8.13 (1H, s), 7.50 (1H, s), 6.33-6.30 (2H, m), 4.97-4.90 (1H, m), 4.39 (1H, dd, J=8.4, 5.5 Hz), 4.17 (2H, q, J=7.1 Hz), 4.00 (1H, dd, J=5.7, 3.8 Hz), 3.29-3.13 (6H, m), 2.47-2.40 (1H, m), 2.34-2.26 (1H, m), 1.84-1.75 (1H, m), 1.71-1.61 (6H, m), 1.45 (3H, t, J=7.1 Hz). LCMS (ESI) m/z 588 [M+H].sup.+.

Reference Example 107

4-Amino-5-[2-(4-benzyloxy-2,6-difluoro-phenyl)ethynyl]-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of 4-(benzyloxy)-2,6-difluorobenzaldehyde

[0738] The title compound was obtained as in step 1 of Reference Example 55, except that 2,6-difluoro-4-hydroxybenzaldehyde and benzylbromide were used in place of 2-fluoro-6-hydroxybenzaldehyde and iodoethane.

[0739] .sup.1H-NMR (CDCl.sub.3) : 10.20 (1H, s), 7.49-7.36 (5H, m), 6.57 (2H, d, J=10.5 Hz), 5.11 (2H, s). LCMS (ESI) m/z 249 [M+H].sup.+

Step 2: Synthesis of 5-(benzyloxy)-2-ethynyl-1,3-difluorobenzene

[0740] The title compound was obtained as in step 1 of Reference Example 51, except that 4-(benzyloxy)-2,6-difluorobenzaldehyde was used in place of 2-fluoro-6-methoxybenzaldehyde.

[0741] .sup.1H-NMR (CDCl.sub.3) : 7.41-7.36 (5H, m), 6.54 (2H, d, J=9.0 Hz), 5.04 (2H, s), 3.42 (1H, s). LCMS (ESI) m/z 245 [M+H].sup.+

Step 3: Synthesis of Reference Example Compound 107

[0742] The title compound was obtained as in step 10 of Reference Example 93, except that 5-(benzyloxy)-2-ethynyl-1,3-difluorobenzene was used in place of 1-ethynylnaphthalene.

[0743] .sup.1H-NMR (CD.sub.3OD) : 8.15 (1H, s), 7.63 (1H, s), 7.45-7.34 (5H, m), 6.78 (2H, d, J=9.5 Hz), 5.13 (2H, s), 4.92-4.88 (1H, m), 4.43-4.40 (1H, m), 4.02-3.98 (1H, m), 3.30-3.13 (2H, m), 2.46-2.40 (1H, m), 2.31-2.28 (1H, m), 1.83-1.78 (1H, m). LCMS (ESI) m/z 585 [M+H].sup.+.

Reference Example 108

3-[4-[2-[4-Amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]-3-ethoxy-5-fluoro-phenyl]-8-oxa-3-azabicyclo[3,2,1]octane

Step 1: Synthesis of 3-(4-ethynyl-3,5-difluorophenyl)-8-oxa-3-azabicyclo[3.2.1]octane

[0744] The title compound was obtained as in step 1 of Reference Example 23, except that 8-oxa-3-azabicyclo[3.2.1]octane was used in place of morpholine.

[0745] .sup.1H-NMR (CDCl.sub.3) : 6.28 (2H, dd, J=13.9, 2.9 Hz), 4.52-4.49 (2H, m), 3.40 (1H, s), 3.26 (2H, d, J=11.3 Hz), 3.08 (2H, dd, J=11.3, 2.7 Hz), 2.04-1.96 (2H, m), 1.89-1.82 (2H, m). LCMS (ESI) m/z 250 [M+H].sup.+

Step 2: Synthesis of 3-(3-ethoxy-4-ethynyl-5-fluorophenyl)-8-oxa-3-azabicyclo[3.2.1]octane

[0746] The title compound was obtained as in step 1 of Reference Example 34, except that 3-(4-ethynyl-3,5-difluorophenyl)-8-oxa-3-azabicyclo[3.2.1]octane was used in place of 4-(4-ethynyl-3,5-difluorophenyl) morpholine.

[0747] .sup.1H-NMR (CDCl.sub.3) : 6.12 (1H, dd, J=12.6, 2.4 Hz), 6.03 (1H, s), 4.51-4.47 (2H, m), 4.09 (2H, q, J=7.0 Hz), 3.40 (1H, s), 3.28 (2H, d, J=11.3 Hz), 3.06 (2H, dd, J=11.3, 2.7 Hz), 2.03-1.92 (2H, m), 1.92-1.84 (2H, m), 1.46 (3H, t, J=7.0 Hz). LCMS (ESI) m/z 276 [M+H].sup.+

Step 3: Synthesis of Reference Example Compound 108

[0748] The title compound was obtained as in step 10 of Reference Example 93, except that 3-(3-ethoxy-4-ethynyl-5-fluorophenyl)-8-oxa-3-azabicyclo[3.2.1]octane was used in place of 1-ethynylnaphthalene.

[0749] .sup.1H-NMR (CD.sub.3OD) : 8.12 (1H, s), 7.49 (1H, s), 6.29 (1H, d, J=1.8 Hz), 6.25 (1H, s), 4.94-4.90 (1H, m), 4.47 (2H, s), 4.39 (1H, dd, J=8.4, 5.9 Hz), 4.18 (2H, q, J=7.1 Hz), 4.00 (1H, dd, J=5.7, 3.8 Hz), 3.45 (2H, d, J=11.0 Hz), 3.26 (1H, dd, J=12.8, 6.2 Hz), 3.17 (1H, dd, J=12.6, 6.8 Hz), 2.97 (2H, dd, J=11.5, 2.4 Hz), 2.48-2.39 (1H, m), 2.35-2.25 (1H, m), 2.00-1.87 (4H, m), 1.84-1.74 (1H, m), 1.45 (3H, t, J=7.0 Hz). LCMS (ESI) m/z 616 [M+H].sup.+.

Reference Example 109

4-Amino-5-[2-(2,3-dihydrobenzothiophen-7-yl)ethynyl]-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of 2,3-dihydrobenzo[b]thiophene-7-carbaldehyde

[0750] 7-Bromo-2,3-dihydrobenzo[b]thiophene (200 mg, 0.93 mmol) was dissolved in tetrahydrofuran (2 mL), and an n-butyllithium solution (1.6 M hexane solution, 1.4 mL, 2.2 mmol) was added thereto at 78 C., followed by stirring at 78 C. for 30 minutes. Thereafter, N,N-dimethylformamide (0.22 mL, 2.8 mmol) was added thereto at 78 C., followed by stirring at 78 C. for 20 minutes and at room temperature for 1 hour. A saturated aqueous ammonium chloride solution, water, and ethyl acetate were added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, and dried over sodium sulfate, followed by distilling off the solvent. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/hexane), thereby obtaining the title compound (74 mg, 49%) as a yellow oil.

[0751] .sup.1H-NMR (CDCl.sub.3) : 10.05 (1H, s), 7.62 (1H, d, J=7.5 Hz), 7.39 (1H, dd, J=7.5, 1.0 Hz), 7.18 (1H, t, J=7.5 Hz), 3.42-3.37 (2H, m), 3.31 (2H, t, J=7.6 Hz). LCMS (ESI) m/z 165 [M+H].sup.+

Step 2: Synthesis of 7-ethynyl-2,3-dihydrobenzo[b]thiophene

[0752] The title compound was obtained as in step 1 of Reference Example 51, except that 2,3-dihydrobenzo[b]thiophene-7-carbaldehyde was used in place of 2-fluoro-6-methoxybenzaldehyde.

[0753] .sup.1H-NMR (CDCl.sub.3) : 7.25 (1H, d, J=7.6 Hz), 7.15 (1H, dd, J=7.6, 1.0 Hz), 6.96 (1H, t, J=7.6 Hz), 3.40-3.31 (5H, m).

Step 3: Synthesis of Reference Example Compound 109

[0754] The title compound was obtained as in step 10 of Reference Example 93, except that 7-ethynyl-2,3-dihydrobenzo[b]thiophene was used in place of 1-ethynylnaphthalene.

[0755] .sup.1H-NMR (CD.sub.3OD) : 8.15 (1H, s), 7.60 (1H, s), 7.23 (1H, d, J=7.6 Hz), 7.20-7.17 (1H, m), 7.02 (1H, dd, J=7.6, 7.6 Hz), 4.97-4.88 (1H, m), 4.43-4.40 (1H, m), 4.02-4.00 (1H, m), 3.44-3.34 (4H, m), 3.29-3.23 (1H, m), 3.20-3.15 (1H, m), 2.48-2.41 (1H, m), 2.32-2.28 (1H, m), 1.86-1.78 (1H, m). LCMS (ESI) m/z 501 [M+H].sup.+.

Reference Example 110

8-[4-[2-[4-Amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]-3-ethoxy-5-fluoro-phenyl]-3-oxa-8-azabicyclo[3,2,1]octane

Step 1: Synthesis of 8-(4-ethynyl-3,5-difluorophenyl)-3-oxa-8-azabicyclo[3.2.1]octane

[0756] The title compound was obtained as in step 1 of Reference Example 23, except that 3-oxa-8-azabicyclo[3.2.1]octane was used in place of morpholine.

[0757] .sup.1H-NMR (CDCl.sub.3) : 6.23 (2H, dd, J=13.6, 3.3 Hz), 4.01-3.98 (2H, m), 3.81 (2H, d, J=11.2 Hz), 3.53 (2H, d, J=11.2 Hz), 3.39 (1H, s), 2.16-2.01 (4H, m). LCMS (ESI) m/z 250 [M+H].sup.+

Step 2: Synthesis of 8-(3-ethoxy-4-ethynyl-5-fluorophenyl)-3-oxa-8-azabicyclo[3.2.1]octane

[0758] The title compound was obtained as in step 1 of Reference Example 34, except that 8-(4-ethynyl-3,5-difluorophenyl)-3-oxa-8-azabicyclo[3.2.1]octane was used in place of 4-(4-ethynyl-3,5-difluorophenyl)morpholine.

[0759] .sup.1H-NMR (CDCl.sub.3) : 6.08 (1H, dd, J=12.1, 2.2 Hz), 6.00 (1H, s), 4.08 (2H, q, J=7.0 Hz), 4.01 (2H, d, J=2.6 Hz), 3.85 (2H, d, J=11.0 Hz), 3.52 (2H, d, J=11.0 Hz), 3.39 (1H, d, J=5.9 Hz), 2.13-2.00 (4H, m), 1.45 (3H, t, J=7.0 Hz). LCMS (ESI) m/z 276 [M+H].sup.+

Step 3: Synthesis of Reference Example Compound 110

[0760] The title compound was obtained as in step 10 of Reference Example 93, except that 8-(3-ethoxy-4-ethynyl-5-fluorophenyl)-3-oxa-8-azabicyclo[3.2.1]octane was used in place of 1-ethynylnaphthalene.

[0761] .sup.1H-NMR (CD.sub.3OD) : 8.13 (1H, s), 7.50 (1H, s), 6.29 (1H, d, J=2.2 Hz), 6.25 (1H, d, J=2.2 Hz), 4.97-4.92 (1H, m), 4.39 (1H, dd, J=8.4, 5.8 Hz), 4.21-4.14 (4H, m), 4.01 (1H, dd, J=5.8, 3.8 Hz), 3.83 (2H, d, J=10.8 Hz), 3.52 (2H, d, J=10.8 Hz), 3.30-3.12 (2H, m), 2.49-2.39 (1H, m), 2.35-2.26 (1H, m), 2.10-1.99 (4H, m), 1.85-1.75 (1H, m), 1.45 (3H, t, J=7.0 Hz). LCMS (ESI) m/z 616 [M+H].sup.+.

Reference Example 111

4-Amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]-5-[2-[2-methylsulfanyl-4-(1-piperidyl)phenyl]ethynyl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of 4-fluoro-2-(methylthio)benzaldehyde

[0762] Sodium thiomethoxide (680 mg, 9.6 mmol) was suspended in toluene (10 mL), and 2,4-difluorobenzaldehyde (1 g, 7.0 mmol) was added thereto, followed by stirring at 80 C. for 2 days. Ethyl acetate and water were added to the reaction solution. Then, the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated saline, and dried over sodium sulfate, followed by distilling off the solvent. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/hexane), thereby obtaining the title compound (499 mg, 42%) as a white solid.

[0763] .sup.1H-NMR (CDCl.sub.3) : 10.15 (1H, s), 7.82 (1H, dd, J=8.3, 6.1 Hz), 7.01 (1H, dd, J=10.1, 2.3 Hz), 6.95 (1H, dt, J=2.3, 8.3 Hz), 2.49 (3H, s). LCMS (ESI) m/z 171 [M+H].sup.+

Step 2: Synthesis of 2-(methylthio)-4-(piperidin-1-yl)benzaldehyde

[0764] 4-Fluoro-2-(methylthio)benzaldehyde (200 mg, 1.2 mmol) and potassium carbonate (220 mg, 1.6 mmol) were suspended in dimethylsulfoxide (2 mL), and piperidine (0.16 ml, 1.6 mmol) was added thereto at room temperature, followed by stirring at 80 C. for 2 hours and 30 minutes. Ethyl acetate and water were added at room temperature to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, and dried over sodium sulfate, followed by distilling off the solvent. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/hexane), thereby obtaining the title compound (345 mg) as a yellow oil.

[0765] .sup.1H-NMR (CDCl.sub.3) : 9.99 (1H, s), 7.64 (1H, d, J=8.7 Hz), 6.68 (1H, dd, J=8.7, 2.3 Hz), 6.64 (1H, d, J=2.3 Hz), 3.43-3.40 (4H, m), 2.47 (3H, s), 1.80-1.70 (6H, m). LCMS (ESI) m/z 236 [M+H].sup.+

Step 3: Synthesis of 1-(4-ethynyl-3-(methylthio)phenyl)piperidine

[0766] The title compound was obtained as in step 1 of Reference Example 51, except that 2-(methylthio)-4-(piperidin-1-yl)benzaldehyde was used in place of 2-fluoro-6-methoxybenzaldehyde.

[0767] .sup.1H-NMR (CDCl.sub.3) : 7.32 (1H, d, J=8.6 Hz), 6.68 (1H, d, J=2.5 Hz), 6.63 (1H, dd, J=8.6, 2.5 Hz), 3.35 (1H, s), 3.24-3.21 (4H, m), 2.49 (3H, s), 1.72-1.58 (6H, m). LCMS (ESI) m/z 232 [M+H].sup.+

Step 4: Synthesis of Reference Example Compound 111

[0768] The title compound was obtained as in step 10 of Reference Example 93, except that 1-(4-ethynyl-3-(methylthio)phenyl)piperidine was used in place of 1-ethynylnaphthalene.

[0769] .sup.1H-NMR (CD.sub.3OD) : 8.13 (1H, s), 7.53 (1H, s), 7.29 (1H, d, J=8.8 Hz), 6.81 (1H, d, J=2.3 Hz), 6.75 (1H, dd, J=8.8, 2.3 Hz), 4.96-4.87 (1H, m), 4.42-4.38 (1H, m), 4.02-4.00 (1H, m), 3.29-3.15 (6H, m), 2.52 (3H, s), 2.48-2.40 (1H, m), 2.28-2.32 (1H, m), 1.85-1.77 (1H, m), 1.72-1.61 (6H, m). LCMS (ESI) m/z 572 [M+H].sup.+.

Reference Example 112

4-[4-[2-[4-Amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]-3-ethoxy-5-fluoro-phenyl]morpholine

[0770] The title compound was obtained as in step 10 of Reference Example 93, except that 4-(3-ethoxy-4-ethynyl-5-fluorophenyl)morpholine was used in place of 1-ethynylnaphthalene.

[0771] .sup.1H-NMR (DMSO-D.sub.6) : 8.12 (1H, s), 7.73 (1H, s), 6.65 (1H, t, J=6.0 Hz), 6.56-6.39 (4H, m), 4.91-4.84 (2H, m), 4.69 (1H, d, J=4.4 Hz), 4.23-4.16 (2H, m), 3.79 (1H, dd, J=8.4, 4.4 Hz), 3.74-3.68 (4H, m), 3.26-3.21 (4H, m), 3.12-3.04 (1H, m), 2.98-2.88 (1H, m), 2.27-2.17 (1H, m), 2.15-2.07 (2H, m), 1.60-1.51 (1H, m), 1.36 (3H, t, J=7.0 Hz). LCMS (ESI) m/z 590 [M+H].sup.+.

Reference Example 113

4-Amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]-5-[2-(4-methoxy-2-methylsulfonyl-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of triisopropyl((4-methoxy-2-(methylsulfonyl)phenyl)ethynyl)silane

[0772] The title compound was obtained as in step 2 of Reference Example 76, except that 1-bromo-2-methanesulfonyl-4-methoxybenzene was used in place of 5-(benzyloxy)-2-bromopyrimidine.

[0773] .sup.1H-NMR (CDCl.sub.3) : 7.61-7.59 (2H, m), 7.06 (1H, dd, J=8.5, 2.7 Hz), 3.88 (3H, s), 3.33 (3H, s), 1.19-1.12 (21H, m). LCMS (ESI) m/z 367 [M+H].sup.+

Step 2: Synthesis of 1-ethynyl-4-methoxy-2-(methylsulfonyl)benzene

[0774] The title compound was obtained as in step 3 of Reference Example 76, except that triisopropyl((4-methoxy-2-(methylsulfonyl)phenyl)ethynyl)silane was used in place of 5-(benzyloxy)-2-((triisopropylsilyl)ethynyl)pyrimidine.

[0775] .sup.1H-NMR (CDCl.sub.3) : 7.64-7.62 (2H, m), 7.09 (1H, dd, J=8.5, 2.7 Hz), 3.90 (3H, s), 3.53 (1H, s), 3.31 (3H, s). LCMS (ESI) m/z 211 [M+H].sup.+

Step 3: Synthesis of Reference Example Compound 113

[0776] The title compound was obtained as in step 10 of Reference Example 93, except that 1-ethynyl-4-methoxy-2-(methylsulfonyl)benzene was used in place of 1-ethynylnaphthalene.

[0777] .sup.1H-NMR (CD.sub.3OD) : 8.16 (1H, s), 7.72 (1H, s), 7.70 (1H, d, J=8.6 Hz), 7.57 (1H, d, J=2.8 Hz), 7.26 (1H, dd, J=8.6, 2.8 Hz), 4.99-4.91 (1H, m), 4.44-4.40 (1H, m), 4.03-4.01 (1H, m), 3.91 (3H, s), 3.30 (3H, s), 3.39-3.24 (1H, m), 3.21-3.16 (1H, m), 2.50-2.42 (1H, m), 2.35-2.28 (1H, m), 1.87-1.79 (1H, m). LCMS (ESI) m/z 551 [M+H].sup.+.

Reference Example 114

4-Amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]-5-[2-(2-ethylsulfonyl-6-fluoro-4-pyrrolidin-1-yl-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine

[0778] The title compound was obtained as in step 10 of Reference Example 93, except that 1-(3-(ethylsulfonyl)-4-ethynyl-5-fluorophenyl)pyrrolidine was used in place of 1-ethynylnaphthalene.

[0779] .sup.1H-NMR (CD.sub.3OD) : 8.13 (1H, s), 7.62 (1H, s), 6.99 (1H, d, J=2.6 Hz), 6.64 (1H, dd, J=12.4, 2.6 Hz), 4.98-4.90 (1H, m), 4.43-4.39 (1H, m), 4.02-4.00 (1H, m), 3.49 (2H, q, J=7.4 Hz), 3.39-3.34 (4H, m), 3.28-3.24 (1H, m), 3.20-3.15 (1H, m), 2.48-2.40 (1H, m), 2.34-2.28 (1H, m), 2.09-2.06 (4H, m), 1.85-1.77 (1H, m), 1.24 (3H, t, J=7.4 Hz). LCMS (ESI) m/z 622 [M+H].sup.+.

Reference Example 115

4-Amino-5-[2-[2,6-difluoro-4-[(3R)-3-fluoropyrrolidin-1-yl]phenyl]ethynyl]-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]pyrrolo[2,3-d]pyrimidine

[0780] The title compound was obtained as in step 10 of Reference Example 93, except that (3R)-1-(4-ethynyl-3,5-difluorophenyl)-3-fluoropyrrolidine was used in place of 1-ethynylnaphthalene.

[0781] .sup.1H-NMR (CD.sub.3OD) : 8.12 (1H, s), 7.54 (1H, s), 6.25 (2H, d, J=10.6 Hz), 5.38 (1H, d, J=53.2 Hz), 5.04-4.95 (1H, m), 4.40 (1H, dd, J=8.4, 5.9 Hz), 4.01 (1H, dd, J=5.5, 3.7 Hz), 3.64-3.10 (6H, m), 2.49-2.38 (1H, m), 2.37-2.26 (2H, m), 2.22-2.12 (1H, m), 1.84-1.75 (1H, m). LCMS (ESI) m/z 566 [M+H].sup.+.

Reference Example 116

4-Amino-5-[2-[2,6-difluoro-4-[(3S)-3-fluoropyrrolidin-1-yl]phenyl]ethynyl]-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of (3S)-1-(4-ethynyl-3,5-difluorophenyl)-3-fluoropyrrolidine

[0782] The title compound was obtained as in step 1 of Reference Example 23, except that (S)-3-fluoropyrrolidine was used in place of morpholine.

[0783] .sup.1H-NMR (CDCl.sub.3) : 6.06 (2H, d, J=10.3 Hz), 5.38 (1H, d, J=53.5 Hz), 3.62-3.39 (5H, m), 2.47-2.36 (1H, m), 2.28-2.07 (1H, m). LCMS (ESI) m/z 226 [M+H].sup.+

Step 2: Synthesis of Reference Example Compound 116

[0784] The title compound was obtained as in step 10 of Reference Example 93, except that (3S)-1-(4-ethynyl-3,5-difluorophenyl)-3-fluoropyrrolidine was used in place of 1-ethynylnaphthalene.

[0785] .sup.1H-NMR (CD.sub.3OD) : 8.11 (1H, s), 7.53 (1H, s), 6.22 (2H, d, J=10.6 Hz), 5.38 (1H, d, J=53.2 Hz), 4.93-4.90 (1H, m), 4.42-4.37 (1H, m), 4.01 (1H, dd, J=5.5, 4.0 Hz), 3.62-3.15 (6H, m), 2.49-2.40 (1H, m), 2.34-2.27 (2H, m), 2.22-2.08 (1H, m), 1.84-1.76 (1H, m). LCMS (ESI) m/z 566 [M+H].sup.+.

Reference Example 117

4-Amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]-5-[2-(1,1-dioxo-2,3-dihydrobenzothiophen-7-yl)ethynyl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of 7-ethynyl-2,3-dihydrobenzo[b]thiophene 1,1-dioxide

[0786] The title compound was obtained as in step 3 of Reference Example 70, except that 7-ethynyl-2,3-dihydrobenzo[b]thiophene was used in place of 2-(ethylthio)-6-fluoro-4-(pyrrolidin-1-yl)benzaldehyde.

[0787] .sup.1H-NMR (CDCl.sub.3) : 7.57-7.51 (2H, m), 7.36 (1H, d, J=7.1 Hz), 3.57-3.52 (3H, m), 3.35 (2H, t, J=7.2 Hz). LCMS (ESI) m/z 193 [M+H].sup.+

Step 2: Synthesis of Reference Example Compound 117

[0788] The title compound was obtained as in step 10 of Reference Example 93, except that 7-ethynyl-2,3-dihydrobenzo[b]thiophene 1,1-dioxide was used in place of 1-ethynylnaphthalene.

[0789] .sup.1H-NMR (CD.sub.3OD) : 8.15 (1H, s), 7.74 (1H, s), 7.64 (1H, t, J=7.6 Hz), 7.58 (1H, d, J=7.6 Hz), 7.45 (1H, d, J=7.6 Hz), 5.00-4.89 (1H, m), 4.44-4.40 (1H, m), 4.03-4.00 (1H, m), 3.62 (2H, t, J=7.1 Hz), 3.41 (2H, t, J=7.1 Hz), 3.22-3.11 (2H, m), 2.48-2.42 (1H, m), 2.32-2.26 (1H, m), 1.87-1.77 (1H, m). LCMS (ESI) m/z 533 [M+H].sup.+.

Reference Example 118

4-Amino-5-[2-[4-(azetidin-1-yl)-2,6-difluoro-phenyl]ethynyl]-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]pyrrolo[2,3-d]pyrimidine

[0790] The title compound was obtained as in step 10 of Reference Example 93, except that 1-(4-ethynyl-3,5-difluorophenyl)azetidine was used in place of 1-ethynylnaphthalene.

[0791] .sup.1H-NMR (CD.sub.3OD) : 8.14 (1H, s), 7.56 (1H, s), 6.03 (2H, d, J=10.0 Hz), 4.99-4.89 (1H, m), 4.40 (1H, dd, J=8.5, 5.6 Hz), 4.01 (1H, dd, J=5.6, 3.7 Hz), 3.94 (4H, t, J=7.4 Hz), 3.28-3.09 (2H, m), 2.46-2.36 (3H, m), 2.34-2.24 (1H, m), 1.85-1.72 (1H, m). LCMS (ESI) m/z 534 [M+H].sup.+.

Reference Example 119

4-Amino-5-[2-[2,6-difluoro-4-(4-hydroxy-1-piperidyl)phenyl]ethynyl]-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of 1-(4-ethynyl-3,5-difluorophenyl)piperidin-4-ol

[0792] The title compound was obtained as in step 1 of Reference Example 23, except that piperidin-4-ol was used in place of morpholine.

[0793] .sup.1H-NMR (CDCl.sub.3) : 6.36 (2H, d, J=11.2 Hz), 3.93-3.87 (1H, m), 3.58 (2H, dt, J=13.0, 4.9 Hz), 3.40 (1H, s), 3.06-3.00 (2H, m), 2.21-2.10 (1H, m), 1.99-1.91 (2H, m), 1.65-1.55 (2H, m). LCMS (ESI) m/z 238 [M+H].sup.+

Step 2: Synthesis of Reference Example Compound 119

[0794] The title compound was obtained as in step 10 of Reference Example 93, except that 1-(4-ethynyl-3,5-difluorophenyl)piperidin-4-ol was used in place of 1-ethynylnaphthalene.

[0795] .sup.1H-NMR (CD.sub.3OD) : 8.19 (1H, s), 7.57 (1H, s), 6.57 (2H, d, J=11.5 Hz), 4.98-4.89 (1H, m), 4.40 (1H, t, J=6.3 Hz), 4.01 (1H, dd, J=5.5, 3.8 Hz), 3.85-3.78 (1H, m), 3.70-3.65 (2H, m), 3.30-3.14 (2H, m), 3.08-3.00 (2H, m), 2.49-2.40 (1H, m), 2.36-2.25 (1H, m), 1.97-1.88 (2H, m), 1.85-1.75 (1H, m), 1.60-1.50 (2H, m). LCMS (ESI) m/z 578 [M+H].sup.+.

Reference Example 120

4-Amino-5-[2-[2,6-difluoro-4-[(3R)-3-hydroxypyrrolidin-1-yl]phenyl]ethynyl]-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]pyrrolo[2,3-d]pyrimidine

[0796] The title compound was obtained as in step 10 of Reference Example 93, except that (3R)-1-(4-ethynyl-3,5-difluorophenyl)-pyrrolidin-3-ol was used in place of 1-ethynylnaphthalene.

[0797] .sup.1H-NMR (CD.sub.3OD) : 8.22 (1H, s), 7.55 (1H, s), 6.20 (2H, d, J=11.0 Hz), 4.98-4.90 (1H, m), 4.55-4.51 (1H, m), 4.43-4.36 (1H, m), 4.01 (1H, dd, J=5.5, 3.8 Hz), 3.51-3.42 (2H, m), 3.40-3.33 (1H, m), 3.27-3.14 (3H, m), 2.48-2.40 (1H, m), 2.34-2.26 (1H, m), 2.20-2.09 (1H, m), 2.08-2.00 (1H, m), 1.84-1.75 (1H, m). LCMS (ESI) m/z 564 [M+H].sup.+.

Reference Example 121

4-Amino-5-[2-[2,6-difluoro-4-[(3S)-3-hydroxypyrrolidin-1-yl]phenyl]ethynyl]-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of (3S)-1-(4-ethynyl-3,5-difluorophenyl)-pyrrolidin-3-ol

[0798] The title compound was obtained as in step 1 of Reference Example 23, except that (S)-pyrrolidin-3-ol was used in place of morpholine.

[0799] .sup.1H-NMR (CDCl.sub.3) : 6.03 (2H, d, J=10.5 Hz), 4.64-4.60 (1H, m), 3.51-3.43 (2H, m), 3.39 (1H, s), 3.34 (1H, dt, J=3.2, 9.0 Hz), 3.22 (1H, d, J=10.7 Hz), 2.22-2.12 (1H, m), 2.12-2.05 (1H, m). LCMS (ESI) m/z 224 [M+H].sup.+

Step 2: Synthesis of Reference Example Compound 121

[0800] The title compound was obtained as in step 10 of Reference Example 93, except that (3S)-1-(4-ethynyl-3,5-difluorophenyl)-pyrrolidin-3-ol was used in place of 1-ethynylnaphthalene.

[0801] .sup.1H-NMR (CD.sub.3OD) : 8.23 (1H, s), 7.55 (1H, s), 6.20 (2H, d, J=10.7 Hz), 4.97-4.89 (1H, m), 4.54-4.49 (1H, m), 4.46-4.35 (1H, m), 4.03-3.96 (1H, m), 3.51-3.41 (2H, m), 3.40-3.33 (1H, m), 3.27-3.12 (3H, m), 2.48-2.39 (1H, m), 2.35-2.25 (1H, m), 2.19-2.09 (1H, m), 2.08-2.00 (1H, m), 1.84-1.74 (1H, m). LCMS (ESI) m/z 564 [M+H].sup.+.

Reference Example 122

8-[2-[4-amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]-7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine

Step 1: The Title Compound was Obtained as in Step 10 of Reference Example 93, Except that 8-ethynyl-7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine was Used in Place of 1-ethynylnaphthalene

[0802] .sup.1H-NMR (DMSO-D.sub.6) : 8.17-8.12 (2H, m), 7.84 (1H, s), 6.77-6.64 (3H, m), 6.53 (2H, s), 4.88 (1H, dd, J=18.7, 8.4 Hz), 4.43 (2H, t, J=4.2 Hz), 4.21 (1H, dd, J=8.6, 5.3 Hz), 3.80 (1H, dd, J=5.1, 3.3 Hz), 3.25 (2H, t, J=4.2 Hz), 3.12-3.04 (1H, m), 2.96-2.89 (1H, m), 2.82 (3H, s), 2.24-2.19 (1H, m), 2.15-2.08 (1H, m), 1.56 (1H, dd, J=20.9, 11.0 Hz). LCMS (ESI) m/z 532.3 [M+H].sup.+.

Step 2: Synthesis of 8-[2-[4-amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]-7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine hydrochloride

[0803] The title compound hydrochloride was obtained as in step 5 of Reference Example 1.

[0804] .sup.1H-NMR (DMSO-D.sub.6) : 8.45 (1H, s), 8.24 (1H, s), 6.81-6.74 (2H, m), 4.98 (1H, dd, J=19.1, 8.8 Hz), 4.47 (2H, t, J=4.2 Hz), 4.20 (1H, dd, J=9.0, 5.3 Hz), 3.80 (1H, dd, J=5.1, 2.9 Hz), 3.27 (2H, t, J=4.4 Hz), 3.08 (1H, dd, J=12.8, 6.6 Hz), 2.93 (1H, dd, J=12.5, 7.3 Hz), 2.84 (3H, s), 2.29-2.22 (1H, m), 2.17-2.10 (1H, m), 1.58 (1H, dd, J=20.7, 10.8 Hz). LCMS (ESI) m/z 532.4 [M+H].sup.+

Reference Example 123

4-Amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]-5-[2-(1,1-dioxo-3,4-dihydro-2H-thiochromen-8-yl)ethynyl]pyrrolo[2,3-d]pyrimidine

[0805] The title compound was obtained as in step 10 of Reference Example 93, except that 8-ethynyl thiochroman 1,1-dioxide was used in place of 1-ethynylnaphthalene.

[0806] .sup.1H-NMR (CD.sub.3OD) : 8.16 (1H, s), 7.73 (1H, s), 7.57 (1H, d, J=7.7 Hz), 7.50 (1H, t, J=7.7 Hz), 7.31 (1H, d, J=7.7 Hz), 5.03-4.89 (1H, m), 4.44-4.40 (1H, m), 4.04-4.02 (1H, m), 3.56-3.53 (2H, m), 3.30-3.25 (1H, m), 3.22-3.17 (1H, m), 3.09 (2H, t, J=6.0 Hz), 2.50-2.39 (3H, m), 2.36-2.27 (1H, m), 1.87-1.79 (1H, m). LCMS (ESI) m/z 547 [M+H].sup.+.

Reference Example 124

4-Amino-5-[2-(2,6-difluorophenyl)ethynyl]-7-[(2R,4S,5R)-4-hydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of (2R,3S,5R)-5-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(aminoethyl)tetrahydrofuran-3-ol

[0807] The title compound was obtained as in step 2 of Reference Example 1, except that (2R,3S,5R)-5-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)tetrahydrofuran-3-ol was used in place of [(3aR,4R,6R,6aR)-4-(4-amino-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol.

[0808] .sup.1H-NMR (CD.sub.3OD) : 8.09 (1H, s), 7.48 (1H, s), 6.52 (1H, t, J=7.0 Hz), 4.37 (1H, dt, J=6.6, 4.0 Hz), 3.89 (1H, dt, J=7.0, 4.0 Hz), 2.91 (1H, dd, J=13.2, 4.0 Hz), 2.83 (1H, dd, J=13.2, 7.0 Hz), 2.66-2.59 (1H, m), 2.33 (1H, ddd, J=13.9, 7.0, 3.7 Hz). LCMS (ESI) m/z 376 [M+H].sup.+

Step 2: Synthesis of tert-butyl-N-[[(2R,3S,5R)-5-(4-amino-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)-3-hydroxy-tetrahydrofuran-2-yl]methyl sulfamoyl]carbamate

[0809] The title compound was obtained as in step 3 of Reference Example 1, except that (2R,3S,5R)-5-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(aminoethyl)tetrahydrofuran-3-ol was used in place of 7-((3aR,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine.

[0810] .sup.1H-NMR (DMSO-D.sub.6) : 10.84 (1H, s), 8.09 (1H, s), 7.61 (1H, s), 6.76-6.61 (2H, brm), 6.35 (1H, dd, J=8.8, 5.9 Hz), 5.33 (1H, d, J=4.0 Hz), 4.28-4.26 (1H, brm), 3.90-3.87 (1H, m), 3.16-3.10 (2H, m), 2.59-2.52 (1H, m), 2.11-2.06 (1H, m), 1.36 (9H, s). LCMS (ESI) m/z 555 [M+H].sup.+

Step 3: Synthesis of Reference Example Compound 124

[0811] tert-Butyl-N-[[(2R,3S,5R)-5-(4-amino-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)-3-hydroxy-tetrahydrofuran-2-yl]methyl sulfamoyl]carbamate (40 mg, 0.072 mmol), 2-ethynyl-1,3-difluorobenzene (15 mg, 0.11 mmol), bis(triphenylphosphine)palladium (II) dichloride (10 mg, 0.014 mmol), copper iodide (2.7 mg, 0.014 mmol), and diisopropylethylamine (0.030 mL, 0.18 mmol) were suspended in tetrahydrofuran (0.5 mL). The reaction solution was stirred at 70 C. overnight. Thereafter, trifluoroacetic acid (0.5 mL) was added thereto at room temperature, followed by stirring at room temperature overnight. After the solvent was distilled off, the residue was purified by silica gel column chromatography (developing solvent: methanol/chloroform), thereby obtaining the title compound (1.2 mg, 4%) as a white powder.

[0812] .sup.1H-NMR (DMSO-D.sub.6) : 8.18 (1H, s), 8.00 (1H, s), 7.53-7.47 (1H, m), 7.29-7.24 (1H, m), 7.18-7.15 (1H, m), 6.58 (2H, s), 6.43 (1H, dd, J=8.8, 5.6 Hz), 5.35 (1H, d, J=4.1 Hz), 4.39-4.35 (1H, brm), 3.98-3.94 (1H, brm), 3.18-3.03 (2H, brm), 2.66-2.59 (1H, m). LCMS (ESI) m/z 465 [M+H].sup.+.

Reference Example 125

4-Amino-7-[(2R,4S,5R)-4-hydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(1-naphthyl)ethynyl]pyrrolo[2,3-d]pyrimidine

[0813] The title compound was obtained as in step 3 of Reference Example 124, except that 1-ethynylnaphthalene was used in place of 2-ethynyl-1,3-difluorobenzene.

[0814] .sup.1H-NMR (CD.sub.3OD) : 8.39 (1H, d, J=8.4 Hz), 8.35 (1H, s), 8.07 (1H, s), 7.96 (1H, brs), 7.94 (1H, brs), 7.85 (1H, d, J=7.3 Hz), 7.67-7.46 (3H, m), 6.59 (1H, dd, J=7.7, 6.2 Hz), 4.62-4.59 (1H, m), 4.18-4.15 (1H, m), 3.41-3.34 (2H, m), 2.77 (1H, ddd, J=13.9, 7.7, 6.2 Hz), 2.45 (1H, ddd, J=13.9, 6.2, 2.9 Hz). LCMS (ESI) m/z 479 [M+H].sup.+.

Reference Example 126

4-[4-Amino-7-[(2R,4S,5R)-4-hydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]-2-(o-tolyl)thiazole

[0815] The title compound was obtained as in Reference Example 2, except that tert-butyl-N-[[(2R,3S,5R)-5-(4-amino-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)-3-hydroxy-tetrahydrofuran-2-yl]methyl sulfamoyl]carbamate was used in place of tert-butyl N-(((3aR,4R,6R,6aR)-6-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)sulfamoyl carbamate.

[0816] .sup.1H-NMR (CD.sub.3OD) : 8.37 (1H, s), 8.26 (1H, s), 8.15 (1H, s), 8.04-8.01 (1H, m), 7.66 (1H, d, J=7.7 Hz), 7.49-7.35 (3H, m), 6.68 (1H, dd, J=7.7, 6.2 Hz), 4.61-4.58 (1H, m), 4.16 (1H, dt, J=5.9, 3.3 Hz), 3.44 (1H, dd, J=13.6, 4.0 Hz), 3.39 (1H, dd, J=13.6, 4.8 Hz), 2.72-2.65 (1H, m), 2.55 (3H, s), 2.47 (1H, ddd, J=13.6, 6.2, 3.3 Hz). LCMS (ESI) m/z 502 [M+H].sup.+.

Reference Example 127

4-Amino-5-[2-(2-ethoxy-6-fluoro-phenyl)ethynyl]-7-[(2R,4S,5R)-4-hydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine

[0817] The title compound was obtained as in step 3 of Reference Example 124, except that 1-ethoxy-2-ethynyl-3-fluorobenzene was used in place of 2-ethynyl-1,3-difluorobenzene.

[0818] .sup.1H-NMR (DMSO-D.sub.6) : 8.17 (1H, s), 7.88 (1H, s), 7.37 (1H, ddd, J=8.8, 8.4, 7.0 Hz), 7.19 (1H, dd, J=7.0, 5.5 Hz), 6.97 (1H, d, J=8.4 Hz), 6.91 (1H, t, J=8.8 Hz), 6.57 (2H, s), 6.42 (1H, dd, J=8.4, 5.5 Hz), 5.37 (1H, d, J=4.0 Hz), 4.37 (1H, brs), 4.22 (2H, q, J=7.0 Hz), 3.99-3.93 (1H, m), 3.22-3.04 (2H, m), 2.67-2.61 (1H, m), 2.17 (1H, dd, J=13.6, 5.5 Hz), 1.37 (3H, t, J=7.0 Hz). LCMS (ESI) m/z 491 [M+H].sup.+.

Reference Example 128

4-Amino-5-[2-(2,6-difluorophenyl)ethynyl]-7-[(1R,4R,5S)-4,5-dihydroxy-3-[(sulfamoylamino)methyl]cyclopent-2-en-1-yl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of ((3aS,4R,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol

[0819] (3aR,6aR)-6-(((tert-Butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl-3aH-cyclopenta[d][1,3]dioxol-4(6aH)-one (1.0 g, 2.36 mmol) and cerium chloride heptahydrate (881 mg, 2.36 mmol) were suspended in methanol (5 mL), and sodium borohydride (92%, 146 mg, 3.54 mmol) was added thereto with stirring at 0 C. After the mixture was stirred at 0 C. for 2 hours, water (20 mL) was added thereto. Acetic acid was then added thereto until the pH of the reaction liquid became about 5. After the reaction liquid was partitioned between ethyl acetate and water, the organic layer was separated. The obtained organic layer was sequentially washed with a saturated aqueous ammonium chloride solution and saturated saline, and dried over magnesium sulfate, followed by distilling off the solvent. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/hexane), thereby obtaining the title compound (960 mg) as a colorless oil.

[0820] .sup.1H-NMR (CDCl.sub.3) : 7.72-7.66 (4H, m), 7.45-7.37 (6H, m), 5.85 (1H, s), 4.88 (1H, d, J=5.5 Hz), 4.76 (1H, dd, J=6.2, 5.9 Hz), 4.58-4.55 (1H, brm), 4.39 (1H, d, J=14.7 Hz), 4.29 (1H, d, J=14.7 Hz), 1.37 (3H, s), 1.34 (3H, s), 1.08 (9H, s). LCMS (ESI) m/z 425 [M+H].sup.+

Step 2: Synthesis of 7-((3aS,4R,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine

[0821] (3aS,4R,6aR)-6-(((tert-Butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (960 mg, 2.26 mmol), 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (632 mg, 2.26 mmol), and triphenylphosphine (889 mg, 3.39 mmol) were dissolved in tetrahydrofuran (7 mL). Then, diisopropyl azodicarboxylate (667 L, 3.39 mmol) was added thereto dropwise with stirring at 0 C. After the reaction liquid was stirred at room temperature for 14 hours, the reaction liquid was concentrated, and the residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/hexane), thereby obtaining the title compound (1.33 g) as a colorless amorphous substance.

[0822] .sup.1H-NMR (CDCl.sub.3) : 8.69 (1H, s), 7.72-7.69 (4H, m), 7.49-7.39 (6H, m), 7.15 (1H, s), 5.88-5.86 (1H, brm), 5.84-5.82 (1H, brm), 5.21 (1H, d, J=5.5 Hz), 4.56 (1H, d, J=5.5 Hz), 4.49 (2H, d, J=14.7 Hz), 1.44 (3H, s), 1.31 (3H, s), 1.11 (9H, s). LCMS (ESI) m/z 687 [M+H].sup.+

Step 3: Synthesis of ((3aR,6R,6aS)-6-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol

[0823] 7-((3aS,4R,6aR)-6-(((tert-Butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (16.2 g, 23.6 mmol) was suspended in 1,4-dioxane (50 mL) and aqueous ammonia (28%, 50 mL), followed by heating with stirring at 100 C. for 24 hours in a pressure-resistant container. After the solvent was distilled off, tetrahydrofuran (50 mL) was added to the residue, and tetrabutylammonium fluoride (a 1 M tetrahydrofuran solution, 47 mL) was added thereto with stirring at room temperature, followed by stirring at room temperature overnight. After the reaction solution was partitioned between ethyl acetate and water, the aqueous layer was separated, and extracted with ethyl acetate. The organic layers were combined and washed with saturated saline, followed by distilling off the solvent. The residue was purified by silica gel column chromatography (developing solvent: methanol/chloroform), thereby obtaining the title compound (7.4 g) as a milky-white solid.

[0824] .sup.1H-NMR (DMSO-D.sub.6) : 8.12 (1H, s), 7.18 (1H, s), 6.63 (2H, brs), 5.63-5.61 (1H, brm), 5.59-5.59 (1H, brm), 5.29 (1H, d, J=5.5 Hz), 5.06 (1H, dd, J=5.7, 5.5 Hz), 4.49 (1H, d, J=5.9 Hz), 4.13 (2H, d, J=5.9 Hz), 1.36 (3H, s), 1.25 (3H, s). LCMS (ESI) m/z 429 [M+H].sup.+

Step 4: Synthesis of tert-butyl(((3aR,6R,6aS)-6-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(sulfamoyl)carbamate

[0825] ((3aR,6R,6aS)-6-(4-Amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol (100 mg, 0.233 mmol), tert-butyl sulfamoylcarbamate (60 mg, 0.30 mmol), and triphenylphosphine (92 mg, 0.35 mmol) were dissolved in tetrahydrofuran (1 mL). Then, diisopropyl azodicarboxylate (69 L, 0.35 mmol) was added thereto dropwise with stirring at 0 C. After the reaction liquid was stirred for 3 hours under ice-cooling, methanol (1 mL) was added thereto, followed by stirring at room temperature for 10 minutes. The reaction liquid was concentrated, and the residue was purified by silica gel column chromatography (developing solvent: methanol/chloroform), thereby obtaining the title compound (60 mg) as a colorless amorphous substance.

[0826] .sup.1H-NMR (CDCl.sub.3) : 8.22 (1H, s), 6.91 (1H, s), 6.36-6.07 (4H, brm), 5.81 (1H, brs), 5.69 (1H, brs), 5.32 (1H, d, J=5.9 Hz), 4.66-4.52 (3H, m), 1.55 (9H, s), 1.48 (3H, s), 1.34 (3H, s). LCMS (ESI) m/z 607 [M+H].sup.+

Step 5: Synthesis of Reference Example Compound 128

[0827] tert-Butyl (((3aR,6R,6aS)-6-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(sulfamoyl)carbamate (60 mg, 0.099 mmol), 2-ethynyl-1,3-difluorobenzene (27.3 mg, 0.198 mmol), bis(triphenylphosphine)palladium (II) dichloride (3.5 mg, 0.005 mmol), copper iodide (1 mg, 0.0053 mmol), and diisopropylethylamine (0.034 mL, 0.19 mmol) were suspended in tetrahydrofuran (0.7 mL). After the reaction solution was stirred at 50 C. for 1 hour, the reaction liquid was concentrated, and the residue was roughly purified by silica gel column chromatography (developing solvent: methanol/chloroform). The obtained residue was dissolved at room temperature in acetonitrile (0.5 mL) and concentrated hydrochloric acid (0.2 mL), followed by stirring at room temperature overnight. After the reaction liquid was concentrated, the residue was purified by basic silica gel column chromatography (developing solvent: methanol/chloroform), thereby obtaining the title compound (5.7 mg, 12%) as a white solid.

[0828] .sup.1H-NMR (CD.sub.3OD) : 8.16 (1H, s), 7.56 (1H, s), 7.45-7.38 (1H, m), 7.11-7.05 (2H, m), 5.94 (1H, brs), 5.63 (1H, d, J=5.5 Hz), 4.68 (1H, d, J=5.5 Hz), 4.27 (1H, t, J=5.5 Hz), 3.95 (1H, d, J=16.5 Hz), 3.87 (1H, d, J=16.5 Hz). LCMS (ESI) m/z 477 [M+H].sup.+.

Reference Example 129

4-Amino-7-[(1R,4R,5S)-4,5-dihydroxy-3-[(sulfamoylamino)methyl]cyclopent-2-en-1-yl]-5-[2-(2-ethoxy-6-fluoro-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine

[0829] The title compound was obtained as in step 5 of Reference Example 128, except that 1-ethoxy-2-ethynyl-3-fluorobenzene was used in place of 2-ethynyl-1,3-difluorobenzene.

[0830] .sup.1H-NMR (CD.sub.3OD) : 8.14 (1H, s), 7.45 (1H, s), 7.30 (1H, ddd, J=8.8, 8.4, 6.6 Hz), 6.88 (1H, d, J=8.4 Hz), 6.78 (1H, t, J=8.8 Hz), 5.94 (1H, brs), 5.61 (1H, d, J=4.8 Hz), 4.68 (1H, d, J=5.5 Hz), 4.27 (1H, dd, J=5.5, 4.8 Hz), 4.24 (2H, q, J=7.0 Hz), 3.94 (1H, d, J=16.1 Hz), 3.91 (1H, d, J=16.1 Hz), 1.48 (3H, t, J=7.0 Hz). LCMS (ESI) m/z 503 [M+H].sup.+.

Reference Example 130

4-Amino-7-[(1R,4R,5S)-4,5-dihydroxy-3-[(sulfamoylamino)methyl]cyclopent-2-en-1-yl]-5-[2-(2-fluoro-6-methylsulfanyl-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine

[0831] The title compound was obtained as in step 5 of Reference Example 128, except that 2-ethynyl-1-fluoro-3-methanesulfanyl-benzene was used in place of 2-ethynyl-1,3-difluorobenzene.

[0832] .sup.1H-NMR (DMSO-D.sub.6) : 8.17 (1H, s), 7.62 (1H, s), 7.41 (1H, ddd, J=8.8, 8.8, 6.2 Hz), 7.15 (1H, d, J=8.8 Hz), 7.11 (1H, t, J=8.8 Hz), 6.80 (1H, t, J=5.7 Hz), 6.64 (2H, s), 5.74 (1H, s), 5.56 (1H, brs), 5.10 (1H, d, J=6.2 Hz), 5.01 (1H, d, J=6.2 Hz), 4.48 (1H, t, J=6.2 Hz), 4.11-4.06 (1H, m), 3.73-3.59 (2H, m), 2.55 (3H, s). LCMS (ESI) m/z 505 [M+H].sup.+.

Reference Example 131

[(2R,3S,4R,5R)-5-[4-amino-5-(2-phenylethynyl)pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2-yl]methyl sulfamate

Step 1: Synthesis of ((3aR,4R,6R,6aR)-6-(4-amino-5-(phenylethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol

[0833] [(3aR,4R,6R,6aR)-4-(4-Amino-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol (1 g, 2.3 mmol), phenylacetylene (354 mg, 3.5 mmol), bis(triphenylphosphine)palladium (II) dichloride (161 mg, 0.23 mmol), and copper iodide (44 mg, 0.23 mmol) were suspended in tetrahydrofuran (10 mL), Then, nitrogen purging was performed, and after diisopropylethylamine (0.78 mL, 4.6 mmol) was added thereto, the reaction solution was stirred at 70 C. for 2 hours. The reaction solution was filtered through a celite bed and washed with chloroform, followed by distilling off the solvent. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/hexane), thereby obtaining the title compound (800 mg, 85%) as a yellow amorphous substance.

[0834] .sup.1H-NMR (CDCl.sub.3) : 8.27 (1H, s), 7.51-7.49 (2H, m), 7.39-7.36 (3H, m), 7.27-7.25 (1H, m), 6.52 (1H, d, J=10.7 Hz), 5.85-5.72 (2H, brs), 5.72 (1H, d, J=5.1 Hz), 5.24 (1H, t, J=5.5 Hz), 5.12-5.09 (1H, m), 4.52-4.50 (1H, brs), 4.00-3.96 (1H, m), 3.83-3.76 (1H, m), 1.64 (3H, s), 1.37 (3H, s). LCMS (ESI) m/z 407 [M+H].sup.+

Step 2: Synthesis of ((3aR,4R,6R,6aR)-6-(4-amino-5-(phenylethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl sulfamate

[0835] ((3aR,4R,6R,6aR)-6-(4-Amino-5-(phenylethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (50 mg, 0.12 mmol) was dissolved in acetonitrile (0.5 mL). Then, triethylamine (0.084 mL, 0.59 mmol) was added thereto at room temperature, and sulfamoyl chloride (0.5 M acetonitrile solution, 0.27 mL) was added thereto in an ice bath. After the resulting mixture was stirred for 40 minutes in an ice bath, the solvent was distilled off. Then, chloroform and an aqueous sodium hydrogen carbonate solution were added thereto, and the aqueous layer was extracted with a liquid mixture of chloroform/methanol=5/1. The organic layer was washed with saturated saline and dried over sodium sulfate, followed by distilling off the solvent. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/hexane), thereby obtaining the title compound (39 mg, 67%) as a yellow amorphous substance.

[0836] .sup.1H-NMR (CDCl.sub.3) : 8.29 (1H, s), 7.52-7.49 (2H, m), 7.37-7.36 (3H, m), 7.30 (1H, s), 6.08 (1H, d, J=2.7 Hz), 5.72-5.68 (2H, brs), 5.35 (1H, dd, J=6.3, 2.9 Hz), 5.13-5.11 (1H, m), 4.50-4.43 (3H, m), 1.62 (3H, s), 1.39 (3H, s). LCMS (ESI) m/z 486 [M+H].sup.+

Step 3: Synthesis of Reference Example Compound 131

[0837] ((3aR,4R,6R,6aR)-6-(4-Amino-5-(phenylethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl sulfamate (380 mg, 0.79 mmol) was dissolved in tetrahydrofuran (4 mL), and a mixed solution (9.5 mL) of trifluoroacetic acid/water=4/1 was added thereto, followed by stirring at room temperature for 8 hours. After the solvent was distilled off, methanol was added, and the solvent was distilled off again. The residue was purified by basic silica gel column chromatography (developing solvent: methanol/chloroform), thereby obtaining the title compound (323 mg, 92%) as a white powder.

[0838] .sup.1H-NMR (CD.sub.3OD) : 8.15 (1H, s), 7.67 (1H, s), 7.55-7.52 (2H, m), 7.39-7.37 (3H, m), 6.22 (1H, d, J=5.6 Hz), 4.90-4.80 (1H, m), 4.47-4.26 (4H, m). LCMS (ESI) m/z 446 [M+H].sup.+.

Reference Example 132

[(2R,3S,4R,5R)-5-[4-Amino-5-[2-(2,6-difluorophenyl)ethynyl]pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2-yl]methyl sulfamate

[0839] The title compound was obtained as in Reference Example 131, except that 2-ethynyl-1,3-difluorobenzene was used in place of phenylacetylene.

[0840] .sup.1H-NMR (DMSO-D.sub.6) : 8.20 (1H, s), 7.97 (1H, s), 7.55-7.50 (1H, m), 7.31-7.25 (2H, m), 6.45-6.37 (2H, brs), 6.13 (1H, d, J=5.9 Hz), 4.47-4.43 (1H, m), 4.28-4.23 (1H, m), 4.20-4.09 (5H, m). LCMS (ESI) m/z 482 [M+H].sup.+.

Reference Example 133

[(2R,3S,4R,5R)-5-[4-Amino-5-[2-(1-naphthyl)ethynyl]pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2-yl]methyl sulfamate

[0841] The title compound was obtained as in Reference Example 131, except that 1-ethynylnaphthalene was used in place of phenylacetylene.

[0842] .sup.1H-NMR (CD.sub.3OD) : 8.41 (1H, d, J=8.0 Hz), 8.19 (1H, s), 7.94-7.90 (2H, m), 7.86 (1H, s), 7.80 (1H, d, J=4.0 Hz), 7.69-7.48 (3H, m), 6.29 (1H, d, J=5.1 Hz), 4.87-4.80 (1H, m), 4.52-4.26 (4H, m). LCMS (ESI) m/z 496 [M+H].sup.+.

Reference Example 134

[(2R,3S,5R)-5-[4-Amino-5-(2-phenylethynyl)pyrrolo[2,3-d]pyrimidin-7-yl]-3-hydroxy-tetrahydrofuran-2-yl]methyl sulfamate

[0843] The title compound was obtained as in Reference Example 131, except that (2R,3S,5R)-5-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)tetrahydrofuran-3-ol was used in place of [(3aR,4R,6R,6aR)-4-(4-amino-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol.

[0844] .sup.1H-NMR (CD.sub.3OD) : 8.14 (1H, s), 7.67 (1H, s), 7.54-7.52 (2H, m), 7.39-7.36 (3H, m), 6.65 (1H, dd, J=7.8, 6.1 Hz), 4.57-4.55 (1H, m), 4.32 (1H, dd, J=11.0, 3.9 Hz), 4.29 (1H, dd, J=11.0, 3.9 Hz), 4.18 (1H, dt, J=3.2, 3.9 Hz), 2.60 (1H, ddd, J=13.7, 7.8, 6.1 Hz), 2.39 (1H, ddd, J=13.7, 6.1, 3.2 Hz). LCMS (ESI) m/z 430 [M+H].sup.+.

Reference Example 135

[(2R,3S,5R)-5-[4-Amino-5-(1-benzylpyrazol-4-yl)pyrrolo[2,3-d]pyrimidin-7-yl]-3-hydroxy-tetrahydrofuran-2-yl]methyl sulfamate

Step 1: Synthesis of (2R,3S,5R)-5-(4-amino-5-(1-benzyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)tetrahydrofuran-3-ol

[0845] (2R,3S,5R)-5-(4-Amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)tetrahydrofuran-3-ol (100 mg, 0.265 mmol), tetrakis(triphenylphosphine)palladium(0) (15.3 mg, 0.013 mmol), and 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (98 mg, 0.34 mmol) were suspended in a 2 M aqueous sodium carbonate solution (0.66 mL) and 1,2-dimethoxyethane (2 mL), followed by stirring at 100 C. for 3 hours. The reaction solution was partitioned between ethyl acetate and water, and the organic layer was washed with water, followed by concentration. The residue was purified by silica gel column chromatography (developing solvent: methanol/chloroform), thereby obtaining the target product (66 mg, 61%) as a yellow oil.

[0846] .sup.1H-NMR (CDCl.sub.3) : 8.18 (1H, brs), 7.59 (1H, s), 7.44 (1H, s), 7.38-7.32 (3H, m), 7.27-7.23 (2H, m), 6.90 (1H, s), 6.24 (1H, dd, J=8.8, 5.5 Hz), 5.42-5.38 (2H, m), 5.32 (2H, s), 4.71 (1H, d, J=4.0 Hz), 4.15 (1H, s), 3.91 (1H, d, J=12.5 Hz), 3.75 (1H, d, J=12.5 Hz), 3.05-2.98 (1H, m), 2.25 (1H, dd, J=12.8, 5.5 Hz). LRMS (ESI) m/z 407 [M+H].sup.+

Step 2: Synthesis of Reference Example Compound 135

[0847] (2R,3S,5R)-5-(4-amino-5-(1-benzyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)tetrahydrofuran-3-ol (53 mg, 0.13 mmol) was dissolved in acetonitrile (1 mL). Then, 1-aza-4-azoniabicyclo[2.2.2]octan-4-ylsulfonyl(tert-butoxycarbonyl)azanido: 1,4-diazabicyclo[2.2.2]octane monohydrochloride (Reference: Organic Letters, 2012, 10, 2626-2629) (114 mg, 0.26 mmol) was added thereto at room temperature. After the reaction solution was stirred at 40 C. overnight, trifluoroacetic acid (0.3 mL) was added to the reaction liquid, followed by stirring at room temperature overnight. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (developing solvent: methanol/chloroform), thereby obtaining the title compound (4.7 mg, 7%) as a milky-white solid.

[0848] .sup.1H-NMR (CD.sub.3OD) : 8.12 (1H, s), 7.88 (1H, s), 7.69 (1H, s), 7.41 (1H, s), 7.37-7.28 (5H, m), 6.71 (1H, t, J=7.0 Hz), 5.39 (2H, s), 4.57-4.52 (1H, brm), 4.29-4.28 (2H, brm), 4.18-4.15 (1H, brm), 2.62-2.55 (1H, m), 2.39-2.35 (1H, m). LCMS (ESI) m/z 486 [M+H].sup.+.

Reference Example 136

[(1R,2R,3S,4R)-4-[4-Amino-5-(1-benzylpyrazol-4-yl)pyrrolo[2,3-d]pyrimidin-7-yl]-2,3-dihydroxy-cyclopentyl]methyl sulfamate

[0849] The title compound was obtained as in Reference Example 135, except that ((3aR,4R,6R,6aS)-6-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol was used in place of (2R,3S,5R)-5-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)tetrahydrofuran-3-ol.

[0850] .sup.1H-NMR (CD.sub.3OD) : 8.10 (1H, s), 7.85 (1H, s), 7.66 (1H, s), 7.37-7.21 (6H, m), 5.39 (2H, s), 5.07-4.98 (1H, m), 4.32 (1H, dd, J=8.2, 5.7 Hz), 4.25 (2H, d, J=4.9 Hz), 4.05 (1H, dd, J=5.7, 3.5 Hz), 2.48-2.34 (2H, m), 1.82-1.76 (1H, m). LCMS (ESI) m/z 500 [M+H].sup.+.

Reference Example 137

[(2R,3S,5R)-5-[4-Amino-5-[1-[(3,4-dimethylphenyl)methyl]pyrazol-4-yl]pyrrolo[2,3-d]pyrimidin-7-yl]-3-hydroxy-tetrahydrofuran-2-yl]methyl sulfamate

Step 1: Synthesis of 1-(3,4-dimethylbenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

[0851] 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.0 g, 5.2 mmol), cesium carbonate (2.18 g, 6.7 mmol), and 3,4-dimethylbenzylchloride (0.98 mL, 6.7 mmol) were suspended in acetonitrile (10 mL). After the mixture was stirred at room temperature overnight, the solid was filtered off through celite, and the filtrate was concentrated. The residue was purified by basic silica gel column chromatography (developing solvent: ethyl acetate/hexane), thereby obtaining the title compound (1.29 g, 80%) as a light-yellow oil.

[0852] .sup.1H-NMR (CDCl.sub.3) : 7.80 (1H, s), 7.63 (1H, s), 7.14-6.97 (3H, m), 5.21 (2H, s), 2.25 (3H, s), 2.25 (3H, s), 1.29 (12H, s). LRMS (ESI) m/z 313 [M+H].sup.+

Step 2: Synthesis of Reference Example Compound 137

[0853] The title compound was obtained as in Reference Example 135, except that 1-(3,4-dimethylbenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used in place of 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.

[0854] .sup.1H-NMR (CD.sub.3OD) : 8.12 (1H, s), 7.83 (1H, s), 7.66 (1H, s), 7.39 (1H, s), 7.11 (1H, d, J=7.8 Hz), 7.09 (1H, s), 7.02 (1H, d, J=7.8 Hz), 6.70 (1H, dd, J=7.9, 6.2 Hz), 5.29 (2H, s), 4.57-4.52 (1H, m), 4.28 (2H, m), 4.16 (1H, m), 3.60 (1H, dd, J=14.1, 7.1 Hz), 2.62-2.55 (1H, m), 2.40-2.34 (1H, m), 2.25 (3H, s), 2.23 (3H, s). LCMS (ESI) m/z 514 [M+H].sup.+.

Reference Example 138

[(1R,2S,4R)-4-[4-Amino-5-[1-[(3,4-dimethylphenyl)methyl]pyrazol-4-yl]pyrrolo[2,3-d]pyrimidin-7-yl]-2-hydroxy-cyclopentyl]methyl sulfamate

Step 1: Synthesis of (1S,2R,4R)-4-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)cyclopentanol

[0855] The title compound was obtained as in step 2, step 5, and step 7 of Reference Example 93, except that (1S,2R,4R)-4-amino-2-(hydroxymethyl)cyclopentanol was used in place of ((3aR,4R,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol.

[0856] .sup.1H-NMR (DMSO-D.sub.6) : 8.06 (1H, s), 7.54 (1H, s), 6.64 (2H, brs), 5.23-5.14 (1H, m), 4.73 (1H, brs), 4.61 (1H, brs), 4.01 (1H, m), 3.48-3.44 (1H, m), 3.41-3.36 (1H, m), 2.23-2.16 (1H, m), 2.08-2.01 (1H, m), 1.96-1.85 (2H, m), 1.58-1.50 (1H, m). LCMS (ESI) m/z 375 [M+H].sup.+

Step 2: Synthesis of Reference Example Compound 138

[0857] The title compound was obtained as in Reference Example 135, except that (1S,2R,4R)-4-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)cyclopentanol and 1-(3,4-dimethylbenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole were used in place of (2R,3S,5R)-5-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)tetrahydrofuran-3-ol and 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.

[0858] .sup.1H-NMR (CD.sub.3OD) : 8.10 (1H, s), 7.79 (1H, s), 7.64 (1H, s), 7.26 (1H, s), 7.10 (1H, d, J=7.8 Hz), 7.09 (1H, s), 7.02 (1H, d, J=7.8 Hz), 5.39-5.31 (1H, m), 5.29 (2H, s), 4.30-4.20 (3H, m), 2.53-2.46 (1H, m), 2.38-2.15 (3H, m), 2.24 (3H, s), 2.23 (3H, s), 1.87-1.79 (1H, m). LCMS (ESI) m/z 512 [M+H].sup.+.

Reference Example 139

[(2R,3S,5R)-5-[4-Amino-5-[2-(o-tolyl)thiazol-4-yl]pyrrolo[2,3-d]pyrimidin-7-yl]-3-hydroxy-tetrahydrofuran-2-yl]methyl sulfamate

[0859] The title compound was obtained as in Reference Example 135, except that 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(o-tolyl)thiazole was used in place of 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.

[0860] .sup.1H-NMR (CD.sub.3OD) : 8.07 (1H, s), 8.04 (1H, s), 7.92 (1H, s), 7.67 (1H, d, J=7.3 Hz), 7.42-7.36 (2H, m), 7.34-7.30 (1H, m), 6.75 (1H, t, J=7.0 Hz), 4.62-4.59 (1H, m), 4.39 (1H, dd, J=11.0, 3.2 Hz), 4.35 (1H, dd, J=11.0, 3.2 Hz), 4.22 (1H, dd, J=6.1, 3.2 Hz), 2.59-2.56 (1H, m), 2.56 (3H, s), 2.46-2.41 (1H, m). LCMS (ESI) m/z 503 [M+H].sup.+.

Reference Example 140

4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-ethylsulfonyl-6-fluoro-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine

Step 1: Synthesis of tert-butyl N-(((3aR,4R,6R,6aR)-6-(4-amino-5-((2-(ethylthio)-6-fluorophenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)sulfamoylcarbamate

[0861] tert-Butyl N-(((3aR,4R,6R,6aR)-6-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)sulfamoylcarbamate (39 mg, 0.064 mmol), ethyl(2-ethynyl-3-fluorophenyl)sulfane (23 mg, 0.13 mmol), bis(triphenylphosphine)palladium (II) dichloride (4.5 mg, 0.0064 mmol), copper iodide (1.2 mg, 0.0064 mmol), and diisopropylethylamine (0.022 mL, 0.13 mmol) were suspended in tetrahydrofuran (1 mL). After the reaction solution was stirred at 50 C. for 3 hours, the solvent was distilled off, and the residue was purified by silica gel column chromatography (developing solvent: methanol/chloroform), thereby obtaining the title compound (28 mg, 66%) as a yellow powder.

[0862] .sup.1H-NMR (CDCl.sub.3) : 9.15 (1H, d, J=8.1 Hz), 8.52 (1H, s), 7.31 (1H, s), 7.24-7.20 (1H, m), 7.06 (1H, d, J=8.1 Hz), 6.91 (1H, t, J=8.1 Hz), 6.74-6.59 (2H, brm), 5.68 (1H, d, J=4.8 Hz), 5.30 (1H, dd, J=6.2, 4.8 Hz), 5.11 (1H, dd, J=6.2, 2.2 Hz), 4.51 (1H, d, J=2.2 Hz), 3.72-3.66 (1H, m), 3.60 (1H, d, J=12.8 Hz), 3.02 (3H, q, J=7.3 Hz), 1.61 (3H, s), 1.45 (9H, s), 1.37 (3H, t, J=7.3 Hz), 1.35 (3H, s).

Step 2: Synthesis of Reference Example Compound 140

[0863] tert-Butyl N-(((3aR,4R,6R,6aR)-6-(4-amino-5-((2-(ethylthio)-6-fluorophenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)sulfamoylcarbamate (55 mg, 0.0829 mmol) was suspended with stirring under ice-cooling in 1,4-dioxane (0.5 mL) and water (0.5 mL) while oxone (102 mg, 0.166 mmol) was added thereto. After the reaction liquid was stirred at room temperature for 3 hours, the reaction solution was partitioned between ethyl acetate and water, and the organic layer was extracted. After the solvent was distilled off, acetonitrile (0.5 mL), water (0.1 mL), and trifluoroacetic acid (0.5 mL) were sequentially added to the residue, and the reaction solution was stirred at room temperature for 3 hours. The reaction liquid was concentrated, and the residue was purified by basic silica gel column chromatography (developing solvent: methanol/chloroform), thereby obtaining the title compound (20 mg) as a light-yellow solid.

[0864] .sup.1H-NMR (DMSO-D.sub.6) : 8.16 (1H, s), 8.04 (1H, s), 7.82 (2H, d, J=8.1 Hz), 7.77 (2H, t, J=8.1 Hz), 7.70 (1H, dd, J=8.1, 5.5 Hz), 7.35 (1H, dd, J=7.7, 4.8 Hz), 6.58 (2H, s), 5.92 (1H, d, J=7.0 Hz), 5.38 (1H, d, J=6.2 Hz), 5.22 (1H, brs), 4.62-4.58 (1H, m), 4.09-4.07 (1H, brm), 4.05-4.02 (1H, m), 3.49 (2H, q, J=7.3 Hz), 3.22-3.17 (1H, m), 3.14-3.06 (1H, m), 1.14 (3H, t, J=7.3 Hz). LCMS (ESI) m/z 555 [M+H].sup.+.

Reference Example 141

4-Amino-5-[2-(4-benzyloxy-2-methylsulfonyl-phenyl)ethynyl]-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]pyrrolo[2,3-d]pyrimidine

Step 1: (5-(Benzyloxy)-2-iodophenyl)(methyl)sulfane

[0865] The title compound was obtained as in step 1 of Reference Example 76, except that 4-iodo-3-(methylsulfanyl)phenol was used in place of 2-bromopyrimidin-5-ol.

[0866] .sup.1H-NMR (CDCl.sub.3) : 7.63 (1H, d, J=8.6 Hz), 7.43-7.34 (5H, m), 6.74 (1H, d, J=2.9 Hz), 6.51 (1H, dd, J=8.6, 2.8 Hz), 5.06 (2H, s), 3.63 (3H, s). LCMS (ESI) m/z 356 [M+H].sup.+

Step 2: Synthesis of (5-(benzyloxy)-2-ethynylphenyl)(methyl)sulfane

[0867] The title compound was obtained as in step 2 and step 3 of Reference Example 76, except that (5-(benzyloxy)-2-iodophenyl)(methyl)sulfane was used in place of 5-(benzyloxy)-2-bromopyrimidine.

[0868] .sup.1H-NMR (CDCl.sub.3) : 7.41-7.34 (6H, m), 6.76 (1H, d, J=2.3 Hz), 6.69 (1H, dd, J=8.4, 2.3 Hz), 5.08 (2H, s), 3.39 (1H, s), 2.45 (3H, s). LCMS (ESI) m/z 255 [M+H].sup.+

Step 3: Synthesis of Reference Example Compound 141

[0869] The title compound was obtained as in Reference Example 140, except that (5-(benzyloxy)-2-ethynylphenyl)(methyl)sulfane was used in place of ethyl(2-ethynyl-3-fluorophenyl)sulfane.

[0870] .sup.1H-NMR (CD.sub.3OD) : 8.20 (1H, s), 7.82 (1H, s), 7.73 (1H, d, J=8.4 Hz), 7.67 (1H, d, J=2.8 Hz), 7.47 (2H, d, J=6.8 Hz), 7.42-7.32 (4H, m), 5.23 (2H, s), 5.05-4.95 (1H, m), 4.43-4.39 (1H, m), 4.03-4.00 (1H, m), 3.30 (3H, s), 3.27-3.12 (2H, m), 2.50-2.42 (1H, m), 2.32-2.28 (1H, m), 1.87-1.79 (1H, m). LCMS (ESI) m/z 627 [M+H].sup.+.

Reference Example 142

4-Amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]-5-[2-(2-ethylsulfonyl-6-fluoro-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine

[0871] The title compound was obtained as in Reference Example 140, except that tert-butyl N-(((3aR,4R,6R,6aS)-6-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl) sulfamoylcarbamate was used in place of tert-butyl N-(((3aR,4R,6R,6aR)-6-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl) sulfamoylcarbamate.

[0872] .sup.1H-NMR (DMSO-D.sub.6) : 8.13 (1H, s), 7.99 (1H, s), 7.81 (1H, d, J=8.1 Hz), 7.76 (1H, t, J=8.1 Hz), 7.68 (1H, dd, J=8.1, 5.1 Hz), 6.63 (1H, t, J=6.2 Hz), 6.50 (2H, s), 4.89 (2H, d, J=7.0 Hz), 4.67 (1H, d, J=4.4 Hz), 4.27-4.22 (1H, m), 4.08 (1H, q, J=5.3 Hz), 3.79-3.76 (1H, m), 3.49 (2H, q, J=7.3 Hz), 3.10-3.03 (1H, m), 2.94-2.87 (1H, m), 2.24-2.17 (1H, m), 2.12-2.06 (1H, m), 1.60-1.52 (1H, m), 1.14 (3H, t, J=7.3 Hz). LCMS (ESI) m/z 553 [M+H].sup.+.

Reference Example 143

4-Amino-5-[2-(2-ethylsulfonyl-6-fluoro-phenyl)ethynyl]-7-[(2R,4S,5R)-4-hydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine

[0873] The title compound was obtained as in Reference Example 140, except that tert-butyl N-[[(2R,3S,5R)-5-(4-amino-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)-3-hydroxy-tetrahydrofuran-2-yl]methyl sulfamoyl]carbamate was used in place of tert-butyl N-(((3aR,4R,6R,6aR)-6-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)sulfamoylcarbamate.

[0874] .sup.1H-NMR (DMSO-D.sub.6) : 8.18 (1H, s), 8.03 (1H, s), 7.87-7.83 (1H, m), 7.80-7.75 (1H, m), 7.73-7.68 (1H, m), 7.16 (1H, t, J=5.9 Hz), 6.56 (2H, s), 6.43 (1H, dd, J=8.7, 5.7 Hz), 4.37 (1H, brs), 3.97 (1H, dt, J=2.0, 4.6 Hz), 3.50 (2H, q, J=7.4 Hz), 3.20-3.14 (1H, m), 3.12-3.05 (1H, m), 2.71-2.62 (1H, m), 2.21-2.16 (1H, m), 1.15 (3H, t, J=7.4 Hz). LCMS (ESI) m/z 539 [M+H].sup.+.

Comparative Example

[0875] N-[(1S)-1-indanyl]-7-[(1R)-3-hydroxy-4-(sulfamoyloxymethyl)cyclopentyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (MLN4924) was obtained by performing the synthesis in accordance with the method disclosed in Patent Document 1.

##STR00020##

[0876] The following tables show the structural formulae of the Reference Example compounds of the present application.

##STR00021##

TABLE-US-00002 TABLE 1 X Y R.sub.1 R.sub.2 R.sub.3 R.sub.4 R.sub.5 Reference Example 1 single O NH OH OH [00022] bond [00023] Reference Example 2 single O NH OH OH [00024] bond [00025] Reference Example 3 single O NH OH OH [00026] bond [00027] Reference Example 4 single O NH OH OH [00028] bond [00029] Reference Example 5 single O NH OH OH [00030] bond [00031] Reference Example 6 single O NH OH OH [00032] bond [00033] Reference Example 7 single O NH OH OH [00034] CH.sub.2 [00035] Reference Example 8 single O NH OH OH [00036] bond [00037] Reference Example 9 single O NH OH OH [00038] bond [00039] Reference Example 10 single O NH OH OH [00040] [00041] [00042]

TABLE-US-00003 TABLE 2 X Y R.sub.1 R.sub.2 R.sub.3 R.sub.4 R.sub.5 Reference Example 11 single O NH OH OH [00043] bond [00044] Reference Example 12 single O NH OH OH [00045] bond [00046] Reference Example 13 single O NH OH OH [00047] bond [00048] Reference Example 14 single O NH OH OH [00049] bond [00050] Reference Example 15 single O NH OH OH [00051] bond [00052] Reference Example 16 single O NH OH OH [00053] bond [00054] Reference Example 17 single O NH OH OH [00055] bond [00056] Reference Example 18 single O NH OH OH [00057] bond [00058] Reference Example 19 single O NH OH OH [00059] bond [00060] Reference Example 20 single O NH OH OH [00061] bond [00062]

TABLE-US-00004 TABLE 3 X Y R.sub.1 R.sub.2 R.sub.3 R.sub.4 R.sub.5 Reference Example 21 single O NH OH OH [00063] bond [00064] Reference Example 22 single O NH OH OH [00065] bond [00066] Reference Example 23 single O NH OH OH [00067] bond [00068] Reference Example 24 single O NH OH OH [00069] bond [00070] Reference Example 25 single O NH OH OH [00071] bond [00072] Reference Example 26 single O NH OH OH [00073] bond [00074] Reference Example 27 single O NH OH OH [00075] bond [00076] Reference Example 28 single O NH OH OH [00077] bond [00078] Reference Example 29 single O NH OH OH [00079] bond [00080] Reference Example 30 single O NH OH OH [00081] bond [00082]

TABLE-US-00005 TABLE 4 X Y R.sub.1 R.sub.2 R.sub.3 R.sub.4 R.sub.5 Reference Example 31 single O NH OH OH [00083] CH.sub.2 [00084] Reference Example 32 single O NH OH OH [00085] bond [00086] Reference Example 33 single O NH OH OH [00087] bond [00088] Reference Example 34 single O NH OH OH [00089] bond [00090] Reference Example 35 single O NH OH OH [00091] bond [00092] Reference Example 36 single O NH OH OH [00093] CH.sub.2 [00094] Reference Example 37 single O NH OH OH [00095] bond [00096] Reference Example 38 single O NH OH OH [00097] bond [00098] Reference Example 39 single O NH OH OH [00099] bond [00100] Reference Example 40 single O NH OH OH [00101] bond [00102]

TABLE-US-00006 TABLE 5 X Y R.sub.1 R.sub.2 R.sub.3 R.sub.4 R.sub.5 Reference Example 41 single O NH OH OH [00103] bond [00104] Reference Example 42 single O NH OH OH [00105] bond [00106] Reference Example 43 single O NH OH OH [00107] bond [00108] Reference Example 44 single O NH OH OH [00109] bond [00110] Reference Example 45 single O NH OH OH [00111] bond [00112] Reference Example 46 single O NH OH OH [00113] bond [00114] Reference Example 47 single O NH OH OH [00115] bond [00116] Reference Example 48 single O NH OH OH [00117] bond [00118] Reference Example 49 single O NH OH OH [00119] bond [00120] Reference Example 50 single O NH OH OH [00121] CH.sub.2 [00122]

TABLE-US-00007 TABLE 6 X Y R.sub.1 R.sub.2 R.sub.3 R.sub.4 R.sub.5 Reference Example 51 single O NH OH OH [00123] bond [00124] Reference Example 52 single O NH OH OH [00125] bond [00126] Reference Example 53 single O NH OH OH [00127] bond [00128] Reference Example 54 single O NH OH OH [00129] bond [00130] Reference Example 55 single O NH OH OH [00131] bond [00132] Reference Example 56 single O NH OH OH [00133] bond [00134] Reference Example 57 single O NH OH OH [00135] bond [00136] Reference Example 58 single O NH OH OH [00137] bond [00138] Reference Example 59 single O NH OH OH [00139] bond [00140] Reference Example 60 single O NH OH OH [00141] bond [00142]

TABLE-US-00008 TABLE 7 X Y R.sub.1 R.sub.2 R.sub.3 R.sub.4 R.sub.5 Reference Example 61 single O NH OH OH [00143] bond [00144] Reference Example 62 single O NH OH OH [00145] bond [00146] Reference Example 63 single O NH OH OH [00147] bond [00148] Reference Example 64 single O NH OH OH [00149] bond [00150] Reference Example 65 single O NH OH OH [00151] bond [00152] Reference Example 66 single O NH OH OH [00153] bond [00154] Reference Example 67 single O NH OH OH [00155] bond [00156] Reference Example 68 single O NH OH OH [00157] bond [00158] Reference Example 69 single O NH OH OH [00159] bond [00160] Reference Example 70 single O NH OH OH [00161] bond [00162]

TABLE-US-00009 TABLE 8 X Y R.sub.1 R.sub.2 R.sub.3 R.sub.4 R.sub.5 Reference Example 71 single O NH OH OH [00163] bond [00164] Reference Example 72 single O NH OH OH [00165] bond [00166] Reference Example 73 single O NH OH OH [00167] bond [00168] Reference Example 74 single O NH OH OH [00169] bond [00170] Reference Example 75 single O NH OH OH [00171] bond [00172] Reference Example 76 single O NH OH OH [00173] bond [00174] Reference Example 77 single O NH OH OH [00175] bond [00176] Reference Example 78 single O NH OH OH [00177] bond [00178] Reference Example 79 single O NH OH OH [00179] bond [00180] Reference Example 80 single O NH OH OH [00181] bond [00182]

TABLE-US-00010 TABLE 9 X Y R.sub.1 R.sub.2 R.sub.3 R.sub.4 R.sub.5 Reference Example 81 single O NH OH OH [00183] bond [00184] Reference Example 82 single O NH OH OH [00185] bond [00186] Reference Example 83 single O NH OH OH [00187] bond [00188] Reference Example 84 single O NH OH OH [00189] bond [00190] Reference Example 85 single O NH OH OH [00191] bond [00192] Reference Example 86 single O NH OH OH [00193] bond [00194] Reference Example 87 single O NH OH OH [00195] bond [00196] Reference Example 88 single O NH OH OH [00197] bond [00198] Reference Example 89 single O NH OH OH [00199] bond [00200] Reference Example 90 single O NH OH OH [00201] bond [00202]

TABLE-US-00011 TABLE 10 X Y R.sub.1 R.sub.2 R.sub.3 R.sub.4 R.sub.5 Reference Example 91 single O NH OH OH [00203] bond [00204] Reference Example 92 single O NH OH OH [00205] bond [00206] Reference Example 93 single C NH OH OH [00207] bond [00208] Reference Example 94 single C NH OH OH [00209] bond [00210] Reference Example 95 single C NH OH OH [00211] bond [00212] Reference Example 96 single C NH OH OH [00213] bond [00214] Reference Example 97 single C NH OH OH [00215] bond [00216] Reference Example 98 single C NH OH OH [00217] bond [00218] Reference Example 99 single C NH OH OH [00219] bond [00220] Reference Example 100 single C NH OH OH [00221] bond [00222]

TABLE-US-00012 TABLE 11 X Y R.sub.1 R.sub.2 R.sub.3 R.sub.4 R.sub.5 Reference Example 101 single C NH OH OH [00223] bond [00224] Reference Example 102 single C NH OH OH [00225] bond [00226] Reference Example 103 single C NH OH OH [00227] bond [00228] Reference Example 104 single C NH OH OH [00229] bond [00230] Reference Example 105 single C NH OH OH [00231] bond [00232] Reference Example 106 single C NH OH OH [00233] bond [00234] Reference Example 107 single C NH OH OH [00235] bond [00236] Reference Example 108 single C NH OH OH [00237] bond [00238] Reference Example 109 single C NH OH OH [00239] bond [00240] Reference Example 110 single C NH OH OH [00241] bond [00242]

TABLE-US-00013 TABLE 12 X Y R.sub.1 R.sub.2 R.sub.3 R.sub.4 R.sub.5 Reference Example 111 single C NH OH OH [00243] bond [00244] Reference Example 112 single C NH OH OH [00245] bond [00246] Reference Example 113 single C NH OH OH [00247] bond [00248] Reference Example 114 single C NH OH OH [00249] bond [00250] Reference Example 115 single C NH OH OH [00251] bond [00252] Reference Example 116 single C NH OH OH [00253] bond [00254] Reference Example 117 single C NH OH OH [00255] bond [00256] Reference Example 118 single C NH OH OH [00257] bond [00258] Reference Example 119 single C NH OH OH [00259] bond [00260] Reference Example 120 single C NH OH OH [00261] bond [00262]

TABLE-US-00014 TABLE 13 X Y R.sub.1 R.sub.2 R.sub.3 R.sub.4 R.sub.5 Reference Example 121 single C NH OH OH [00263] bond [00264] Reference Example 122 single C NH OH OH [00265] bond [00266] Reference Example 123 single C NH OH OH [00267] bond [00268] Reference Example 124 single O NH OH H [00269] bond [00270] Reference Example 125 single O NH OH H [00271] bond [00272] Reference Example 126 single O NH OH H [00273] bond [00274] Reference Example 127 single O NH OH H [00275] bond [00276] Reference Example 128 double C NH OH OH [00277] bond [00278] Reference Example 129 double C NH OH OH [00279] bond [00280] Reference Example 130 double C NH OH OH [00281] bond [00282]

TABLE-US-00015 TABLE 14 X Y R.sub.1 R.sub.2 R.sub.3 R.sub.4 R.sub.5 Reference Example 131 single O O OH OH [00283] bond [00284] Reference Example 132 single O O OH OH [00285] bond [00286] Reference Example 133 single O O OH OH [00287] bond [00288] Reference Example 134 single O O OH H [00289] bond [00290] Reference Example 135 single O O OH H [00291] CH.sub.2 [00292] Reference Example 136 single C O OH OH [00293] CH.sub.2 [00294] Reference Example 137 single O O OH H [00295] CH.sub.2 [00296] Reference Example 138 single C O OH H [00297] CH.sub.2 [00298] Reference Example 139 single O O OH H [00299] bond [00300] Reference Example 140 single O NH OH OH [00301] bond [00302]

TABLE-US-00016 TABLE 15 X Y R.sub.1 R.sub.2 R.sub.3 R.sub.4 R.sub.5 Reference Example 141 single C NH OH OH [00303] bond [00304] Reference Example 142 single C NH OH OH [00305] bond [00306] Reference Example 143 single O NH OH H [00307] bond [00308]

Test Example 1: Nedd8 Conjugation Inhibitory Activity

[0877] A purified NAE (heterodimer of APPBP1 and UBA3) solution was prepared in the following manner. The human APPBP1 gene (NCBI Reference Sequence number: NM_003905) region corresponding to amino acids 1 to 534 of human APPBP1 protein (NCBI Reference Sequence number: NP_003896, full length: 534 amino acids) was inserted in pBacPAK9 (produced by Clontech) to construct a plasmid pBacPAK9-APPBP1 for expressing APPBP1 full-length protein having a His tag and a TEV protease-recognition sequence at the N-terminus. Next, the human UBA3 gene (NCBI Reference Sequence number: NM_003968) region corresponding to amino acids 1 to 463 of human UBA3 protein (NCBI Reference Sequence number: NP_003959, full length: 463 amino acids) was inserted in pBacPAK9 to construct a plasmid pBacPAK9-UBA3 for expressing UBA3 full-length protein. The pBacPAK9-APPBP1 or pBacPAK9-UBA3, and BacPAK6 DNA were cotransfected into insect cells (Sf9, produced by Clontech) to produce a recombinant baculovirus containing APPBP1 or UBA3 gene. The APPBP1 gene recombinant baculovirus was mixed with the UBA3 gene recombinant baculovirus, and the resulting mixture was used to infect Sf9 cells. The baculovirus-infected Sf9 cells were incubated at 28 C. with shaking for 72 hours in Grace's Insect Medium (produced by Gibco), and the collected cells were suspended in a lysis buffer (50 mM Tris-HCl, 200 mM NaCl, and 10% glycerol (pH 7.4)), followed by sonication. The sonicated cell solution was centrifuged (40,000g, for 30 minutes) to obtain the supernatant as a crude extract. The crude extract was fractionated on a HisTrap HP column (produced by GE Healthcare) and a TALON Superflow column (produced by Clontech), followed by the addition of a TEV protease. Then, a His-tag cleavage reaction was performed at 4 C. overnight. The resulting solution was subjected to TALON Superflow column chromatography, and the unadsorbed fraction was collected. This fraction was applied to a HiLoad 16/60 Superdex 75 prep grade column equilibrated with 50 mM Tris-HCl, 200 mM NaCl, and 10% glycerol (pH 7.4), and fractionated. A fraction containing an APPBP1/UBA3 complex was concentrated to obtain a purified NAE solution. The purification above was performed entirely at 4 C. The purified NAE solution was stored at 80 C. until use.

[0878] A purified GST-UBC12 solution was prepared in the following manner. The human UBC12 gene (NCBI Reference Sequence number: NM_003969) region corresponding to amino acids 1 to 183 of human UBC12 protein (NCBI Reference Sequence number: NP_003960, full length: 183 amino acids) was inserted in pGEX-4T-2 (produced by GE Healthcare) to construct a plasmid pGEX-UBC12 for expressing UBC12 full-length protein having a GST tag at the N-terminus. The pGEX-UBC12 was introduced into Escherichia coli (BL21 (DE3), produced by Stratagene), followed by culture at 37 C. for 2 hours in the presence of 1 mM isopropyl-beta-D-thiogalactopyranoside (produced by Sigma-Aldrich). The collected Escherichia coli was suspended in PBS, followed by sonication. The sonicated cell solution was centrifuged (40,000g, for 5 minutes) to obtain the supernatant as a crude extract. A Glutathione Sepharose 4B carrier (produced by GE Healthcare) was added to the crude extract, and eluted with 50 mM Tris-HCl (pH 7.9), 150 mM NaCl, and a 10 mM reduced glutathione solution, followed by dialysis with 50 mM HEPES (pH 7.5) and a 0.05% BSA solution to obtain a purified GST-UBC12 solution. The purified GST-UBC12 solution was divided and stored at 80 C. until use.

[0879] The Nedd8 conjugation inhibitory activity was measured using an AlphaScreen assay system. Each of the purified NAE solution and GST-UBC12 solution was diluted with an assay buffer (50 mM HEPES (pH 7.5), 5 mM MgCl.sub.2, 1 mM DTT, 0.05% BSA) and added to a 384-well plate (#3673, produced by Corning) containing the test compound. After reaction at room temperature for 30 minutes, a solution obtained by diluting ATP and Biotin-Nedd8 (produced by Boston Biochem) with the assay buffer was added thereto, followed by reaction for 90 minutes.

[0880] Detection mix (50 mM HEPES (pH 7.5), 0.05% BSA, 0.04 mg/mL anti-GST Acceptor beads, 0.04 mg/mL Streptavidin Donor beads) (#6760603M, produced by Perkin Elmer) was added to each well in the same amount as that of the reaction solution. Then, after reaction in a dark place at room temperature for 1 hour, the fluorescence intensity was measured using an EnVision (produced by Perkin Elmer) multilabel plate reader. The Neddylation inhibition rate (%) achieved by the compound of Reference Examples was determined by the equation (equation A) below using the fluorescence signal of a test compound-free group as a positive control, and the fluorescence signal of the test compound- and ATP-free group as a negative control. The concentration at which the Nedd8 conjugation was reduced with the addition of each compound to 50% of the control was calculated (IC.sub.50 (M)) and used as a relative index of the Nedd8 conjugation inhibitory activity.

Inhibition rate (%)=100(TB)/(CB)100(equation A)

T: Signal in a well to which a test compound was added
C: Signal in a well to which a test compound was not added
B: Signal in a well to which a test compound and ATP were not added

[0881] Table 16 below show the results.

TABLE-US-00017 TABLE 16 IC50 (M) Reference 0.0030 Example 1 Reference 0.0071 Example 2 Reference 0.029 Example 8 Reference 0.024 Example 10 Reference 0.0078 Example 11 Reference 0.0096 Example 16 Reference 0.0054 Example 17 Reference 0.027 Example 18 Reference 0.028 Example 19 Reference 0.0091 Example 20 Reference 0.015 Example 21 Reference 0.0030 Example 22 Reference 0.0030 Example 23 Reference 0.0030 Example 24 Reference 0.0048 Example 25 Reference 0.012 Example 26 Reference 0.0071 Example 29 Reference 0.027 Example 30 Reference 0.0030 Example 33 Reference 0.024 Example 34 Reference 0.0041 Example 35 Reference 0.011 Example 37 Reference 0.0035 Example 38 Reference 0.0030 Example 39 Reference 0.0030 Example 40 Reference 0.0030 Example 41 Reference 0.0043 Example 42 Reference 0.0076 Example 43 Reference 0.029 Example 44 Reference 0.013 Example 46 Reference 0.0093 Example 47 Reference 0.018 Example 49 Reference 0.0035 Example 51 Reference 0.008 Example 52 Reference 0.0045 Example 54 Reference 0.0030 Example 55 Reference 0.0053 Example 56 Reference 0.0058 Example 57 Reference 0.0030 Example 58 Reference 0.0085 Example 59 Reference 0.0085 Example 60 Reference 0.0038 Example 61 Reference 0.016 Example 62 Reference 0.011 Example 63 Reference 0.0094 Example 64 Reference 0.0071 Example 66 Reference 0.0085 Example 67 Reference 0.015 Example 69 Reference 0.013 Example 70 Reference 0.014 Example 71 Reference 0.0044 Example 72 Reference 0.0030 Example 74 Reference 0.0030 Example 75 Reference 0.0051 Example 76 Reference 0.0032 Example 79 Reference 0.014 Example 80 Reference 0.0056 Example 81 Reference 0.01 Example 82 Reference 0.019 Example 83 Reference 0.0097 Example 84 Reference 0.0054 Example 86 Reference 0.018 Example 88 Reference 0.011 Example 89 Reference 0.0056 Example 90 Reference 0.018 Example 91 Reference 0.021 Example 94 Reference 0.013 Example 95 Reference 0.0092 Example 96 Reference 0.0088 Example 97 Reference 0.0083 Example 98 Reference 0.019 Example 99 Reference 0.0076 Example 101 Reference 0.013 Example 103 Reference 0.0089 Example 104 Reference 0.028 Example 106 Reference 0.013 Example 110 Reference 0.015 Example 112 Reference 0.0030 Example 113 Reference Example 114 0.0030 Reference Example 115 0.004 Reference Example 116 0.0051 Reference Example 117 0.0043 Reference Example 118 0.0068 Reference Example 119 0.0042 Reference Example 120 0.0043 Reference Example 121 0.0062 Reference Example 122 0.02 Reference Example 123 0.0091 Reference Example 127 0.019 Reference Example 128 0.0033 Reference Example 129 0.0030 Reference Example 130 0.004 Reference Example 131 0.0030 Reference Example 132 0.0030 Reference Example 133 0.025 Reference Example 134 0.018 Reference Example 136 0.012 Reference Example 137 0.019 Reference Example 138 0.0065 Reference Example 139 0.017 Reference Example 142 0.009 Reference Example 143 0.024 Comp. Example 0.033

[0882] These results show that the compounds of Reference Examples exhibited excellent Nedd8 conjugation inhibitory activity, compared with the Comparative Example.

Test Example 2: Cell Growth Inhibition 1

[0883] The ability of test compounds to inhibit cell growth was determined by quantifying ATP from viable cells using a CellTiter-Glo Luminescent Cell Viability Assay (#G7573, produced by Promega, Inc.). The human acute T lymphoblastic leukemia CCRF-CEM cell lines (distributed by Dainippon Pharmaceutical Co., Ltd. (currently Sumitomo Dainippon Pharma Co., Ltd.)) were seeded in a 96-well plate (#165305, produced by Thermo Scientific Nunc) at a concentration of 1,000 cells/100 L medium per well. The cells were cultured in a 5% CO.sub.2 incubator at 37 C. overnight, and the test compound was added thereto, followed by culture for another 72 hours. A CellTiter-Glo Luminescent Cell Viability Assay reagent in an amount equal to the medium was added to each well, stirred for 5 minutes on a shaker under shading conditions, and then left to stand at room temperature for about 30 minutes. The luminescence intensity was measured using a microplate reader (EnSpire Multimode Plate Reader, produced by PerkinElmer Japan Co., Ltd.), and used as an index of the number of viable cells in each well. The cell growth inhibition rate (%) achieved by the compound was determined by the following equation (equation B) by using the luminescence intensity of a drug untreated group (control) as a control. The concentration at which the number of cells are reduced with the addition of each compound to 50% of the control was calculated (IC.sub.50 (M))

Inhibition rate (%)=(CT)/C100(equation B)

T: Luminescence intensity in a well to which a test compound was added
C: Luminescence intensity in a well to which a test substance was not added

[0884] Table 17 below shows the results.

TABLE-US-00018 TABLE 17 CCRF-CEM IC50 (M) Reference Example 1 0.0062 Reference Example 24 0.0027 Reference Example 25 0.0017 Reference Example 29 0.004 Reference Example 31 0.6 Reference Example 32 2.5 Reference Example 33 0.037 Reference Example 34 0.0061 Reference Example 35 0.002 Reference Example 36 0.25 Reference Example 37 0.006 Reference Example 38 0.014 Reference Example 39 0.0078 Reference Example 40 0.019 Reference Example 43 0.0027 Reference Example 55 0.0022 Reference Example 60 0.0051 Reference Example 61 0.003 Reference Example 64 0.0058 Reference Example 66 0.0043 Reference Example 70 0.015 Reference Example 71 0.045 Reference Example 72 0.088 Reference Example 73 0.071 Reference Example 74 0.16 Reference Example 83 0.056 Reference Example 84 0.23 Reference Example 85 0.038 Reference Example 86 0.0055 Reference Example 97 0.0031 Reference Example 98 0.0073 Reference Example 120 0.035 Reference Example 122 0.0088 Reference Example 123 0.097 Reference Example 129 0.0021 Reference Example 130 0.0032 Reference Example 132 0.0018 Comp. Example 0.089

[0885] These results indicate that the compounds inhibited the growth of human leukemia CCRF-CEM cell lines.

Test Example 3: Cell Growth Inhibition 2

[0886] The ability of test compounds to inhibit cell growth was determined as in Test Example 2, except that the cell lines, the culture plate, and the number of cells seeded per well were as shown in Table 18. For the culture plate, a 384-well plate (#3571, produced by Corning) was used.

[0887] Table 19 below shows the results.

TABLE-US-00019 TABLE 18 Seeding number (per 1 well) Cell Name Origin Obtained from Plate (cells/L medium) HCT116 Colon cancer ATCC 384 wells 250 cells/20 L Capan-1 Pancreatic cancer ATCC 384 wells 500 cells/20 L A-427 Lung cancer ATCC 384 wells 250 cells/20 L MDA-MB-453 Breast cancer ATCC 384 wells 500 cells/20 L LNCaP. FGC Prostate cancer Dainippon Pharmaceutical 384 wells 500 cells/20 L Co., Ltd. (currently DS Pharma Biomedical Co., Ltd.) SJCRH30 Osteo- and soft ATCC 384 wells 250 cells/20 L tissue sarcoma U266B1 Multiple myeloma ATCC 384 wells 3000 cells/20 L A-431 Skin cancer ATCC 384 wells 400 cells/20 L MV-4-11 Acute leukemia ATCC 384 wells 400 cells/20 L DB B-cell lymphoma ATCC 384 wells 1500 cells/20 L

TABLE-US-00020 TABLE 19 HCT116 Capan-1 A-427 MDA-MB-453 LNCaP.FGC Reference IC50 IC50 IC50 IC50 IC50 Examples (M) (M) (M) (M) (M) 1 0.016 0.73 0.022 0.46 0.65 25 0.0064 0.38 0.0054 0.48 0.5 55 0.012 0.87 0.007 0.094 0.26 130 0.012 0.21 0.0064 0.032 0.46 29 0.014 0.56 0.049 0.64 0.28 122 0.018 0.89 0.022 0.076 0.51 64 0.014 1.2 0.091 0.14 0.68 Comp. 0.089 1.5 0.18 1.9 0.41 Example SJCRH30 U266B1 A-431 MV-4-11 DB Reference IC50 IC50 IC50 IC50 IC50 Examples (M) (M) (M) (M) (M) 1 >10 0.11 0.73 0.021 0.26 25 5.1 0.22 0.12 0.011 0.12 55 0.55 0.031 0.48 0.0067 0.061 130 0.17 0.024 0.16 0.025 0.13 29 6.6 0.42 0.56 0.02 0.15 122 0.13 0.27 1.6 0.038 0.12 64 0.56 0.11 0.71 0.032 0.11 Comp. >10 1.4 0.75 0.11 0.56 Example

[0888] According to the above results, these compounds inhibited the growth of human colon cancer HCT116 cell line, human pancreatic cancer Capan-1 cell line, human lung cancer A-427 cell line, human breast cancer MDA-MB-453 cell line, human prostate cancer LNCAP.FGC cell line, human osteo- and soft tissue sarcoma SJCRH30 cell line, human multiple myeloma U266B1 cell line, human skin cancer A-431 cell line, human acute leukemia MV-4-11 cell line, and human diffuse large B-cell lymphoma DB cell line.

Example 1: Potentiation of Antitumor Effect of Proteasome Inhibitor

(1) Cell Growth Inhibition Test

[0889] Table 20 shows the tumor cell lines and their culture medium used. All cell lines were obtained from ATCC, Sumitomo Dainippon Pharma Co., Ltd., or Health Science Research Resources Bank. TMD8 was obtained from Tokyo Medical and Dental University (Leuk Res. 2006 November; 30 (11):1385-90.).

TABLE-US-00021 TABLE 20 Number of Seeded Cells Cell Line Medium [cells/20 L/well] U266B1 ATCC formulated RPMI-1640 Medium 3000 (containing 15% fetal bovine serum) MM.1S ATCC formulated RPMI-1640 Medium 4000 (containing 10% fetal bovine serum) MOLT-4 ATCC formulated RPMI-1640 Medium 250 (containing 10% fetal bovine serum) NCI-H1975 ATCC formulated RPMI-1640 Medium 250 (containing 10% fetal bovine serum) SNU-16 ATCC formulated RPMI-1640 Medium 400 (containing 10% fetal bovine serum) HOS MEM medium (containing 2 mM L- 250 glutamine, 0.1 mM NEAA, 1 mM Na- pyruvate, and 10% fetal bovine serum) A549 DMEM medium (containing 10% fetal 250 bovine serum) A431 ATCC formulated DMEM medium 400 (containing 10% fetal bovine serum) TMD8 MEM medium (containing 10% fetal 400 bovine serum) VERC-RCW MEM medium (containing 10% fetal 400 bovine serum) HCT116 McCoy's 5A medium (containing 10% 250 fetal bovine serum) HL-60 1MDM medium (containing 20% fetal 400 bovine serum) MV4-11 1MDM medium (containing 10% fetal 250 bovine serum)

[0890] Cells were seeded in a 384-well culture plate (#3571, Corning Incorporated) at 20 L/well under the following conditions. The cells seeded in the plate were cultured in an incubator set at 5% CO.sub.2 and 37 C. On the following day the seeding, a novel pyrrolopyrimidine compound (Reference Example Compound 55) was adjusted to prepare medicinal solutions of 8 different concentrations in geometric progression (including 0 nM) by serial dilution with an RPMI-1640 medium, and other compounds having an antitumor effect were also adjusted to prepare medicinal solutions of 10 different concentrations in geometric progression (including 0 nM) by serial dilution with an RPMI-1640 medium. These were mixed to prepare 80 solutions of different compound concentrations. These mixed compounds were added to the plate at 5 L/well, and further cultured at 37 C. in 5% CO.sub.2 for 3 days. After 3 days, CellTiter-Glo (Promaga) was added thereto at 25 L/well and the chemiluminescence was measured with a plate reader.

(2) Analysis Method

[0891] The potentiating effect of a combined use of drugs was evaluated by a known method (a method disclosed in Trends Pharmacol. Sci. 4, 450-454, 1983, and Pharmacol Rev. 2006; 58(3):621-81).

[0892] Specifically, cells treated with a single drug of the novel pyrrolopyrimidine compound or other compounds having an antitumor effect were compared with control cells to determine a standardized cell survival rate T/C (Treatment/Control Ratio, %) From each of the determined T/C value, the half maximal inhibitory concentration (IC.sub.50) of each drug was determined by a curve fitting regression analysis tool using a regression analysis tool XLfit 5.3 (IDBS Ltd.).

[0893] The ratio of IC.sub.50 for each single drug (IC.sub.50 ratio) was determined by equation I.

IC.sub.50Ratio=[IC.sub.50 of Novel Pyrrolopyrimidine Compound]:[IC.sub.50 of another compound having an antitumor effect](Equation I)

[0894] The IC.sub.50 ratio determined by calculation is not equal to the concentration ratio of the novel pyrrolopyrimidine compound to another compound having an antitumor effect that have been mixed and actually used in an experiment. Thus, of the mixed compounds having various concentration ratios actually used in experiments, a line of concentration ratios close to the IC.sub.50 ratio was identified. From the T/C ratio of the line of the concentration ratios, a half maximal inhibitory concentration (ED.sub.50) in use of both the pyrrolopyrimidine compound and another compounds having an antitumor effect was determined, and then, a combination index (CI) for that ED.sub.50 was determined. The CI value was determined using a median effect analysis software CalcuSyn 2.0 (CalcuSyn, Inc.), which calculates the median-effect principle.

[0895] As details are shown in Table 21, the determined CI values were evaluated as follows: a CI value significantly exceeding 1 is antagonistic, a CI value substantially equal to 1 is additive, and a CI value significantly less than 1 is synergistic (Table 21). The comprehensive evaluation was made based on the result of lower potentiating action among the results from treatment with compounds mixed at a concentration ratio close to their IC.sub.50 ratio.

TABLE-US-00022 TABLE 21 Details of Combination Index (CI) CI Range Details (Determination) <0.1 Very strong synergism 0.1-0.3 Strong synergism 0.3-0.7 Synergism 0.7-0.85 Moderate synergism 0.85-0.9 Slight synergism 0.9-1.10 Additive 1.10-1.20 Slight antagonism 1.20-1.45 Moderate antagonism 1.45-3.3 Antagonism 3.3-10 Strong antagonism >10 Very strong antagonism
(3) Combined Use with a Proteasome Inhibitor

[0896] A cell growth inhibition test was performed using a novel pyrrolopyrimidine compound (Reference Example Compound 55) with highest concentrations, other compounds having an antitumor effect with highest doses, and tumor cell lines shown in Table 22. Table 23 shows the IC.sub.50 ratios, CI values, and evaluation results.

[0897] The results indicated that the use of the novel pyrrolopyrimidine compound in combination with a proteasome inhibitor synergistically enhances the antitumor effect.

TABLE-US-00023 TABLE 22 Novel Other Compounds Pyrrolopyrimidine Having an Compound Antitumor Effect Other Compounds Highest Highest Having an Tumor Cell Concentration Concentration Antitumor Effect Line (nM) (nM) Bortezomib U266B1 5000 1000 Carfilzomib U266B1 5000 750 Ixazomib HL-60 300 1000

TABLE-US-00024 TABLE 23 Novel Pyrrolopyrimidine Other Compounds Compound:Another Having an IC.sub.50 Compound Having an Comprehensive Antitumor Effect Ratio Antitumor Effect CI Evaluation Bortezomib 0.05 1:0.02 0.56 Synergism 1:0.07 0.51 Carfilzomib 0.30 1:015 0.64 Synergism 1:045 0.66 Ixazomib 19 1:10 0.82 Additive 1:30 0.94

Example 2: Potentiation of Antitumor Effect of Tyrosine Kinase Inhibitor

[0898] In the same manner as in Example 1, a cell growth inhibition test was performed using the novel pyrrolopyrimidine compound with highest concentrations, other compounds having an antitumor effect with highest doses, and tumor cell lines shown in Table 24. Table 25 shows the IC.sub.50 ratios, CI values, and evaluation results. In the following Examples 2 to 15, Reference Example Compound 55 was used as a novel pyrrolopyrimidine compound as in Example 1.

[0899] The results indicate that the use of the novel pyrrolopyrimidine compound in combination with an ALK inhibitor, a HER family inhibitor (an EGFR inhibitor and HER2 inhibitor), a CBR-ABL inhibitor, an FLT3 inhibitor, a VEGFR inhibitor, a c-kit inhibitor, a Janus kinase inhibitor, or a multi-kinase inhibitor additively or synergistically enhances the antitumor effect.

TABLE-US-00025 TABLE 24 Novel Other Compounds Pyrrolopyrimidine Having an Compound Antitumor Effect Other Compounds Highest Highest Having an Anti- Tumor Cell Concentration Concentration tumor Effect Line (nM) (nM) Alectinib MM.1S 100 100000 Crizotinib MM.1S 100 100000 Afatinib A549 10000 50000 Erlotinib A549 10000 100000 Gefitinib A431 10000 50000 Osimertinib NCI-H1975 100000 10000 Lapatinib A431 10000 100000 ARRY380 A431 10000 40000 Dasatinib HCT116 1000 100000 Imatinib A549 10000 100000 Quizartinib MOLT-4 300 100000 Gilteritinib MOLT-4 500 10000 Sunitinib SNU-16 10000 100000 Regorafenib SNU-16 10000 50000 Lenvatinib SNU-16 10000 100000 Pazopanib SNU-16 10000 100000 Crenolanib MV4-11 300 10000 Masitinib MOLT-4 300 10000 Ponatinib MOLT-4 300 10000 Ruxolitinib MV4-11 300 10000

TABLE-US-00026 TABLE 25 Novel Pyrrolopyrimidine Other Compounds Compound:Other Having an Anti- IC.sub.50 Compounds Having Comprehensive tumor Effect Ratio an Antitumor Effect CI Evaluation Alectinib 4592 1:3000 0.58 Synergism 1:9000 0.59 Crizotinib 94 1:37 0.87 Slight 1:111 0.74 synergism Afatinib 3 1:1.7 0.70 Synergism 1:5 0.48 Erlotinib >110 1:10 0.54 Synergism 1:30 0.45 Gefitinib 11 1:5 0.33 Synergism 1:15 0.32 Osimertinib 0.02 1:0.01 0.96 Additive 1:0.03 0.99 Lapatinib 46 1:10 0.15 Strong 1:30 0.19 synergism ARRY380 65 1:36 0.34 Synergism Dasatinib 298 1:300 0.83 Additive 1:900 0.96 Imatinib 23 1:10 0.31 Synergism 1:30 0.35 Quizartinib 286 1:111 0.39 Synergism 1:333 0.44 Gilteritinib 33 1:20 0.96 Additive 1:60 0.88 Sunitinib 5 1:3.3 0.86 Additive 1:10 0.91 Regorafenib 17 1:15 0.88 Additive 1:45 1.06 Lenvatinib 4 1:3.3 0.44 Synergism 1:10 0.63 Pazopanib 91 1:30 0.71 Slight 1:90 0.52 synergism Crenolanib 4 1:3.7 0.91 Additive 1:11 0.83 Masitinib 70 1:33 0.31 Synergism 1:100 0.20 Ponatinib 11 1:3.7 0.46 Synergism 1:11 0.36 Ruxolitinib 483 1:300 0.82 Moderate synergism * For ARRY380, the CI value was calculated only at 1:36. * For Ruxolitinib, the CI value was calculated only at 1:300.

Example 3: Potentiation of Antitumor Effect of Serine-Threonine Kinase Inhibitor

[0900] A cell growth inhibition test was performed in the same manner as in Example 1 except for the use of the novel pyrrolopyrimidine compound with highest concentrations, other compounds having an antitumor effect with highest doses, and tumor cell lines shown in Table 26. Table 27 shows the IC.sub.50 ratios, CI values, and evaluation results.

[0901] The results indicate that the use of the novel pyrrolopyrimidine compound in combination with a PI3K inhibitor, an Akt inhibitor, a mTOR inhibitor, or a PLK inhibitor synergistically enhances the antitumor effect.

TABLE-US-00027 TABLE 26 Novel Other Compounds Pyrrolopyrimidine Having an Compound Antitumor Effect Other Compounds Highest Highest Having an Anti- Tumor Cell Concentration Concentration tumor Effect Line (nM) (nM) Everolimus VMRC-RCW 5000 10000 Rapamycin A549 10000 1000 AZD5363 VMRC-RCW 5000 100000 MK2206 A549 10000 10000 Idelalisib TMD-8 300 10000 Duvelisib TMD-8 300 10000 Volasertib HL-60 300 10000

TABLE-US-00028 TABLE 27 Novel Pyrrolopyrimidine Other Compounds Compound:Another Having an Anti- IC.sub.50 Compound Having Comprehensive tumor Effect Ratio an Antitumor Effect CI Evaluation Everolimus 6 1:2 0.32 Synergism 1:6 0.37 Rapamycin 0.1 1:0.03 0.62 Synergism 1:0.1 0.56 AZD5363 67 1:60 0.33 Synergism 1:180 0.38 MK2206 5 1:3 0.31 Synergism 1:9 0.35 Idelalisib 23 1:11 0.57 Synergism 1:33 0.64 Duvelisib 2 1:1.2 0.42 Synergism 1:3.7 0.43 Volasertib 14 1:11 0.95 Additive 1:33 0.82 Duvelisib 2 1:1.2 0.42 Synergism 1:3.7 0.43 Volasertib 14 1:11 0.95 Additive 1:33 0.82

Example 4: Potentiation of Antitumor Effect of PARP Inhibitor

[0902] A cell growth inhibition test was performed in the same manner as in Example 1 except for the use of the novel pyrrolopyrimidine compound with a highest concentration, another compound having an antitumor effect with highest dose, and a tumor cell line shown in Table 28. Table 29 shows the IC.sub.50 ratio, CI value, and evaluation result.

[0903] The result indicates that the use of the novel pyrrolopyrimidine compound in combination with a PARP inhibitor synergistically enhances the antitumor effect.

TABLE-US-00029 TABLE 28 Novel Other Compounds Pyrrolopyrimidine Having an Compound Antitumor Effect Other Compounds Highest Highest Having an Anti- Tumor Cell Concentration Concentration tumor Effect Line (nM) (nM) Olaparib A549 10000 100000

TABLE-US-00030 TABLE 29 Novel Pyrrolopyrimidine Other Compounds Compound:Another Having an Anti- IC.sub.50 Compound Having Comprehensive tumor Effect Ratio an Antitumor Effect CI Evaluation Olaparib 21 1:10 0.61 Synergism 1:30 0.69

Example 5: Potentiation of Antitumor Effect of Steroid

[0904] A cell growth inhibition test was performed in the same manner as in Example 1 except for the use of the novel pyrrolopyrimidine compound with highest concentrations, other compounds having an antitumor effect with highest doses shown, and tumor cell lines shown in Table 30. Table 31 shows the IC.sub.50 ratios, CI values, and evaluation results.

[0905] The results indicate that the use of the novel pyrrolopyrimidine compound in combination with steroid synergistically enhances the antitumor effect.

TABLE-US-00031 TABLE 30 Novel Other Compounds Pyrrolopyrimidine Having an Compound Antitumor Effect Other Compounds Highest Highest Having an Anti- Tumor Cell Concentration Concentration tumor Effect Line (nM) (nM) Prednisolone MM.1S 1000 10000 Dexamethasone MM.1S 1000 1000

TABLE-US-00032 TABLE 31 Novel Pyrrolopyrimidine Other Compounds Compound:Another Having an Anti- IC.sub.50 Compound Having Comprehensive tumor Effect Ratio an Antitumor Effect CI Evaluation Prednisolone 8.3 1:3.3 0.54 Synergism 1:10 0.44 Dexamethasone 0.4 1:0.3 0.51 Synergism 1:1 0.39

Example 6: Potentiation of Antitumor Effect of Immunomodulator

[0906] A cell growth inhibition test was performed in the same manner as in Example 1 except for the use of the novel pyrrolopyrimidine compound with highest concentrations, other compounds having an antitumor effect with highest doses, and tumor cell lines shown in Table 32. Table 33 shows the IC.sub.50 ratios, CI values, and evaluation results.

[0907] The results indicate that the use of the novel pyrrolopyrimidine compound in combination with an immunomodulator synergistically enhances the antitumor effect.

TABLE-US-00033 TABLE 32 Novel Other Compounds Pyrrolopyrimidine Having an Compound Antitumor Effect Other Compounds Highest Highest Having an Anti- Tumor Cell Concentration Concentration tumor Effect Line (nM) (nM) Lenalidomide MM.1S 1000 10000 Pomalidomide MM.1S 1000 1000 Thalidomide MM.1S 1000 100000

TABLE-US-00034 TABLE 33 Novel Pyrrolopyrimidine Other Compounds Compound:Other Having an Anti- IC.sub.50 Compounds Having Comprehensive tumor Effect Ratio an Antitumor Effect CI Evaluation Lenalidomide 14 1:10 0.75 Moderate 1:30 0.69 synergism Poma1idomide 3 1:1 0.81 Moderate 1:3 0.66 synergism Thalidomide 6603 1:900 0.63 Synergism * For thalidomide, the CI value was calculated only at 1:900.

Example 7: Potentiation of Antitumor Effect of Exportin-1 Inhibitor

[0908] A cell growth inhibition test was performed in the same manner as in Example 1 except for the use of the novel pyrrolopyrimidine compound with a highest concentration, another compound having an antitumor effect with a highest dose, and a tumor cell line shown in Table 34. Table 35 shows the IC.sub.50 ratio, CI value, and evaluation result.

[0909] The result indicates that the use of the novel pyrrolopyrimidine compound in combination with an exportin-1 inhibitor synergistically enhances the antitumor effect.

TABLE-US-00035 TABLE 34 Novel Other Compounds Pyrrolopyrimidine Having an Compound Antitumor Effect Other Compounds Highest Highest Having an Anti- Tumor Cell Concentration Concentration tumor Effect Line (nM) (nM) KPT-330 HCT116 300 10000

TABLE-US-00036 TABLE 35 Novel Pyrrolopyrimidine Other Compounds Compound:Other Having an Anti- IC.sub.50 Compounds Having Comprehensive tumor Effect Ratio an Antitumor Effect CI Evaluation KPT-330 21 1:11 0.69 Moderate 1:33 0.75 synergism

Example 8: Potentiation of Antitumor Effect of BTK Inhibitor

[0910] A cell growth inhibition test was performed in the same manner as in Example 1 except for the use of the novel pyrrolopyrimidine compound with a highest concentration, another compound having an antitumor effect with a highest dose, and a tumor cell line shown in Table 36. Table 37 shows the IC.sub.50 ratio, CI value, and evaluation result.

[0911] The result indicates that the use of the novel pyrrolopyrimidine compound in combination with a BTK inhibitor synergistically enhances the antitumor effect.

TABLE-US-00037 TABLE 36 Novel Other Compounds Pyrrolopyrimidine Having an Compound Antitumor Effect Other Compounds Highest Highest Having an Anti- Tumor Cell Concentration Concentration tumor Effect Line (nM) (nM) Ibrutinib MV-4-11 100 100000

TABLE-US-00038 TABLE 37 Novel Pyrrolopyrimidine Other Compounds Compound:Another Having an Anti- IC.sub.50 Compound Having Comprehensive tumor Effect Ratio an Antitumor Effect CI Evaluation Ibrutinib 140 1:111 0.70 Moderate 1:333 0.72 synergism

Example 9: Potentiation of Antitumor Effect of BCL-2 Inhibitor

[0912] A cell growth inhibition test was performed in the same manner as in Example 1 except for the use of the novel pyrrolopyrimidine compound with a highest concentration, another compound having an antitumor effect with highest dose, and a tumor cell line shown in Table 38. Table 39 shows the IC.sub.50 ratio, CI value, and evaluation result.

[0913] The result indicates that the use of the novel pyrrolopyrimidine compound in combination with a BCL-2 inhibitor synergistically enhances the antitumor effect.

TABLE-US-00039 TABLE 38 Other Compounds Novel Having an Pyrrolopyrimidine Antitumor Effect Other Compounds Compound Highest Having an Tumor Highest Concentration Antitumor Effect Cell Line Concentration (nM) (nM) ABT-199 MOLT-4 500 10000

TABLE-US-00040 TABLE 39 Novel Pyrrolopyrimidine Other Compounds Compound:Another Having an IC.sub.50 Compound Having an Comprehensive Antitumor Effect Ratio Antitumor Effect CI Evaluation ABT-199 119 1:60 0.37 Synergism 1:180 0.40

Example 10: Potentiation of Antitumor Effect of HDAC Inhibitor

[0914] A cell growth inhibition test was performed in the same manner as in Example 1 except for the use of the novel pyrrolopyrimidine compound with highest concentrations, other compounds having an antitumor effect with highest doses, and tumor cell lines shown in Table 40. Table 41 shows the IC.sub.50 ratios, CI values, and evaluation results.

[0915] The results indicate that the use of the novel pyrrolopyrimidine compound in combination with a HDAC inhibitor additively enhances the antitumor effect.

TABLE-US-00041 TABLE 40 Other Compounds Novel Having an Pyrrolopyrimidine Antitumor Effect Other Compounds Compound Highest Having an Tumor Highest Concentration Antitumor Effect Cell Line Concentration (nM) (nM) Panobinostat U266B1 5000 10000 Vorinostat U266B1 5000 10000

TABLE-US-00042 TABLE 41 Novel Pyrrolopyrimidine Other Compounds Compound:Another Having an IC.sub.50 Compound Having an Comprehensive Antitumor Effect Ratio Antitumor Effect CI Evaluation Panobinostat 0.08 1:0.07 0.90 Additive 1:0.22 0.61 Vorinostat 4.4 1:2 0.91 Additive 1:6 0.88

Example 11: Potentiation of Antitumor Effect of Antimetabolite

[0916] A cell growth inhibition test was performed in the same manner as in Example 1 except for the use of the novel pyrrolopyrimidine compound with highest concentrations, other compounds having an antitumor effect with highest doses, and tumor cell lines shown in Table 42. Table 43 shows the IC.sub.50 ratios, CI values, and evaluation results.

[0917] The results indicate that the use of the novel pyrrolopyrimidine compound in combination with an antimetabolite additively or synergistically enhances the antitumor effect.

TABLE-US-00043 TABLE 42 Other Compounds Novel Having an Pyrrolopyrimidine Antitumor Effect Other Compounds Compound Highest Having an Tumor Highest Concentration Antitumor Effect Cell Line Concentration (nM) (nM) Fluorouracil A431 10000 50000 Gemcitabine A431 10000 200 Cytarabine HCT116 1000 10000 6-Mercaptopurine MM.1S 100 10000 Pemetrexed HCT116 1000 50000 Trifluridine A431 10000 10000

TABLE-US-00044 TABLE 43 Novel Pyrrolopyrimidine Other Compounds Compound:Another Having an IC.sub.50 Compound Having Comprehensive Antitumor Effect Ratio an Antitumor Effect CI Evaluation Fluorouracil 0.8 1:0.56 0.44 Synergism 1:1.67 0.20 Gemcitabine 0.01 1:0.007 0.70 Synergism 1:0.02 0.49 Cytarabine 48 1:30 0.52 Synergism 1:90 0.66 6-Mercaptopurine 169 1:100 0.61 Moderate 1:300 0.80 synergism Pemetrexed 34 1:17 0.73 Moderate 1:50 0.55 synergism Trifluridine 0.5 1:0.33 1.06 Additive 1:1 0.74

Example 12: Potentiation of Antitumor Effect of Platinum-Based Antitumor Agent (Platinum Complex)

[0918] A cell growth inhibition test was performed in the same manner as in Example 1 except for the use of the novel pyrrolopyrimidine compound with highest concentrations, other compounds having an antitumor effect with highest doses, and tumor cell lines shown in Table 44. Table 45 shows the IC.sub.50 ratios, CI values, and evaluation results.

[0919] The results indicate that the use of the novel pyrrolopyrimidine compound in combination with a platinum-based antitumor agent (platinum complex) synergistically enhances the antitumor effect.

TABLE-US-00045 TABLE 44 Other Compounds Novel Having an Pyrrolopyrimidine Antitumor Effect Other Compounds Compound Highest Having an Tumor Highest Concentration Antitumor Effect Cell Line Concentration (nM) (nM) Cisplatin HCT116 1000 10000 Carboplatin A549 10000 500000 Oxaliplatin HL-60 500 50000

TABLE-US-00046 TABLE 45 Novel Pyrrolopyrimidine Other Compounds Compound:Another Having an IC.sub.50 Compound Having an Comprehensive Antitumor Effect Ratio Antitumor Effect CI Evaluation Cisplatin 343 1:333 0.44 Moderate 1:1000 0.72 synergism Carboplatin 38 1:17 0.41 Slight 1:50 0.87 synergism Oxaliplatin 132 1:100 0.65 Synergism 1:300 0.70

Example 13: Potentiation of Antitumor Effect of Microtubule Inhibitor

[0920] A cell growth inhibition test was performed in the same manner as in Example 1 except for the use of the novel pyrrolopyrimidine compound with highest concentrations, other compounds having an antitumor effect with highest doses, and tumor cell lines shown in Table 46. Table 47 shows the IC.sub.50 ratios, CI values, and evaluation results.

[0921] The results indicate that the use of the novel pyrrolopyrimidine compound in combination with a microtubule inhibitor additively enhances the antitumor effect.

TABLE-US-00047 TABLE 46 Other Compounds Novel Having an Pyrrolopyrimidine Antitumor Effect Other Compounds Compound Highest Having an Tumor Highest Concentration Antitumor Effect Cell Line Concentration (nM) (nM) Eribulin A549 10000 1000 Paclitaxel A549 10000 5000

TABLE-US-00048 TABLE 47 Novel Pyrrolopyrimidine Other Compounds Compound:Another Having an IC.sub.50 Compound Having an Comprehensive Antitumor Effect Ratio Antitumor Effect CI Evaluation Eribulin 0.01 1:0.01 1.02 Additive 1:0.03 0.89 Paclitaxel 0.04 1:0.02 0.98 Additive 1:0.06 0.77

Example 14: Potentiation of Antitumor Effect of Alkylating Agent

[0922] A cell growth inhibition test was performed in the same manner as in Example 1 except for the use of the novel pyrrolopyrimidine compound with highest concentrations, other compounds having an antitumor effect with highest doses, and tumor cell lines shown in Table 48. Table 49 shows the IC.sub.50 ratios, CI values, and evaluation results.

[0923] The results indicate that the use of the novel pyrrolopyrimidine compound in combination with an alkylating agent additively or synergistically enhances the antitumor effect.

TABLE-US-00049 TABLE 48 Other Compounds Novel Having an Pyrrolopyrimidine Antitumor Effect Other Compounds Compound Highest Having an Tumor Highest Concentration Antitumor Effect Cell Line Concentration (nM) (nM) Trabectedin HOS 1000 10000 Ifosfamide MV4-11 100 100000 Dacarbazine MV4-11 100 100000

TABLE-US-00050 TABLE 49 Novel Pyrrolopyrimidine Other Compounds Compound:Another Having an IC.sub.50 Compound Having Comprehensive Antitumor Effect Ratio an Antitumor Effect CI Evaluation Trabectedin 0.2 1:0.1 0.83 Additive 1:0.3 1.01 Ifosfamide 6315 1:3000 0.57 Synergism 1:9000 0.60 Dacarbazine 6582 1:3000 0.92 Additive 1:9000 0.95

Example 15: Potentiation of Antitumor Effect of Anthracycline-Based Antitumor Agent

[0924] A cell growth inhibition test was performed in the same manner as in Example 1 except for the use of the novel pyrrolopyrimidine compound with highest concentrations, other compounds having an antitumor effect with highest doses, and tumor cell lines shown in Table 50. Table 51 shows the IC.sub.50 ratios, CI values, and evaluation results.

[0925] The results indicate that the use of the novel pyrrolopyrimidine compound in combination with an anthracycline-based antitumor agent synergistically enhances the antitumor effect.

TABLE-US-00051 TABLE 50 Other Compounds Novel Having an Pyrrolopyrimidine Antitumor Effect Other Compounds Compound Highest Having an Tumor Highest Concentration Antitumor Effect Cell Line Concentration (nM) (nM) Doxorubicin HOS 10000 50000 Pixantrone MM.1S 100 10000

TABLE-US-00052 TABLE 51 Novel Pyrrolopyrimidine Other Compounds Compound:Another Having an IC.sub.50 Compound Having an Comprehensive Antitumor Effect Ratio Antitumor Effect CI Evaluation Doxorubicin 2 1:1.7 0.77 Moderate 1:5 0.61 synergism Pixantrone 8.4 1:3.7 0.73 Moderate 1:11 0.84 synergism

Example 16: Potentiation of Tumor Growth Inhibitory Effect on Tumor Cells Transplanted into Mice by Combinational Treatment with Bortezomib

[0926] Human multiple myeloma (MM) KMS-26 cell lines were washed in PBS and suspended in 50% PBS and 50% Martigel basement membrane matrix (#356237, Corning Incorporated) to give a concentration of 110.sup.8 cells/mL. 0.1 mL of this cell suspension was subcutaneously implanted into the right chest of 6-week-old CB17/Icr-Prkdc.sup.scid/CrlCrlj mice (Charles River, Japan)

[0927] The length and the width of the implanted tumor and the body weight were measured. The tumor volume (TV) was calculated using the following equation (equation C). The unit for the length and width is mm.

TV (mm.sup.3)={(length)(width).sup.2}/2(equation C)

[0928] When the TV reached 100 to 310 mm.sup.3, the animals were assigned to different groups in accordance with a stratified randomization procedure. This day was determined to be day 1, the TV on this day was determined to be TV1, and the body weight on this day was determined to be BW1. The test ended on day 15.

[0929] A necessary amount of the test compound was weighed to prepare a solution to administer to the mice. Mice with tumors (6 mice/group) were intravenously administered with hydrochloride of Reference Example Compound 55 in an amount of 100 mg/kg/day (on a free-base dose basis) once a week (day 1 and 8) or twice a week (day 1, 4, 8, and 11) or intravenously administered with bortezomib in an amount of 1 mg/kg/day twice a week (day 1, 4, 8, and 11). A group for combinational treatment was administered with a combination of the reference example compound and bortezomib, and whether the tumor growth inhibitory effect was increased by the combinational treatment was evaluated. The control group was administered with the vehicle for Reference Example Compound 55.

[0930] Thereafter, the length and the width of the tumor and the body weight (BWn) on day n were measured over time in the same manner, and the TVn of each mouse was calculated. Further, the relative tumor volume (RTVn) was calculated based on the TVn of each mouse using the following equation (equation D); the treatment/control (T/Cn) value (%) on day n was calculated based on the mean RTVn of each drug administration group using the following equation (equation E); and the body weight change rate (BWCn) was calculated using the following equation (equation F).

RTVn=TVn/TV1(equation D)

T/Cn (%)=(mean RTV of each drug administration group on day n)/(mean RTV of the control group on day n)100(equation E)

BWCn (%)=(BWnBW1)/BW1100(equation F)

[0931] An RTV15 comparison using Dunnett's test revealed that the RTV of the group administered with the reference example compound was significantly lower than that of the control group. Further, a comparison using Aspin-Welch's t-test revealed that the RTV15 of the group treated with the combination of the reference example compound in an amount of 100 mg/kg/day twice a week and bortezomib in an amount of 1 mg/kg/day twice a week was significantly lower than the RTV15 of the groups treated with their respective single drugs. FIG. 1 shows the changes in RTV of this test.

[0932] Moreover, the RTV 15 of the group treated with the combination of the reference example compound in an amount of 100 mg/kg/day once a week and bortezomib in an amount of 1 mg/kg/day twice a week was also significantly lower than the RTV15 of the groups treated with their respective single drugs. Table 52 shows the results.

[0933] The change in average body weight of the group of combinational treatment on the last day of the test showed no enhanced toxicity compared with the groups treated with their respective single drugs.

[0934] The results indicated that the use of the reference example compound in combination enhances the tumor growth inhibitory effect of bortezomib.

TABLE-US-00053 TABLE 52 Dose Administration Number RTV15 BWC15 (%) Group (mg/kg/day) Day of Mice Mean SD T/C15 (%) Mean SD Control 1, 8 6 10.4 5.0 100 4.4 12.8 Bortezomib 1 1, 4, 8, 11 6 6.9 3.2 66 1.3 3.2 Reference 100 1, 8 6 4.3 1.0 42 2.3 3.3 Example Compound Reference 100 1, 4, 8, 11 6 3.1 0.8 30 6.0 4.4 Example Compound Bortezomib/ 1/100 1, 4, 8, 11/1, 8 6 2.0 0.6 20 2.0 6.2 Reference Example Compound Bortezomib/ 1/100 1, 4, 8, 11/1, 6 0.6 0.2 6 5.8 2.6 Reference 4, 8, 11 Example Compound

Example 17: Potentiation of Tumor Growth Inhibitory Effect on Tumor Cells Transplanted into Mice by Combinational Treatment with Gilteritinib

[0935] In accordance with the disclosure of Example 16, human acute myelogenous leukemia (AML) MV-4-11 cell lines were transplanted into 6-week old BALB/cAJcl-nu/nu mice (CLEA Japan, Inc.). When the TV reached 80 to 220 mm.sup.3, the animals were assigned to different groups in accordance with a stratified randomization procedure. This day was determined to be day 1, the TV on this day was determined to be TV1, and the body weight on this day was determined to be BW1. The test ended on day 15.

[0936] Mice with tumors were intravenously administered with hydrochloride of Reference Example Compound 55 in an amount of 50 mg/kg/day or 100 mg/kg/day (both on a free-base dose basis) once a week (day 1 and 8) or orally administered with gilteritinib in an amount of 3 mg/kg/day daily. A group for combinational treatment was administered with a combination of the reference example compound and gilteritinib, and whether the tumor growth inhibitory effect on human tumors was increased by the combinational treatment with gilteritinib was evaluated. The control group was administered with the vehicle for the reference example compound.

[0937] An RTV15 comparison using Dunnett's test revealed that the RTV of the group administered with reference example compound and the group administered with gilteritinib was significantly lower than that of the control group. Further, a comparison using Aspin-Welch's t-test revealed that the RTV15 of the group treated with the combination of the reference example compound in an amount of 50 mg/kg/day once a week and gilteritinib in an amount of 3 mg/kg/day daily was significantly lower than the RTV15 of the groups treated with their respective single drugs. FIG. 2 shows the changes in RTV of this test.

[0938] Moreover, the RTV 15 of the group treated with the combination of the reference example compound in an amount of 100 mg/kg/day once a week (day 1, 8) and gilteritinib in an amount of 3 mg/kg/day daily was also significantly lower than the RTV15 of the groups treated with their respective single drugs. Table 53 shows the results.

[0939] The change in average body weight of the group of combinational treatment on the last day of the test showed no enhanced toxicity compared with the groups treated with their respective single drugs.

[0940] The results indicated that the use of the reference example compound in combination enhances the tumor growth inhibitory effect of gilteritinib.

TABLE-US-00054 TABLE 53 Number Dose Administration of RTV15 BWC15 (%) Group (mg/kg/day) Day Mice Mean SD T/C15 (%) Mean SD Control 1, 8 6 4.5 0.8 100 9.8 3.0 Gilteritinib 3 1-14 6 1.9 0.5 41 5.8 3.0 Reference 50 1, 8 6 3.3 0.7 74 8.1 3.8 Example Compound Reference 100 1, 8 6 2.0 0.5 46 9.1 2.2 Example Compound Gilteritinib/ 3/50 1-14/1, 8 6 0.9 0.4 21 9.6 3.4 Reference Example Compound Gilteritinib/ 3/100 1-14/1, 8 6 0.8 0.3 18 6.2 1.0 Reference Example Compound

Example 18: Potentiation of Tumor Growth Inhibitory Effect on Tumor Cells Transplanted into Mice by Combinational Treatment with Doxorubicin

[0941] In accordance with the disclosure of Example 16, human clear cell sarcoma SU-CCS-1 cell lines were transplanted into 7-week old BALB/cAJcl-nu/nu mice (CLEA Japan, Inc.). When the TV reached 100 to 150 mm.sup.3, the animals were assigned to different groups in accordance with a stratified randomization procedure. This day was determined to be day 0, the TV on this day was determined to be TV0, and the body weight on this day was determined to be BW0. The test ended on day 22.

[0942] Mice with tumors were intravenously administered with hydrochloride of Reference Example Compound 55 in an amount of 12.5 mg/kg/day or 25 mg/kg/day (both on a free-base dose basis) on day 1 and 8 or intravenously administered with doxorubicin hydrochloride in an amount of 8 mg/kg/day on day 1. A group for combinational treatment was administered with a combination of the reference example compound and doxorubicin hydrochloride, and whether the tumor growth inhibitory effect on human tumors was increased by the combinational treatment with doxorubicin hydrochloride was evaluated. The control group was untreated.

[0943] An RTV22 comparison using Dunnett's test revealed that the RTV of the group administered with the reference example compound and the group administered with doxorubicin hydrochloride was significantly lower than that of the control group. Further, a comparison using Aspin-Welch's t-test revealed that the RTV22 of the group treated with the combination of the reference example compound in an amount of 25 mg/kg/day on day 1 and 8 and doxorubicin hydrochloride in an amount of 8 mg/kg/day on day 1 was significantly lower than the RTV22 of the groups treated with their respective single drugs. FIG. 3 shows the changes in RTV of this test.

[0944] Moreover, the RTV22 of the group treated with the combination of the reference example compound in an amount of 12.5 mg/kg/day on day 1 and 8 and doxorubicin in an amount of 8 mg/kg/day on day 1 was also significantly lower than the RTV22 of the groups treated with their respective single drugs. Table 54 shows the results.

[0945] The change in average body weight of the group of combinational treatment on the last day of the test showed no enhanced toxicity compared with the groups treated with their respective single drugs.

[0946] The results indicated that the use of the reference example compound in combination enhances the tumor growth inhibitory effect of doxorubicin.

TABLE-US-00055 TABLE 54 Number Dose Administration of RTV22 BWC22 (%) Group (mg/kg/day) Day Mice Mean SD T/C22 (%) Mean SD Control 6 8.9 0.9 100 3.7 4.3 Doxorubicin 8 1 6 6.6 0.8 74 0.3 2.6 Hydrochloride Reference 12.5 1, 8 6 3.7 0.8 42 5.0 5.3 Example Compound Reference 25 1, 8 6 2.2 0.4 25 4.1 4.1 Example Compound Doxorubicin 8/12.5 1/1, 8 6 1.2 0.4 14 7.1 7.5 Hydrochloride/ Reference Example Compound Doxorubicin 8/25 1/1, 8 6 0.6 0.2 7 9.6 6.9 Hydrochloride/ Reference Example Compound

Example 19: Potentiation of Tumor Growth Inhibitory Effect on Tumor Cells Transplanted into Mice by Combinational Treatment with Rituximab 1

[0947] In accordance with the disclosure of Example 16, human diffuse large B-cell lymphoma (DLBCL) WILL-2 cell lines were transplanted into 6-week old CB17/Icr-Prkdc.sup.scid/CrlCrlj mice (Charles River, Japan). When the TV reached 120 to 220 mm.sup.3, the animals were assigned to different groups in accordance with a stratified randomization procedure. This day was determined to be day 1, the TV on this day was determined to be TV1, and the body weight on this day was determined to be BW1. The test ended on day 15.

[0948] Mice with tumors were intravenously administered with hydrochloride of Reference Example Compound 55 in an amount of 50 mg/kg/day or 100 mg/kg/day (both on a free-base dose basis) once a week (Day 1 and 8) or intravenously administered with rituximab in an amount of 10 mg/kg/day on day 1. A group for combinational treatment was administered with a combination of the reference example compound and rituximab, and whether the tumor growth inhibitory effect on human tumors was increased by the combinational treatment with rituximab was evaluated. The control group was administered with the vehicle for the reference example compound.

[0949] An RTV15 comparison using Dunnett's test revealed that the RTV of the group administered with the reference example compound and the group administered with rituximab was significantly lower than that of the control group. Further, a comparison using Aspin-Welch's t-test revealed that the RTV15 of the group treated with a combination of the reference example compound in an amount of 50 mg/kg/day once a week and rituximab in an amount of 10 mg/kg/day on day 1 was significantly lower than the RTV15 of the groups treated with their respective single drugs. FIG. 4 shows the changes in RTV of this test.

[0950] Moreover, the RTV15 of the group treated with the combination of the reference example compound in an amount of 100 mg/kg/day once a week and rituximab in an amount of 10 mg/kg/day on day 1 was also significantly lower than the RTV15 of the groups treated with their respective single drugs. Table 55 shows the results.

[0951] The change in average body weight of the group of combinational treatment on the last day of the test showed no enhanced toxicity compared with the groups treated with their respective single drugs.

[0952] The results indicated that the use of the reference example compound in combination enhances the tumor growth inhibitory effect of rituximab.

TABLE-US-00056 TABLE 55 Dose Administration Number RTV15 BWC15 (%) Group (mg/kg/day) Day of Mice Mean SD T/C15 (%) Mean SD Control 1, 8 6 15.0 3.1 100 9.8 1.6 Rituximab 10 1 6 8.0 2.3 53 2.3 4.7 Reference 50 1, 8 6 2.1 0.3 14 2.0 6.2 Example Compound Reference 100 1, 8 6 1.5 0.4 10 5.1 3.0 Example Compound Rituximab/ 1/50 1/1, 8 6 0.8 0.2 5 4.3 1.7 Reference Example Compound Rituximab/ 1/100 1/1, 8 6 0.6 0.2 4 6.0 2.8 Reference Example Compound

Example 20: Potentiation of Tumor Growth Inhibitory Effect on Tumor Cells Transplanted into Mice by Combinational Treatment with Rituximab 2

[0953] In accordance with the disclosure of Example 16, human diffuse large B-cell lymphoma (DLBCL) OCI-LY18 cell lines were transplanted into 6-week old BALB/cAJcl-nu/nu mice (CLEA Japan, Inc.). When the TV reached 120 to 210 mm.sup.3, the animals were assigned to different groups in accordance with a stratified randomization procedure. This day was determined to be day 1, the TV on this day was determined to be TV1, and the body weight on this day was determined to be BW1. The test ended on day 15.

[0954] Mice with tumors were intravenously administered with hydrochloride of Reference Example Compound 55 in an amount of 100 mg/kg/day (on a free-base dose basis) on day 1, 3, and 5 or twice a week (day 1, 4, 8, and 11) or intravenously administered or intravenously administered with rituximab in an amount of 10 mg/kg/day on day 1. A group for combinational treatment was administered with a combination of the reference example compound and rituximab, and whether the tumor growth inhibitory effect on human tumors was increased by the combinational treatment with rituximab was evaluated. The control group was administered with the vehicle for the reference example compound.

[0955] An RTV15 comparison using Dunnett's test revealed that the RTV of the group administered with the reference example compound and the group administered with rituximab was significantly lower than that of the control group. Further, a comparison using Aspin-Welch's t-test revealed that the RTV15 of the group treated with the combination of the reference example compound in an amount of 100 mg/kg/day on day 1, 3, and 5 and rituximab in an amount of 10 mg/kg/day on day 1 was significantly lower than the RTV15 of the groups treated with their respective single drugs. FIG. 5 shows the changes in RTV of this test.

[0956] Moreover, the RTV15 of the group treated with the combination of the reference example compound in an amount of 100 mg/kg/day twice a week and rituximab in an amount of 10 mg/kg/day on day 1 was also significantly lower than the RTV15 of the groups treated with their respective single drugs. Table 56 shows the results.

[0957] The change in average body weight of the group of combinational treatment on the last day of the test showed no enhanced toxicity compared with the groups treated with their respective single drugs.

[0958] The results indicated that the use of the reference example compound in combination intermediately enhances the tumor growth inhibitory effect of rituximab.

TABLE-US-00057 TABLE 56 Dose Administration Number RTV15 BWC15 (%) Group (mg/kg/day) Day of Mice Mean SD T/C15 (%) Mean SD Control 1, 4, 8, 11 6 10.9 2.8 100 12.2 2.6 Rituximab 10 1 6 5.2 1.8 48 9.8 4.2 Reference 100 1, 3, 5 6 3.5 1.8 32 12.5 4.8 Example Compound Reference 100 1, 4, 8, 11 6 1.9 0.7 17 6.1 4.9 Example Compound Rituximab/ 1/100 1/1, 3, 5 6 0.6 0.2 5 9.0 3.0 Reference Example Compound Rituximab/ 1/100 1/1, 4, 8, 11 6 0.4 0.1 4 0.7 3.5 Reference Example Compound

Example 21: Potentiation of Tumor Growth Inhibitory Effect on Tumor Cells Transplanted into Mice by Combinational Treatment with Azacytidine

[0959] In accordance with the disclosure of Example 16, human acute myelogenous leukemia (AML) THP-1 cell lines were transplanted into 7-weeks old BALB/cAJcl-nu/nu mice (CLEA Japan, Inc.). When the TV reached 90 to 180 mm.sup.3, the animals were assigned to different groups in accordance with a stratified randomization procedure. This day was determined to be day 1, the TV on this day was determined to be TV1, and the body weight on this day was determined to be BW1. The test ended on day 22.

[0960] Mice with tumors were intravenously administered with hydrochloride of Reference Example Compound 55 in an amount of 12.5 mg/kg/day (on a free-base dose basis) twice a week (Day 1, 4, 8, 11, 15, and 18) or intraperitoneally administered with azacytidine in an amount of 20 mg/kg/day twice a week (day 1, 4, 8, 11, 15, and 18). A group for combinational treatment was administered with a combination of the reference example compound and azacytidine, and whether the tumor growth inhibitory effect on human tumors was increased by the combinational treatment with azacytidine was evaluated. The control group was administered with the vehicle for the reference example compound.

[0961] An RTV22 comparison using Dunnett's test revealed that the RTV of the group administered with the reference example compound in an amount of 12.5 mg/kg/day twice a week and the group administered with azacytidine in an amount of 20 mg/kg/day twice a week was significantly lower than that of the control group. Further, a comparison using Aspin-Welch's t-test revealed that the RTV22 of the group of combinational treatment was significantly lower than the RTV22 of the groups treated with their respective single drugs. FIG. 6 and Table 57 show the results of this test.

[0962] The change in average body weight of the group of combinational treatment on the last day of the test showed no enhanced toxicity compared with the groups treated with their respective single drugs.

[0963] The results indicated that the use of the reference example compound in combination intermediately enhances the tumor growth inhibitory effect of azacytidine.

TABLE-US-00058 TABLE 57 Number Dose Administration of RTV22 BWC22 (%) Group (mg/kg/day) Day Mice Mean SD T/C22 (%) Mean SD Control 1, 4, 8, 11, 6 19.6 6.6 100 17.2 3.9 15, 18 Azacytidine 20 1, 4, 8, 11, 6 8.8 2.0 45 3.6 4.5 15, 18 Reference 12.5 1, 4, 8, 11, 6 7.1 2.3 36 12.7 2.3 Example 15, 18 Compound Azacytidine/ 20/12.5 1, 4, 8, 11, 6 1.7 0.5 8 4.4 5.6 Reference 15, 18/1, 4, Example 8, 11, 15, 18 Compound

Example 22: Potentiation of Antitumor Effect of IAP Antagonist

[0964] A cell growth inhibition test was performed in the same manner as in Example 1 except for the use of the novel pyrrolopyrimidine compound with highest concentration, other compounds having an antitumor effect with highest concentration, and tumor cell lines shown in Table 58. Table 59 shows the IC.sub.50 ratio, CI values, and evaluation results.

[0965] The result indicates that the use of the novel pyrrolopyrimidine compound in combination with an IAP antagonist synergistically enhances the antitumor effect.

TABLE-US-00059 TABLE 58 Other Compounds Novel Having an Pyrrolopyrimidine Antitumor Effect Other Compounds Compound Highest Having an Tumor Cell Highest Concentration Antitumor Effect Line Concentration (nM) (nM) GDC-0152 HL-60 100 30000

TABLE-US-00060 TABLE 59 Novel Pyrrolopyrimidine Other Compounds Compound:Another Having an IC.sub.50 Compound Having an Comprehensive Antitumor Effect Ratio Antitumor Effect CI Evaluation GDC-0152 2122 1:90 0.45 Synergism 1:270 0.62