WO2017133664A1

WO2017133664A1 - Bicyclic pyridine and pyrimidine derivatives and their use in the treatment， amelioration or prevention of influenza

Info

Publication number: WO2017133664A1
Application number: PCT/CN2017/072829
Authority: WO
Inventors: Xuefei Tan; Katrin Groebke Zbinden; Bernd Kuhn; Lisha Wang; Yongfu Liu; Jun Wu; Hong Shen; Tianlai SHI
Original assignee: Savira Pharmaceuticals Gmbh; European Molecular Biology Laboratory
Priority date: 2016-02-05
Filing date: 2017-02-03
Publication date: 2017-08-10

Abstract

The present invention relates to a compound having the formula (I), optionally in the form of a pharmaceutically acceptable salt, solvate, polymorph, prodrug, codrug, cocrystal, tautomer, racemate, enantiomer, or diastereomer or mixture thereof, which is useful in treating, ameloriating or preventing influenza.

Description

Bicyclic pyridine and pyrimidine derivatives and their use in the treatment， amelioration or prevention of influenza

Field of the invention

The present invention relates to a compound having the formula (I) ， optionally in the form of a pharmaceutically acceptable salt， solvate， polymorph， prodrug， codrug， cocrystal， tautomer， racemate， enantiomer， or diastereomer or mixture thereof，

which is useful in treating， ameloriating or preventing influenza.

Background of the invention

Influenza viruses belong to the Orthomyxoviridae family of RNA viruses. Based on antigenic differences of viral nucleocapsid and matrix proteins， influenza viruses are further divided into three types named influenza A， B， and C viruses. All influenza viruses have an envelope and their genomes are composed of eight or seven single-stranded， negative-sensed RNA segments. These viruses cause respiratory diseases in humans and animals with a significant morbidity and mortality. The influenza pandemic of 1918， Spanish flu， is thought to have killed up to 100 million people. The reassortment of avian flu RNA fragments with circulating human viruses caused the other two pandemics in 1957 H2N2 ″Asian influenza″ and 1968 H3N2 ″Hong Kong influenza″ . Now， people around the world face the challenges of influenza from various angles： seasonal influenza epidemics affect about 5-15％of the world′s population with an annual mortality ranging from 250,000 to 500,000. Infections of avian flu strains， mostly H5N1， have been reported in many Asian countries. Although no frequent human-to-human spreading has been observed， avian flu infection is serious and associated with a high mortality of up to 60％of infected persons. In 2009， an H1N1 swine flu infection appeared initially in North America and evolved into a new pandemic. Currently， seasonal trivalent influenza vaccines and vaccines specific for H5N1 or swine flu are either available or in the phase of clinical trials. The prophylaxis is an effective method， at least in some populations， for preventing influenza virus infection and its potentially severe complications. However， continuous viral antigenicity shifting and drifting makes future circulating flu strains unpredictable. Furthermore， due to the limitations of mass production of vaccines within a relatively short period of time during a pandemic， other anti-flu approaches such as anti-flu drugs are highly desirable. On the market， there are two types of anti-flu drugs available： neuraminidase inhibitors such as oseltamivir phosphate (Tamilflu) and zanamivir (Relenza) ； and M2 ion channel blockers such as amantadine and rimantadine. To increase the effectiveness of current anti-flu drugs and prevent or attenuate appearance of drug-resistant viruses， it is invaluable to discover compounds with new mechanisms of anti-influenza action that can be used as a therapeutic or prophylactic agent alone or combined with current anti-flu drugs.

It appears realistic that H5N1 and related highlv pathogenic avian influenza viruses could acquire mutations rendering them more easily transmissible between humans. In addition， the new A/H1N1 could become more virulent and only a single point mutation would be enough to confer resistance to oseltamivir (Neumann et al.， Nature 2009， 18， 459 (7249) ， 931-939) . This has already happenend in the case of some seasonal H1N1 strains which have recently been identified (Dharan et al.， The Journal of the American Medical Association， 2009， 301 (10) ， 1034-1041； Moscona et al.， The New England Journal of Medicine 2009， 360 (10) ， 953-956) . The unavoidable delay in generating and deploying a vaccine could in such cases be catastrophically costly in human lives and societal disruption.

In view of the currently elevated risk of infections of pandemic H1N1 swine flu， highly pathogenic H5N1 avian flu， and drug-resistant seasonal flu， the development of new anti-influenza drugs have again become high priority.

In many cases， the development of anti-viral medicament may be facilitated by the availability of structural data of viral proteins. The availability of structural data of influenza virus surface antigen neuraminidase has， e.g. led to the design of improved neuraminidase inhibitors (Von Itzstein et al.， Nature 1993， 363， 418-423) . Examples of active compounds which have been developed based on such structural data include zanamivir (Glaxo) and oseltamivir (Roche) . However， although these medicaments may lead to a reduction of the duration of the disease， there remains an urgent need for improved medicaments which may also be used for curing these diseases.

Adamantane-containing compounds such as amantadine and rimantadine are another example of active compounds which have been used in order to treat influenza. However， they often lead to side effects and have been found to be ineffective in a growing number of cases (Magden et al.， Appl. Microbiol. Biotechnol. 2005， 66， 612-621) .

More unspecific viral drugs have been used for the treatment of influenza and other virus infections (Eriksson et al.， Antimicrob. Agents Chemother. 1977， 11， 946-951) ， but their use is limited due to side effects (Furuta et al.， Antimicrobial Agents and Chemotherapy 2005， 981-986) .

Influenza viruses being Orthomyxoviridae， as described above， are negative-sense ssRNA viruses. Other examples of viruses of this group include Arenaviridae， Bunyaviridae， Ophioviridae， Deltavirus， Bornaviridae， Filoviridae， Paramyxoviridae， Rhabdoviridae and Nyamiviridae. These viruses use negative-sense RNA as their genetic material. Single-stranded RNA viruses are classified as positive or negative depending on the sense or polarity of the RNA. Before transcription， the action of an RNA polymerase is necessary to produce positive RNA from the negative viral RNA. The RNA of a negative-sense virus (vRNA) alone is therefore considered non-infectious.

The trimeric viral RNA-dependent RNA polymerase， consisting of polymerase basic protein 1 (PB1) ， polymerase basic protein 2 (PB2) and polymerase acidic protein (PA) subunits， is responsible for the transcription and replication of the viral RNA genome segments. Structural data of the two key domains of the polymerase， the mRNA cap-binding domain in the PB2 subunit (Guilligay et al.， Nature Structural &Molecular Biology 2008， 15 (5) ， 500-506) and the endonuclease-active site in the PA subunit (Dias et al.， Nature 2009， 458， 914-918) has become available.

The ribonucleoprotein (RNP) complex represents the minimal transcriptional and replicative machinery of an influenza virus. The polymerase， when comprised in the RNP complex， is also referred to as vRNP enzyme. During replication， the viral RNA polymerase generates a complementary RNA (cRNA) replication intermediate， a full-length complement of the vRNA that serves as a template for the synthesis of new copies of vRNA.

During transcription， the viral RNA polymerase comprised in the RNP complex synthesizes capped and polyadenylated mRNA using 5′ capped RNA primers. This process involves a mechanism called cap snatching. The influenza polymerase uses host cell transcripts (capped pre-mRNAs) as primers for the synthesis of viral transcripts. The nucleoprotein is an essential component of the viral transcriptional machinery. The polymerase complex which is responsible for transcribing the single-stranded negative-sense viral RNA into viral mRNAs and for replicating the viral mRNAs， is thus a promising starting points for developing new classes of compounds which may be used in order to treat influenza (Fodor， Acta virologica 2013， 57， 113-122) . This finding is augmented by the fact that the polymerase complex contains a number of functional active sites which are expected to differ to a considerable degree from functional sites present in proteins of cells functioning as hosts for the virus (Magden et al.， Appl. Microbiol. Biotechnol. 2005， 66， 612-621) . As one example， a substituted 2， 6-diketopiperazine has been identified which selectively inhibits the cap-dependent transcriptase of influenza A and B viruses without having an effect on the activities of other polymerases (Tomassini et al.， Antimicrob. Agents Chemother. 1996， 40， 1189-1193) . In addition， it has been reported that phosphorylated 2′-deoxy-2′-fluoroguanosine reversibly inhibits influenza virus replication in chick embryo cells. While primary and secondary transcription of influenza virus RNA were blocked even at low concentrations of the compound， no inhibition of cell protein synthesis was observed even at high compound concentrations (Tisdale et al.， Antimicrob. Agents Chemother. 1995， 39， 2454-2458) .

WO 2010/148197， WO 2012/083121， WO 2012/083117， WO 2012/083122 and WO 2013/184985 refer to specific compounds which are stated to be useful in inhibiting the replication of influenza viruses.

WO 2008/068171 discloses substituted pyrimidines and their use as modulators of c-Jun N-terminal kinases (JNK) .

WO 2008/040753 relates to certain indazolyl derivatives which are stated to be useful as potassium channel modulating agents.

it is an object of the present invention to identify compounds which specifically target the influenza virus cap-binding domain and hence are effective against influenza and which have improved pharmacological properties.

Summary of the invention

Accordingly， in a first embodiment， the present invention provides a compound having the formula (I) .

It is understood that throughout the present specification the term ″a compound having the formula (I) ″ encompasses pharmaceutically acceptable salt， solvate， polymorph， prodrug， codrug， cocrystal， tautomer， racemate， enantiomer， or diastereomer or mixture thereof unless mentioned otherwise.

A further embodiment of the present invention relates to a pharmaceutical composition comprising a compound having the formula (I) and optionally one or more pharmaceutically acceptable excipient (s) and/or carrier (s) .

The compounds having the formula (I) are useful for treating， ameliorating or preventing influenza.

Detailed description of the invention

Before the present invention is described in detail below， it is to be understood that this invention is not limited to the particular methodology， protocols and reagents described herein as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only， and is not intended to limit the scope of the present invention which will be limited only by the appended claims. Unless defined otherwise， all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.

Preferably， the terms used herein are defined as described in ″A multilingual glossary of biotechnological terms： (IUPAC Recommendations) ″ ， Leuenberger， H.G.W， Nagel， B. and

H. eds. (1995) ， Helvetica Chimica Acta， CH-4010 Basel， Switzerland) .

Throughout this specification and the claims which follow， unless the context requires otherwise， the word ″comprise″ ， and variations such as ″comprises″ and ″comprising″ ， will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. In the following passages different aspects of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular， any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.

Several documents are cited throughout the text of this specification. Each of the documents cited herein (including all patents， patent applications， scientific publications， manufacturer′s specifications， instructions， etc. ) ， whether supra or infra， are hereby incorporated by reference in their entirety. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.

Definitions

The term ″alkyl″ refers to a saturated straight or branched carbon chain， which preferably has 1 to 6 carbon atoms.

The term ″aryl″ preferably refers to an aromatic monocyclic ring containing 5 or 6 carbon atoms， an aromatic bicyclic ring system containing 10 carbon atoms or an aromatic tricyclic ring system containing 14 carbon atoms. Examples are phenyl， naphthyl or anthracenyl， preferably phenyl.

″Halogen″ represents F， Cl， Br and I， more preferably F or Cl， even more preferably F.

The term ″heteroaryl″ preferably refers to a five or six-membered aromatic ring wherein one or more of the carbon atoms in the ring have been replaced by 1， 2， 3， or 4 (for the five membered ring) or 1， 2， 3， 4， or 5 (for the six membered ring) of the same or different heteroatoms， whereby the heteroatoms are seiected from O， N and S. Examples of the heteroaryl group are given below.

The term ″heterocyclyl″ covers any mono-， bi-or polycyclic ring system which includes one or more heteroatoms in the ring system， whereby the heteroatoms are the same or different and are selected from O， N and S. Preferably the ring system includes 3 to 15 ring atoms. More preferably the ring system is mono-or bicyclic and has 5 to 10 ring atoms， even more preferably the ring system is monocyciic and has 5 or 6 ring atoms. Typically the ring system can include 1 to 4， more typically 1 or 2 heteroatoms at available positions. The term ″heterocyclyl″ also covers heteroaryl rings. Examples include pyrrole， pyrroiidine， oxolane， furan， imidazolidine， imidazole， pyrazole， oxazolidine， oxazole， thiazole， piperidine， pyridine， morpholine， piperazine， and dioxolane.

The term ″carbocyclyl″ covers any mono-， bi-or polycyclic ring system which does not include heteroatoms in the ring. Preferably the ring system includes 3 to 15 ring atoms. More preferably the ring system is mono-or bicyclic and has 5 to 10 ring atoms， even more preferably the ring system is monocyclic and has 5 or 6 ring atoms. The term ″carbocyclic ring″ also covers aryl rings. A further example of a ″carbocyclic ring″ is a C_3-6 cycloalkyl ring.

The term ″saturated monocyclic carbocyclic ring″ refers to any saturated monocyclic ring which does not include heteroatoms in the ring.

The term ″saturated bridged carbocyclic ring having 5 to 8 ring carbon atoms and 1 to 3 carbon atoms in the bridge″ refers to any saturated monocyclic ring having 5 to 8 ring carbon atoms which does not include heteroatoms in the ring， wherein two carbon atoms of the ring are connected to each other by an alkylene bridge having 1 to 3 carbon atoms (i.e.， - (CH₂) _q-with q ＝ 1 to 3) .

The term ″saturated bridged heterocyclic ring having 5 to 8 ring carbon atoms and 0 to 2 heteroatoms in the ring， and 0 to 2 carbon atoms and 0 to 2 heteroatoms in the bridge″ refers to any saturated monocyclic ring having 5 to 8 ring carbon atoms which may or may not include heteroatoms in the ring， and which may or may not contain carbon atoms and/or heteroatoms in the bridge， provided that there is at least one carbon atom or at least one heteroatom in the bridge. The bridge may be formed by connecting two atoms of the ring via the bridge. The saturated bridged heterocyclic ring has at least one heteroatom， either in the ring or in the bridge and may contain up to two heteroatoms in the ring and/or the bridge.

If a compound or moiety is referred to as being ″optionally substituted″ it can in each instance include one or more of the indicated substituents， whereby the substituents can be the same or different.

The term ″pharmaceutically acceptable salt″ refers to a salt of a compound of the present invention Suitable pharmaceutically acceptable salts include acid addition salts which may， for example， be formed by mixing a solution of compounds of the present invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid， sulfuric acid， fumaric acid， maleic acid， succinic acid， acetic acid， benzoic acid， citric acid， tartaric acid， carbonic acid or phosphoric acid. Furthermore， where the compound carries an acidic moiety， suitable pharmaceutically acceptable salts thereof may include alkali metal salts (e.g.， sodium or potassium salts) ； alkaline earth metal salts (e.g.， calcium or magnesium salts) ； and salts formed with suitable organic ligands (e.g.， ammonium， quaternary ammonium and amine cations formed using counteranions such as halide， hydroxide， carboxylate， sulfate， phosphate， nitrate， alkyl sulfonate and aryl sulfonate) . Illustrative examples of pharmaceutically acceptable salts include， but are not limited to， acetate， adipate， alginate， ascorbate， aspartate， benzenesulfonate， benzoate， bicarbonate， bisulfate， bitartrate， borate， bromide， butyrate， calcium edetate， camphorate， camphorsulfonate， camsylate， carbonate， chloride， citrate， clavulanate， cyclopentanepropionate， digluconate， dihydrochloride， dodecylsulfate， edetate， edisylate， estolate， esylate， ethanesulfonate， formate， fumarate， gluceptate， glucoheptonate， gluconate， glutamate， glycerophosphate， glycolylarsanilate， hemisulfate， heptanoate， hexanoate， hexylresorcinate， hydrabamine， hydrobromide， hydrochloride， hydroiodide， 2-hydroxy-ethanesulfonate， hydroxynaphthoate， iodide， isothionate， lactate， lactobionate， laurate， lauryl sulfate， malate， maleate， malonate， mandelate， mesylate， methanesulfonate， methylsulfate， mucate， 2-naphthalenesulfonate， napsylate， nicotinate， nitrate， N-methylglucamine ammonium salt， oleate， oxalate， pamoate (embonate) ， palmitate， pantothenate， pectinate， persulfate， 3-phenylpropionate， phosphate/diphosphate， picrate， pivalate， polygalacturonate， propionate， salicylate， stearate， sulfate， subacetate， succinate， tannate， tartrate， teoclate， tosylate， triethiodide， undecanoate， valerate， and the like (see， for example， S.M. Berge et al.， ″Pharmaceutical Salts″ ， J. Pharm. Sci.， 66， pp. 1-19 (1977)) .

When the compounds of the present invention are provided in crystalline form， the structure can contain solvent molecules. The solvents are typically pharmaceutically acceptable solvents and include， among others， water (hydrates) or organic solvents. Examples of possible solvates include ethanolates and iso-propanolates.

The term ″codrug″ refers to two or more therapeutic compounds bonded via a covalent chemical bond. A detailed definition can be found， e.g.， in N. Das et al.， European Journal of Pharmaceutical Sciences， 41， 2010， 571-588.

The term ″cocrystal″ refers to a multiple component crystal in which all components are solid under ambient conditions when in their pure form. These components co-exist as a stoichiometric or non-stoichometric ratio of a target molecule or ion (i.e. compound of the present invention) and one or more neutral molecular cocrystal formers. A detailed discussion can be found， for example， in Ning Shan et al.， Drug Discovery Today， 13 (9/10) ， 2008， 440-446 and in D.J. Good et al.， Cryst. Growth Des.， 9 (5) ， 2009， 2252-2264.

The compounds of the present invention can also be provided in the form of a prodrug， namely a compound which is metabolized in vivo to the active metabolite. Common groups which can be attached to the compounds of the present invention are disclosed in Nature Reviews-Drug Discovery 2008， vol. 7， pages 255 to 270， the entire content of which is included herein by reference， in particular the examples of groups suitable for prodrugs.

In the following， specific examples of groups are exemplified which may be used in prodrugs. This list is， however， not to be regarded as limiting on the scope of the present invention as many more groups are known to the skilled person which can be used to convert a drug into a prodrug.

Carboxyl groups， in general， can be converted into esters， thioesters， carbonates， amides or carbamates. This applies in particular to carboxyl groups in and on Rings A and B.

Hydroxyl functionalities can be converted into esters， carbonates， ethers or phosphates. Such esters include esters formed by reaction with one or more amino acids. Futhermore， prodrugs of compounds having hydroxyl functionalities may be formed by oxidation of the hydroxyl functionalities to carboxyl functionalities.

Thiol functionalities can be converted into thioesters or thioethers.

Amino functionalities can be converted into amides， carbamates， N-mannich bases， oximes， imines or phosphates. The phosphates may also be attached via C_1-4-alkyleneglycol linkers， e.g. resulting in phosphonooxyalkyl amides. The amides include amides formed by reaction with one or more amino acids.

Substitued thiol functionalities can be converted into sulfoxides or sulfones.

Carbonyl groups can he converted into oximes or imines. This applies in particular to ketones， amidines and guanidines.

Phosphonates can be converted into phosphonate esters or phosphonate phosphates.

Compounds having the formula (I)

The present invention provides a compound having the formula (I) ：

wherein

is a single or double bond；

R¹ is selected from the group consisting of-H， -halogen， -CN， -C (O) R^＊＊， -COOR^＊＊， -C (O) NR^＊＊R^＊＊， -NR^＊＊R^＊＊， -NR^＊＊-C (O) R^＊＊， -N (R^＊＊) -C (O) -OR^＊＊， -N (R^＊＊) -C (O) -NR^＊＊R^＊＊， -N (R^＊＊) -S (O) ₂R^＊＊， - (optionally substituted C_1-6 alkyl) ， -OR^＊＊， - (optionally substituted heterocyclyl) ， - (optionally substituted C_1-4 alkylene) - (optionally substituted heterocyclyl) ， - (optionally substituted carbocyclyl) ， and- (optionally substituted C_1-4 alkylene) - (optionally substituted carbocyclyl) ， wherein R^＊＊is H， - (optionally substituted C_1-6 alkyl) ， - (optionally substituted heterocyclyl) ， or- (optionally substituted carbocyclyl) . The- (optionaiiy substituted) can be independently-halogen， -CN， -NO₂， oxo， -C (O) R^＊＊＊， -COOR^＊＊＊， -C (O) NR^＊＊＊R^＊＊＊， -NR^＊＊＊R^＊＊＊， -NR^＊＊＊-C (O) R^＊＊＊， -N (R^＊＊＊) -C (O) -OR^＊＊＊， -N (R^＊＊＊) -C (O) -NR^＊＊＊R^＊＊＊， -N (R^＊＊＊) -S (O) ₂R^＊＊＊， -OR^＊＊＊， -O-C (O) R^＊＊＊， -O-C (O) -NR^＊＊＊R^＊＊＊， -SR^＊＊＊， -S (O) R^＊＊＊， -S (O) ₂R^＊＊＊， -S (O) ₂-NR^＊＊＊R^＊＊＊， -N (R^＊＊＊) -S (O) ₂-NR^＊＊＊R^＊＊＊， -P (O) (OR^＊＊＊) ₂， or-O-P (O) (OR^＊＊＊) ₂. In the case of- (optionally substituted heterocyclyl) or- (optionally substituted carbocyclyl) the- (optionally substituted) can be any of the aforementioned substituents or can be C_1-6 alkyl. R^＊＊＊is H， C_1-6 alkyl， heterocyclyl or carbocyclyl. Preferably R¹ is selected from the group consisting of-H， -halogen， -CN， - (optionally substituted C_1-6 alkyl) ， - (optionally substituted C_3-6 cycloalkyl) ， and-OR^＊＊， wherein R^＊＊is H， - (optionally substituted C_1-6 alkyl) ， - (optionally substituted heterocyclyl) ， - (optionally substituted carbocyclyl) . The- (optionally substituted) can be independently-halogen， -CN， -NO₂， oxo， -C (O) R^＊＊＊， -COOR^＊＊＊， -C (O) NR^＊＊＊R^＊＊＊， -NR^＊＊＊R^＊＊＊， -NR^＊＊＊-C (O) R^＊＊＊， -N (R^＊＊＊) -C (O) -OR^＊＊＊， -N (R^＊＊＊) -C (O) -N R^＊＊＊R^＊＊＊， -N (R^＊＊＊) -S (O) ₂R^＊＊＊， -OR^＊＊＊， -O-C (O) R^＊＊＊， -O-C (O) -NR^＊＊＊R^＊＊＊， -SR^＊＊＊， -S (O) R^＊＊＊， -S (O) ₂R^＊＊＊， -S (O) ₂-NR^＊＊＊R^＊＊＊， -N (R^＊＊＊) -S (O) ₂-N R^＊＊＊R^＊＊＊， -P (O) (OR^＊＊＊) ₂， or -O-P (O) (OR^＊＊＊) ₂. In the case of- (optionally substituted heterocyclyl) or- (optionally substituted carbocyclyl) the- (optionally substituted) can be any of the aforementioned substituents or can be C_1-6 alkyl. R^＊＊＊is H， C_1-6 alkyl， heterocyclyl or carbocyclyl. More preferably R¹ is selected from the group consisting of-H， -halogen， -CN， - (optionally substituted C_1-6 alkyl) ， and- (optionally substituted C_3-6 cycloalkyl) . The- (optionally substituted) is preferred to be halogen. Even more preferably R¹ is selected from-H， -halogen， -CN， -CH₃， -CH₂CH₃， -CH (CH₃) ₂， -cyc opropyl， -CF₃， -CHF₂， and-CH₂F. Most preferably R¹ is selected from-H， -F， -Cl， -CN， -CH₃， and-cyclopropyl.

R² and R³ are linked together to form， with the carbon atoms to which they are attached， a carbocyclic or heterocyclic 5 to 7-membered ring which optionally comprises 0 to 3 heteroatoms (e.g.， selected from N， O and S， particularly N or O， more particularly N) in the ring and which may be substituted with one or more substituents independently selected from R⁶. Preferably R² and R³ are linked together to form， with the carbon atoms to which they are attached， a 5 or 6-membered carbocyclic or heterocyclic ring which comprises 0， 1 or 2 heteroatoms (e.g.， selected from N， O and S， particularly N or O， more particularly N) in the ring and which may be substituted with one or more substituents independently selected from R⁶.

In the present invention， when R² and R³ are linked together to form， with the carbon atoms to which they are attached， a carbocyclic or heterocyclic 5 to 7-membered ring and optionally comprises 0 to 3 heteroatoms in the ring， the substructure

can be chosen from the following non-limiting examples：

Preferred examples of

are the following

More preferred is

and

particularly

It is to be understood that in any examples of

in which one or more C-H groups are indicated， these may each optionally be replaced by C-R⁶. Furthermore， any CH₂ groups in the examples of

may be replaced by CR⁶R⁶.

R⁴ is selected from the group consisting of -H and - (optionally substituted C_1-6 alkyl) ， - (optionally substituted carbocyclyl) ， and - (optionally substituted heterocyclyl) ， wherein the - (optionally substituted) can be independently -halogen， -CN， -NO₂， oxo， -C (O) R^＊＊， -COOR^＊＊， -C (O) NR^＊＊R^＊＊， -NR^＊＊R^＊＊， -NR^＊＊-C (O) R^＊＊， -N (R^＊＊) -C (O) -OR^＊＊， -N(R^＊＊) -C (O) -NR^＊＊R^＊＊， -N (R^＊＊) -S (O) ₂R^＊＊， -OR^＊＊， -O-C (O) R^＊＊-， -O-C (O) -NR^＊＊R^＊＊， -SR^＊＊， -S (O) R^＊＊， -S (O) ₂R^＊＊， -S (O) ₂-NR^＊＊R^＊＊， -N (R^＊＊) -S (O) ₂-NR^＊＊R^＊＊， -P (O) (OR^＊＊) ₂， -O-P (O) (OR^＊＊) ₂， -P (O) ₂OR^＊＊. In the case of - (optionally substituted heterocyclyl) or - (optionally substituted carbocyclyl) the - (optionally substituted) can be any of the aforementioned substituents or can be C_1-6 alkyl. R^＊＊ is H， C_1-6 alkyl or C_3-6 cycloalkyl which can optionally be substituted with halogen. Preferably R⁴ is -C_1-6 alkyl or -H， more preferably -H.

R^5a is selected from the group consisting of -halogen， -OR^＊， and -CN， wherein R^＊ is - (optionally substituted C_1-6 alkyl) ， - (optionally substituted heterocyclyl) ， or - (optionally substituted carbocyclyl) . Preferably R^5a is selected from the group consisting of -halogen， -CN， and -O- (optionally substituted C_1-6 alkyl) .

R^5b is selected from the group consisting of -H， - (optionally substituted C_1-6 alkyl) ， - (optionally substituted heterocyclyl) ， - (optionally substituted carbocyclyl) ， - (optionally substituted C_1-4 alkylene) - (optionally substituted heterocyclyl) and - (optionally substituted C_1-4 alkylene) - (optionally substituted carbocyclyl) ， wherein R^＊ is - (optionally substituted C_1-6 alkyl) ， - (optionally substituted heterocyclyl) ， or - (optionally substituted carbocyclyl) . Preferably R⁵ is selected from the group consisting of -H， - (optionally substituted C_1-6 alkyl) ， - (optionally substituted heterocyclyl) ， and - (optionally substituted carbocyclyl) . Preferably R^5b is selected from the group consisting of -H， - (optionally substituted C_1-6 alkyl) ， - (optionally substituted heterocyclyl) ， and - (optionally substituted carbocyclyl) .

The - (optionally substituted heterocyclyl) and - (optionally substituted carbocyclyl) may furthermore be bridged and the bridge may contain 0 to 2 carbon atoms and 0 to 2 heteroatoms.

The - (optionally substituted) can be independently -halogen， -CN， -CF₃， -CHF₂， -CH₂F， -OCF₃， -OCHF₂， -OCH₂F， -NR^＊R^＊， -NR^＊COR^＊， -NR^＊C (O) NR^＊R^＊， -NR^＊S (O₂) NR^＊R^＊， -C (O) OR^＊， -C (O) NR^＊R^＊， -OR^＊， or -O-C_1-6 alkyl， wherein each R^＊ is H， C_1-6 alkyl or C_3-6 cycloalkyl. In the case of - (optionally substituted heterocyclyl) or - (optionally substituted carbocyclyl) the - (optionally substituted) can be any of the aforementioned substituents or can be C_1-6 alkyl.

R⁶ is independently selected from the group consisting of -H， -Hal， -OR^＊＊， oxo， -CN， -NO₂， -C (O) R^＊＊， -COOR^＊＊， -C (O) NR^＊＊R^＊＊， -NR^＊＊R^＊＊， -NR^＊＊C (O) R^＊＊， -NR^＊＊C (O) NR^＊＊R^＊＊， -NR^＊＊S (O₂) NR^＊＊R^＊＊， - (CH₂) _pSR^＊＊， - (CH₂) _pS (O) R^＊＊， - (CH₂) _pSO₂R^＊＊， - (CH₂) _pSO₂NR^＊＊， - (optionally substituted C_1-6 alkyl) ， -O- (optionally substituted C_1-6 alkyl) ， - (optionally substituted carbocyclyl) and - (optionally substituted heterocyclyl) ， wherein R^＊＊ is H， - (optionally substituted C_1-6 alkyl) ， - (optionally substituted C_1-4 alkylene) -O- (optionally substituted C_1-6 alkyl) . The - (optionally substituted) can be independently -H， -halogen， -OH， and -CN. In the case of - (optionally substituted heterocyclyl) or - (optionally substituted carbocyclyl) the - (optionally substituted) can be any of the aforementioned substituents or can be C_1-6 alkyl. Preferably， R⁶ is independently selected from the group consisting of -H， -Hal， -OR^＊＊， -CN， -NO₂， -C (O) R^＊＊， -COOR^＊＊， -C (O) NR^＊＊R^＊＊， -NR^＊＊R^＊＊， -NR^＊＊C (O) R^＊＊， -NR^＊＊C (O) NR^＊＊R^＊＊， -NR^＊＊S (O₂) NR^＊＊R^＊＊， - (CH₂) _pSR^＊＊， - (CH₂) _pS (O) R^＊＊， - (CH₂) _pSO₂R^＊＊， - (CH₂) _pSO₂NR^＊＊， - (optionally substituted C_1-6 alkyl) ， -O- (optionaily substituted C_1-6 alkyl) ， - (optionally substituted carbocyclyl) and - (optionally substituted heterocyclyl) ， wherein R^＊＊ is H， - (optionally substituted C_1-6 alkyl) ， - (optionally substituted C_1-4 alkylene) -O- (optionally substituted C_1-6 alkyl) . The - (optionally substituted) can be independently -H， -halogen， -OH， and -CN. In the case of - (optionally substituted heterocyclyl) or - (optionally substituted carbocyclyl) the - (optionally substituted) can be any of the aforementioned substituents or can be C_1-6 alkyl. Preferably， R⁶ is selected from the group consisting of -H， -Hal， and - (optionally substituted C_1-6 alkyl) . The optionally substituted is preferred to be -halogen.

R⁷ is selected from the group consisting of of -H and -C_1-6 alkyl. Preferably R⁷ is -H or -CH₃， more preferably R⁷ is -H.

R⁸ is independently selected from the group consisting of -H， -Hal， -CN， -NR^＊＊R^＊＊， - (optionally substituted C_1-6 alkyl) ， -OR^＊＊， - (optionally substituted heterocyclyl) ， - (optionally substituted carbocyclyl) ， wherein R^＊＊ is H， - (optionally substituted C_1-6 alkyl) ， - (optionally substituted heterocyclyl) ， or - (optionally substituted carbocyclyl) . The - (optionally substituted) is preferably halogen. Preferably R⁸ is -H.

R⁹ is independently selected from the group consisting of -H， -C_1-6 alkyl， -Hal， -OR^＊， -NR^＊R^＊， -CN and CF₃ wherein R^＊ is -H or -C_1-6 alkyl. Preferably R⁹ is -H or -Hal.

R¹⁰ is independently selected from the group consisting of -H， -Hal， -CN， -NO₂， - (optionally substituted C_1-6 alkyl) ， -NR^＊R^＊， and -OR^＊， wherein R^＊ is -H， or - (optionally substituted C_1-6 alkyl) . The - (optionally substituted) is preferably halogen. Preferably R¹⁰ is -H.

X¹ is selected from the group consisting of N and C. In one embodiment， X¹ is N. In another embodiment X¹ is C.

X² is selected from the group consisting of N and CR⁹. In one embodiment， X² is N. In another embodiment， X² is CR⁹.

When X² is C-R⁹ and R⁹ is -OH， e.g.， resulting in the partial structure

any compound containing the tautomer thereof having the following partial structure

is also comprised.

X³ is selected from the group consisting of N， NR⁹， CR⁹ and CR⁹ ₂， as valency permits. In one embodment， if ″X²

X³″ is ″X²-X³″ ， then X³ is NR⁹. In another embodiment， if X²

X³″ is ″X²＝X³″ then X³ is CR⁹.

X⁴ is selected from the group consisting of N and CR⁹. In one embodiment， X⁴ is N. In further embodiment， X⁴ is CR⁹. In a further embodiment， X⁴ is C-Hal (e.g.， C-F) ， wherein Hal may be any halogen isotope.

X⁵ is selected from the group consisting of N and CR⁸. In one embodiment， X⁵ is N. In another embodiment， X⁵ is CR⁸.

X⁶ is selected from the groupconsisting of N and CR¹. In one embodiment， X⁶ is N. In another embodiment， X⁶ is CR¹， wherein R¹ is preferably -H， -halogen， -CN， -CH₃， -CH₂CH₃， -CH (CH₃) ₂， -cyclopropyl， -CF₃， -CHF₂， and-CH₂F.

X⁷ is selected from the group consisting of N and CR⁸. In one embodiment， X⁷ is N. In another embodiment， X⁷ is CR⁸.

The above definitions apply with the proviso that X¹

X²

X³ is X¹-X²＝X³ if X¹is N and X¹

X²

X³ is X¹＝X²-X³ if X¹ is C； and with the further proviso that at least one of X¹， X²， and X³ is N or NR⁹.

X⁸ is selected from the group consisting of N and CR¹⁰. In one embodiment， X⁸ is N. In another embodiment， X⁸ is CR¹⁰.

T is selected from the group consisting of

and

In a preferred embodiment， the ring T is

The ring A is a saturated monocyclic carbocyclic ring having 5 to 8 ring carbon atoms or a saturated bridged carbocyclic ring having 5 to 8 ring carbon atoms and 1 to 3 carbon atoms in the bridge or a saturated bridged heterocyclic ring having 5 to 8 ring carbon atoms and 0 to 2 heteroatoms (e.g.， selected from N， O and S) in the ring， and 0 to 2 carbon atoms and 0 to 2 heteroatoms (e.g.， selected from N， O and S) in the bridge， provided that there is at least one heteroatom in the saturated bridged heterocyclic ring， which may be either in the main ring or in the bridge. Preferably the ring A is a saturated monocyclic carbocyclic ring having 5 or 6 ring carbon atoms or a saturated bridged carbocyclic ring having 6 or 7 ring carbon atoms and 1 or 2 carbon atoms in the bridge or a saturated bridged heterocyclic ring having 6 or 7 ring carbon atoms， and 1 or 2 carbon atoms and 1 to 2 hetero atoms in the bridge (e.g.， selected from N， O and S) . Preferred examples of the ring A include

wherein each W is independently selected from C， N， O and S， wherein A can be substituted in any available position by one or two substituents which are selected from the group consisting of -L-R⁵.

It is to be understood that the corners of the ring A in

and

are not limited to represent substituted or unsubstituted carbon atoms but one or more of these corners may also represent substituted or unsubstituted heteroatoms (e.g.， selected from N， O and S) .

The ring A can be optionally substituted in any available position by one or more substituents which are selected from the group consisting of -L-R⁵. In a preferred embodiment the ring A is substituted， for example by one or two substituents.

The ring A can be attached to the -N (R⁴) -moiety at any available position.

The ring B is fused to the ring A. The ring B is a saturated monocyclic carbocyclic ring having 3 to 6 ring carbon atoms. Preferably the ring B is a saturated monocyclic carbocyclic ring having 3 ring carbon atoms. A preferred example of the ring B is

The ring B can be optionally substituted in any available position by one or more substituents which are selected from the group consisting of -L-R⁵. Preferably the ring is unsubstituted.

-L-R⁵ is selected from -L^a-R^5a and -L^b-R^5b， preferably-L-R⁵ is -L^b-R^5b.

L^a is selected from the group consisting of - (CH₂) _p-C (O) -， - (CH₂) _p-CR⁷ (OR⁷) -， - (CH₂) _p-C (O) -N (R⁷) - (CH₂) _p-， - (C H₂) _p-N (R⁷) -C (O) - (CH₂) _p-， - (CH₂) _p-N (R⁷) -S (O) ₂-， - (CR⁷R⁷) _p-S (O) -， - (CR⁷R⁷) _p-S (O) ₂-， - (CR⁷R⁷) _p-S (O) - (CR⁷R⁷) _p-， - (CR⁷R⁷) _p-S (O) ₂- (CR⁷R⁷) _p-， - (CR⁷R⁷) _p- (optionally substituted heterocyclylene) -and a bond. The optionally substituent of the heterocyclyene is independently selected from one or more groups selected from -Hal， -CN， -NO₂， -OH and -NH₂. The substituted heterocyclylene is preferably selected from 5- or 6-membered heterocyclene containing 1 to 4 heteroatoms independently selected from N， O and S. Specific examples of substituted heterocyclylenes are the following：

L^b is selected from the group consisting of- (CH₂) _p-C (O) -O-， - (CH₂) _p-C (O) -， - (CH₂) _p-CR⁷ (OR⁷) -， - (CH₂) _p-C (O) -N (R⁷) - (CH₂) _p-， - (CH₂) _p-N (R⁷) -， - (CH₂) _p-N (R⁷) -C (O) - (CH₂) _p-， - (CH₂) _p-N (R⁷) -C (O) -C (O) -， - (CH₂) _p-N (R⁷) -C (O) -O-， - (CH₂) _p-N (R⁷) -C (O) -N (R⁷) -， - (CH₂) _p-N (R⁷) -S (O) ₂-， -N (R⁷) -S (O) ₂-N (R⁷) -， - (CH₂) _p， -O-C (O) -， - (CH₂) _p-O-C (O) -N (R⁷) -， - (CR⁷R⁷) _p-O-， - (CR⁷R⁷) _p-S (O) -，

- (CR⁷R⁷) p-S( O) ₂ -， - (CR⁷R⁷) _p-S- (CR⁷R⁷) _p-， - (CR⁷R⁷) _p-S (O) - (CR⁷R⁷) _p-， - (CR⁷R⁷) _p-S (O) ₂- (CR⁷R⁷) _p-， - (CR⁷R⁷) _p-S (O) ₂-N (R⁷) -， - (CR⁷R⁷) _p-S (O) ₂-N (R⁷) -C (O) -， - (CR⁷R⁷) _p-P (O) (OR⁷) O-， -O-P (O) (OR⁷) O-， -P (O) ₂O-， - (CR⁷R⁷) _p- (optionally substituted heterocyclylene) -and a bond. The optionally substituent of the heterocyclyene is independently selected from one or more groups selected from -Hal， -CN， -NO₂， -OH and -NH₂. The substituted heterocyclylene is preferably selected from 5- or 6-membered heterocyclene containing 1 to 4 heteroatoms independently selected from N， O and S. Specific examples of substituted heterocyclylenes are shown above.

Preferably L^b is selected from the group consisting of -C (O) -O-， -C (O) -N (R⁷) -， -N (R⁷) -C (O) -， -N (R⁷) -C (O) -N (R⁷) -， and - (CR⁷R⁷) _p-O-. In more preferred examples， L^b is -C (O) -O-， -N (R⁷) -C (O) -or-N (R⁷) -C (O) -N (R⁷) -.

In one preferred embodiment， ring A is selected from

and

and L^b is -C (O) O-.

In another preferred embodiment， ring A is

and

and L^b is selected from -N (R⁷) -C (O) -and -N (R⁷) -C (O) -N (R⁷) .

In one embodiment， L^b is - (CR⁷R⁷) _p-O-. In this embodiment R^5b is preferably -H or - (optionally substituted C_1-6 alkyl) ， more preferably-H or-C_1-6 alkyl.

In another embodiment， L^b is selected from the group consisting of -C (O) -O-， -O-C (O) -， -C (O) -N (R⁷) -， -N (R⁷) -C (O) -， -N (R⁷) -C (O) -N (R⁷) ， and R^5b is selected from the group consisting of -H， - (optionally substituted C_1-6 alkyl) ， - (optionally substituted heterocyclyl) ， and - (optionally substituted carbocyclyl) ， more preferably R^5b is selected from the group consisting of -H， -C_1-6 alkyl， - (optionally substituted heterocyclyl) ， and - (optionally substituted carbocyclyl) .

m is 1 to 3. Preferably m is 2 or 3.

n is 1 to 4. Preferably n is 1.

p is 0 to 6. Preferably p is 0 to 4， more preferably p is 0 or 1.

Examples of the fused ring system provided by rings A and B include：

and

Preferred examples include

and

Preferred examples include

and

Even more preferred are

and

In the present invention，

can be chosen from the following non-limiting examples：

wherein Hal is selected from F， Cl， Br and I， preferably F.

Preferably，

is selected from the group consisting of

wherein Hal is selected from F， Cl， Br and I， preferably F.

More preferably，

is selected from the group consisting of

wherein X⁶ is CR¹. Preferably， R¹ is selected from -H， -halogen， -CN， -CH₃， -CH₂CH₃， -CH (CH₃) ₂， -cyclopropyl， -CF₃， -CHF₂， and -CH₂F.

Even more preferably，

is selected from

wherein each X⁶ is CR¹. Preferably， R¹ is selected from -H， -halogen， -CN， -CH₃， -CH₂CH₃， -CH (CH₃) ₂， -cyclopropyl， -CF₃， -CHF₂， and-CH₂F.

It is to be understood that in any examples of

in which one or more of X¹， X²， X³， X⁴， X⁵ and X⁷ is/are shown as CH， the CH may also be replaced by C-R⁸ for X⁵ and X⁷， C-R⁹ for X¹， X²， and X³， and C-R¹ for X⁶.

Generic Synthesis /Assay Description

The compounds having the formula (I) can be prepared by any desired route. In one illustrative embodiment which is not limiting， the method comprises a step of reacting compound 1 with compound 2 to form a compound 3， which after protection group cleavage to give the compound having the formula (Ia) ， as shown in Scheme A below.

Scheme A

Azaindole or azaindazole compounds 1 with G¹ ＝ halogen (preferably iodine) are known. They can be prepared by methods described in the exemplary synthesis of intermediates A or by methods known to a person skilled in the art. If desired， the amine group of the compounds 1 can be protected by an amine protecting group， PG. Any known amine protecting group such as THP， SEM， Ts， or Boc can be employed. Azaindole or azaindazole compounds 1 with G¹ ＝ H can then be converted to the corresponding azaindole or azaindazole 3-boronated intermediate. Any suitable reaction condition known in the art can be used for the generation of azaindole or azaindazole 3-boronated intermediate. For example， reaction of compound 1 with a boronic ester like 4， 4， 5， 5-tetramethyl-2- (4， 4， 5， 5-tetramethyl-1， 3， 2-dioxaborolan-2-yl) -1， 3， 2-dioxaborolane in a solvent like DMSO or dioxane in the presence of a base like potassium acetate and a catalyst like PdCl₂ (dppf) at an elevated temperature about 70 ℃ can be used. If desired， the azaindole or azaindazole 3-boronated intermediate (G¹ ＝ boronic acid/ester) can be purified by silica gel flash chromatography. Alternatively， it can be used without purification in the next reaction step. The azaindole or azaindazole 3-boronated intermediate (G¹ ＝ boronic acid/ester) can then be reacted with a suitable heteroaryl halide， compound 2 (G² ＝ halogen， bromine and chlorine preferred) in the presence of catalyst like Pd₂ (dba) ₃， and in the presence of a base， such as K₃PO₄， and in a solvent， such as dioxane and H₂O， and in an inert atmosphere such as argon or nitrogen at a temperature range preferably from room temperature to about 130 ℃ to give a Suzuki coupling product， compound 3 (step a) . Alternatively， compound 3 can also be synthesized via a Stille coupling reaction known in the art. For example， reaction of compound 2 (G² ＝ halogen， chlorine preferred) with a trialkyl tin reagent such as hexa-n-butylditin in a solvent like dioxane， in the presence of catalyst like Pd (PPh₃) ₄ at an elevated temperature about 125 ℃ can be used. The organo tin intermediate， obtained either in situ or after silica gel flash chromatography purification， can then be reacted with a suitable azaindole or azaindazole halide， compound 1 (G¹ ＝ halogen， iodine preferred) in a solvent like dioxane， and in the presence of catalyst like Pd (PPh₃) ₄， and in an inert atmosphere such as argon or nitrogen at an elevated temperature of about 140 ℃ to give a Stille coupling product， compound 3 (step a) . The Suzuki or Stille coupling product， compound 3 is then de-protected using conditions known in the art to give a compound represented by the formula (Ia) ， where the azaindole or azaindazole N1 substitution is H (step b) . Specific conditions are described in the Examples Section below.

In another embodiment which is illustrated in Scheme B， the compounds of formula (Ia) can be prepared by a method which comprises the steps of reacting 2-chloro-6-methyl sulfide pyrimidine compound 4 with an organo tin intermediate compound 1 (G¹ ＝ trialkylstannane) ， which was generated in situ or by silica gel flash chromatography purification from reaction of azaindole or azaindazole compound 1 (G1 ＝ halogen， iodine preferred) with a trialkyl tin reagent like Bu₆Sn₂ in solvent like dioxane， and in the presence of a catalyst like Pd (PPh₃) ₄ at an elevated temperature of about 100 ℃ (step c) . The Stille coupling product， compound 5， then underwent oxidation using an oxidant such as mCPBA in a solvent like DCM to give a compound 6 (step d) . Subsequent displacement of the sulfinyl compound 6 with an amine TNH₂ in the presence of a base， such as DIPEA， in a solvent like i-PrOH at an elevated temperature then affords compound 7 (step e) . The definitions of structural formula (Ia) ， compounds 1， 2， 3， 4， 5， 6， and 7 are independently as defined in any of the embodiments described above. PG is a protecting group and can be for example THP， SEM， Ts， or Boc. The de-protecting reaction using conditions known in the art then generates the compounds of formula (Ia) ， where azaindole or azaindazole N1 substitution is H (step f) . Specific conditions are described in the Examples Section below.

Scheme B

In another embodiment which illustrated in Scheme C， the compounds of formula (Ib) can be prepared by a method via reaction of azaindole or azaindole compound 8 with a suitable heteroaryl halide， compound 2 (G² ＝ halogen， bromine and chlorine preferred) in a solvent like dioxane， in the presence of a catalyst like Cul， a ligand like (1R， 2S) -cyclohexane-1， 2-dioamine， and a base like potassium phosphate at elevated temperature about 120 ℃ to give a Ullman couping reaction product， compound (Ib) (step g) . The definitions of structural formula (Ib) and compounds 2 and 8 are independently as defined in any of the embodiments described above. Specific conditions are described in the Examples Section below.

Scheme C

In another embodiment which illustrated in Scheme D， the compounds of formula (Ic) can be prepared by a method via reaction of 4-halogen substituted indole/azaindole or indazole/azaindazole compound 9 with a suitable heteroaryl halide， compound 2 (G² ＝ halogen， bromine and chlorine preferred) in a solvent like dioxane， in the presence of a catalyst like Cul， a ligand like (1R， 2S) -cyclohexane-1， 2-dioamine， and a base like potassium phosphate at elevated temperature about 120 ℃ to give a Ullman couping reaction product， compound (Ic) (step h) . The definitions of structural formula (Ic) and compounds 2 and 9 are independently as defined in any of the embodiments described above. Specific conditions are described in the Examples Section below.

Scheme D

In another embodiment which is not limiting， the compounds of formula (Id) can be prepared by the method comprises a step of reacting compound 10 with compound 2 to form a compound 11， which after protection group cleavage to give the compound having the formula (Id) ， as shown in Scheme E below.

7-halogen substituted (preferably fluorine) indole/azaindole or indazole/azaindazole compounds 1 0 with G¹ ＝ halogen (preferably iodine) are known. They are either commercially available or can be prepared by methods described in the exemplary synthesis of intermediates A or by methods known to a person skilled in the art. If desired， the amine group of the compounds 10 can be protected by an amine protecting group， PG. Any known amine protecting group such as THP， SEM， Ts， or Boc can be employed.

7-halogen substituted (preferably fluorine) indole/azaindole or indazole/azaindazole compounds 10 with G¹ ＝ halogen (preferably iodine) can be converted to the corresponding 7-halogen substituted (preferably fluorine) indole/azaindole or indazole/azaindazole 3-boronated intermediate. Any suitable reaction condition known in the art can be used for the generation of corresponding 3-boronated intermediate. For example， reaction of compound 10 with a boronic ester like 4， 4， 5， 5-tetramethyl-2- (4， 4， 5， 5-tetramethyl-1， 3， 2-dioxaborolan-2-yl) -1， 3， 2-dioxaborolane in a solvent like DMSO or dioxane in the presence of a base like potassium acetate and a catalyst like PdCl₂ (dppf) at an elevated temperature about 70 ℃can be used. If desired， the indole/azaindole or indazole/azaindazole 3-boronated intermediate (G¹ ＝ boronic acid/ester) can be purified by silica gel flash chromatography. Alternatively， it can be used without purification in the next reaction step. The 7-halogen substituted (preferably fluorine) indole/azaindole or indazole/azaindazole 3-boronated intermediate (G¹ ＝ boronic acid/ester) can then be reacted with a suitable heteroaryl halide 2 in the presence of a catalyst like Pd₂ (dba) ₃， and in the presence of a base， such as K₃PO₄， and in a solvent， such as dioxane and H₂O， andin aninert atmosphere such as argon or nitrogen at a temperature range preferably from room temperature to about 130 ℃to give a Suzuki coupling reaction product， compound 11 (step i) . Alternatively， compound 11 can also be synthesized via a Stille coupling reaction known in the art For example， reaction of compound 2 (G² ＝ halogen， bromine or chlorine preferred) with a trialkyl tin reagent such as hexa-n-butylditin in a solvent like dioxane， in the presence of catalyst like Pd (PPh₃) ₄ at an elevated temperature about 125 ℃ can be used. The organo tin intermediate， obtained either in situ or after silica gel flash chromatography purification， can then be reacted with a suitable 7-halogen substituted (preferably fluorine) indole/azaindole or indazole/azaindazole halide， compound 10 (G¹ ＝ halogen， iodine preferred) in a solvent like dioxane， and in the presence of catalyst like Pd (PPh₃) ₄， and in an inert atmosphere such as argon or nitrogen at an elevated temperature of about 140 ℃ to give a Stille coupling product， compound 11 (step i) . The Suzuki or Stille coupling product， compound 11 is then de-protected using conditions known in the art to give a compound represented by the formula (Id) ， where the 7-halogen substituted (preferably fluorine) indole/azaindole or indazole/azaindazole N1 substitution is H (step j) . The definitions of structural formula (Id) ， compounds 2， 10， and 11 are independently as defined in any of the embodiments described above. PG is a protecting group and can be for example THP， SEM， Ts， or Boc. Specific conditions are described in the Examples Section below.

Scheme E

In another embodiment， cyclopropanation methodology that is known in the art is used to synthesize compounds 13. Specific exemplary conditions are described in the exemplary synthesis of intermediate B or known to a person skilled in the art. Using a Simmons Smith reaction as an example (Scheme F) ， a cyclic alkene compound 12 was reacted with iodomethyl zinc iodide， which was generated by a zinc reagent such as diethyl zinc in the presence of diiodomethane. Alternatively， the in situ generated iodomethyl zinc can be reacted in the presence of TFA， which could give a different stereochemical cyclopropanation product.

The variables of compounds 12 and 13 are independently as defined in any of the embodiments described above. PG can be Boc or CBz.

Scheme F

The compounds of the present invention can be administered to a patient in the form of a pharmaceutical composition which can optionally comprise one or more pharmaceutically acceptable excipient (s) and/or carrier (s) .

The compounds of the present invention can be administered by various well known routes， including oral， rectal， intragastrical， intracranial and parenteral administration， e.g. intravenous， intramuscular， intranasal， intradermal， subcutaneous， and similar administration routes. Oral， intranasal and parenteral administration are particularly preferred. Depending on the route of administration different pharmaceutical formulations are required and some of those may require that protective coatings are applied to the drug formulation to prevent degradation of a compound of the invention in， for example， the digestive tract.

Thus， preferably， a compound of the invention is formulated as a syrup， an infusion or injection solution， a spray， a tablet， a capsule， a capslet， lozenge， a liposome， a suppository， a plaster， a band-aid， a retard capsule， a powder， or a slow release formulation. Preferably the diluent is water， a buffer， a buffered salt solution or a salt solution and the carrier preferably is selected from the group consisting of cocoa butter and vitebesole.

Particular preferred pharmaceutical forms for the administration of a compound of the invention are forms suitable for injectionable use and include sterile aqueous solutions or dispersions and sterile powders forthe extemporaneous preparation of sterile injectable solutions or dispersion. In all cases the final solution or dispersion form must be sterile and fluid. Typically， such a solution or dispersion will include a solvent or dispersion medium， containing， for example， water-buffered aqueous solutions， e.g. biocompatible buffers， ethanol， polyol， such as glycerol， propylene glycol， polyethylene glycol， suitable mixtures thereof， surfactants or vegetable oils. A compound of the invention can also be formulated into liposomes， in particular for parenteral administration. Liposomes provide the advantage of increased half life in the circulation， if compared to the free drug and a prolonged more even release of the enclosed drug.

Sterilization of infusion or injection solutions can be accomplished by any number of art recognized techniques including but not limited to addition of preservatives like anti-bacterial or anti-fungal agents， e.g. parabene， chlorobutanol， phenol， sorbic acid or thimersal. Further， isotonic agents， such as sugars or salts， in particular sodium chloride may be incorporated in infusion or injection solutions.

Production of sterile injectable solutions containing one or several of the compounds of the invention is accomplished by incorporating the respective compound in the required amount in the appropriate solvent with various ingredients enumerated above as required followed by sterilization. To obtain a sterile powder the above solutions are vacuum-dried or freeze-dried as necessary. Preferred diluents of the present invention are water， physiological acceptable buffers， physiological acceptable buffer salt solutions or salt solutions. Preferred carriers are cocoa butter and vitebesole. Excipients which can be used with the various pharmaceutical forms of a compound of the invention can be chosen from the following non-limiting list：

a) binders such as lactose mannitol， crystalline sorbitol， dibasic phosphates， calcium phosphates， sugars， microcrystalline cellulose， carboxymethyl cellulose， hydroxyethyl cellulose， polyvinyl pyrrolidone and the like；

b) lubricants such as magnesium stearate， talc， calcium stearate， zinc stearate， stearic acid， hydrogenated vegetable oil， leucine， glycerids and sodium stearyl fumarates，

c) disintegrants such as starches， croscaramellose， sodium methyl cellulose， agar， bentonite alginic acid， carboxymethyl cellulose， polyvinyl pyrrolidone and the like.

In one embodiment the formulation is for oral administration and the formulation comprises one or more or all of the following ingredients： pregelatinized starch， talc povidone K 30， croscarmellose sodium， sodium stearyl fumarate， gelatin， titanium dioxide， sorbitol， monosodium citrate， xanthan gum， titanium dioxide， flavoring， sodium benzoate and saccharin sodium.

If a compound of the invention is administered intranasally in a preferred embodiment， it may be administered in the form of a dry powder inhaler or an aerosol spray from a pressurized container， pump， spray or nebulizer with the use of a suitable propellant， e.g.， dichlorodifluoromethane， trichlorofluoromethane， dichlorotetrafluoroethane， a hydrofluoro-alkane such as 1， 1， 1， 2-tetrafluoroethane (HFA 134A^TM) or 1， 1， 1， 2， 3， 3， 3-heptafluoropropane (HFA 227EA^TM) ， carbon dioxide， or another suitable gas. The pressurized container， pump， spray or nebulizer may contain a solution or suspension of the compound of the invention， e.g.， using a mixture of ethanol and the propellant as the solvent， which may additionally contain a lubricant， e.g.， sorbitan trioleate.

Other suitable excipients can be found in the Handbook of Pharmaceutical Excipients， published by the American Pharmaceutical Association， which is herein incorporated by reference.

It is to be understood that depending on the severity of the disorder and the particular type which is treatable with one of the compounds of the invention， as well as on the respective patient to be treated， e.g. the general health status of the patient， etc.， different doses of the respective compound are required to elicit a therapeutic or prophylactic effect. The determination of the appropriate dose lies within the discretion of the attending physician. It is contemplated that the dosage of a compound of the invention in the therapeutic or prophylactic use of the invention should be in the range of about 0.1 mg to about 1 g of the active ingredient (i.e. compound of the invention) per kg body weight. However， in a preferred use of the present invention a compound of the invention is administered to a subject in need thereof in an amount ranging from 1.0 to 500 mg/kg body weight， preferably ranging from 1 to 200 mg/kg body weight. The duration of therapy with a compound of the invention will vary， depending on the severity of the disease being treated and the condition and idiosyncratic response of each individual patient. In one preferred embodiment of a prophylactic or therapeutic use， between 1 00 mg to 200 mg of the compound is orally administered to an adult per day， depending on the severity of the disease and/or the degree of exposure to disease carriers.

As is known in the art， the pharmaceutically effective amount of a given composition will also depend on the administration route. In general the required amount will be higher， if the administration is through the gastrointestinal tract， e.g.， by suppository， rectal， or by an intragastric probe， and lower if the route of administration is parenteral， e.g.， intravenous. Typically， a compound of the invention will be administered in ranges of 50 mg to 1 g/kg body weight， preferably 100 mg to 500 mg/kg body weight， if rectal or intragastric administration is used and in ranges of 10 to 100 mg/kg body weight， if parenteral administration is used.

If a person is known to be at risk of developing a disease treatable with a compound of the invention， prophylactic administration of the biologically active blood serum or the pharmaceutical composition according to the invention may be possible. In these cases the respective compound of the invention is preferably administered in above outlined preferred and particular preferred doses on a daily basis. Preferably， from 0.1 mg to 1 g/kg body weight once a day， preferably 10 to 200 mg/kg body weight. This administration can be continued until the risk of developing influenza has lessened. In most instances， however， a compound of the invention will be administered once a disease/disorder has been diagnosed. In these cases it is preferred that a first dose of a compound of the invention is administered one， two， three or four times daily.

The compounds of the present invention are particularly useful for treating， ameliorating， or preventing influenza. Preferably the compounds of the present invention are employed to treat infiuenza. Within the present invention， the term ″influenza″ includes influenza A， B， C， isavirus and thogotovirus and also covers bird flu and swine flu. The subject to be treated is not particularly restricted and can be any vertebrate， such as birds and mammals (including humans) .

The present inventors have found that the compounds of the present invention are not only capable of inhibiting transcription but， surprisingly， also inhibit replication in viruses， in particular， in influenza viruses.

Without wishing to be bound by theory it is assumed that the compounds of the present invention are capable of inhibiting binding of host mRNA cap structures to the cap-binding domain (CBD) ， particularly of the influenza virus. More specifically it is assumed that they directly interfere with the CBD of the influenza PB2 protein. However， delivery of a compound into a cell may represent a problem depending on， e.g.， the solubility of the compound or its capabilities to cross the cell membrane. The present invention not only shows that the claimed compounds have in vitro polymerase inhibitory activity but also in vivo antiviral activity.

The compounds having the formula (I) can be used in combination with one or more other medicaments. The type of the other medicaments is not particularly limited and will depend on the disorder to be treated. Preferably the other medicament will be a further medicament which is useful in treating， ameloriating or preventing a viral disease， more preferably a further medicament which is useful in treating， ameloriating or preventing influenza.

The further medicament can be selected， for example， from endonuclease inhibitors (particularly targeting influenza) ， cap binding inhibitors (particularly targeting influenza) ， (preferably influenza) polymerase inhibitors， neuramidase inhibitors， M2 channel inhibitors， alpha glucosidase inhibitors， ligands of other influenza targets， antibiotics， anti-inflammatory agents like COX inhibitors (e.g.， COX-1/COX-2 inhibitors， selective COX-2 inhibitors) ， lipoxygenase inhibitors， EP ligands (particularly EP4 ligands) ， bradykinin ligands， and/or cannabinoid ligands (e.g.， CB2 agonists) .

Various modifications and variations of the invention will be apparent to those skilled in the art without departing from the scope of the invention. Although the invention has been described in connection with specific preferred embodiments， it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed， various modifications of the described modes for carrying out the invention which are obvious to those skilled in the relevant fields are intended to be covered by the present invention.

The following examples are merely illustrative of the present invention and should not be construed to limit the scope of the invention as indicated by the appended claims in any way.

EXAMPLES

The invention will be more fully understood by reference to the following examples. They should not， however， be construed as limiting the scope of the invention.

Abbreviations

AcOH： acetic acid

MeCN： acetonitrile

CBz： benzyloxycarbonyl

HATU： 1- [bis (dimethylamino) methylene] -1H-1， 2， 3-triazolo [4， 5-b] pyridinium 3-oxid

hexafluorophosphate

Boc： t-butoxycarbonyl

mCPBA： m-chloroperoxybenzoic acid

TIPSCI： chloro (triisopropyl) silane

CDCl₃： deuterated chloroform

DCM： dichloromethane

DCE： dichloroethane

DIEPA： diisopropylethylamine

DMF： dimethyl formamide

DCC： dicyclohexylcarbodiimide

Xphos： 2-dicyclohexylphosphino-2′， 4′， 6′-triisopropylbiphenyl

DHP： 3， 4-dihydro-2H-pyran

DIEPA： diisopropylethylamine

DMAP： 4-dimethylaminopyridine

DMSO： dimethylsulfoxide

DPPA： diphenylphosphoryl azide

EtOAc： ethyl acetate

Hz： hertz

NIS： N-iodosuccinimide

LDA： lithium diisopropylamide

MS (ESI) ： mass spectroscopy (electron spray ionization)

MHz： megahertz

TsOH： 4-methylbenzenesulfonic acid

μg： microgram

μL： microliter

μM： micromoles per liter

mg： milligram

mL： milliliter

mmol： millimole

EC₅₀： The molar concentration of an agonist， which produces 50％of the maximum

possible response for that agonist.

NMR： nuclear magnetic resonance

Pre-HPLC： preparation-high performance liquid chromatography

PG： protective group

PTS： puridinium p-toluenesulfonate

SFC： supercritical fluid chromatography

THF： tetrahydrofuran

THP： tetrahydropyran-2-yl

Pd (PPh₃) ₄： tetrakis (triphenylphosphine) palladium

TLC： thin layer chromatography

Ts： p-totuenesulfonyl

TEA： triethylamine

TFA： 2， 2， 2-trifluoroacetic acid

TFAA： trifluoroacetic anhydride

Tf₂O： trifluoromethanesulfonic anhydride

SEM： 2- (trimethylsilyl) ethoxymethyl

SEMCl： 2- (trimethylsilyl) ethoxymethyl chloride

Pd₂ (dba) ₃： tris (dibenzylideneacetone) dipalladium

General Experimental Conditions

Intermediates and final compounds were purified by flash chromatography using one of the following instruments： i) Biotage SP1 system and the Quad 12/25 Cartridge module. ii) ISCO combi-flash chromatography instrument. Silica gel Brand and pore size： i) KP-SIL

particle size： 40-60 μm； ii) CAS registry NO： Silica Gel： 63231-67-4， particle size： 47-60 micron silica gel； iii) ZCX from Qingdao Haiyang Chemical Co.， Ltd， pore： 200-300 or 300-400.

Intermediates and final compounds were purified by preparative HPLC on a reversed phase column using X Bridge^TM Perp C₁₈ (5 μm， OBD^TM 30 × 100 mm) column or SunFire^TM Perp C₁₈ (5 μm， OBD^TM 30 × 100 mm) column.

LC/MS spectra were obtained using a Waters UPLC-SQD Mass. Standard LC/MS conditions were as follows (running time 3 minutes) ：

Acidic condition： A： 0.1％formic acid and 1％acetonitrile in H₂O； B： 0.1％formic acid in acetonitrile；

Basic condition： A： 0.05％NH₃·H₂O in H₂O； B： acetonitrile.

Mass spectra (MS) ： generally only ions which indicate the parent mass are reported， and unless otherwise statedthe mass ion quoted is the positive mass ion (M+H) ⁺.

NMR Spectra were obtained using Bruker Avance 400MHz.

All reactions involving air-sensitive reagents were performed under an argon atmosphere. Reagents were used as received from commercial suppliers without further purification unless otherwise noted.

Biological Assays and Data

Luciferase Reporter Assay (LRA)

Assay purpose and principle

This in vitro， cell-based assay， is used to identify small molecule inhibitors of influenza A virus and relies upon a replication competent influenza reporter virus. This virus was generated in a A/WSN background (Szretter K J， Balish AL， Katz JM. Curr Protoc Microbiol. Influenza： propagation， quantification， and storage. 2006 Dec； Chapter 15： Unit 15G. 1. doi： 10.1002/0471729256. mc15g01s3) and contains the extremely bright luciferase variant， NanoLuc (Promega) ， which has been appended to the C-terminus of the polymerase subunit， PA. The reporter virus replicates with near native properties both in cell culture and in vivo. Thus， NanoLuc luciferase activity can be used as a readout of viral infection.

In order to identify small molecule inhibitors of influenza A virus， A549 (human non-small cell lung cancer) cells are infected with the reporter virus and following infection， the cells are treated with serially diluted compounds. The inhibitory effect of the small molecules tested is a direct measure of viral levels and can be rapidly obtained by measuring a reduction in luciferase activity.

Determination of viral replication inhibition by Luciferase Reporter Assay (LRA)

A549 cells were plated in 384-well plates at a density of 10,000 cells per well in Dulbecco’s modified Eagle’s medium with Glutamax (DMEM， Invitrogen) supplemented 10％fetal bovine serum (FBS， Invitrogen) and 1X penicillin/streptomycin (Invitrogen) ， herein referred to as complete DMEM， and incubated at 37℃， 5％CO₂ overnight. The following day， cells were washed once with 1X PBS and then infected with virus， MOI 0.1 in 10μl of infection media for 60 min. 15μl of complete media and diluted compounds (1％DMSO final) added to the wells， and the plates were incubated for 24 h at 37℃， 5％CO₂. 15μl of Nano-Glo reagent (Promega) was added to each well and luminescence was read using a Paradigm Microplate reader (Molecular Devices) . Cell viability was determined similarly， in the absence of virus， by measurement of ATP levels with CellTiter-Glo reagent (Promega) . EC₅₀ and CC₅₀ values were calculated by fitting dose-response curves with XLFit 4-parameter model 205 software (IDBS) .

Virus and cell culture methods

A/WSN/33 influenza virus containing the NanoLuc reporter construct was obtained from the laboratory of Andrew Mehle (University of Wisconsin) . A549 human lung carcinoma cells were purchased (ATCC) . All studies were performed with A549 cells cultured in complete DMEM. Influenza virus stocks were propagated in MDBK cells (ATCC) using standard methods (Szretter KJ， Balish AL， Katz JM. Curr Protoc Microbiol. Influenza： propagation， quantification， and storage. 2006 Dec； Chapter 15： Unit 15G. 1. doi： 10.1002/0471729256. mc15g01s3) and stocks frozen at -80℃. Viral infections were carried out using DMEM Glutamax supplemented with 0.3％BSA (Sigma) ， 25mM Hepes (Sigma) ， and 1X penicillin/streptomycin (Invitrogen) .

Influenza A or B Filter RNP Transcription and Influenza A RNP-based Replication Assay

Preparation of virus lysate containing native influenza vRNP complex

Influenza purified virus (Influenza A/PR/8/34， Influenza B\Lee\40) was obtained from Charles River Laboratories International Inc. as suspension in HEPES buffer. Virons were disrupted by incubation with an equal volume of 2％Trition X-100 for 30 minutes at room temperature in a buffer containing 40 mM Tris-HCl， pH 8， 5 mM MgCl₂， 200 mM KCl， 100 mM NaCl， 10 mM dithiothreitol [DTT] ， 5％Glycerol， 40 U/ml RNAse Inhibitor， 10 mM 2-Mercaptoethanol， and 2 mg/ml Lysolechithin. The virus lysate was aliquot and stored at-80℃ in aliquots.

Assay Purpose & Principle of Influenza A or B Filter RNP Transcription Assay

This in vitro assay is developed to identify inhibitors of Cap-binding， endonuclease and polymerase activities of the Influenza A or B virus. Influenza ribonucleoprotein complexes (RNPs) are responsible for the transcription and replication of viral genomic negative strain RNA to positive strain mRNA and positive strain cRNA respectively. The transcription is initiated by the “cap-snatching’ mechanism which consists of two steps： The cap-binding of cellular mRNA by the PB2 subunit and the cleavage of the capped RNA by the PA subunit. The resulting 9-13 nucleotide long， capped RNA oligo serves as a primer for the subsequent synthesis of viral mRNA by the polymerase subunit PB1. During the mRNA synthesis， radiolabeled nucleotide will be incorporated into the mRNA product， which will be captured on a specific filter plate by TCA precipitation. The efficiency of nucleotide incorporation is then determined by scintillation counting of captured mRNA on the filter plate. A higher rate of mRNA synthesis leads to higher signals. Due to the essential involvement of cap-binding and cleavage reaction prior to polymerization of mRNA， it is possible to inhibit transcription by either blocking the endonuclease active site of PA or the cap-binding site of PB2 and therefore to determine IC50 values of both endonuclease and cap-binding inhibitors.

Material and methods for Filter RNP transcription assay：

Virus lysate (H1N1 Influenza strain A/PR/8/34， Charles River， Cat #10100374； Influenza B\Lee\40， Charles River， Cat# 10100379) was pre-incubated with compounds for 30 min at 30℃ in the reaction buffer containing 24 mM HEPES (pH 7.5) ， 118 mM NaOAC， 1 mM Mg (OAC) ₂， 0.1 mM Mn (OAC) ₂， 0.1 mM EDTA， 2 mM DTT， 0.3 U RNase inhibitor (Riboguard) ， 70 mM ATP/CTP/UTP， 14 mM GTP and 0.175 μCi ³³P-GTP. Then capped RNA substrate was added to the reaction at 0.07 uM (5’m⁷G-ppp-GAA UAC UCA AGC UAU GCA UC-3′， 5’-triphosphorylated RNA was purchased from Fidelity Systems and the capping reaction was performed using the ScriptCap Capping System from CellScript) . The Cap-snatching and subsequent mRNA synthesis reactions were performed for 90 min at 30℃ before the reactions were terminated by EDTA addition. Synthesized mRNA products were precipitated on the filter plate (Millipore) using 20％TCA at 4 ℃ for 35 min and followed by three times wash with 10％TCA and 1 time with 70％ethanol on the vacuum manifold system (Millipore) . After complete dry of the filter plate， Microsint 20 solution was added to the wells and scintillation counting was performed on the TopCount equipment for 1min/well.

Assay Purpose & Principle of Influenza A RNP-based Replication Assay

This in vitro assay is developed to identify inhibitors targeting polymerase activities of the Influenza A virus. Influenza ribonucleoprotein complexes (RNPs) are responsible not only for the transcription of negative-sense viral genomic RNA (vRNA) to positive-sense mRNA， but also for the replication of full-length complementary genomic RNA (cRNA) . A pppApG dinucleotide is provided to the RNPs to initiate the cRNA synthesis and during the elongation process， radiolabeled nucleotide will be incorporated into the cRNA product， which will be captured on a specific filter plate by TCA precipitation. The efficiency of nucleotide incorporation is then determined by scintillation counting of captured cRNA on the filter plate. A higher rate of cRNA synthesis leads to higher signals. Due to the essential involvement of polymerase subunit for the polymerization of cRNA， it is possible to inhibit replication by either directly blocking the polymerase active site of PB1 or by preventing the conformational changes of RNP that is required for the realignment of polymerase complex on the vRNA template. Therefore this assay is able to determine IC50 values of replication inhibitors.

Material and methods for replication assay：

The concentrations refer to final concentrations unless mentioned otherwise. Cap-binding inhibitors were serially diluted 4 fold in 40％DMSO and 2ul of diluted compound was added to 17 ul reaction mix containing 0.35 nM vRNP enzyme， 20 mM HEPES (pH 7.5) ， 100 mM NaOAC， 1 mM Mg (OAC) ₂， 0.1 mM Mn (OAC) ₂， 0.1 mM EDTA， 2 mM DTT， 0.25 U RNase inhibitor (Epicentre) ， 70 uM ATP/CTP/UTP， 1.4 uM GTP and 0.175 μCi ³³P-GTP for 30 minutes at 30℃. pppApG dinucleotide was added to the reaction at 75 uM as final concentration. Reactions were performed for 3 hours at 30℃ and then stopped by adding EDTA to a final concentration of 56 mM. Synthesized cRNA products from the replication reaction were precipitated on the filter plate (Millipore) using 20％TCA at 4℃ for 35 minutes and followed by three times wash with 10％TCA and 1 time with 70％ethanol on the vacuum manifold system (Millipore) . After complete air dry of the filter plate， Microsint 20 solution was added to the wells and scintillation counting was performed on the TopCount equipment for 1 min/well. Dose-response curves were analyzed using 4-parameter curve fitting methods. The concentration of test compound resulting in 50％inhibition to that of the control wells were reported as IC50.

Results Obtained For The Example Using The Bio-Assays

Table 1.

Table 2.

Intermediate A-1

5-Fluoro-3-iodo-1-tetrahydropyran-2-yl-pyrazolo [3， 4-b] pyridine

[A] 2， 6-Dichloro-5-fluoro-pyridine-3-carboxamide

A stirred solution of 2， 6-dichloro-5-fluoronicotinonitrile (100 g， 0.526 mol) in conc. H₂SO₄ (1000 mL) was heated at 60 ℃ for 2 h. After cooling to room temperature， the mixture was poured into ice water， and extracted with EtOAc (300 mL × 3) . The combined organic layers were dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo. The crude residue， after being washed with hexane several times gave the title compound (90 g， 83％yield) as a yellow solid. MS： 207.0 [M-H] ⁺.

[B] 2-Chloro-5-fluoro-pyridine-3-carboxamide

To a stirred solution of 2， 6-dichloro-5-fluoro-pyridine-3-carboxamide (95 g， 0.45 mol) in MeOH (45 mL) and AcOH (450 mL) was added Zn powder (41.92 g， 0.645 mol) . The resulting reaction mixture was heated at 85 ℃ for 15 h. After TLC (petroleum ether∶EtOAc ＝ 1∶1) showed the completion of the reaction， the reaction mixture was diluted with saturated aqueous NaHCO₃ solution and extracted with EtOAc. The organic layer was dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo. The residue， after being washed with hexane several times gave the title compound (70 g， 88％yield) as a solid. MS： 173.0 [M-H] ⁺.

[C] 2-Chloro-5-fluoro-pyridine-3-carbonitrile

To a stirred solution of 2-chloro-5-fluoro-pyridine-3-carboxamide (60 g， 0.34 mol) and Et₃N (105.6 mL ) in DCM (400 mL) was added TFAA (60 mL) drop wise at 0 ℃ and resulting reaction mixture was stirred at 0 ℃ for 1.5 h . The reaction was quenched with saturated aqueous NaHCO₃ solution and extracted with DCM (400 mL × 3) . The combined organic layers were dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to afford a crude title compound (55 g， 87％yield) as a brown solid. MS： 157.1 [M+H] ⁺.

[D] 5-Fluoro-1H-pyrazolo [3， 4-b] pyridin-3-amine

A stirred solution of 2-chloro-5-fluoro-pyridine-3-carbonitrile (50 g， 3.30 mol) and N₂H₄. H₂O (100 mL) in EtOH (500 mL) was heated at 100℃ for 2 h. After TLC (petroleum ether∶EtOAc＝2∶1) showed the completion of the reaction， the solvent was removed under reduced pressure. The residue， after being washed with EtOAc several times afforded the title compound (30.6 g， 62％yield) as a solid. MS： 153.0 [M+H] ⁺.

[E] 5-Fluoro-3-iodo-1H-pyrazolo [3， 4-b] pyridine

To a stirred solution of 5-fluoro-1H-pyrazolo [3， 4-b] pyridin-3-amine (30.6 g， 0.2 mol) in MeCN (500 mL) was added isopentylnitrite (27.11 g， 0.24 mol) and CH₂l₂ (164 g， 0.60 mol) at 0 ℃. After the addition， the resulting reaction mixture was stirred first at 0 ℃ for 2 h and then at 100 ℃ for 20 h. After TLC (petroleum ether∶EtOAc ＝ 5∶1) showed the completion of the reaction， the reaction mixture was concentrated under vacuum. The residue was diluted with water and then extracted with EtOAc. The organic layer was washed with brine (100 mL × 3) ， dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (petroleum ether∶EtOAc ＝ 20∶1) to afford the title compound (18 g， 34％yield) as a solid. MS： 263.9 [M+H] ⁺.

[F] 5-Fluoro-3-iodo-1-tetrahydropyran-2-yl-pyrazolo [3， 4-b] pyridine

To a stirred solution of 5-fluoro-3-iodo-1H-pyrazolo [3， 4-b] pyridine (18 g， 68.4 mmol) in THF (500 mL) was added TsOH (0.1 g) at 0℃ and stirred for 30 min. 3， 4-Dihyro-2H-pyran (6.9 g， 82.1 mmol) was added drop wise to the above mixture at 0 ℃ and the resulting reaction mixture was then heated at 80 ℃ for 6 h before it was concentrated under vacuum. The residue was diluted with water and extracted with EtOAc (200 mL × 3) . The combined organic layers were washed with brine， dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (petroleum ether∶EtOAc ＝ 8∶1) to afford the title compound (16.8 g， 63％yield) as a yellow solid. MS： 348.0 [M+H] ⁺.

Intermediate A-2

2- [ (5-Chloro-3-iodo-pyrazolo [3， 4-b] pyridin-1-yl) methoxy] ethyl-trimethyl-silane

[A] 5-Chloro-2-fluoro-pyridine-3-carbaldehyde

To a stirred solution of 5-chloro-2-fluoropyridine (15 g， 114.5 mmol) in THF (150 mL) was added LDA (85.8 mL， 171.7 mmol) drop wise at -78 ℃. After stirred for 1.5 h， the morpholine-4-carbaldehyde was added to the above solution and the mixture solution was stirred at -78 ℃ for another 2 h. After TLC (petroleum ether∶EtOAc ＝ 5∶1) showed the completion of the reaction， the reaction was quenched by the addition of 10％citric acid. The reaction mixture was then allowed to warm up to room temperature and adjusted to pH ＝5～6. The mixture was extracted with DCM (100 mL × 3) and the combined organic layers were dried over anhydrous Na₂SO₄， filtered and concentrated in vacuo to give a crude title compound (2.8 g， 15％yield) as a while solid. MS： 160.0 [M+H] ⁺. This crude product was used directly in the next step without further purification.

[B] 5-Chloro-2-fluoro-3- (4， 4， 5， 5-tetramethyl-1， 3-dioxolan-2-yl) pyridine

A flask fitted with a Dean-Stark trap was charged with a solution of 5-chloro-2-fluoro-pyridine-3-carbaldehyde (2.8 g， 17.36 mmol) ， 2， 3-dimethylbutane-2， 3-diol (1.3 g， 21 mmol) and PTS (0.14 g， 0.86 mmol) in toluene (50 mL) . The reaction mixture was heated to 120 ℃ for 4 h. After TLC (petroleum ether/EtOAc ＝ 5∶1) showed the completion of the reaction， the reaction mixture was cooled to room temperature and diluted with EtOAc (20 mL) . The organic layer was washed with saturated aqueous NaHCO₃ (20 m × 2) ， brine (50 mL) ， dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude title compound (3 g， 67％yield) as a white solid. MS： 260.0 [M+H] ⁺. This crude product was used directly in the next step without further purification.

[C] [5-Chloro-3- (4， 4， 5， 5-tetramethyl-1， 3-dioxolan-2-yl) -2-pyridyl] hydrazine

To a stirred solution of 5-chloro-2-fluoro-3- (4， 4， 5， 5-tetramethyl-1， 3-dioxolan-2-yl) pyridine (3 g， 14.7 mmol) and DIPEA (3.8 g， 29.4 mmol) in isopropanol (20 mL) was added hydrazine (5.1 g， 102.9 mmol) and the resulting reaction mixture was heated to 65 ℃ for 12 h. After TLC (petroleum ether∶EtOAc ＝ 5∶1) showed the completion of the reaction， the mixture was concentrated in vacuo to give a crude title compound (3.1 g， 78％yield) as a white solid. MS： 272.1 [M+H] ⁺. This crude product was used directly in the next step without further purification.

[D] 5-Chloro-1H-pyrazolo [3， 4-b] pyridine

To a stirred solution of [5-chloro-3- (4， 4， 5， 5-tetramethy-1， 3-dioxolan-2-yl) -2-pyridyl] hydrazine (3.1 g， 14.3 mol) in 40 mL of water and 16 mL of EtOH was added 6 N HCl (8 mL) . The resulting reaction mixture was heated to 45℃ for 6 h. After TLC (petroleum ether∶EtOAc＝2∶1) showed the completion of the reaction， the reaction mixture was neutralized with 6 N NaOH (8mL) and aojusted pH＝8. The mixture was concentrated in vacuo to remove volatile EtOH and the residue was extracted with EtOAc (20 mL × 3) . The combined organic layers were washed with brine， dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude title compound (2.5 g) as a yellow solid. MS： 154.0 [M+H] ⁺. This crude product was used directly in the next step without further purification.

[E] 5-Chloro-3-iodo-1H-pyrazolo [3， 4-b] pyridine

A stirred mixture solution 5-chloro-1H-pyrazolo [3， 4-b] pyridine (2.5 g， 16.2 mmol) and NIS (4 g， 18 mmol) in DCE (10 mL) was heated to 50℃ for 12 h. After TLC (petroleum ether∶EtOAc＝2∶1) showed the completion of the reaction， the mixture was cooled to room temperature and diluted with EtOAc (20 mL) . It was washed with saturated aqueous NaHCO₃ solution (20mL) and brine (20 mL) . The organic layer was dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude title compound (2 g， 44％yield) as a yellow solid. MS： 279.9 [M+H] ⁺. This crude product was used directly in the next step without further purification.

[F] 2- [ (5-Chloro-3-iodo-pyrazolo [3， 4-b] pyridin-1-yl) methoxy] ethyl-trimethyl-silane

To a stirred solution of 5-chloro-3-iodo-1H-pyrazolo [3， 4-b] pyridine (2 g， 13 mmol) ， NaH (0.56 g， 23.4 mmol) in DMF (5 mL) was added SEMCI (3.9 g， 23.4 mmol) drop wise at room temperature and stirred for 1 h. After TLC (petroleum ether∶EtOAc ＝ 10∶1) showed the completion of the reaction， the reaction mixture was diluted with water (5 mL) and extracted with EtOAc (10 mL × 2) . The combined organic layers were dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (petroleum ether∶EtOAc ＝ 10∶1) to afford the title compound (0.3 g， 41％yield) as a white solid. MS： 410.0 [M+H] ⁺.

Intermediate A-3

2- [ (5-Fluoro-3-iodo-pyrrolo [2， 3-b] pyridin-1-yl) methoxy] ethyl-trimethyl-silane

[A] 5-Bromo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2， 3-b] pyridine

To a stirred solution of 5-bromo-1H-pyrrolo [2， 3-b] pyridine (20 g， 100 mol) in DMF (120 mL) was added NaH (5.2 g， 60％dispersion in mineral oil， 130 mmol) at 0℃ and stirred for 1 h before SEMCI (20 g， 120 mmol) was added slowly to the above reaction mixture. After the addition， the mixture was allowed to warm up to room temperature and stirred for addtional 4 h. After TLC (petroleum ether∶EtOAc ＝ 10∶1) showed that the reaction was completed， the mixture was quenched by the addition of water (2 mL) and concentrated in vacuo. The residue was re-dissolved in EtOAc (200 mL) and the organic layer was washed with with brine， dried anhydrous Na₂SO₄ and concentrated in vacuo to give a crude product which was then purified by silica gel flash chomatography (petroleum ether∶EtOAc ＝ 10∶1) to afford the title compound (25 g， 76.9％yield) as oil. MS： 327.1 & 329.1 [M+H] ⁺.

[B] 5-Fluoro-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2， 3-b] pyridine

To a stirred solution of 5-bromo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2， 3-b] pyridine (24 g， 72 mol) in THF (200 mL) was added n-BuLi (43.2 mL， 108 mmol) slowly at -78℃ and stirred for 1 h before NFSI (45.2 g， 144 mmol) was added to the above mixture and stirred for additional 2 h. After TLC (petroleum ether∶EtOAc ＝ 10∶1) showed that the reaction was completed， the reaction mixture was allowed to warm up to room temperature and quenched by the addition of water. The reaction mixture was concentrated in vacuo and the residue was re-dissolved in EtOAc. The organic layer was washed with brine， dried over anhydrous Na₂SO₄ and concentrated in vacuo to give a crude product which was then purified with silica gel flash chomatography (10％EtOAc in petroleum ether) to afford the title compound (10 g， 53％yield) as oil. This crude product was used directly in the next step without further purification.

[C] 5-Fluoro-3-iodo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2， 3-b] pyridine

A mixture solotion of 5-fluoro-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2， 3-b] pyridine (5 g， 18.7 mmol) ， I₂ (4.8 g， 18.7 mmol) and KOH (4.2 g， 75.1 mmol ) in DMF (60 mL) was stirred at room temperature for 12 h. After TLC (petroleum ether∶EtOAc＝10∶1) showed that the reaction was completed， the reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine， dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude title compound (3.2 g) as coloriess oil. MS： 393.4 [M+H] ⁺. This crude product was used directly in the next step without further purification.

Intermediate A-4a

2- [ (5-Chloro-3-iodo-pyrrolo [2， 3-b] pyridin-1-yl) methoxy] ethyl-trimethyl-silane

[A] 5-Chloro-3-iodo-1H-pyrrolo [2， 3-b] pyridine

A mixture solution of 5-chloro-1H-pyrrolo [2， 3-b] pyridine (20 g， 131.5 mmol) ， I₂ (33.4 g， 131.5 mmoL) and KOH (29.4 g， 526 mol) in DMF (300 mL) was stirred at room temperature for 12 h before it was poured into water and extracted with EtOAc (150 mL × 3) . The combined organic layers were washed with brine， dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude title compound (18 g， 49％yield) as a solid. MS： 278.9 [M+H] ⁺. This crude product was used directly in the next step without further purification.

[B] 2- [ (5-Chloro-3-iodo-pyrrolo [2， 3-b] pyridin-1-yl) methoxy] ethyl-trimethyl-silane

To a stirred solution of 5-chloro-3-iodo-1H-pyrrolo [2， 3-b] pyridine (16 g， 57.5 mmol) and NaH (4.2 g， 172.4 mol) in DMF (100 mL) was added (2- (chloromethoxy) ethyl) trimethylsilane (9.57 g， 172.4 mmol) drop wise at 0℃ and stirred for 0.5 h. Afterwards， the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL twice) . The combined organic layers were dried over anhydrous Na₂SO₄， filtered and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (petroleum ether∶EtOAc ＝ 10∶1) to afford the title compound (10 g， 43％yield) as a solid. MS： 409.0 [M+H] ⁺.

Intermediate A-4b

5-Chloro-3-iodo-1-tosyl-1H-pyrrolo [2， 3-b] pyridine

A mixture solution of 5-chloro-3-iodo-1H-pyrrolo [2， 3-b] pyridine (8 g， 28.7 mmol) ， cesium carbonate (18.7 g， 57.5 mmol) and 4-toluenesulfonyl chloride (8.19 g， 43.1 mmol) in DMF (80 mL) was stirred at room temperature for 4 h. Afterwards， the mixture was poured into water and the suspension was filtered. The crude title compound (8.7 g， 70％yield) was collected as filter cake. MS： 433.1 (M+1) ⁺. It was used direclty in the next step without further purification.

Intermediate A-5

5， 7-Difluoro-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole

[A] 5， 7-Difluoro-1H-indazol-3-amine

A stirred solution of 2， 3， 5-trifluoro-benzonitrile (15.7 g， 100 mmol) and hydrazine hydrate (30 mL) in EtOH (150 mL) was heated at 80℃ for 12 h. After TLC showed the completion of the reaction， the mixture was concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (petroleum ether∶EtOAc ＝ 2∶1) to afford the title compound (8 g， 47％yield) a white solid. MS： 170.1 [M+H] ⁺. ¹H NMR (400MHz DMSO-d6) ppm 5.49 (s， 2 H) 7.08-7.23 (m， 1 H) 7.36 (dd， J＝8.78， 2.01 Hz， 1 H) 11.96 (s， 1 H) .

[B] 5， 7-Difluoro-3-iodo-1H-indazole

To a stirred solution of 5， 7-difluoro-1H-indazol-3-amine (7.5 g， 44.3 mmol) in 6 M H₂SO₄ (100 mL) was added sodium nitrite (3.97 g， 57.6 mmol) at 0℃. After stirred for 30 min， the above mixture was added slowly to another flask that contains potassium iodine (73.5 g， 443 mmol) and Cul (8.4 g， 44.3 mmol) in H₂O (100 mL) and the resulting mixture was stirred at 50 ℃ for 2 h. After TLC showed that the reaction was completed， the reaction was quenched with aq. Na₂SO₃ solution (200 mL) ， and extracted with EtOAc (200 mL twice) . The organic layes were washed with brine， dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (petroleum∶EtOAc＝20∶1 to 10∶1) to afford the title compound (5.1 g， 41.2％yield) as a yellow solid. MS： 280.9 [M+H] ⁺. ¹H NMR (300 MHz CHCl₃-d1) δ 7.01-7.04 (m， 2 H) 10.47 (brs， 1H) .

[C] 5， 7-Difluoro-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole

To a stirred mixture solution of 5， 7-difluoro-3-iodo-1H-indazole (2.2 g， 7.86 mmol) and DHP (5.29 g， 62.9 mmol) in toluene (20 mL) was added 2， 2， 2-trifluoroacetic acid (179 mg， 1.57 mmol) and the reaction mixture solution was stirred at 100℃ for 12 h. After cooling to room temperature， the reaction mixture was poured into water (20 mL) and extracted with EtOAc (50 mL twice) . The combined organic layers were washed with brine， dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (0-30％EtOAc-hexane gradient) to afford the title compound (700 mg， 24.5％yield) as a white solid. MS： 365.1 [M+H] ⁺.

Intermediate A-6

7-Fluoro-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [4， 3-c] pyridine

[A] 4-Chloro-5-fluoronicotinaldehyde

To a stirred solution of LDA (114.5 mL， 229 mmol) in THF (200 mL) was added 4-chloro-3-fluoropyridine (15 g， 114.5 mmol) drop wise in THF (50 mL) at -78℃. After the addition， the mixture was stirred at -78℃ for 1 h before DMF (25 g， 343.5 mmol) was added drop wise and the resulting reaction mixture was stirred at -78℃ for another 3 h. The reaction was quenched with saturated aqueous NH₄Cl solution and extracted with EtOAc (200 mL twice) ， The combined organic layers were washed with brine， dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (petroleum ether∶EtOAc ＝ 20∶1 to 5∶1) to afford the title compound (8 g， 44.0％yield) as a yellow solid. ¹H NMR (300MHz， CHCl₃-d1) δ 8.71 (s， 1 H) ， 8.89 (s， 1 H) ， 10.47 (s， 1 H) .

[B] 7-Fluoro-1H-pyrazolo [4， 3-c] pyridine

A mixture solution of 4-chloro-5-fluoronicotinaldehyde (12.5 g， 78.6 mmol) and hydrazine (19.6 g， 392.5 mmol) in n-BuOH (200 mL) was stirred at 130 ℃ for 20 h. After TLC (petroleum ether∶EtOAc ＝ 5∶1) showed the starting material was consumed， the solvent was removed under reduced pressure. The residuel was re-dissolved in EtOAc (500 mL) ， and washed with water， brine. The organic layer was dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude title compound (7 g， 65％yield) as a yellow solid. MS： 138.0 [M+H] ⁺.

[C] 7-Fluoro-3-iodo-1H-pyrazolo [4， 3-c] pyridine

To a stirred solution of 7-fluoro-1H-pyrazolo [4， 3-c] pyridine (7.0 g， 51.1 mmol) and potassium carbonate (11.5 g， 204.4 mmol) in DMF (100 mL) was added iodine (26.2 g， 102.2 mmol) in portions in ice-water bath. After the addition， the reaction mixture was stirred at room tenperature for 3 h before it was quenched with satd. aq， NH₄Cl solution and extracted with EtOAc (200 mL twice) . The combined organic layers were washed with water， brine， dried over anhydrous Na₂SO₄， and concentrated in vacuo to a crude title compound (5.28 g， 40％yield) as a yellow solid. MS： 263.9 M+H] ⁺. ¹H NMR (300 MHz， MeOH-d4) δ ppm 8.34 (d， J＝3.20 Hz， 1 H) ， 8.65 (d， J＝1.88 Hz， 1 H) .

[D] 7-Fluoro-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [4， 3-c] pyridine

To a stirred mixture solution of 7-fluoro-3-iodo-1H-pyrazolo [4， 3-c] pyridine (5 g， 19 mmol) and DHP (12.8 g， 152 mmol) in toluene (20 mL) was added 2， 2， 2-trifluoroacetic acid (434 mg 3.8 mmol) and the resulting reaction mixture solution was stirred at 100 ℃ for 12 h. After cooling to room temperature， the reaction mixture was poured into water (20 mL) and extracted with EtOAc (50 mL twice) . The combined organic layers were washed with brine， dried over anhydrous Na₂SO₄， filtered and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (0-30％EtOAc-hexane gradient) to afford the title compound (3 g， 45.5％yield) as a white solid. MS： 348.1 [M+H] ⁺.

Intermediate A-7

7-Fluoro-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole

To a stirred mixture solution of 7-fluoro-3-iodo-1H-indazole (5 g 19.1 mmol， ) and DHP (12.8 g， 153 mmol) in toluene (20 mL) was added 2， 2， 2-trifluoroacetic acid (435 mg， 3.82 mmol) and the resulting reaction mixture solution was stirred at 100 ℃ for 12 h. After cooling to room temperature， the reaction mixture was poured into water (20 mL) and extracted with EtOAc (50 mL twice) . The combined organic layers were washed with brine， dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (0-30％EtOAc-hexane gradient) to afford the title compound (5.3 g， 80.2％yield) as a white solid. MS： 347.1 [M+H) ⁺.

Intermediate B-1

(rac) -Methyl (2S， 3S) -3- [ [2-chloro-7- (p-tolylsulfonyl) pyrrolo [2， 3-d] pyrimidin-4-yl] amino] bicyclo [2.2.2] octane-2-carboxylate

[A] meso-endo-Tetrahydro-4， 7-ethanoisobenzofuran-1， 3-dione

To a stirred solution of maleic anhydride (24 g， 0.24 mol) in chloroform (200 mL) was added cyclohexa-1， 3-diene (25 mL， 0.26 mol) drop wise at 0 ℃ in the dark. After the addition， the mixture was allowed to slowly warm up to room temperature and stirred for 16 h. The solvent was removed under reduce pressure and the residue was washed with cold MeOH (200 mL) . Vacuum filtration then afforded a crude title compound (30 g， 70％yield) a white solid. This crude product was used directly in the next step without further purification.

[B] (rac) -trans-3- (Methoxycabonyl) bicyclo [2.2.2] oct-5-ene-2-carboxylic acid

To a stirred solution of sodium methoxide (40 g， 0.74 mol) in MeOH (250mL) was added meso-endo-tetrahydro-4， 7-ethanoisobenzofuran-1， 3-dione (15 g， 84.6 mmol) portion-wise at 0 ℃. After the addition， the reaction mixture was allowed to slowly warm up to room temperature and stirred for 60 h. The solvent was removed under reduced pressure and the residue was poured into 1 N HCl solution， and extracted with EtOAc. The organic layer was dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purified by silica gel flash chomatography (petroleum ether∶ EtOAc， 0～100％gradient) to afford a racemic mixture of title compounds (10 g， 67％yield) as white solids. MS： 209.1 [M-H] ⁺.

[C] (rac) - (1S， 2S， 3S， 4R) -Methyl 3- ( ( (benzyloxy) carbonyl) amino) bicyclo [2.2.2] oct-5-ene-2- carboxylate

A mixture solution of (rac) -trans-3- (methoxycabonyl) bicyclo [2.2.2] oct-5-ene-2-carboxylic acid (89 g， 423 mmol) ， diphenylphosphoryl azide (151 g， 119 ml， 550 mmol) and Et₃N (60 g， 593 mmol) in toluene (700 mL) was stirred at room temperature for 30 min and then at 90 ℃ for additonal 2 h. Benzyl alcohol (54.9 g， 508 mmol) was added and the resulting reaciton mixture was stirred at 90 ℃ for 16 h. After cooling to room temperature， the volatile was removed under reduced pressure and the residue was re-dissolved in DCM (300 mL) and washed with 1 N aq. NaOH solution (300 mL x 3) . The organic layer was dried over anhydrous Na₂SO₄， filtered， and then concentrated in vacuo to give a crude product， which was then purified by slilical gel column chomatography (EtOAc： peterolium ether＝ 0 to 20％) to afford the title compound (58g， 43.4％yield) as a yellow liquid. MS： 316.1 (M+1) ⁺.

[D] (rac) - (1S， 2S， 3S， 4R) -Methyl 3-aminobicyclo [2.2.2] oct-5-ene-2-carboxylate

A mixture solution of (rac) - (1S， 2S， 3S， 4R) -methyl 3- ( ( (benzyloxy) carbonyl) amino) bicyclo-[2.2.2] oct-5-ene-2-carboxylate (17 g， 53.9 mmol) and palladium on carbon (1 g， 53.9 mmol) in MeOH (100 mL) was stirred at room temperature under H2 atomosphere (1 atm) for 15 h. Afterwards， the reaction mixture was filtered and the filtration was concentrated in vacuo to give a crude title compound (10 g， 100％yield) as light yellow oil. MS： 184.1 [M+H] ⁺. This crude product was used directly in the next step without further purification.

[E] (rac) -Methyl (2S， 3S) -3- [ [2-chloro-7- (p-tolylsulfonyl) pyrrolo [2， 3-d] pyrimidin-4- yl] amino] bicyclo [2.2.2] octane-2-carboxylate

To a stirred mixture solution of (2S， 3S) -methyl 3-aminobicyclo [2.2.2] octane-2-carboxylate (1.5 g， 8.19 mmol) in THF (20 mL) was added 2， 4-dichloro-7-tosyl-7H-pyrrolo [2， 3-d] pyrimidine (3.08 g， 9 mmol) and DIPEA (1.06 g， 1.43 mL， 8.19 mmol) at room temperature and the resulting reaction mixture solution was stirred at 75 ℃ for 12 h. After cooling to room temperature， the reaction mixture was poured into water (100 mL) and extracted with EtOAc (2 x 150 mL) . The combined organic layers were washed with brine， dried over anhydrous Na₂SO₄， filtered and concentrated in vacuo to afford the title compound (3 g， 70％) as a white foam. MS： 489.1 [M+H] ⁺. SFC chiral separation (Chiral Pak， IC-H， 250 x 30 mm， 5 μm column， 40％Methanoh in CO₂) can afford both enantiomers (-) - (2S， 3S) -methyl 3- ( (2-chloro-7-tosyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate and (+) - (2R， 3R) -methyl 3- ( (2-chloro-7-tosyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] -octane-2-carboxylate as white solids.

Intermediate B-1a

(-) -Methyl (2S， 3S) -3- [ [2-chloro-7- (p-tolylsulfonyl) pyrrolo [2， 3-d] pyrimidin-4-yl] amino] bicyclo [2.2.2] octane-2-carboxylate

To a stirred solution of (rac) - (2S， 3S) -methyl 3-aminobicyclo [2.2.2] octane-2-carboxylate (1.5 g， 8.19 mmol) in THF (20 mL) was added 2， 4-dichloro-7-tosyl-7H-pyrrolo [2， 3-d] pyrimidine (3.08 g， 9 mmol) and DIPEA (1.06 g， 8.19 mmol) at room temperature and the resulting reaction mixture solution was stirred at 75 ℃ for 12 h. After cooling to room temperature， the reaction mixture was poured into water (100 mL) and extracted with EtOAc (150 mL twice) . The combined organic layers were washed with brine， dried over anhydrous Na₂SO₄， filtered and concentrated in vacuo to give a crude title compound (3 g， 70％yield) as white foam. MS： 489.1 [M+H] ⁺.

Intermediate B-2

(rac) - (1R， 2S， 4R， 5S， 6S， 7S) -methyl 7- ( (2-chloro-7-tosyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate

[A] (rac) - (1S， 2R， 4S， 5R， 6R， 7R) -Methyl 7- ( (tert- butoxycarbonyl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate

To a stirred solution of racemic mixture of (1R， 2R， 3R， 4S) -methyl 3- ( (tert-butoxycarbonyl) amino) bicyclo [2.2.2] oct-5-ene-2-carboxylate and (1S， 2S， 3S， 4R) -methyl 3-( (tert-butoxycarbonyl) amino) bicyclo [2.2.2] oct-5-ene-2-carboxylate (1 g， 3.5 mmol) in DCM (20 mL) was added ZnEt₂ (1 M in hexane， 8.0 mL) drop wise at 0 ℃. After the mixture was stirred at 0℃ for15 min， CH₂l₂ (1.5 mL， 18.5 mmol) and additional ZnEt₂ (1 M in hexane， 8.0 mL) were added drop wise to the above mixture and 5 min later， one additional portion of CH₂l₂ (1.5 mL， 18 5 mmol) was added at 0℃. The resulting reaction mixture was then allowed to slowly warm up to room temperature and stirred for 2 h. The reaction was quenched with saturated aqueous NH₄Cl solution and then extracted with DCM. The organic layer was washed with brine， dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude racemic mixture of title compound (2 g) as white solid. MS： 296.2 [M+H] ⁺. This crude product was used directly in the next step without further purification.

[B] (rac) - (1S， 2R， 4S， 5R， 6R， 7R) -Methyl 7-aminotricyclo [3.2.2.02， 4] nonane-6-carboxylate

To a stirred solution of racemic mixture of (1S， 2R， 4S， 5R， 6R， 7R) -methyl 7- ( (tert-butoxycarbonyl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate and (1R， 2S， 4R， 5S， 6S， 7S) -methyl 7- ( (tert-butoxycarbonyl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate (19.5 g， 66 mmol) in DCM (100 mL) was added TFA (118 g， 80 mL， 1.04 mol) and the resulting reaction mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure to give a crude racemic mixture of title compound (20.4 g) as yellow oil. MS： 196.1 [M+H] ⁺. This crude product was used directly in the next step without further purification.

[C] (rac) - (1R， 2S， 4R， 5S， 6S， 7S) -Methyl 7- ( (2- (5-chloro-1-tosyl-1H-pyrrolo [2， 3-b] pyridin-3-yl) - 7-tosyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate

A stirred mixture solution of (rac) - (1S， 2R， 4S， 5R， 6R， 7R) -methyl 7-aminotricyclo [3.2.2.02， 4] nonane-6-carboxylate (1.8 g， 9.22 mmol) ， 2， 4-dichloro-7-tosyl-7H-pyrrolo [2， 3-d] pyrimidine (3 g， 8.77 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.7 g， 13.2 mmol) in THF (40 mL) was heated at 80 ℃ for 16 h. After cooling to room temperature， the solvent was evaporated under reduced pressure to give a crude product， which was then purified by silica-gel flash chomatography (0 to 40％EtOAc-petroleum ether gradient) to afford the title compound (3.5 g， 79.7％yield) as white foam. MS： 501.1 (M+1) ⁺.

Intermediate B-2a and B-2b

(+) - (1R， 2S， 4R， 5S， 6S， 7S) -methyl 7- ( (2-chloro-7-tosyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate and (-) - (1S， 2R， 4S， 5R， 6R， 7R) -methyl 7- ( (2-chloro-7-tosyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate

SFC chiral separation (DAICEL， IC， 250 x 30 mm， 5 μm column， 40％MeOH in CO₂) of Intermediate B-2 (3 g) afforded the enantiomeric title compound (+) - (1R， 2S， 4R， 5S， 6S， 7S) -methyl 7- ( (2-chloro-7-tosyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate (1.38 g， 92％yield) as a light yellow solid， MS： 501.1 (M+H) ⁺ and (-) -(1S， 2R， 4S， 5R， 6R， 7R) -methyl 7- ( (2-chloro-7-tosyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate (1.41 g， 94％yield) as another light yellow solid. MS： 501.1 (M+H) ⁺.

Intermediate B-3

(rac) - (2S， 3S) -Methyl 3- ( (6-chloro-1-tosyl-1H-pyrazolo [3， 4-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate

[A] 4， 6-Dichloro-1-tosyl-1H-pyrazolo [3， 4-d] pyrimidine

To a stirred mixture solution of 4， 6-dichloro-1H-pyrazolo [3， 4-d] pyrimidine (4.2 g， 22.2 mmol) and Cs₂CO₃ (7.24 g， 22.2 mmol) in DMF (5 mL) was added 4-methylbenzene-1-sulfonyl chloride (3.39 g， 17.8 mmol) at 0 ℃. After the addition， the reaction mixture was allowed to warm up to room temperature and strirred for 12 h. The reaction mixture was then extracted with EtOAc (100 mL) and the organic layer was washed with brine， dried over anhydrous Na₂SO₄， filtered and concentrated in vacuo to give a crude product， which was purified by silica gel flash chomatography (0-80％EtOAc-hexane gradient) to afford the title compound (800 mg， 10.5％yield) as a white solid. MS： 343.1 [M+H] ⁺.

[B] (2S， 3S) -Methyl 3- ( (6-chloro-1-tosyl-1H-pyrazolo [3， 4-d] pyrimidin-4- yl) amino) bicyclo [2.2.2] octane-2-carboxylate

To a stirred solution of 4， 6-dichloro-1-tosyl-1H-pyrazolo [3， 4-d] pyrimidine (800 mg， 2.33 mmol) in THF (5 mL) was added (rac) - (2S， 3S) -methyl 3-aminobicyclo [2.2.2] octane-2-carboxylate (427 mg， 233 mmol) and DIPEA (904 mg， 6.99 mmol) and the resulting reaction mixture solution was stirred at 92 ℃ for 12 h. After cooling to the room temperature， the reaction mixture was poured into water (100 mL) and extracted with EtOAc (150 mL twice) . The combined organic layers were washed with brine， dried over anhydrous Na₂SO₄， filtered and concentrated in vacuo to give a crude product， which was purified by silica gel flash chomatography (0-40％EtOAc-hexane gradient) to afford the title compound (600 mg， 52.5％yield) as a yellow solid. MS： 490.1 [M+H] ⁺.

Intermediate B-4

(rac) - (2S， 3S) -Methyl 3- ( (6-chloro-1-methyl-1H-pyrazolo [3， 4-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate

[A] 4， 6-dichloro-1-methyl-1H-pyrazolo [3， 4-d] pyrimidine

To a stirred solution of 2， 4， 6-trichloropyrimidine-5-carbaldehyde (18.5 g， 88.1 mmol) in EtOH (250 mL) was added methyl hydrazine (6.8 g， 88.1 mmol， 60％in water) and Et₃N (26.7 g， 264.4 mmol) at-70℃ and stirred for 30 min before it was allowed to warm up to 0℃ and stirred for another 2 h. After TLC (petroleum ether∶EtOAc ＝ 5∶1) showed that the reaction was completed， the mixture solution was concentrated in vacuo at room temperature. EtOAc (200 mL) was added and the resulting solution was washed washed with saturated aqueous NaHCO₃ solution and brine. The organic layer was dried over anhydrous Na₂SO₄， filtered， and concentrated in vaouoto give a crude product， which was purified by silica gel flash chomatography (petroleum ether∶EtOAc ＝ 20∶1) to afford title compound (8 g， 44.9％yield) as a white solid. MS： 203.2 [M+H] ⁺.

[B] (rac) - (2S， 3S) -Methyl 3- ( (6-chloro-1-methyl-1H-pyrazolo [3， 4-d] pyrimidin-4- yl) amino) bicyclo [2.2.2] octane-2-carboxylate

To a stirred solution of (rac) - (2S， 3S) -methyl 3-aminobicyclo [2.2.2] octane-2-carboxylate (500 mg， 2.73 mmol) in THF (15 mL) was added 4， 6-dichloro-1-methyl-1H-pyrazolo [3， 4-d] pyrimidine (665 mg， 3.28 mmol) nd DIPEA (1.058 g， 8.19 mmol) and the resulting reaction mixture solution was stirred at 80℃ for 36 h. After TLC (petroleum ether∶ EtOAc ＝ 3∶ 1) showed that the reaction was completed， the solvent was removed under reduced pressure to give a crude product， which was then purified by silica gel flash chomatography (petroleum ether∶EtOAc， 10∶1 to 1∶1 gradient) with Petroleum ether∶ EtOAc from 10∶1 to 1∶1 to afford the title compound (200 mg， 21％yield) as a white solid. MS： 350.1 [M+H] ⁺

Intermediate B-5

(rac) - (2S， 3S) -Methyl 3- ( (2-chloro-9-tosyl-9H-purin-6-yl) amino) bicyclo [2.2.2] octane-2-carboxylate

[A] 2， 6-dichloro-9-sulfanyl-purine

To a stirred mixture solution of 2， 6-dichloro-9H-purine (23 g， 122 mmol) and Cs₂CO₃ (43.6 g， 134 mmol) in DMF (150 mL) was added 4-methylbenzene-1-sulfonyl chloride (27.8 g， 146 mmol) at 0 ℃. After the addition， the reaction mixture was allowed to warm up to room temperature and stirred for 12 h. The reaction mixture was then extracted with EtOAc (100 mL) and the organic layer was washed with brine， dried over anhydrous Na₂SO₄， filtered and concentrated in vacuo to give a crude product， which was purified by silica gel flash chomatography (0-80％EtOAc-hexane gradient) to afford the title compound (36 g， 86.2％ yield) as a light yellow solid. MS： 343.1 [M+H] ⁺.

[B] (rac) - (2S， 3S) -Methyl 3- ( (2-chloro-9-tosyl-9H-purin-6-yl) amino) bicyclo [2.2.2] octane-2- carboxylate

To a stirred solution of 2， 6-dichloro-9-tosyl-9H-purine (6.46 g， 18.8 mmol) in THF (35 mL) was added (rac) - (2S， 3S) -methyl 3-aminobicyclo [2.2.2] octane-2-carboxylate (2.3 g， 12.6 mmol) and DIPEA (4.87 g， 6.58 mL， 37.7 mmol) and the resulting reaction mixture solution was stirred at 92 ℃ for 12 h. After cooling to the room temperature， the reaction mixture was poured into water (100 mL) and extracted with EtOAc (150 mL twice) . The combined organic layers were washed with brine， dried over anhydrous Na₂SO₄， filtered and concentrated in vacuo to give a crude product， which was purified by silica gel flash chomatography (0-40％EtOAc-hexane gradient) to afford the title compound (2g， 32.5％ yield) as yellow oil. MS： 490.1 [M+H] ⁺.

Intermediate B-6

(rac) -Methyl (2S， 3S) -3- [ (2-chloro-5， 6， 7， 8-tetrahydfoquinazolin-4-yl) amino] bicyclo [2.2.2] octane-2-carboxylate

To a stirred solution of 2， 4-dichloro-5， 6， 7， 8-tetrahydroquinazoline (2.2 g， 10.8 mmol) in THF (5 mL) was added (rac) - (2S， 3S) -methyl 3-aminobicyclo [2.2.2] octane-2-carboxylate (1.99 g， 10.8 mmol) and DIPEA (4.2 g， 5.68 mL， 32.5 mmol) and the resulting reaction mixture solution was stirred at 70 ℃ for 12 h. After cooling to room temperature， the reaction mixture was poured into water (100 mL) and extracted with EtOAc (150 mL twice) . The combined organic layers were washed with brine， dried over anhydrous Na₂SO₄， filtered and concentrated in vacuo to give a crude product， which was purified by silica gel flash chomatography (0-40％EtOAc-hexane gradient) to afford the title compound (1 g， 26.4％ yield) as white foam. MS： 350.1 [M+H] ⁺.

Intermediate B-7

(rac) -Methyl (2S， 3S) -3- [ (2-chloro-5， 7-dihydrofuro [3， 4-d] pyrimidin-4-yl) amino] bicyclo [2.2.2] octane-2-carboxylate

To a stirred solution of 2， 4-dichloro-5， 7-dihydrofuro [3， 4-d] pyrimidine (870 mg， 4.55 mmol) in THF (5 mL) was added (rac) - (2S， 3S) -methyl 3-aminobicyclo [2.2.2] octane-2-carboxylate (835 mg， 4.55 mmol) and DIPEA (1.77 g， 13.7 mmol) and the resulting reaction mixture was stirred at 70℃ for 12 h. After cooling to room temperature， the reaction mixture was poured into water (100 mL) and extracted with EtOAc (150 mL twice) . The combined organic layers were washed with brine， dried over anhydrous Na₂SO₄， filtered and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (0-40％ EtOAc-hexane gradient) to afford the title compound (770 mg， 50％yield) as yellow oil. MS： 338.1 [M+H] ⁺.

Intermediate B-8

(rac) - (1R， 2S， 4R， 5S， 6S， 7S) -Methyl 7- ( (6-chloro-1-methyl-1H-pyrazolo [3， 4-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate

To a stirred solution of (rac) - (2S， 4R， 6S， 7S) -methyl 7-aminotricyclo [3.2.2.02， 4] nonane-6-carboxylate (3.4 g， 17.4 mmol) in THF (150 mL) was added 4， 6-dichloro-1-methyl-1H-pyrazolo [3， 4-d] pyrimidine (4.24 g， 20.9 mmol) and (3.38 g， 4.52 ml， 26.1 mmol) at room temperature and the resulting reaction mixture solution was stirred at 60 ℃ for 16 h. After cooling to room temperature， the reaction mixture was poured into water (100 mL) and extracted with EtOAc (150 mL twice) . The combined organic layers were washed with brine， dried over anhydrous Na₂SO₄， filtered and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (0-100％EtOAc-hexane gradient) to afford the title racemic compound (4.1 g， 65.1％yield) as a white solid. MS： 362.0 [M+H] ⁺.

Intermediates B-8a and B-8b

SFC chiral separation (Chiral Pak， IC-H， 250 x 30 mm， 5 μm column， 40％methanol in CO₂) of Intermediate B-8 then afforded enantiomers (-) - (1R， 2S， 4R， 5S， 6S， 7S) -methyl 7- ( (6-chloro-1-methyl-1H-pyrazolo [3， 4-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate and (+) - (1S， 2R， 4S， 5R， 6R， 7R) -methyl 7- ( (6-chloro-1-methyl-1H-pyrazolo [3， 4-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate as white solids.

Intermediate B-9

(rac) - (1R， 2S， 4R， 5S， 6S， 7S) -Methyl 7- ( (2-chloro-7-methyl-7H-purin-6-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate

To a stirred mixture solution of 2， 6-dichloro-7-methyl-7H-purine (780 mg， 3.84 mmol) in THF (35 mL) was added (rac) - (1R， 2S， 4R， 5S， 6S， 7S) -methyl 7-aminotricyclo [3.2.2.02， 4] nonane-6-carboxylate (500 mg， 2.56 mmol) and DIPEA (993 mg， 1.34 mL， 7.68 mmol) at room temperature and the resulting reaction mixture solution was stirred at 92 ℃ for 12 h. After cooling to room temperature， the reaction mixture was poured into water (100 mL) and extracted with EtOAc (150 mL twice) . The combined organic layers were washed with brine， dried over anhydrous Na₂SO₄， filtered and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (0-40％EtOAc-hexane gradient) to afford the title compound (600 mg， 64.8％yield) as a white solid. MS： 362.1 (M+H) ⁺.

Intermediates B-10a and B-10b

(+) - (1S， 2R， 4S， 5R， 6R， 7R) -Methyl 7- ( (2-chloro-9-methyl-9H-purin-6-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate and (-) - (1R， 2S， 4R， 5S， 6S， 7S) -methyl 7- ( (2-chloro-9-methyl-9H-purin-6-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate

To a stirred mixture solution of 2， 6-dichloro-9-methyl-9H-purine (7.8 g， 38.4 mmol) in THF (35 mL) was added (rac) - (1R， 2S， 4R， 5S， 6S， 7S) -methyl 7-aminotricyclo [3.2.2.02， 4] nonane-6- carboxylate (5 g， 25.6 mmol) and DIPEA (9.93 g， 13.4 mL， 76.8 mmol) at room temperature and the resulting reaction mixture was stirred at 92 ℃ for 12 h. After cooling to room temperature， the reaction mixture was poured into water (100 mL) and extracted with EtOAc (150 mL twice) . The combined organic layers were washed with brine， dried over anhydrous Na₂SO₄， filtered and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (0-80％EtOAc-hexane gradient) to afford the title compound (7.3 g， 78.8％yield) as a yellow solid. Subsequent SFC chiral separation (DAICEL， IC， 250 x 30 mm， 5 μm column， 40％MeOH in CO₂) then afforded the title enantiomeric compound (+) - (1S， 2R， 4S， 5R， 6R， 7R) -methyl 7- ( (2-chloro-9-methyl-9H-purin-6-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate (3.4g) as a yellow solid， MS： 362.1 (M+H) ⁺， and (-) - (1R， 2S， 4R， 5S， 6S， 7S) -methyl 7- ( (2-chloro-9-methyl-9H-purin-6-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate (3.5 g) as another yellow solid. MS： 362.1 [M+H] ⁺.

Intermediates B-11a and B-11b

(+ or-) (2S， 4R， 6S， 7S) -Methyl 7- ( (2-chloro-7-methyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate and (-or +) (2R， 4S， 6R， 7R) -methyl 7- ( (2-chloro-7-methyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate

A mixture solution of 2， 4-dichloro-7-methyl-7H-pyrrolo [2， 3-d] pyrimidine (5.69 g， 28.2 mmol (rac) - (2S， 4R， 6S， 7S) -methyl 7-aminotricyclo [3.2.2.02， 4] nonane-6-carboxylate (5 g， 25.6 mmol) and DIPEA (3.97 g， 30.7 mmol) in THF (5 mL) was stirred at 60 ℃ for 16 h. After cooling to room temperature， the solvent was removed under reduced pressure and the crude product was purified by silica gel flash chromatography (EtOAc： petroleum ether ＝ 0 to 60％gradient) to give a racemic mixture of the product (6 g， 64.9％yield) . MS： 361.2 [M+H] ⁺. Subsequent chiral separation by SFC afforded the enantiomeric title compounds (+ or -) (2S， 4R， 6S， 7S) -methyl 7- ( (2-chloro-7-methyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate and (-or +) - (2R， 4S， 6R， 7R) -methyl 7- ( (2-chloro-7-methyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate， both as yellow oils. MS： 361.2 [M+H] ⁺.

Example 1

(rac) - (2S， 3S) -3- ( (2- (5-Fluoro-1H-pyrazolo [3， 4-b] pyridin-3-yl) -7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

[A] (rac) - (2S， 3S) -Methyl 3- ( (2- (5-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3， 4- b] pyridin-3-yl) -7-tosyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2- carboxylate

To a stirred mixture solution of (rac) - (2S， 3S) -methyl 3- ( (2-chloro-7-tosyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (Intermediate B-1， 350 mg， 716 μmol) and Pd (PPh₃) ₄ (82.7 mg， 71.6 μmol) in dioxane (4 mL) was added 1， 1， 1， 2， 2， 2- hexabutyldistannane (623 mg， 1.07 mmol) and the resulting reaction mixture solution was stirred at 125 ℃ for 2 h before it was cooled back to room temperature. To the above mixture was then added 5-fluoro-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3， 4-b] pyridine (Intermediate A-1， 373 mg， 1.07 mmol) and Pd (PPh₃) ₄ (82.7 mg， 71.6 μmol) in dioxane (16 mL) and the combined mixture solution was heated at 145 ℃ for 1 h under microwave heating. After cooling to room temperature， the reaction mixture was poured into water (20 mL) and extracted with EtOAc (50 mL twice) . The combined organic layers were washed with brine， dried over anhydrous Na₂SO₄， filtered and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (0-80％EtOAc-hexane gradient) to afford the title compound (100 mg， 20.7％yield) as yellow oil. MS： 674.1 [M+H] ⁺.

[B] (rac) - (2S， 3S) -3- ( (2- (5-Fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3， 4-b] pyridin-3- yl) -7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

To a stirred solution of (rac) - (2S， 3S) -methyl 3- ( (2- (5-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3， 4-b] pyridin-3-yl) -7-tosyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (100 mg， 148 μmol) in THF (4mL) and MeOH (2 mL) was added LiOH (17.8 mg， 742 μmol) in water (1 mL) . The reaction mixture solution was stirred at room temperature for 12 h before it was diluted with water (10 mL) and extracted with diethyl ether (20 mL) The separated aqueous layer was then acidified with concentrated hydrochloric acid to pH 4 and extracted with EtOAc (40 mL x 3) . The combined orgarics were dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude title compound (75 mg， 100％yield) as yellow oil. MS： 506.1 [M+H]⁺. This crude product was used directly in the next step without further purification.

[C] (rac) - (2S， 3S) -3- ( (2- ( 5-Fluoro-1H-pyrazolo [3， 4-b] pyridin-3-yl) -7H-pyrrolo [2， 3-d] pyrimidin- 4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

To a stirred solution of (rac) - (2S， 3S) -3- ( (2- (5-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3， 4-b] pyridin-3-yl) -7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (194 mg， 384 μmol) in DCM (3 mL) was added 2， 2， 2-trifluoroacetic acid (4.44 g， 38.9 mmol) at room temperature and stirred for 12 h. Afterwards， the reaction mixture was concentrated in vacuo to give a crude product， which was purified by Prep-HPLC to afford the title compound (20 mg， 12.4％yield) as white foam. MS： 422.1 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) δ 8.84-8.92 (m， 1H) ， 8.47-8.56 (m， 1H) ， 7.09-7.17 (m， 1H) ， 6.67-6.77 (m， 1H) ， 5.06-5.15 (m， 1H) ， 2.75-2.84 (m， 1H) ， 2.08-2.19 (m， 1H) ， 1.85-2.06 (m， 3H) ， 1.46-1.85 (m， 6H) .

Example 2

(-) - (2S， 3S) -3- ( (2- (5-Fluoro-1H-pyrazolo [3， 4-b] pyridin-3-yl) -7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

In analogy to the synthesis of Example 1， (-) - (2S， 3S) -methyl 3- ( (2-chloro-7-tosyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (Intermediate B-1a， 350 mg， 716μmol) was used in step A， and followed by the same procedures step B and step C， the title compound (18 mg， 19.2％yield) was obtained as white foam after Prep-HPLC purification. MS： 422.1 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) δ 8.78-8.85 (m， 1H) ， 8.37-8.42 (m， 1H) ， 6.96-7.00 (m， 1H) ， 6.57-6.64 (m， 1H) ， 4.95-5.00 (m， 1H) ， 2.42-2.48 (m， 1H) ， 1.92-2.11 (m， 2H) ， 1.69-1.86 (m， 2H) ， 1.48-1.66 (m， 3H) ， 1.28-1.45 (m， 3H) .

Example 3

(rac) - (1R， 2S， 4R， 5S， 6S， 7S) -7- ( (2- (5-chloro-1H-pyrrolo [2， 3-b] pyridin-3-yl) -7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylic acid

[A] (rac) - (1R， 2S， 4R， 5S， 6S， 7S) -Methyl 7- ( (2- (5-chloro-1-tosyl-1H-pyrrolo [2， 3-b] pyridin-3-yl) - 7-tosyl-7H-pyrrolo [2.3-d] pyrimidin-4-yl)amino) tricyclo] 3.2.2.02，4] nonane-6-carboxylate

A stirred mixture solution of (rac) - (1R， 2S， 4R， 5S， 6S， 7S) -methyl 7- ( (2-chloro-7-tosyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate (Intermediate B-2， 250 mg， 499 μmol) ， 1， 1， 1， 2， 2， 2-hexabutyldistannane (347 mg， 599 μmol) and Pd (PPh₃) ₄ (100 mg， 86.5 μmol) in dioxane (10 mL) was heated at 125 ℃ for 3 h before it was cooled back to the room temperature. To the above solution was then adeed 5-chloro-3-iodo-1-tosyl-1H-pyrrolo [2， 3-b] pyridine (Intermediate A-4b， 281 mg， 649 μmol) ， Pd (PPh₃) ₄ (100 mg， 86.5 μmol) in dioxane (10 mL) and the resulting mixture was heated at 145 ℃ for 50 min under microwave heating. After cooling to room temperature， the solvent was evaporated under reduced pressure and the residue was purified by silica gel flash chromatography (0 to 80％EtOAc-petroleum ether gradient) to afford the title compound (100 mg， 26％yield) as yellow oil. MS： 772.1 (M+1) ⁺.

[B] (rac) - (1R， 2S， 4R， 5S， 6S， 7S) -7- ( (2- (5-Chloro-1H-pyrrolo [2， 3-b] pyridin-3-yl) -7H-pyrrolo [2， 3- d] pyrimidin-4-yl) amino) tricyclo[3.2.2.02， 4] nonane-6-carboxylic acid

A mixture solution of (rac) - (1R， 2S， 4R， 5S， 6S， 7S) -methyl 7- ( (2- (5-chloro-1-tosyl-1H-pyrrolo [2， 3-b] pyridin-3-yl) -7-tosyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate (200 mg， 259 μmol) and lithium hydroxide monohydrate (109 mg， 2.59 mmol) in THF (5 mL) and water (5 mL) was stirred at room temperature for 16 h before the reaction mixture was neutralized with TFA. Afterwards， the solvent was evaporated under reduced pressure to give a crude product， which was purified by Prep-HPLC to afford the title compound (20 mg， 17.2％yield) as white foam. MS： 449.1 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) δ 8.87-8.93 (m， 1H) ， 8.65-8.73 (m， 1H) ， 8.19-8.25 (m， 1H) ， 7.17-7.21 (m， 1H) ， 6.91-6.96 (m， 1H) ， 4.40-4.52 (m， 1H) ， 2.63-2.71 (m， 1H) ， 2.54-2.60 (m， 1H) ， 2.48-2.54 (m， 1H) ， 1.76-1.91 (m， 2H) ， 1.61-1.76 (m， 2H) ， 1.14-1.24 (m， 1H) ， 0.96-1.06 (m， 1H) ， 0.78-0.89 (m， 1H) ， 0.54-0.65 (m， 1H) .

Example 4

(rac) - (2S， 3S) -3- ( (6- (5-Fluoro-1H-pyrazolo [3， 4-b] pyridin-3-yl) -1H-pyrazolo [3， 4-d] pyrimidin-4-yl) amino) bicycio [2.2.2] octane-2-carboxylic acid

[A] (rac) - (2S， 3S) -Methyl 3- ( (6- (5-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3， 4- b] pyridin-3-yl) -1-tosyl-1H-pyrazolo [3， 4-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2- carboxylate

In analogy to the synthesis of Example 1/step A， (rac) - (2S， 3S) -methyl 3- ( (6-chloro-1-tosyl-1H-pyrazolo [3， 4-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (Intermediate B-3， 220 mg， 449μmol) was used to afford the title comppoud (70 mg， 23 . 1％yield) as yellow oil after silica gel flash chromatography (0-80％EtOAc-hexane gradient) purification. MS： 675.1 [M+H] ⁺.

[B] (rac) - (2S， 3S) -3- ( (6- (5-Fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3， 4-b] pyridin-3- yl) -1H-pyrazolo [3， 4-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

In analogy to the synthesis of Example 1/step B， (rac) - (2S， 3S) -methyl 3- ( (6- (5-fluoro-1-(tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3， 4-b] pyridin-3-yl) -1-tosyl-1H-pyrazolo [3， 4-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (70 mg， 104 μmol) was used to give a crude title compound (53 mg， 100％yield) as a yellow solid. MS： 507.1 [M+H] ⁺. This crude product was used directly in the next step without further purification.

[C] (rac) - (2S， 3S) -3- ( (6- (5-Fluoro-1H-pyrazolo [3， 4-b] pyridin-3-yl) -1H-pyrazolo [3， 4- d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

In analogy to the synthesis of Example 1/step C， (rac) - (2S， 3S) -3- ( (6- (5-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3， 4-b] pyridin-3-yl) -1H-pyrazolo [3， 4-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (54 mg， 107 μmol) was used to afford the title compound (5 mg， 11.1％yield) as white foam after Prep-HPLC purification. MS： 423.1 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) δ 8.81-8.97 (m， 1H) ， 8.45-8.67 (m， 1H) ， 8.06-8.31 (m， 1H) ， 5.13-5.31 (m， 1H) ， 2.68-2.82 (m， 1H) ， 2.11-2.20 (m， 2H) ， 1.96-2.11 (m， 1H) ， 1.67-1.96 (m， 6H) ， 1.52-1.62 (m， 1H) .

Example 5

(rac) - (1R， 2S， 4R， 5S， 6S， 7S) -7- ( (2- (5-Chloro-1H-pyrazolo [3， 4-b] pyridin-3-yl) -7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylic acid

[A] (rac) - (1R， 2S， 4R， 5S， 6S， 7S) -Methyl 7- ( (2- (5-chloro-1- ( (2- (trimethylsilyl) ethoxy) methyl) - 1H-pyrazolo [3， 4-b] pyridin-3-yl) -7-tosyl-7H-pyrrolo [2， 3-d] pyrimidin-4- yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate

In analogy to the synthsis of Example 3/step A， 5-chloro-3-iodo-1- ( (2-(trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3， 4-b] pyridine (Intermediate A-2， 266 mg， 649 μmol) was used to afford the title compound (100 mg， 26.8％yield) as yellow oil after silica gel flash chromatography (0-80％EtOAc-petroleum ether gradient) purification. MS： 749.1 (M+1) ⁺.

[B] (rac) - (1R， 2S， 4R， 5S， 6S， 7S) -7- ( (2- (5-Chloro-1H-pyrazolo [3， 4-b] pyridin-3-yl) -7H- pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylic acid

A mixture solution of (1R， 2S， 4R， 5S， 6S， 7S) -methyl 7- ( (2- (5-chioro-1 - ( (2-(trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3， 4-b] pyridin-3-yl) -7-tosyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate (200 mg， 267 μmol) and lithium hydroxide monohydrate (112 mg， 2.67 mmol) in THF (5 mL) and water (5 mL) was stirred at room temperature for 16 h. Afterwards， the solvent was removed under reduced pressure and the residue was dissolved in TFA (10 mL) and stirred at room temperature for 16 h. Afterwards， the volatile was evaporated under reduced pressure to give a crude product， which was purified by Prep-HPLC to afford the title compound (10 mg， 8.32％yield) as white foam. MS： 450.1 (M+1) ⁺. ¹H NMR (400 MHz， MeOH-d4) δ 8.97-9.03 (m， 1H) ， 8.38-8.46 (m， 1H) ， 6.99-7.07 (m， 1H) ， 6.59-6.68 (m， 1H) ， 4.64-4.73 (m， 1H) ， 2.59-2.64 (m， 1H) ， 2.50-2.58 (m， 1H) ， 2.38-2.47 (m， 1H) ， 1.80-1.92 (m， 1H) ， 1.50-1.76 (m， 3H) ， 0.99-1.09 (m， 1H) ， 0.92-0.99 (m， 1H) ， 0.77-0.88 (m， 1H) ， 0.31-0.43 (m， 1H) .

Example 6

(rac) - (2S， 3S) -3- ( (2- (5-Fluoro-1H-pyrazolo [3， 4-b] pyridin-3-yl) -9H-purin-6-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

[A] (rac) - (2S， 3S) -Methyl 3- ( (2- (5-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3， 4- b] pyridin-3-yl) -9-tosyl-9H-purin-6-yl) amino) bicyclo [2.2.2] octane-2-carboxylate

In analogy to the synthesis of Example 1/step A， (rac) - (2S， 3S) -methyl 3- ( (2-chloro-9-tosyl-9H-purin-6-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (Intermediate B-5， 220 mg， 449 μmol) was used to afford the title compound (100 mg， 33％yield) as yellow oil after silica gel flash chromatography (0-80％EtOAc-hexane gradient) purification. MS： 675.1 [M+H] ⁺.

[B] (rac) - (2S， 3S) -3- ( (2- (5-Fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3， 4-b] pyridin-3- yl) -9H-purin-6-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

In analogy to the synthesis of Example 1/step B， (rac) - (2S， 3S) -methyl 3- ( (2- (5-fluoro-1-(tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3， 4-b] pyridin-3-yl) -9-tosyl-9H-purin-6-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (100 mg， 0.0148 mmol) was used to give a crude title compound (76 mg， 100％yield) as a yellow solid. MS： 507.1 [M+H] ⁺. This crude product was used directly in the next step without further purification.

[C] (rac) - (2S， 3S) -3- ( (2- (5-Fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3， 4-b] pyridin-3- yl) -9H-purin-6-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

In analogy to the synthesis of Example 1/step C， (rac) - (2S， 3S) -3- ( (2- (5-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3， 4-b] pyridin-3-yl) -9H-purin-6-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (76 mg， 150 μmol) was used to afford the title compound (1.9 mg， 3％yield) as white foam after Prep-HPLC purification. MS： 423.2 [M+H] ⁺.

Example 7

(rac) - (2S， 3S) -3- ( (6- (5-Fluoro-1H-pyrazolo [3， 4-b] pyridin-3-yl) -1-methyl-1H-pyrazolo [3， 4-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

[A] (rac) - (2S， 3S) -Methyl (2R， 3R) -methyl 3- ( (6- (5-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H- pyrazolo [3， 4-b] pyridin-3-yl) -1-methyl-1H-pyrazolo [3， 4-d] pyrimidin-4- yl) amino) bicyclo [2.2.2] octane-2-carboxylate

ln a sealed tube， a mixture solution of (rac) - (2S， 3S) -methyl 3- ( (6-chloro-1-methyl-1H-pyrazolo [3， 4-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (Intermediate B-4， 82 mg， 0.235 mmol) ， 5-fluoro-1- (tetrahydro-2H-pyran-2-yl) -3- (tributylstannyl) -1H-pyrazolo [3， 4-b] pyridine (100 mg， 0.196 mmol) ， Pd₂ (dba) ₃ (27 mg， 0.029 mmol) ， X-Phos (14 mg， 0.029 mmol) and Cul (6 mg， 0.029 mmol) was stirred at 140 ℃ for 3 h under microwave heating. After cooling to room temperature， the reaction mixture was concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (petroleum ether∶EtOAc＝5∶1 to DCM∶MeOH＝20∶1) to afford the title compound (60 mg) as a yellow solid. MS： 535.2 [M+H]⁺.

[B] (rac) - (2R， 3R) -3- ( (6- (5-Fluoro-1H-pyrazolo [3， 4-b] pyridin-3-yl) -1-methyl-1H-pyrazolo [3， 4- d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

A mixture solution of (rac) - (2R， 3R) -methyl 3- ( (6- (5-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3， 4-b] pyridin-3-yl) -1-methyl-1 H-pyrazolo [3， 4-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (80 mg， 0.15 mmol) in HCl/MeOH (4 N， 10 mL) was stirred at 100 ℃ for 12 h. After cooling to room temperature， the reaction mixture was concentrated in vacuo to give a crude product， which was purified by Prep-HPLC to afford the title compound (12 mg， 18.5％yield) as a white solid. MS： 437.2 [M+H] ⁺. ¹H NMR(400MHz， CHCl₃-d1) δ 8.60-8.75 (m， 2H) ， 8.40 (brs， 0.5 H) ， 8.18-8.22 (m， 2H) ， 4.80-4.90 (m， 1H) ， 4.00-4.06 (m， 2H) ， 3.98 (s， 3H) ， 2.01-2.06 (m， 2H) ， 1.75-1.81 (m， 3H) ， 1.75-1.81 (m， 3H) ， 1.57-1.62 (m， 3H) ， 1.40-1.46 (m， 2H) .

Example 8

(rac) - (1R， 2S， 4R， 5S， 6S， 7S) -7- ( (2- (5-Fluro-1H-pyrrolo [2， 3-b] pyridin-3-yl) -7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylic acid

[A] 5-Fluoro-3- (4， 4， 5， 5-tetramethyl- 1， 3， 2-dioxaborola n-2-yl) -1 - ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2， 3-b] pyridine

To a stirred solution of 5-fluoro-3-iodo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2， 3-b] pyridine (Intermediate A-3， 6 g， 15 mmol) in THF (100 mL) was added i-PrMgCl. LiCl (23 mL， 30 mmol) slowly at -20 ℃. After the addition， the reaction mixture was stirred at 0 ℃ for 1 h before 2-methoxy-4， 4， 5， 5-tetramethyl-1， 3， 2-dioxaborolane (4.2 g， 27.0 mmol) was added and the resulting reatin mixture was stirred at 0℃ for additional 3 h. After TLC (petroleum ether∶EtOAc＝10∶1) showed that the reaction was completed， the reaction was quenched with saturated aqueous NH₄Cl solution (1 00 mL) ， poured into water and extracted with EtOAc (200 mL twice) . The combined organics were washed with bnne， d ried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (petroleum ether∶EtOAc＝20∶1 to 5∶1) to afford the title conpound (3.5 g ， 60 3％yield) as yellow oil. MS： 393.2 [M+H] ⁺.

[B] (rac) - (1R， 2S， 4R， 5S， 6S， 7S) -Methyl 7- ( (2- (5-fluoro-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H- pyrrolo [2， 3-b] pyridin-3-yl) -7-tosyl-7H-pyrrolo [2， 3-d] pyrimidin-4- yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate

To a stirred solution of 5-fluoro-3- (4， 4， 5， 5-tetramethyl-1， 3， 2-dioxaborolan-2-yl) -1- ( (2-(trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2， 3-b] pyridine (1 g， 2.54 mmol) and (rac) -(1R， 2S， 4R， 5S， 6S， 7S) -methyl 7- ( (2-chloro-7-tosyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate (Intermediate B-2， 1 g， 2 mmol) in THF (20 mL) was added X-phos biphenyl (156 mg， 0.2 mmol) ， K₃PO₄ (840 mg， 4.0 mmol) and H₂O (4.0 mL) and the resulting mixture was stirred at 60 ℃ for 12 h. After LC-MS showed that the reaction was completed， the mixture solution was extracted with EtOAc (200 mL x 3) . The combined organics were dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (DCM∶MeOH ＝ 100∶1 to 30∶1) to afford the title compound (1.2 g， 82.2％yield) as a white solid. MS： 731.2 [M+H] ⁺.

[C] (rac) - (1R， 2S， 4R， 5S， 6S， 7S) -Methyl 7- ( (2- (5-fluoro-1H-pyrrolo [2， 3-b] pyridin-3-yl) -7H- pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate

A solution of (rac) - (1R， 2S， 4R， 5S， 6S， 7S) -methyl 7- ( (2- (5-fluoro-1- ( (2-(trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2， 3-b] pyridin-3-yl) -7-tosyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate (730 mg， 1 mmol) in TBAF/THF solution (1 0 mL， 20 mmol) was stirred at 80℃ for 4 h. After cooling to room temperature， the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3) . Combined organics were dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (DCM∶MeOH＝100∶1～20∶1) to afford the title compound (300 mg， 67.2％yield) as a yellow solid. MS： 447.2 [M+H]⁺.

[D] (rac) - (1R， 2S， 4R， 5S， 6S， 7S) -7- ( (2- (5-Fluoro-1H-pyrrolo [2， 3-b] pyridin-3-yl) -7H-pyrrolo [2， 3- d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylic acid

To a stirred solution of (rac) - (1R， 2S， 4R， 5S， 6S， 7S) -methyl 7- ( (2- (5-fluoro-1H-pyrrolo [2， 3-b] pyridin-3-yl) -7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate (270 mg， 0.60 mmol) in THF/H₂O (20 mL， 1∶1) was added LiOH (43.0 mg， 1.8 mmol) and the reaction mixture was stirred at room temperature for 12 h. After LC-MS showed that the reaction was completed， the mixture was neutralized with 1N aq. HCl solution and then concentrated in vacuo to give a crude product， which was purified by Prep-HPLC to afford the title compound (93 mg， 85.9％yield) as a white solid. MS： 433.2 [M+H] ⁺. ¹H NMR (400MHz， CHCl₃-d1) δ 8.85-8.81 (m ， 1H) ， 8.49 (s， 1H) ， 8.20-8.19 (m ， 2H) ， 7.10-7.09 (m， 1H) ， 6.77-6.76 (m， 1H) ， 5.02 (m， 1H) ， 2.68-2.67 (m， 1H) ， 2.56 (m， 1H) ， 2.47 (m， 1H) ， 1.77 (m， 1H) ， 1.55 (m， 2H) ， 1.35-1.26 (m， 1H) . 1.15-1.14 (m， 1H) ， 0.88-0.87 (m， 1H) ， 0.59-0.54 (m， 1 H) .

Example 9

(rac) - (2S， 3S) -3- ( (2- (5-Fluoro-1H-pyrazolo [3， 4-b] pyridin-3-yl) -5， 6， 7， 8-tetrahydroquinazolin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

[A] (rac) - (2S， 3S) -Methyl 3- ( (2- (5-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3，4- b] pyridin-3-yl) -5， 6， 7， 8-tetrahydroquinazolin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate

To a stirred mixture solution of (rac) - (2S， 3S) -methyl 3- ( (2-chloro-5， 6， 7， 8-tetrahydroquinazolin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (Intermediate B-6， 250 mg， 715 μmol) and Pd (PPh₃) ₄ (82.6 mg， 71.5 μmol) in dioxane (4 mL) was added 1， 1， 1， 2， 2， 2-hexabutyldistannane (497 mg， 450 μL， 857 μmol) and the resulting reaction mixture solution was stirred at 125 ℃ for 2 h before it was cooled back to room temperature. To the above mixture， it was then added 5-fluoro-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3， 4-b] pyridine (Intermediate A-1， 372 mg， 1.07 mmol) and Pd (PPh₃) ₄ (82.6 mg， 71.5 μmol) in dioxane (10 mL) . The resulting reaction mixture was stirred at 145 ℃ for 1 h under microwave heating. After cooling to room temperature， the reaction mixture was poured into water (20mL) and extracted with EtOAc (50 mL twice) . The combined organic layers were washed with brine， dried over anhydrous Na₂SO₄， filtered and concentrated in vacuo to give a crude product， which was purified by silica gel flash chomatography (0-80％EtOAc-hexane gradient) to afford the title compound (90 mg， 23.6％yield) as yellow oil. MS： 535.1 [M+H] ⁺.

[B] (rac) - (2S， 3S) -3- ( (2- (5-Fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3， 4-b] pyridin-3- yl) -5， 6， 7， 8-tetrahydroquinazolin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

To a stirred solution of (2S， 3S) -methyl 3- ( (2- (5-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3， 4-b] pyridin-3-yl) -5， 6， 7， 8-tetrahydroquinazolin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (180 mg， 337 μmol) in THF (6 mL) and MeOH (3 mL) was added LiOH (24.2 mg， 1.01 mmol) in water (3 mL) at room temperature and stirred for 12 h. Afterwards， the reaction mixture was diluted with water (10 mL) and extracted with diethyl ether (20 mL) . The separated aqueous layer was then acidified with concentrated hydrochloric acid to pH 4 and extracted with EtOAc (40 mL x 3) . The combined organics were dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude title compound (176 mg， 100％yield) . MS： 521.1 [M+H] ⁺. This crude product was used directly in the next step without further purification.

[C] (2S， 3S) -3- ( (2- (5-Fluoro-1H-pyrazolo [3， 4-b] pyridin-3-yl) -5， 6， 7， 8-tetrahydroquinazolin-4- yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

To a stirred solution of (2S， 3S) -3- ( (2- (5-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3， 4-b] pyridin-3-yl) -5， 6， 7， 8-tetrahyd roquinazolin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (176 mg， 338 μmol) in DCM (3 mL) was added 2， 2， 2-trifluoroacetic acid (4.44 g， 3 mL， 38.9 mmol) at room temperature and stirred for 12 h. Afterwards， the reaction mixture solution was concentrated in vacuo to give a crude product， which was purified by Prep-HPLC to afford the title compound (40mg， 27.1％yield) as white foam. MS： 437.1 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) δ 8.51-8.56 (m， 1H) ， 8.45-8.48 (m， 1H) ， 4.99-5.05 (m， 1H) ， 2.77-2.83 (m， 1H) ， 2.69-2.75 (m， 2H) ， 2.37-2.46 (m， 2H) ， 2.03-2.08 (m， 1H) ， 1.87-1.93 (m， 1H) ， 1.36-1.87 (m， 13H) .

Example 10

(rac) - (2S， 3S) -3- ( (2- (5-Fluoro-1H-pyrazolo [3， 4-b] pyridin-3-yl) -5， 7-dihydrofuro [3， 4-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

[A] (rac) - (2S， 3S) -Methyl 3- ( (2- (5-fiuoro-1 - (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3， 4- b] pyridin-3-yl) -5， 7-dihydrofuro [3， 4-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate

To a stirred mixture solution of (2S， 3S) -methyl 3- ( (2-chloro-5， 7-dihyurofuro [3， 4-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (Intermediate B-7， 250 mg， 740 μmol) and Pd (PPh₃) ₄ (85.5 mg， 74 μmol) in dioxane (4 mL) was added 1， 1， 1， 2，2， 2-hexabutyldistannane (515 mg， 466 μL， 888 μmol) and the resulting reaction mixture was stirred at 125 ℃ for 2 h before it was cooled back to room temperature. To the above mixture， it was then added 5-fluoro-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazoio [3， 4-b]pyridine (Intermediate A-1， 385 mg， 1.11 mmol) and Pd (PPh₃) ₄ (85.5 mg， 74 μmol) in dioxane (16 mL) and the resulting reaction mixture solution was stirred at 145 ℃ for 1 h under microwave heating. After cooling to room temperature， the reaction mixture was poured into water (20 mL) and extracted with EtOAc (50 mL twice) . The combined organic layers were washed with brine， dried over anhydrous Na₂SO₄， filtered and concentrated in vacuo to give a crude product， which was then purified by silica gel flash chromatography (0-100％EtOAc-hexane gradient) to afford the title compound (80 mg， 20.6％yield) as yellow oil. MS： 523.1 [M+H] ⁺.

[B] (rac) - (2S， 3S) -3- ( (2- (5-Fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3， 4-b] pyridin-3- yl) -5， 7-dihydrofuro [3， 4-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

To a stirred solution of (rac) - (2S， 3S) -methyl 3- ( (2- (5-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3， 4-b] pyridin-3-yl) -5， 7-dihydrofuro [3， 4-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (160 mg， 306 μmol) in THF (6 mL) and MeOH (3 mL) was added LiOH (22 mg， 919 μmol) in water (3 mL) at room temperature and stirred for 12 h. Afterwards， the reaction mixture was diluted with water (10 mL) and extracted with diethyl ether (20 mL) . The separated aqueous layer was then acidified with concentrated hydrochloric acid to pH ＝4 and extracted with EtOAc (40 mL x 3) . The combined organics were dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude title compound (156 mg， 100％yield) as a yellow solid. MS： 509.1 [M+H] ⁺. This crude product was used directly in the next step without further purification.

[C] (rac) - (2S， 3S) -3- ( (2- (5-Fluoro-1H-pyrazolo [3， 4-b] pyridin-3-yl) -5， 7-dihydrofuro [3， 4- d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

To a stirred solution of (2S， 3S) -3- ( (2- (5-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3， 4-b] pyridin-3-yl) -5， 7-dihydrofuro [3， 4-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (156 mg， 307 μmol) in DCM (3 mL) was added 2， 2， 2-trifluoroacetic acid (4.44 g， 38.9 mmol) at room temperature and stirred for 12 h. Afterwards， the reaction mixture solution was concentrated in vacuo to give a crude product， which was purified by Prep-HPLC to afford the title compound (30 mg， 23％yield) as white foam. MS： 425.1 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) δ 8.57-8.66 (m， 1H) ， 8.36-8.46 (m， 1H) ， 4.93-4.99 (m， 2H) ， 4.81-4.87 (m， 3H) ， 2.59-2.65 (m， 1H) ， 1.99-2.05 (m， 1H) ， 1.70-1.77 (m， 2H) ， 1.51-1.68 (m， 5H) ， 1.37-1.50 (m， 2H) .

Example 11

(+ or -) - (2S， 3S) -3- ( (2- (5， 7-Difluoro-1H-indazol-3-yl) -7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) -bicyclo [2.2.2] octane-2-carboxylic acid

[A] (+ or -) - (2S， 3S) -Methyl 3- ( (2- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) - 7-tosyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate

To a stirred mixture solution of (-) - (2S， 3S) -methyl 3- ( (2-chloro-7-tosyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (Intermediate B-1a， 350 mg， 716 μmol) and Pd (PPh₃) ₄ (82.7 mg， 71.6 μmol) in dioxane (4 mL) was added 1， 1， 1， 2， 2， 2-hexabutyldistannane (623 mg， 1.07 mmol) at room temperature and the reaction mixture solution was stirred at 125 ℃ for 2 h before it was cooled back to room temperature. To the above solution was then added 5， 7-difluoro-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (Intermediate A-5， 391 mg， 1.07 mmol) and Pd (PPh₃) ₄ (82.7 mg， 71.6 μmol) in dioxane (16 mL) . The resulting reaction mixture solution was stirred at 145 ℃ for 1 h under microwave heating. After cooling to room temperature， the reaction mixture was poured into water (20 mL) and extracted with EtOAc (50 mL x2) . The combined organics were washed with brine， dried over anhydrous Na₂SO₄， filtered and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (0-80％EtOAc-hexane gradient) to afford the title compound (120 mg， 24.3％yield) as yellow oil. MS： 691.1 [M+H] ⁺

[B] (+ or -) - (2S， 3S) -3- ( (2- (5， 7-Difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -7H- pyrrolo [2， 3-d] pyrimidin-4-yl)amino) bicyclo [2.2.2] octane-2-carboxylic acid

To a stirred mixture solution of (2S， 3S) -methyl 3- ( (2- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -7-tosyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (120 mg， 174 μmol) in THF (4mL) and MeOH (2 mL) was added LiOH (41.6 mg， 1.74 mmol) in water (1mL) . The reaction mixture solution was stirred at room temperature for 12 h before being diluted with water (10 mL) and extracted with diethyl ether (20 mL) . The separated aqueous layer was then acidified with concentrated HCl to pH ＝ 4 and extracted with EtOAc (40 mL x 3) . The combined organics were dried over anhydrous Na₂SO₄， filtered， and concentrated to give a crude title compound (90.8 mg， 100％yield) as yellow oil. MS： 523.1 [M+H] ⁺. This crude product was used directly in the next step without further purification.

[C] (+ or -) - (2S 3S) -3- ( (2- (5， 7-difluoro-1H-indazol-3-yl) -7H-pyrrolo [2， 3-d] pyrimidin-4- yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

To a stirred mixture solution of (2S， 3S) -3- ( (2- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (90 mg， 172 μmol) in DCM (3 mL) was added 2， 2， 2-trifluoroacetic acid (4.44 g， 3 mL， 38.9 mmol) at room temperature and stirred for 12 h. The reaction mixture was concentrated in vacuo to give a crude product， which was purified by Prep-HPLC to afford the title compound (1 mg， 1.32％yield) as white foam. MS： 439.1 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) δ 7.99-8.06 (m， 1H) ， 7.09-7.16 (m， 2H) ， 6.83-6.88 (m， 1H) ， 2.55-2.57 (m， 1H) ， 2.10-2.14 (m， 1H) ， 1.93-2.02 (m， 1H) ， 1.76-1.84 (m， 2H) ， 1.59-1.72 (m， 4H) ， 1.48-1.56 (m， 3H) .

Example 12

(+ or -) - (2S， 3S) -3- ( (2- (7-Fluoro-1H-pyrazolor4， 3-c] pyridin-3-yl) -7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

[A] (+ or -) - (2S， 3S) -Methyl 3- ( (2- (7-fluoro-1- (tetrahydro-2H-pyran-2-yl)-1H-pyrazolo [4， 3- c]pyridin-3-yl) -7-tosyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2- carboxylate

In analogy to the synthesis of Example 11/Step A， 7-fluoro-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [4， 3-c] pyridine (Intermediate A-6， 373 mg， 1.07 mmol) was used to obtain the title compound (110 mg， 22： 8％yield) as yellow oil after silica gel flash chomatography (0-80％EtOAc-hexane gradient) purification. MS： 674.1 [M+H] ⁺.

[B] (+ or -) - (2S， 3S) -3- ( (2- (7-Fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [4， 3-c] pyridin-3- yl) -7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

In analogy to the synthesis of Example 11/step B， (+ or -) - (2S， 3S) -methyl 3- ( (2- (7-fluoro-1-(tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [4， 3-c] pyridin-3-yl) -7-tosyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (120 mg， 178 μmol) was used to give a crude title compound (90 mg， 100％yield) as yellow oil. MS： 506.1 [M+H] ⁺. This crude product was used directly in the next step without further purification.

[C] (+ or -) - (2S， 3S) -3- ( (2- (7-fluoro-1H-pyrazolo [4， 3-c] pyridin-3-yl) -7H-pyrrolo [2， 3-d] pyrimidin- 4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

In analogy to the synthesis of Example 11/step C， (+ or -) - (2S， 3S) -3- ( (2- (7-fluoro-1-(tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [4， 3-c] pyridin-3-yl) -7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) bicyclo- [2.2.2] octane-2-carboxylic acid (90 mg， 178μmol) was used to afford the title compound (10 mg， 13％yield) as white foam after Prep-HPLC purification. MS： 422.1 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) δ 8.36-8.39 (m， 1H) ， 7.18-7.62 (m， 2H) ， 6.70-6.98 (m， 1H) ， 4.83-5.11 (m， 1H) ， 2.08-2.15 (m， 1H) ， 1.90-1.98 (m， 1H) ， 1.74-1.89 (m， 3H) ， 1.56-1.72 (m， 4H) ， 1.44-1.56 (m， 2H) .

Example 13

(+ or -) - (2S， 3S) -3- ( (2- (7-fluoro-1H-indazol-3-yl) -7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) -bicyclo [2.2.2] octane-2-carboxylic acid

[A] (+ or -) - (2S， 3S) -Methyl 3- ( (2- (7-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -7- tosyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate

In analogy to the synthesis of Example 11/Step A， 7-fluoro-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (Intermediate A-7， 372 mg， 1.07 mmol) was used to obtain the title compound (280 mg， 58.1％yield) as yellow oil after silica gel flash chromatography (0-80％EtOAc-hexane gradient) purification. MS： 673.1 [M+H] ⁺.

[B] (+ or -) - (2S， 3S) -3- ( (2- (7-Fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -7H- pyrrolo [2， 3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

In analogy to the synthesis of Example 11/step B， (+ or -) - (2S， 3S) -methyl 3- ( (2- (7-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -7-tosyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) bicycio [2.2.2] octane-2-carboxylate (280 mg， 416 μmol) was used to obtain a crude title compound (211mg， 100％yield) as yellow oil. MS： 505.1 [M+H] ⁺. This crude product was used directly in the next step without further purification.

[C] (+ or -) - (2S， 3S) -3- ( (2- (7-fluoro-1H-indazol-3-yl) -7H-pyrrolo [2， 3-d] pyrimidin-4- yl) amiro) bicyclo- [2.2.2] octane-2-carboxylic acid

In analogy to the synthesis of Example 11/step C， (+ or -) - (2S， 3S) -3- ( (2- (7-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (211 mg， 418 μmol) was used to obtain the title compound (18 mg， 10.2％yield) as white foam after Prep-HPLC purification. MS： 422.1 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) δ 8.33-8.53 (m， 1H) ， 6.94-7.26 (m， 3H) ， 6.54-6.70 (m， 1H) ， 4.87-5.07 (m， 1H) ， 2.58-2.78 (m， 1H) ， 1.94-2.10 (m， 2H) ， 1.67-1.94 (m， 4H) ， 1.33-1.67 (m， 5H) .

Example 14

(rac) - (2S， 3S) -3- [ [2- (7-fluoro-1H-indazol-3-yl) -7-methyl-pyrrolo [2， 3-d] pyrimidin-4-yl] amino] bicyclo [2.2.2] octane-2-carboxylic acid

[A] (rac) - (3S) -Methyl 3- ( (2- (7-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -7-methyl- 7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate

A mixture solution of (rac) - (2S， 3S) -methyl 3- ( (2-chloro-7-methyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (250 mg， 717 μmol) ， 1， 1， 1， 2， 2， 2-hexabutyldistannane (499 mg， 860 μmol) and Pd (PPh₃) ₄ (100 mg， 86.5 μmol) in dioxane (10 mL) was heated at 125 ℃ for 2 h before it was cooled back to room temperature. To the above solution， it was then added 7-fluoro-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (Intermediate A-7， 322 mg， 932 μmol) ， Pd (PPh₃) ₄ (100 mg， 86.5 μmol) in dioxane (10 mL) . The resulting mixture solution was then heated at 145 ℃ for 50 min under microwave heating. After cooling to room temperature， the solvent was removed under reduced pressure to give a crude product， which was purified by silica gel flash chromatography (petroleum ether： EtOAc ＝0 to 80％) to afford the title compound (40 mg， 10.5 ％yield) as yellow oil. MS： 533.2 [M+H] ⁺.

[B] (rac) - (2S 3S) -3- ( (2- (7-Fluoro-1H-indazol-3-yl) -7-methyl-7H-pyrrolo [2， 3-d] pyrimidin-4- yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

A mixture solution of (rac) - (2S， 3S) -methyl 3- ( (2- (7-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -7-methyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (40 mg， 75.1 μmol) and LiOH monohydrate (31.5 mg， 751 μmol) in THF (5 mL) and water (5 mL) was stirred at room temperature for 16 h. Afterwards， the solvent was removed under reduced pressure and the residue was re-dissolved in TFA (10 mL) at room temperature and stirred for 16h. After reaction mixture was concentrated in vacuo， the crude product was then purified by Prep-HPLC to afford the title compound (10 mg， 30.6 ％yield) as white foam. MS： 435.2 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) δ 8.41 (br d， J＝6.97 Hz， 1H) ， 6.89-7.23 (m， 3H) ， 6.64 (br s， 1H) ， 4.88 (br s， 1H) ， 3.79 (s， 3H) ， 2.63 (br s， 1H) ， 2.04 (br s， 1H) ， 1.97 (br s， 1H) ， 1.69-1.89 (m， 3H) ， 1.53-1.69 (m， 3H) ， 1.37-1.50 (m， 2H) .

Example 15

(rac) - (2S， 3S) -3- [ [2- (5， 7-difluoro-1H-indazol-3-yl) -7-methyl-pyrrolo [2， 3-d] pyrimidin-4-yl] amino] bicyclo [2.2.2] octane-2-carboxylic acid

[A] (rac) - (3S) -Methyl 3- ( (2- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -7- methyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate

In analogy to the synthesis of Example 14/Step A， 5， 7-difluoro-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (Intermediate A-5， 339 mg， 932 μmol) was used to afford the title compound (60 mg， 15.2％yield) as yellow oil after silica gel flash chromatography (petroleum ether： EtOAc ＝ 0 to 80％) purification. MS： 551.2 [M+H] ⁺.

[B] (rac) - (2S， 3S) -3- ( (2- (5， 7-difluoro-1H-indazol-3-yl) -7-methyl-7H-pyrrolo [2， 3-d] pyrimidin-4- yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

In analogy to the synthesis of Example 14/Step B， (rac) - (2S， 3S) -methyl 3-( (2- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) - 1H-indazol-3-yl) -7-methyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (60 mg， 109 μmol) was used to afford the title compound (20 mg， 40.6％ yield) as white foam after Prep-HPLC purification. MS：453.2 [M+H]⁺. ¹H NMR (400 MHz， MeOH-d4) δ 8.16 (br d， J＝8.68 Hz， 1H) ， 7.40-7.49 (m， 1H) ， 6.99 (br d， J＝8.80 Hz， 1H) ， 6.60 (d， J＝3.30 Hz， 1H) ， 4.91 (br s， 1H) ， 3.78 (s， 3H) ， 2.65 (br d， J＝5.99 Hz， 1H) ， 1.95-2.06 (m， 2H) ， 1.72-1.93 (m， 3H) ， 1.51-1.69 (m， 3H) ， 1.38-1.49 (m， 2H) .

Example 16

(rac) - (2S， 3S) -3- [ [6- (7-Fluoro-1H-indazol-3-yl) -1H-pyrazolo [3， 4-d] pyrimidin-4-yl] amino] bicycio [2.2.2] octane-2-carboxyiic acid

[A] (rac) -Methyl (2S， 3S) -3- [ [6- (7-fluoro-1-tetrahydropyran-2-yl-indazol-3-yl) -1- (p-tolylsulfonyl) pyrazolo [3， 4-d] pyrimidin-4-yl] amino] bicycio [2.2.2] octane-2-carboxylate

In analogy to the synthesis of Example 4/Step A， (rac) - (2S， 3S) -methyl 3- ( (6-chloro-1-tosyl-1H-pyrazolo [3， 4-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (Intermediate B-3， 220 mg， 449 μmol) and 7-fluoro-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (Intermediate A-7， 233 mg， 674μmol) were used to afford the title compound (50 mg， 16.5％yield) as yellow oil after silica gel flash chromatography (0-80％EtOAc-hexane gradient) purification. MS： 674.1 [M+H] ⁺.

[B] (rac) - (2S， 3S) -3- [ [6- (7-fluoro-1-tetrahydropyran-2-yl-indazol-3-yl) -1H-pyrazolo [3， 4-d] pyrimidin-4-yl] amino] bicyclo [2.2.2] octane-2-carboxylic acid

To a stirred mixture solution of (rac) - (2S， 3S) -methyl 3- ( (6- (7-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -1 -tosyl-1H-pyrazolo [3， 4-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (50 mg， 74.2 μmol) in THF (16 mL) and MeOH (4 mL) was added LiOH (17.8 mg， 742 μmol) in water (4 mL) . The reaction mixture solution was stirred at room temperature for 12 h before being diluted with water (10 mL) and extracted with diethyl ether (20 mL) . The separated aqueous layer was then acidified with concentrated aq. HCl solution to pH ＝ 4 and extracted with EtOAc (40 mL x 3) . The combined organics were dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude title compound (99 mg， 100％yield) as a yellow solid. MS： 506.1 [M+H] ⁺. This crude product was used directly in the next step without further purification.

[C] (rac) - (2S， 3S) -3- [ [6- (7-Fluoro-1H-indazol-3-yl) -1H-pyrazolo [3， 4-d] pyrimidin-4-yl] amino] bicyclo [2.2.2] octane-2-carboxylic acid

To a stirred mixture solution of (2S， 3S) -3- ( (6- (7-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -1H-pyrazolo [3， 4-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (40 mg， 79.1 μmol) in DCM (3 mL) was added 2， 2， 2-trifluoroacetic acid (5.92 g， 51.9 mmol， ) at room temperature and stirred for 12 h. The reaction mixture solution was then concentrated in vacuo to give a crude product， which was purified by Prep-HPLC to afford the title compound (1 mg， 3％yield) as white foam. MS： 422.1 [M+H] ⁺.

Example 1 7

(rac) - (2S， 3S) -3- ( (6- (5， 7-Difluoro-1H-indazol-3-yl) -1H-pyrazolo [3， 4-d] pyrimidin-4-yl) amino) -bicyclo [2.2.2] octane-2-carboxylic acid

[A] (rac) - (2S， 3S) -Methyl 3- ( (6- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -1- tosyl-1H-pyrazolo [3， 4-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate

In analogy to the synthesis of Example 4/Step A， 5， 7-difluoro-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (Intermediate A-5， 245 mg， 674 μmol) was used to afford the title compound (70 mg， 22.5％yield) as yellow oil after silica gel flash chromatography (0-80％EtOAc-hexane gradient) purification. MS： 692.1 [M+H] ⁺.

[B] (rac) - (2S， 3S) -3- ( (6- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -1H- pyrazolo [3， 4-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

In analogy to the synthesis of Example 16/Step B， (rac) - (2S， 3S) -methyl 3- ( (6- (5， 7-difluoro-1-(tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -1-tosyl-1H-pyrazolo [3， 4-d] pyrimidin-4-yl) amino) bicycio [2.2.2] octane-2-carboxylate (70 mg， 101μmol) was used to afford a crude title compound (54 mg， 100％yield) as a yellow solid. MS： 524.1 [M+H] ⁺. This crude product was used directly in the next step without further purification.

[C] (2S， 3S) -3- ( (6- (5， 7-difluoro-1H-indazol-3-yl) -1H-pyrazolo [3， 4-d] pyrimidin-4- yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

In analogy to the synthesis of Example 16/Step C， (rac) - (2S， 3S) -3- ( (6- (5， 7-difluoro-1-(tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -1H-pyrazolo [3， 4-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] -octane-2-carboxylic acid (54 mg， 103 μmol) was used to obtain the title compound (1 mg， 2.2％yield) as white foam after Prep-HPLC purification. MS： 440.1 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) δ 8.19-8.41 (m， 1H) ， 7.99-8.21 (m， 1H) ， 6.94-7.16 (m， 1H) ， 5.03-5.19 (m， 1H) ， 2.64-2.80 (m， 1H) ， 2.07-2.13 (m， 1H) ， 1.99-2.07 (m， 1H) ， 1.89-1.97 (m， 1H) ， 1.75-1.82 (m， 2H) ， 1.58-1.71 (m， 3H) ， 1.43-1.56 (m， 1H) ， 1.16-1.27 (m， 1H) .

Example 18

(+ or -) - (1R， 2S， 4R， 5S， 6S， 7S) -7- ( (2- (5， 7-difluoro-1H-indazol-3-yl) -7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylic acid

[A] (+ or -) - (1R， 2S， 4R， 5S， 6S， 7S) -Methyl 7- ( (2- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H- indazol-3-yl) -7-tosyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02，4] nonane-6- carboxylate

To a stirred mixture solution of (-) - (1R， 2S， 4R， 5S， 6S， 7S) -methyl 7- ( (2-chloro-7-tosyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate (Intermediate B-2， (-) -enantiomer， 400 mg， 798 μmol) and Pd (PPh₃) ₄ (92.3 mg， 79.8 μmol) in dioxane (4 mL) was added 1， 1， 1， 2， 2， 2-hexabutyldistannane (695 mg， 1.2 mmol) and the resulting reaction mixture solution was stirred at 125 ℃ for 2 h before it was cooled back to room temperature. To the above stirred mixture solution was added 5， 7-difluoro-3-iodo-1-(tetrahydro-2H-pyran-2-yl) -1H-indazole (Intermediate A-5， 436 mg， 1.2 mmol) and Pd (PPh₃) ₄ (92.3 mg， 79.8μmol) in dioxane (16 mL) and the resulting reaction mixture was re-heated at 145 ℃ for 1 h under microwave heating. After cooling to room temperature， the reaction mixture was poured into water (20 mL) and extracted with EtOAc (50 mL twice) . The combined organics were washed with brine， dried over anhydrous Na₂SO₄， filtered and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (0-80％EtOAc-hexane gradient) to afford the title compound (130 mg， 23.2％yield) as yellow oil. MS： 703.1 [M+H] ⁺

[B] (+ or -) - (1R， 2S， 4R， 5S， 6S， 7S) -7- ( (2- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol- 3-yl) -7H-pyrrolo [2， 3-d] pyrimidin-4-yl)amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylic acid

To a stirred mixture solution of (+ or -) - (1R， 2S， 4R， 5S， 6S， 7S) -methyl 7- ( (2- (5， 7-difluoro-1-(tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -7-tosyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate (130 mg， 185 μmol) in THF (16 mL) and MeOH (4 mL) was added LiOH (44.3 mg， 1.85 mmol) pre-dissolyed in water (4 mL) . The reaction mixture solution was stirred at room temperature for 12 h before it was diluted with water (10 mL) and extracted with diethyl ether (20 mL) . The separated aqueous layer was the acidified with concentrated HCl to pH ＝ 4 and extracted with EtOAc (40 mL x 3) . The combined organics were dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude title compound (99 mg， 100％ yield) as yellow oil. MS： 535.1 [M+H] ⁺. This crude product was used directly in the next step without further purification.

[C] (+ or -) - (1R， 2S， 4R， 5S， 6S， 7S) -7- ( (2- (5， 7-difluoro-1H-indazol-3-yl) -7H-pyrrolo [2， 3- dlpyrimidin-4-y) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylic acid

To a stirred mixture solution of (+ or -) - (1R， 2S， 4R， 5S， 6S， 7S) -7- ( (2- (5， 7-difluoro-1-(tetranydro-2H-pyran-2-yl) -1H-indazol-3-yl) -7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] -nonane-6-carboxylic acid (99 mg， 185 μmol) in DCM (3 mL) was added 2， 2， 2-trifluoroacetic acid (4.44 g， 38.9 mmol) at room temperature. The reaction mixture solution was stirred at room temperature for 12 h before concentrated in vaeuo to give a crude profuct， whieh was purified by Prep-HPLC to afford the title compound (5 mg， 6％yield) as white foam. MS： 451.1 [M+H] ⁺. ¹HNMR (400 MHz， MeOH-d4) δ 7.86-8.13 (m， 1H) ， 6.98-7.24 (m， 2H) ， 6.62-6.88 (m， 1H) ， 4.49-4.67 (m， 1H) ， 2.40-2.64 (m， 3H) ， 1.43-1.87 (m， 4H) ， 0.99-1.17 (m， 1H) ， 0.73-0.93 (m， 2H) ，0.27-0.55 (m， 1H) .

Example 19

(+ or -) - (1R， 2S， 4R， 5S， 6S， 7S) -7- ( (2- (7-Fluoro-1H-indazol-3-yl) -7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylic acid

[A] (+ or-) - (1R， 2S， 4R， 5S， 6S， 7S) -Methyl 7- ( (2- (7-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H- indazol-3-yl) -7-tosyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6- carboxylate

In analogy to the synthesis of Exampe 18/step A， 7-fluoro-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (Intermediate A-7， 415 mg， 1.2 mmol) was used to obtain the title compound (120 mg， 21.9％yield) as yellow oil after silica gel flash chromatography (0-80％EtOAc-hexane gradient) purification. MS： 685.1 [M+H] ⁺

[B] (+ or -) ) - (1R， 2S， 4R， 5S， 6S， 7S) ) -7- ( (2- (7-Fluoro-1- (tetrahydro-2H-pyran-2-yl) ) -1H-indazol-3- yl) -7H-pyrrolo[2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylic acid

In analogy to the synthesis of Example 18/Step B， (+ or -) - (1R， 2S， 4R， 5S， 6S， 7S) -methyl 7-( (2- (7-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -7-tosyl-7H-pyrrolo [2， 3-d] pyrimdin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate (120 mg， 175 μmol) was used to give a crude title compound (91 mg， 100％yield) as yellow oil. MS： 517.1 [M+H] ⁺. This crude product was used directly in the next step without further purification.

[C] (+ or -) - (1R， 2S， 4R， 5S， 6S， 7S) -7- ( (2- (7-Fluoro-1H-indazol-3-yl) -7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylic acid

In analogy to the synthesis of Example 18/step C， (+ or -) - (1R， 2S， 4R， 5S， 6S， 7S) -7- ( (2- (7-Fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol--yl) -7H-pyrrolo [2， 3-d] pyrimidin -4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylic acid (90 mmg， 174 μmol) was used to obtain the title compound (5 mg， 6.2％yield) as white foam after Prep-HPLC purification. MS： 433.1 [M+H] ⁺. ¹H NMR (400 MHz， MeOD-d4) δ 8.17-8.37 (m， 1H) ， 6.98-7.26 (m， 3H) ， 6.66-6.84 (m， 1H) ， 4.53-4.65 (m， 1H) ， 2.42-2.68 (m， 3H) ， 1.47-1.83 (m， 4H) ， 0.93-1.15 (m， 1H) ， 0.73-0.89 (m， 2H) ， 0.29-0.61 (m， 1H) .

Example 20

(rac) - (2S， 3S) -3- ( (2- (5-Fluoro-1H-pyrrolo [2， 3-b] pyridin-3-yl) -6-oxo-6， 7-dihydro-5H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

[A] (rac) - (2S， 3S) -Methyl 3- ( (2-chloro-7H-pyrrolo [2， 3-d] pyrimidin-4- yl) amino) bicyclo [2.2.2] octane-2-carboxylate

A mixture solution of (rac) - (2S， 3S) -methyl3- ( (2-chloro-7-tosyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (Intermediate B-1， 2.1 g， 4.3 mmol) and K₂CO₃ (5 g， 36 mmol) in MeOH (20 mL) was stirred at 50 ℃ for 2 h. After cooling to room temperature， the reaction mixture was concentrated and filtered. The filtrate was concentrated in vacuo to give a crude product (0.75 g， 52％yield) as a yellow soiid. MS： 335.1 [M+H] ⁺. This crude product was used directly in the hext step without further purification.

[B] (rac) - (2S， 3S) -Methyl 3- ( (2-chloro-6-oxo-6， 7-dihydro-5H-pyrrolo [2， 3-d] pyrimidin-4- yl) amino) bicyclo [2.2.2] octane-2-carboxylate

To a stirred solution of (rac) - (2S， 3S) -methyl 3- ( (2-chloro-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (0.7 g， 0.6 mmol) in tert-butanol (10 mL) was added portionwise pyridine tribromide (2.32 g， 7.35 mmol) and the resulting reaction mixture was stirred at 30 ℃ for 1 h. After TLC (petroleum ether∶EtOAc ＝ 1∶1) showed that the reaction was completed， solvent was removed under reduced pressure. To the remaining residue was added water (10 mL) and EtOAc (20 mL) and the mixture solution was filtered by suction. The separated organic layer was concentrated in vacuo to give a residue (1 g) ， which was re-dissolved in THF (10 mL) and saturated aqueous NH₄Cl solution (5 mL) followed by the addition of Zn powder (0.65 g， 10.0 mmol) . The resulting mixture was stirred at room temperature for an additional 1 h until LC-MS showed that the reaction was completed. The mixture solution was then filtered and the filtrate was extracted with EtOAc (20 mL twice) . The organic layer was washed with brine， dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude produt， which was purified by silica gel flash chromatography (petroleum ether∶EtOAc ＝5∶1) to afford the title compound (0.2 g， 27.3％yield) as a yellow solid. MS： 351.1 [M+H] ⁺.

[C] (rac) - (2S， 3S) -Methyl 3- ( (2- (5-fluoro-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2， 3- b] pyridin-3-yl) -6-oxo-6， 7-dihydro-5H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane- 2-carboxylate

To a stirred solution of (rac) - (2S， 3S) -methyl 3- ( (2-chloro-6-oxo-6， 7-dihydro-5H-pyrrolo [2， 3 -d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (0.2g， 0.57mmol) ， 5-fluoro-3-(4， 4， 5， 5-tetramethyl -1， 3， 2-dioxaborolan-2-yl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2， 3-b] pyridine (0.23 g， 0.6 mmol) in H₂O/THF (0.5/5 mL) was added K₃PO₄ (0.36 g， 1.7 mmol) and X-phos Biphenyl (0.024 g， 0.05mmol) and the resulting reaction mixture was heated at 60 ℃ for 2 h. After cooling to room temperature， solvent was removed under reduced pressure to give a crude product， which was purified by silica gel flash chromatography (petroleum ether∶EtOAC ＝ 5∶1) to afford the title compound (0.1 g， 30％yield) as a yellow solid. MS： 581.1 [M+1] ⁺.

[D] (rac) - (2S 3S) -3- ( (2- (5-Fluoro-1H-pyrrolo [2， 3-b] pyridin-3-yl) -6-oxo-6， 7-dihydro-5H- pyrrolo [2， 3-d] pyrimidin-4-yl) ) amino) bicyclo [2.2.2] octane-2-carboxylic acid

A mixture solution of (rac) - (2S， 3S) -methyl 3- ( (2- (5-fluoro-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrold [2， 3-b] pyridin-3-yl) -6-oxo-6， 7-dihydro-5H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (0.1 g， 0.17 mmol) in TFA (1 mL) and 2 N aq. HCl solution (0.5 mL) was stirred at 80 ℃ for 14 h. After cooling to room temperature， solvent was removed under reduced pressure to give a crude product， which was purified by prep-HPLC to afford the title compound (2.5 mg， 3.3％yield) as a white solid. MS： 437.2 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) δ ppm 1.44 -1.59 (m， 2 H) 1.61-2.02 (m， 7 H) 2.09 (br. s.， 1H) 2.65-2.71 (m， 1H) 3.10 -3.15 (m， 1H) 3.44 -3.50 (m， 2 H) 8.17 (br. s.， 1H) 8.28 (s， 1H) 8.72 (dd， J＝9.54， 2.76 Hz， 1H) .

Example 21

(-) - (1R， 2S， 4R， 5S， 6S， 7S) -7- ( (2- (5-Fluoro-1H-pyrazolo [3， 4-b] pyridin-3-yl) -7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylic acid

[A] (+or -) - (1R， 2S， 4R， 5S， 6S， 7S) -Methyl 7- ( (2- (5-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H- pyrazolo [3， 4-b] pyridin-3-yl) -7-tosyl-7H-pyrrolo [2， 3-d] pyrimidin-4- yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate

To a stirred mixture solution of (+) - (1R， 2S， 4R， 5S， 6S， 7S) -methyl 7- ( (2-chloro-7-tosyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate (Intermediate B-2a， 300 mg， 599 μmol) and Pd (PPh₃) ₄ (69.2 mg， 59.9 μmol) in dioxane (4 mL) was added 1， 1， 1， 2， 2， 2-hexabutyldistannane (521 mg， 472 μL， 898 μmol) at room temperature and the resulting reaction mixture solution was stirred at 125 ℃ for 2 h before being cooled back to room temperature. To the above stirred mixture solution in dioxane (16 mL) were added 5-fluoro-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3， 4-b] pyridine (Intermediate A-1a， 312 mg， 898 μmol) and Pd (PPh₃) ₄ (69.2 mg， 59.9 μmol) . Then the reaction mixture solution was stirred at 145 ℃ for another 1 h under microwave heating. After cooling to room temperature， the reaction mixture was poured into water (20 mL) and extracted with EtOAc (50 mL twice) . The combined organic layers were washed with brine， dried over anhydrous Na₂SO₄， filtered and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (0-80％EtOAc-hexane gradient) to afford the title compound (100 mg， 24.4％yield) as a yellow oil. MS： 686.1 (M+H) ⁺.

[B] (+ or -) - (1R， 2S， 4R， 5S， 6S， 7S) -7- ( (2- (5-Fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H- pyrazolo [3， 4-b] pyridin-3-yl) -7H-pyrrolo [2， 3-d] pyrimidin-4- yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylic acid

To a stirred mixture solution of (+ or -) - (1R， 2S， 4R， 5S， 6S， 7S) -methyl 7- ( (2- (5-fluoro-1-(tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3， 4-b] pyridin-3-yl) -7-tosyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxyiate (100 mg， 146 μmol) in THF (6 mL) and MeOH (3 mL) was added LiOH (17.5 mg， 729 μmol) pre-dissolved in water (3 mL) . The reaction mixture solution was stirred at room temperature for 12 h before being diluted with water (10 mL) and extracted with diethyl ether (20 mL) . The organic layer was discarded and the aqueous layer was acidified with concentrated hydrochloric acid to pH 4 and extracted with EtOAc (40 mL x 3) . Combined organics were then dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude product (77 mg， 100％yield) as a yellow solid. MS： 518.1 (M+H) ⁺. This crude product was used directly in the next step without further purification.

[C] (-) - (1R， 2S， 4R， 5S， 6S， 7S) -7- ( (2- (5-Fluoro-1H-pyrazolo [3， 4-b] pyridin-3-yl) -7H-pyrrolo [2， 3- d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylic acid

To a stirred mixture solution of (+ or -) - (1R， 2S， 4R， 5S， 6S， 7S) -7- ( (2- (5-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3， 4-b] pyridin-3-yl) -7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylic acid (100 mg， 193 μmol) in DCM (3 mL) was added 2， 2， 2-trifluoroacetic acid (4.44 g， 3 mL， 38.9 mmol) and the resulting reaction mixture solution was stirred at room temperature for 12 h. After solvent was removed under reduced pressure， the crude product was purified by prep-HPLC to afford the title compound (12 mg， 14.3％yield) as a white foam. MS： 434.1 (M+H) ⁺. ¹H NMR (400 MHz， MeOH-d₄) δ 8.59-8.71 (m， 1H) ， 8.37-8.46 (m， 1H) ， 6.98-7.11 (m， 1H) ， 6.53-6.69 (m， 1H) ， 4.57-4.69 (m， 1H) ， 2.57-2.63 (m， 1H) ， 2.49-2.55 (m， 1H) ， 2.40-2.47 (m， 1H) ， 1.47-1.86 (m， 4H) ， 0.99-1.09 (m， 1H) ， 0.88-0.98 (m， 1H) ， 0.78-0.88 (m， 1H) ， 0.34-0.45 (m， 1H) .

Example 22

(-) - (1R， 2S， 4R， 5S， 6S， 7S) -7- ( (2- (5， 7-difluoro-1H-indazol-3-yl) -7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylic acid

[A] (+ or-) - (1R， 2S， 4R，5S，6S， 7S) -methyl 7- ( (2- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H- indazol--3-yl) -7-tosyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6- carboxylate

Similar to the synthesis of Example 18/step A， (+) - (1R， 2S， 4R， 5S， 6S， 7S) -methyl 7- ( (2-chloro-7-tosyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate (Intermediate B-2a， 300 mg， 599 μmol) was used instead to afford the title compound (100 mg， 23.8％yield) after silica gel flash chromatography purification (0-80％EtOAc-hexane gradient) as a yellow oil MS： 703.1 (M+H) ⁺.

[B] (+ or-) - (1R， 2S， 4R， 5S， 6S， 7S) -7- ( (2- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol- 3-yl) -7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2. 02， 4] nonane-6-carboxylic acid

Similar to the synthesis of Example 18/step B， (+ or -) - (1R， 2S， 4R， 5S， 6S， 7S) -methyl 7- ( (2-(5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -7-tosyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate (100 mg， 142 μmol) was used instead to give a crude product(77 mg， 100％yield) . MS： 535.1 (M+H) ⁺. It was used directly in the next step without furtehr purification.

[C] (-) - (1R， 2S， 4R， 5S， 6S， 7S) -7- ( (2- (5， 7-difluoro-1H-indazol-3-yl) -7H-pyrrolo [2， 3-d] pyrimidin- 4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylic acid

Similar to the synthesis of Example 18/step C， (+ or -) - (1R， 2S， 4R， 5S， 6S， 7S) -7- ( (2- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylic acid (100 mg， 187 μmol) was used instead to afford the title compound (14 mg， 16.6％yield) after prep-HPLC purification as a white foam. MS： 451.1 (M+H) ⁺. ¹H NMR (400 MHz， METHANOL-d₄) δ 7.89-7.96 (m， 1H) ， 7.09-7.21 (m， 1H) ， 6.97-7.07 (m， 1H) ， 6.74-6.83 (m， 1H) ， 4.54-4.61 (m， 1H) ， 2.56-2.64 (m， 1H) ， 2.45-2.53 (m， 2H) ， 1.68-1.82 (m， 2H) ， 1.51-1.66 (m， 2H) ， 1.03-1.13 (m， 1H) ， 0.76-0.94 (m， 2H) ， 0.40-0.52 (m， 1H) .

Example 23

(rac) - (1R， 2S， 4R， 5S， 6S， 7S) -7- ( (6- (5-Chloro-1H-pyrrolo [2， 3-b] pyridin-3-yl) -1H-pyrazolo [3， 4-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylic acid

[A] (rac) - (1R， 2S， 4R， 5S， 6S， 7S) -methyl 7- ( (6- (5-chloro-1-tosyl-1H-pyrrolo [2， 3-b] pyridin-3-yl) - 1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3， 4-d] pyrimidin-4- yl) amino) tricyclo [3.2.2. 02， 4] nonane-6-carboxylate

To a stirred mixture solution of (rac) - (2S， 4R， 6S， 7S) -methyl 7- ( (6-chloro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3， 4-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate (250 mg， 579 μmol) and Pd (PPh₃) ₄ (66.9 mg， 57.9 μmol) in dioxane (4 mL) was added 1， 1， 1， 2， 2， 2-hexabutyldistannane (403 mg， 365 μL， 695 μmol) and the resulting reaction mixture solution was stirred at 125 ℃ for 2 h before it was cooled back to room temperature. To the above mixture， were then added 5-chloro-3-iodo-1-tosyl-1H-pyrrolo [2， 3-b] pyridine (376 mg， 868 μmol) and Pd (PPh₃) ₄ (66.9 mg， 57.9 μmol) in dioxane (10 mL) . The resulting reaction mixture was stirred at 145 ℃ for 1 h under microwave heating. After cooling to room temperature， the reaction mixture was poured into water (20 mL) and extracted with EtOAc (50 mL twice) . The combined organic layers were washed with brine， dried over anhydrous Na₂SO₄， filtered and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (0-100％EtOAc-hexane gradient) to afford the product (80 mg， 19.7％yield) as a yellow oil. MS： 702.2 [M+H] ⁺

[B] (rac) - (1R， 2S， 4R， 5S， 6S， 7S) -7- ( (6- (5-chloro-1H-pyrrolo [2， 3-b] pyridin-3-yl) -1H- pyrazolo [3， 4-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylic acid

A mixture of (rac) - (1R， 2S， 4R， 5S， 6S， 7S) -methyl 7- ( (6- (5-chloro-1-tosyl-1H-pyrrolo [2， 3-b] pyridin-3-yl) -1- (tetrahydro-2H-pyran-2-yl) _1H-pyrazolo [3， 4-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate (160 mg， 228 μmol) and lithium hydroxide hydrate (95.6 mg， 2.28 mmol) in THF/H₂O (20 mL， 1∶1) was stirred at room temperature for 16 h. After solvent was removed under reduced pressure， the residue was re-dissolved in TFA (10 mL) and stirred at room temperature for 16 h. After LC-MS showed that the reaction was completed， the solvent was evaporated in vacuo and the residue was purified by prep-HPLC to afford the title compound (25 mg， 24.4％yield) as a white solid. MS： 450.0 [M+H] ⁺. ¹H NMR (400 MHz， DMSO-d6) δ 13.21 (s， 1H) ， 12.31 (s， 1H) ， 8.92 (d， J＝2.20 Hz， 1H) ， 8.26-8.31 (m， 2H) ， 8.16 (s， 1H) ， 7.70 (d， J＝4.89 Hz， 1H) ， 4.51 (s， 1H) ， 2.62 (d， J＝9.66 Hz， 2H) ， 2.41 (s， 1H) ， 1.82 (s， 1H) ， 1.70 (s， 1H) ， 1.56 (s， 2H) ， 1.04 (s， 2H) ， 0.84 (d， J＝7.09 Hz， 2H) ， 0.32-0.41 (m， 1H) .

Example 24

(-) - (1R， 2S， 4R， 5S， 6S， 7S) -7- ( (6- (5-Chloro-1H-pyrazolo [3， 4-b] pyridin-3-yl) -1-methyl-1H-pyrazolo [3， 4-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylic acid

[A] (+ or -) - (1R， 2S， 4R， 5S， 6S， 7S) -methyl 7- ( (6- (5-chloro-1- ( (2- (trimethylsilyl) ethoxy) methyl) - 1H-pyrazolo [3， 4-b] pyridin-3-yl) -1-methyl-1H-pyrazolo[3.4-d] pyrimidin-4- yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate

To a stirred mixture solution of (-) - (1R， 2S， 4R， 5S， 6S， 7S) -methyl 7- ( (6-chloro-1-methyl-1H-pyrazolo [3， 4-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate (Intermediate B-8a， 250 mg， 691 μmol) and Pd (PPh₃) ₄ (79.8 mg， 69.1 μmol) in dioxane (4 mL) was added 1， 1， 1， 2， 2， 2-hexabutyldistannane (481 mg， 435 μL， 829 μmol) and the resulting reaction mixture solution was stirred at 125 ℃ for 2 h before it was cooled back to room temperature. To the above mixture， were then added 5-chloro-3-iodo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3， 4-b] pyridine (425 mg， 1.04 mmol) and Pd (PPh₃) ₄ (79.8 mg， 69.1 μmol) in dioxane (10 mL) . The resulting reaction mixture was stirred at 145 ℃ for 1 h under microwave heating. After cooling to room temperature， the reaction mixture was poured into water (20 mL) and extracted with EtOAc (50 mL twice) . The combined organic layers were washed with brine， dried over anhydrous Na₂SO₄， filtered and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (0-100％EtOAc-hexane gradient) to afford the title compound (55 mg， 13％yield) as a yellow oil. MS： 609.1 [M+H] ⁺.

[B] (-) - (1R， 2S， 4R， 5S， 6S， 7S) -7- ( (6- (5-chloro-1H-pyrazolo [3， 4-b] pyridin-3-yl) -1-methyl-1H- pyrazolo [3， 4-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylic acid

A mixture of (+ or -) - (1R， 2S， 4R， 5S， 6S， 7S) -methyl 7- ( (6- (5-chloro-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3， 4-b] pyridin-3-yl) -1-methyl-1H-pyrazolo [3， 4-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate (220 mg， 361 μmol) and lithium hydroxide hydrate (30.3 mg， 722 μmol) in THF/H₂O (20 mL， 1∶1) was stirred at room temperature for 16 h. After solvent was removed under reduced pressure， the residue was re-dissolved in TFA (10 mL) and stirred at room temperature for 16 h. After LC-MS showed that the reaction was completed， the solvent was evaporated and the residue was purified by prep-HPLC to afford the title compound (35 mg， 20.4％yield) as a white solid. MS： 465.1 [M+H]⁺.¹H NMR (400 MHz， METHANOL-d4) δ 8.91 (s， 1H) ， 8.43 (d， J＝2.08 Hz， 1H) ， 8.08 (s， 1H) ， 3.97 (s， 3H) ， 2.61 (d， J＝6.11 Hz， 1H) ， 2.56 (d， J＝4.40 Hz， 1H) ， 2.45 (s， 1H) ， 1.89 (s， 1H) ， 1.68-1.77 (m， 1H) ， 1.52-1.66 (m， 2H) ， 1.05 (s， 1H) ， 0.79-0.93 (m， 3H) ， 0.39 (d， J＝6.60 Hz， 1H) .

Example 25

(rac) - (1R， 2S， 4R， 5S， 6S， 7S) -7- ( (2- (5-Chloro-1H-pyrazolo [3， 4-b] pyridin-3-yl) -7-methyl-7H-purin-6-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylic acid

[A] (rac) - (1R， 2S， 4R， 5S， 6S， 7S) -Methyl 7- ( (2- (5-chloro-1- ( (2- (trimethylsilyl) ethoxy) methyl) - 1H-pyrazolo [3， 4-b] pyridin-3-yl) -7-methy -7H-purin-6-yl) amino) tricyclo [3.2.2.02， 4] nonane-6- carboxylate

To a stirred mixture solution of (rac) - (1R， 2S， 4R， 5S， 6S， 7S) -methyl 7- ( (2-chloro-7-methyl-7H-purin-6-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate (Intermediate B-9， 250 mg， 691 μmol) and Pd (PPh₃) ₄ (100 mg， 86.5 μmol， eq： 0.125) in dioxane (4 mL) was added 1， 1， 1， 2， 2， 2-hexabutyldistannane (481 mg， 435 μL， 829 μmol) at room temperature and the resulting reaction mixture solution was stirred at 125 ℃ for 2 h before being cooled back to room temperature. To the above stirred mixture solution in dioxane (16 mL) were then added 5-chloro-3-iodo-1- ( (2- (trimethylsilyl)ethoxy) methyl) -1H-pyrazolo [3， 4-b] pyridine (Intermediate A-3， 425 mg， 1.04 mmol) and Pd (PPh₃) ₄ (100 mg， 86.5 μmol) and the reaction mixture solution was stirred at 145 ℃ for another 1 h under microwave heating. After cooling to room temperature， the reaction mixture was poured into water (20 mL) and extracted with EtOAc (50 mL twice) . The combined organic layers were washed with brine， dried over anhydrous Na₂SO₄， filtered and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (0-80％EtOAc-hexane gradient， then methanol-DCM gradient) to afford the title compound (60 mg， 14.3％yield) as yellow oil. MS： 608.9 [M+H] ⁺.

[B] (rac) - (1R， 2S， 4R， 5S， 6S， 7S) -7- ( (2- (5-Chloro-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H- pyrazolo [3， 4-b] pyridin-3-yl) -7-methyl-7H-purin-6-yl) amino) tricyclo [3.2.2.02， 4] nonane-6- carboxylic acid

To a stirred mixture solution of (rac) - (1R， 2S， 4R， 5S， 6S， 7S) -methyl 7- ( (2- (5-chloro-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3， 4-b] pyridin-3-yl) -7-methyl-7H-purin-6-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate (60 mg， 98.5 μmol) in THF (5 mL) and MeOH (5 mL) was added LiOH (23.6 mg， 985 μmol) pre-dissolved in water (5 ml) . The reaction mixture solution was stirred at room temperature for 12 h before being diluted with water (10 mL) and extracted with diethyl ether (20 mL) . The organic layer was discarded and the aqueous layer was acidified with concentrated hydrochloric acid to pH 4 and extracted with EtOAc (40 mL x 3) . Combined organics were dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude product (59 mg， 100％yield) as a yellow solid. MS： 595.1 [M+H) ⁺. This crude product was used directly in the next step without further purification.

[C] (rac) - (1R， 2S， 4R， 5S， 6S， 7S) -7- ( (2- (5-Chloro-1H-pyrazolo [3， 4-b] pyridin-3-yl) -7-methyl-7H- purin-6-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylic acid

To a stirred mixture solution of (rac) - (1R， 2S， 4R， 5S， 6S， 7S) -7- ( (2- (5-chloro-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3， 4-b] pyridin-3-yl) -7-methyl-7H-purin-6-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylic acid (52 mg， 87.4 μmol) in DCM (3 mL) was added 2， 2， 2-trifluoroacetic acid (4.44 g， 3 mL， 38.9 mmol) and the resultting reaction mixture solution was stirred at room temperature for 12 h. After solvent was removed under reduced pressure， the crude product was purified by prep-HPLC to afford the title compound (4.5 mg， 9.8％yield) as a white foam. MS： 465.1 [M+H) ⁺. ¹H NMR (400 MHz， MeOH-d₄) δ 9.07-9.10 (m， 1H) ， 8.61-8.67 (m， 1H) ， 8.37-8.41 (m， 1H) ， 5.20-5.27 (m， 1H) ， 4.26 (s， 3H) ， 2.56-2.64 (m， 1H) ， 2.45-2.53 (m， 2H) ， 1.68-1.82 (m， 2H) ， 1.51-1.66 (m， 2H) ， 1.03-1.13 (m， 1H) ， 0.76-0.94 (m， 2H) ， 0.40-0.52 (m， 1H) .

Example 26

(-) - (1S， 2R， 4S， 5R， 6R， 7R) -7- ( (2- (5-Chloro-1H-pyrazolo [3， 4-b] pyridin-3-yl) -9-methyl-9H-purin-6-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylic acid

[A] (+ or -) - (1S， 2R， 4S， 5R， 6R， 7R) -Methyl 7- ( (2- (5-chloro-1- ( (2- (trimethylsilyl) ethoxy) methyl） - 1H-pyrazolo [3， 4-b] pyridin-3-yl) -9-methyl-9H-purin-6-yl) amino) tricyclo [3.2.2.02， 4] nonane-6- carboxylate

To a stirred mixture solution of (+) - (1S， 2R， 4S， 5R， 6R， 7R) -methyl 7- ( (2-chloro-9-methyl-9H-purin-6-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate (Intermediate B-10a， 250 mg， 691 μmol) and Pd (PPh₃) ₄ (100 mg， 86.5 μmol) in dioxane (4 mL) was added 1， 1， 1， 2， 2， 2-hexabutyldistannane (481 mg， 435 μL， 829 μmol) at room temperature and the resulting reaction mixture solution was stirred at 125 ℃ for 2 h before being cooled back to room temperature. To the above stirred mixture solution in dioxane (16 mL) were added 5-chloro-3-iodo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3， 4-b] pyridine (Intermediate A-3， 425 mg， 1.04 mmol) and Pd (PPh₃) ₄ (100 mg， 86.5 μmol) and the reaction mixture solution was stirred at 145 ℃ for 1 h under microwave heating. After cooling to room temperature， the reaction mixture was poured into water (20 mL) and extracted with EtOAc (50 mL twice) . The combined organic layers were washed with brine， dried over anhydrous Na₂SO₄， filtered and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (0-80％EtOAc-hexane gradient， then 0-5％MeOH-DCM gradient) to afford the title compound (80 mg， 19％yield) as a yellow oil. MS： 608.9 [M+H] ⁺.

[B] (+ or -) - (1S， 2R， 4S， 5R， 6R， 7R) -7- ( (2- (5-Chloro-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1-H- pyrazolo [3， 4-b] pyridin-3-yl) -9-methyl-9H-purin-6-yl) amino) tricyclo [3.2.2.02， 4] nonane-6- carboxylic acid

To a stirred mixture solution of (+ or -) - (1S， 2R， 4S， 5R， 6R， 7R) -methyl 7- ( (2- (5-chloro-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3， 4-b] pyridin-3-yl) -9-methyl-9H-purin-6-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate (320mg， 525 μmol) in THF (5 mL) and MeOH (5mL) was added LiOH (126 mg， 5.25 mmol) pre-dissolved in water (5 mL) . The reaction mixture solution was stirred at room temperature for 12 h before being diluted with water (10 mL) and extracted with diethyl ether (20 mL) . The organic layer was discarded and the aqueous layer was acidified with concentrated hydrochloric acid to pH 4 and extracted with EtOAc (40 mL x 3) . Combined organics were dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude product (314 mg， 100％yield) . MS： 595.1 [M+H] ⁺. This crude product was used directly in the next step without further purification.

[C] (-) - (1S， 2R， 4S， 5R， 6R， 7R) -7- ( (2- (5-Chloro-1H-pyrazolo [3， 4-b] pyridin-3-yl) -9-methyl-9H- purin-6-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylic acid

To a stirred mixture solution of (+ or -) - (1S， 2R， 4S， 5R， 6R， 7R) -7- ( (2- (5-chloro-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3， 4-b] pyridin-3-yl) -9-methyl-9H-purin-6-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylic acid (300 mg， 504 μmol) in DCM (3 mL) was added 2， 2， 2-trifluoroacetic acid (4.44 g， 3 mL， 38.9 mmol) and the resulting reaction mixture solution was stirred at room temperature for 12 h. Solvent was removed under reduced pressure and the crude product was then purified by prep-HPLC to afford the title compound (90 mg， 38.4％yield) as a white foam. MS： 465.1 [M+H) ⁺. ¹H NMR (400 MHz， CHCl₃-d) δ 8.71-8.81 (m， 1H) ， 8.41-8.52 (m， 1H) ， 7.85-7.98 (m， 1H) ， 4.34-4.47 (m， 1H) ， 3.89 (s， 3H) ， 2.57-2.63 (m， 1H) ， 2.49-2.55 (m， 1H) ， 2.40-2.47 (m， 1H) ， 1.47-1.86 (m， 4H) ， 0.99-1.09 (m， 1H) ， 0.88-0.98 (m， 1H) ， 0.78-0.88 (m， 1H) ， 0.34-0.45 (m， 1H) .

Example 27

(+) - (1R， 2S， 4R， 5S， 6S， 7S) -7- ( (2- (5-Chloro-1H-pyrazolo [3， 4-b] pyridin-3-yl) -9-methyl-9H-purin-6-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxyiic acid

[A] (+ or -) - (1R， 2S， 4R， 5S， 6S， 7S) -Methyl 7- ( (2- (5-chloro-1- ( (2- (trimethylsilyl) ethoxy) methyl) - 1H-pyrazolo [3， 4-b] pyridin-3-yl) -9-methyl-9H-purin-6-yl) amino) tricyclo [3.2.2.02， 4] nonane-6- carboxylate

Similar to the synthesis of Example 26/step A， (-) - (1R， 2S， 4R， 5S， 6S， 7S) -methyl 7- ( (2-chloro-9-methyl-9H-purin-6-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate (Intermediate B-10b， 250 mg， 691 μmol) was used instead to afford the title compound (50 mg， 11.9％yield) after silica gel flash chromatography (0-80％EtOAc-hexane gradient， then 0-5％MeOH-DCM gradient) as a yellow oil. MS： 608.9 [M+1] ⁺.

[B] (+ or -) - (1R， 2S， 4R， 5S， 6S， 7S) -7- ( (2- (5-Chloro-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H- pyrazolo [3， 4-b] pyridin-3-yl) -9-methyl-9H-purin-6-yl) amino) tricyclo [3.2.2.02， 4] nonane-6- carboxylic acid

Similar to the synthesis of Example 26/step B， (+ or -) - (1R，2S，4R，5S，6S，7S) -methyl 7- ( (2- (5-chloro-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3， 4-b] pyridin-3-yl) -9-methyl-9H-purin-6-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate (300 mg， 492 μmol) was used instead to give a crude product (294 mg， 100％yield) as a yellow solid. MS： 595.1 [M+H] ⁺. This crude product was used directly in the next step without further purification.

[C] (+) - (1R， 2S， 4R， 5S， 6S， 7S) -7- ( (2- (5-Chloro-1H-pyrazolo [3， 4-b] pyridin-3-yl) -9-methyl-9H- purin-6-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylic acid

Similar to the synthesis of Example 26/step C， (+ or -) - (1R， 2S， 4R， 5S， 6S， 7S) -7- ( (2- (5-chloro-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3， 4-b] pyridin-3-yl) -9-methyl-9H-purin-6-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylic acid (300 mg， 504 μmol) was used instead to afford the title compound (45 mg， 19.1％yield) after prep-HPLC purification. MS： 465.1 [M+H) ⁺. ¹H NMR (400 MHz， CHCl₃-d) δ 8.83-8.96 (m， 1H) ， 8.50-8.62 (m， 1H) ， 7.83-8.03 (m， 1H) ， 4.35-4.56 (m， 1H) ， 4.10 (s， 3H) ， 2.57-2.63 (m， 1H) ， 2.49-2.55 (m， 1H) ， 2.40-2.47 (m， 1H) ， 1.47-1.86 (m， 4H) ， 0.99-1.09 (m， 1H) ， 0.88-0.98 (m， 1H) ， 0.78-0.88 (m， 1H) ， 0.34-0.45 (m， 1H) .

Example 28

(+) - (1S， 2R， 4S， 5R， 6R， 7R) -7- ( (6- (5-Chloro-1H-pyrazolo [3， 4-b] pyridin-3-yl) -1-methyl-1H-pyrazolo [3， 4-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylic acid

[A] (+ or -) (1S， 2R， 4S， 5R， 6R， 7R） -Methyl 7- ( (6- (5-chloro-1- ( (2-trimethylsilyl) ethoxy) methyl) - 1H-pyrazolo [3， 4-b] pyridin-3-yl) -1-methyl-1H-pyrazolo [3， 4-d] pyrimidin-4- yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate

Similar to the synthesis of Example 24/step A， (+) - (1S， 2R， 4S， 5R， 6R， 7R) -methyl 7- ( (6-chloro-1-methyl-1H-pyrazolo [3， 4-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate (Intermediate B-8b， 250 mg， 691 μmol) was used instead to afford the title compound (90 mg， 21％yield) after silica gel flash chromatography (0-100％EtOAc-hexane gradient) as an off-white oil. MS： 609.2 [M+H] ⁺.

[B] (+) - (1S， 2R， 4S， 5R， 6R， 7R) -7- ( (6- (5-Chloro-1H-pyrazolo [3， 4-b] pyridin-3-yl) -1-methyl-1H- pyrazolo [3， 4-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylic acid

Similar to the synthesis of Example 24/step B， (+ or -) - (1S， 2R， 4S， 5R， 6R， 7R) -methyl 7- ( (6- (5-chioro-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3， 4-b] pyridin-3-yl) -1-methyl-1H-pyrazolo [3， 4-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate (360 mg， 591 μmol) was used instead to afford the title compound (40 mg， 14.3％ yield) after prep-HPLC purification as a white solid. MS： 465.0 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) δ 8.91 (s， 1H) ， 8.43 (d， J＝2.20 Hz， 1H) ， 8.08 (s， 1H) ， 3.97 (s， 3H) ， 2.62 (d， J＝5.99 Hz， 1H) ， 2.56 (d J＝4.52 Hz， 1H) ， 2.45 (s， 1H) ， 1.89 (s， 1H) ， 1.72 (s， 1H) ， 1.53-1.64 (m， 2H) ， 1.05 (s， 1H) ， 0.90 (s， 1H) ， 0.83 (s， 2H) ， 0.39 (d， J＝6.97 Hz， 1H) .

Example 29

(-) - (1R， 2S， 4R， 5S， 6S， 7S) -7- ( (6- (5-Chloro-1H-pyrrolo [2， 3-b] pyridin-3-yl) -1-methyl-1H-pyrazolo [3， 4-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylic acid

[A] (+ or -) - (2S， 4R， 6S， 7S) -Methyl 7- ( (6- (5-chloro-1-tosyl-1H-pyrrolo [2， 3-b] pyridin-3-yl) -1- methyl-1H-pyrazolo [3， 4-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate

To a stirred mixture solution of (-) - (1R， 2S， 4R， 5S， 6S， 7S) -methyl 7- ( (6-chloro-1-methyl-1H-pyrazolo [3， 4-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate (Intermediate B-8a， 250 mg， 691 μmol) and Pd (PPh₃) ₄ (79.8 mg， 69.1 μmol) in dioxane (4 mL) was added 1， 1， 1， 2， 2， 2-hexabutyldistannane (481 mg， 435 μL， 829 μmol) and the resulting reaction mixture solution was stirred at 125 ℃ for 2 h before it was cooled back to room temperature. To the above mixture， were then added 5-chloro-3-iodo-1-tosyl-1H-pyrrolo [2， 3-b] pyridine (448 mg， 1.04 mmol) and Pd (PPh₃) ₄ (79.8 mg， 69.1 μmol) in dioxane (10 mL) . The resulting reaction mixture was stirred at 145 ℃ for 1 h under microwave heating. After cooling to room temperature， the reaction mixture was poured into water (20 mL) and extracted with EtOAc (50 mL twice) . The combined organic layers were washed with brine， dried over anhydrous Na₂SO₄， filtered and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (0-100％EtOAc-hexane gradient) to afford the product (13 mg， 2.98％yield) as an off-white oil. MS： 632.1 [M+H] ⁺.

[B] (-) - (1R， 2S， 4R， 5S， 6S， 7S) -7- ( (6- (5-Chloro-1H-pyrrolo [2， 3-b] pyridin-3-yl) -1-methyl-1H- pyrazolo [3， 4-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylic acid

A stirred mixture solution of (+ or -) (2S， 4R， 6S， 7S) -methyl 7- ( (6- (5-chloro-1-tosyl-1H-pyrrolo [2， 3-b] pyridin-3-yl) -1-methyl-1H-pyrazolo [3， 4-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate (60 mg， 94.9 μmol) and lithium hydroxide hydrate (7.97 mg， 190 μmol) in THF/H₂O (20 mL， 1∶1) was stirred at room temperature for 16 h. After solvent was removed under reduced pressure， the residue was re-dissolved in TFA (10 mL) and stirred at room temperature for another 16 h. After LC-MS showed that the reaction was completed， the solvent was evaporated in vacuo and the crude product was purified by prep-HPLC to afford the title compound (28 mg， 62.3％yield) as a white solid. MS： 464.2 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) δ 8.92 (d， J＝2.32 Hz， 1H) ， 8.34 (s， 1H) ， 8.10 (d， J＝2.20 Hz， 1H) ， 8.02 (s， 1H) ， 4.45 (d， J＝4.16 Hz， 1H) ， 3.93 (s， 3H) ， 2.46 (d， J＝11.13 Hz， 2H) ， 2.33 (s， 1H) ， 1.61-1.82 (m， 3H) ， 1.51 (d， J＝11.98 Hz， 1H) ， 1.00-1.09 (m， 1H) ， 0.82-0.90 (m， 2H) ， 0.40 (q， J＝8.27 Hz， 1H) .

Example 30

(+) - (1S， 2R， 4S， 5R， 6R， 7R) -7- ( (2- (5-Chloro-1H-pyrazolo [3， 4-b] pyridin-3-yl) -7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricycio [3.2.2.02， 4] nonane-6-carboxylic acid

[A] (+ or -) (1S， 2S， 4R， 5R， 6S， 7S) -Methyl 7- ( (2- (5-chloro-1- ( (2- (trimethylsilyl) ethoxy) methyl) - 1H-pyrazolo [3， 4-b] pyridin-3-yl) -7-tosyl-7H-pyrrolo [2， 3-d] pyrimidin-4- yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate and (- or +) - (1R， 2R， 4S， 5S， 6R， 7R) -methyl 7- ( (2- (5-chloro-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3， 4-b] pyridin-3-yl) -7-tosyl - 7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate

To a stirred mixture solution of (rac) - (1S， 2S， 4R， 5R， 6S， 7S) -methyl 7- ( (2-chloro-7-tosyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate (Intermediate B-2， 400 mg， 798 μmol) and Pd (PPh₃) ₄ (100 mg， 86.5 μmol) in dioxane (4 mL) was added 1， 1， 1， 2， 2， 2-hexabutyldistannane (556 mg， 958 μmol) at room temperature and the resulting reaction mixture was stirred at 125 ℃ for 2 h before being cooled back to room temperature. To the above stirred mixture solution in dioxane (16 mL) were then added 5-chloro-3-iodo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3， 4-b] pyridine (491 mg， 1.2 mmol) and Pd (PPh₃) ₄ (100 mg， 86.5 μmol) and the reaction mixture solution was stirred at 145 ℃ for another 1 hour under microwave heating. After cooling to room temperature， the reaction mixture was poured into water (20 mL) and extracted with EtOAc (50 mL twice) . The combined organic layers were washed with brine， dried over anhydrous Na₂SO₄， filtered and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (0-80％EtOAc-hexane gradient) to give a racemic mixture of the product (50 mg， 13.4％yield) as a yellow oil. MS： 478.2 [M+H] ⁺. Subsequent chiral separation by SFC afforded enantiomer title compound (+ or -) (1S， 2S， 4R， 5R， 6S， 7S) -methyl 7- ( (2- (5-chloro-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3，4-b] pyridin-3-yl) -7-tosyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricycio [3.2.2.02， 4] nonane-6-carboxyiate； MS： 478.2 [M+H] ⁺； and (- or +) - (1R， 2R， 4S， 5S， 6R， 7R) -methyl 7- ( (2- (5-chloro-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3， 4-b] pyridin-3-yl) -7-tosyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate； MS： 478.2 [M+H] ⁺.

[B] (+) - (1S， 2R， 4S， 5R， 6R， 7R) -7- ( (2- (5-Chloro-1H-pyrazolo [3， 4-b] pyridin-3-yl) -7H-pyrrolo [2， 3- d] pyrimidin-4-yl) amind) tricyclo [3.2.2.02， 4] nonane-6-carboxylic acid

A mixture solution of (- or +) - (1R， 2R， 4S， 5S， 6R， 7R) -methyl 7- ( (2- (5-chloro-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3， 4-b] pyridin-3-yl) -7-tosyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate (488 mg， 652 μmol) and LiOH.H₂O (274 mg， 6.52 mmol) in THF (5 mL) ， MeOH (5 mL) and TFA (15 mL) was stirred at 50 ℃ for 10 h. After cooling to room temperature， solvent was removed under reduced pressure， and the residue was re-dissolved in TFA (15 mL) and the mixture solution was stirred at room temperature for 24 h. Solvent was evaporated under reduced pressure and the crude product was purified by silica gel flash chromatography to afford the title compound (50 mg， 17 ％yield) as a white solid. MS： 450.1 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) δ 9.00 (s， 1H) ， 8.62 (d， J＝2.08 Hz， 1H) ， 7.18-7.54 (m， 1H) ， 6.95 (br d， J＝3.18 Hz， 1H) ， 4.77 (br d， J＝4.52 Hz， 1H) ， 2.76 (br s， 1H) ， 2.54-2.70 (m， 2H) ， 1.79-2.04 (m， 2H) ， 1.71 (br d， J＝6.11 Hz， 2H) ， 1.20 (br s， 1H) ， 0.99 (br d， J＝5.14 Hz， 2H) ， 0.58 (br d， J＝6.60 Hz， 1H) .

Example 31

(-) - (1R， 2S， 4R， 5S， 6S， 7S) -7- ( (2- (5-Chloro-1H-pyrazolo [3， 4-b] pyridin-3-yl) -7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylic acid

Similar to the synthesis of Example 30/step B， (+ or -) (1S， 2S， 4R， 5R， 6S， 7S) -methyl 7- ( (2- (5-chloro-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3， 4-b] pyridin-3-yl) -7-tosyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate (488 mg， 652 μmol) was used instead to afford the title compound (60 mg， 20.5％yield) after silica gel flash chromatography purification as a white solid. MS： 450.1. [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) δ 9.00 (s， 1H) ， 8.62 (d， J＝2.08 Hz， 1H) ， 7.18-7.54 (m， 1H) ， 6.95 (br d， J＝3.18 Hz， 1H) ， 4.77 (br d， J＝4.52 Hz， 1H) ， 2.76 (br s， 1H) ， 2.54-2.70 (m， 2H) ， 1.79-2.04 (m， 2H) ， 1.71 (br d， J＝6.11 Hz， 2H) ， 1.20 (br s， 1H) ， 0.99 (br d， J＝5.14 Hz， 2H) ， 0.58 (br d， J＝6.60 Hz， 1H) .

Example 32

(+) - (1R， 2S， 4R， 5S， 6S， 7S) -7- ( (2- (5-chloro-1H-pyrrolo [2， 3-b] pyridin-3-yl) -9-methyl-9H-purin-6-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylic acid

[A] (+ or -) - (1R， 2S， 4R， 5S， 6S， 7S) -Methyl 7- ( (2- (5-chloro-1-tosyl-1H-pyrrolo [2， 3-b] pyridin-3- yl) -9-methyl-9H-purin-6-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate

To a stirred mixture solution of (-) - (1R， 2S， 4R， 5S， 6S， 7S) -methyl 7- ( (2-chloro-9-methyl-9H-purin-6-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate (Intermediate B-10b， 250 mg， 691 μmol) and Pd (PPh₃) ₄ (100 mg， 86.5 μmol) in dioxane (4 mL) was added 1， 1， 1， 2， 2， 2-hexabutyldistannane (442 mg， 400 μL， 762 μmol) at room temperature and the resulting reaction mixture solution was stirred at 145 ℃ for 1 h under microwave heating. After cooling to room temperature， 5-chloro-3-iodo-1-tosyl-1H-pyrrolo [2， 3-b] pyridine (448 mg， 1.04 mmol) and Pd (PPh₃) ₄ (100 mg， 86.5 μmol) were added to the above stirred mixture solution in dioxane (16 mL) . The reaction mixture solution was then stirred at 125 ℃ for an additional 1 h under microwave heating. After cooling to room temperature， the reaction mixture was poured into water (20 mL) and extracted with EtOAc (50 mL twice) . The combined organic layers were washed with brine， dried over anhydrous Na₂SO₄， filtered and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (0-80％ EtOAc-hexane gradient， then 0-5％ MeOH-DCM gradient) to afford the title compound (80 mg， 18.3％ yield) as a yellow oil. MS： 632.1 (M+H) ⁺.

[B] (+) - (1R， 2S， 4R， 5S， 6S， 7S) -7- ( (2- (5-Chloro-1H-pyrrolo [2， 3-b] pyridin-3-yl) -9-methyl-9H- purin-6-yl) amino)tricyclo [3.2.2.02， 4] nonane-6-carboxylic acid

To a stirred mixture solution of (+ or -) - (1R， 2S， 4R， 5S， 6S， 7S) -methyl 7- ( (2- (5-chloro-1-tosyl-1H-pyrrolo [2， 3-b] pyridin-3-yl) -9-methyl-9H-purin-6-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate (80 mg， 127 μmol)in THF (5 mL) and MeOH (5 mL) was added LiOH (30.3 mg， 1.27 mmol) pre-dissolved in water (5 mL) . The reaction mixture solution was stirred at room temperature for 12 h before being diluted with water (10 mL) and extracted with diethyl ether (20 mL) . The organic layer was discarded and the aqueous layer was acidified with concentrated hydrochloric acid to pH 4 and extracted with EtOAc (40 mL x 3) . Combined organics were then dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude poduct， which was purified by prep-HPLC to afford the title compound (23 mg， 39.2％ yield) as a white foam. MS： 464.1 (M+H) ⁺. ¹H NMR (400 MHz， MeOH-d₄) δ 8.85-8.89 (m， 1H) ， 8.52-8.57 (m， 1H) ， 8.33-8.40 (m， 1H) ， 8.23-8.28 (m， 1H) ， 4.48-4.55 (m， 1H) ， 3.96 (s， 3H) ， 2.62-2.67 (m， 1H) ， 2.56-2.61 (m， 1H) ， 2.46-2.53 (m， 1H) ， 1.82-1.92 (m， 2H) ， 1.62-1.74 (m， 2H) ， 1.16-1.27 (m， 1H) ， 0.99-1.10 (m， 1H) ， 0.82-0.91 (m， 1H) ， 0.58-0.68 (m， 1H) .

Example 33

(-) - (1S， 2R， 4S， 5R， 6R， 7R) -7- ( (2- (5-Chloro-1H-pyrrolo [2， 3-b] pyridin-3-yl) -9-methyl-9H-purin-6-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylic acid

[A] (-or ) - (1S， 2R， 4S， 5R， 6R， 7R) -Methyl 7- ( (2- (5-chloro-1-tosyl-1H-pyrrolo [2， 3-b] pyridin-3- yl) -9-methyl-9H-purin-6-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate

Similar to the synthesis of Example 32/step A， (+) - (1S， 2R， 4S， 5R， 6R， 7R) -methyl 7- ( (2-chioro-9-methyl-9H-purin-6-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate (Intermediate B-10a， 250 mg， 691 μmol) was used instead to afford the title compound (80 mg， 18.3％yield) after silica gel flash chromatography (0-80％EtOAc-hexane gradient， then 0-5％MeOH-DCM gradient) purification as a yellow oil. MS： 632.1 (M+1) ⁺.

[B] (-) - (1S， 2R， 4S， 5R， 6R， 7R) -7- ( (2- (5-Chloro-1H-pyrrolo [2， 3-b] pyridin-3-yl) -9-methyl-9H- purn-6-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylic acid

Similar to the synthesis of Example 32/step B， (-or +) - (1S， 2R， 4S， 5R， 6R， 7R) -methyl 7- ( (2- (5-chloro-1-tosyl-1H-pyrrolo [2， 3-b] pyridin-3-yl) -9-methyl-9H-purin-6-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate (80 mg， 127 μmol) was used instead to afford the title compound (23 mg， 392％yield) after prep-HPLC purification as a white foam. MS： 464.1 (M+H) ⁺. ¹H NMR (400 MHz， MeOH-d₄) δ 8.79-8.86 (m， 1H) ， 8.50-8.58 (m， 1H) ， 8.34-8.43 (m， 1H) ， 8.21-8.28 (m， 1H) ， 4.45-4.54 (m， 1H) ， 4.00 (s， 3H) ， 2.61-2.66 (m， 1H) ， 2.56-2.61 (m， 1H) ， 2.46-2.53 (m， 1H) ， 1.80-1.91 (m， 2H) ， 1.63-1.75 (m， 2H) ， 1.17-1.25 (m， 1H) ， 1.00-1.09 (m， 1H) ， 0.81-0.89 (m， 1H) ， 0.57-0.68 (m， 1H) .

Example 34

(+) - (1S， 2R， 4S， 5R， 6R， 7R) -7- ( (2- (5-chloro-1H-pyrazolo [3， 4-b] pyridin-3-yl) -7-methyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylic acid

[A] (+ or-) (1S， 2R， 4S， 5R， 6R， 7R) -Methyl 7- ( (2- (5-chloro-1- ( (2- (trimethylsilyl) ethoxy) methyl) - 1H-pyrazolo [3， 4-b] pyridin-3-yl) -7-methyl-7H-pyrrolo [2， 3-d] pyrimidin-4- yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate

To a stirred mixture solution of (-or +) (1S， 2R， 4S， 5R， 6R， 7R) -methyl 7- ( (2-chloro-7-methyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.22.02， 4] nonane-6-carboxylate (Intermediate B-11b， 300 mg， 831 μmol) and Pd (PPh₃) ₄ (100 mg， 86.5 μmol) in dioxane (4 mL) was added 1， 1， 1， 2， 2， 2-hexabutyldistannane (579 mg， 998 μmol) at room temperature.

The resulting reaction mixture solution was stirred at 125 ℃ for 2 h before being cooled back to room temperature. To the above stirred mixture solution in dioxane (16 mL) were added 5-chloro-3-iodo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3， 4-b] pyridine (511 mg， 1.25 mmol) and Pd (PPh₃) ₄ (100 mg， 86.5 μmol) and the reaction mixture solution was stirred at 145 ℃ for another 1 h under microwave heating. After cooling to room temperature， the reaction mixture was poured into water (20 mL) and extracted with EtOAc (50 mL twice) . The combined organic layers were washed with brine， dried over anhydrous Na₂SO₄， filtered and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (0-80％EtOAc-hexane gradient) to afford the title compound (50 mg， 13.4％yield) as a yellow oil. MS： 609.2 [M+H] ⁺.

[B] (+) - (1S， 2R， 4S， 5R， 6R， 7R) -7- ( (2- (5-Chloro-1H-pyrazolo [3， 4-b] pyridin-3-yl) -7-methyl-7H- pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylic acid

A mixture solution of (+ or -) - (1S， 2R， 4S， 5R， 6R， 7R) -methyl 7- ( (2- (5-chloro-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3， 4-b] pyridin-3-yl) -7-methyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate (200 mg， 329 μmol) and LiOH. H₂O (138 mg， 3.29 mmol) in THF (5 mL) and MeOH (5 mL) was stirred at 50 ℃ for 10 h. After cooling to room temperature， the solvent was removed under reduced pressure and the residue was re-dissolved in TFA (15 mL) and the mixture was stirred at room temperature for another 24 h. Solvent was evaporated in vacuo and the crude product was purified by silica gel flash chromatography to afford the title compound (45 mg， 29.5％yield) as a white solid. MS： 464.1 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) δ 9.00 (d， J＝2.45 Hz， 1H) ， 8.43 (d， J＝2.45 Hz， 1H) ， 6.98 (d， J＝3.42 Hz， 1H) ， 6.61 (d， J＝3.42 Hz， 1H) ， 4.66 (br d， J＝6.36 Hz， 1H) ， 3.66-3.86 (m， 3H) ， 2.50-2.59 (m， 2H) ， 2.42 (br d， J＝2.20 Hz， 1H) ， 1.80-1.93 (m， 1H) ， 1.58-1.74 (m， 2H) ， 1.45-1.58 (m， 1H) ， 0.98-1.07 (m， 1H) ， 0.89-0.98 (m， 1H) ， 0.80 (td， J＝4.14， 7.98 Hz， 1H) ， 0.35 (q， J＝7.70 Hz， 1H) .

Example 35

(-) - (1R， 2S， 4R， 5S， 6S， 7S) -7- ( (2- (5-chloro-1H-pyrazolo [3， 4-b] pyridin-3-yl) -7-methyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylic acid

[A] (- or +) (1R， 2S， 4R， 5S， 6S， 7S) -Methyl 7- ( (2- (5-chloro-1- ( (2- (trimethylsilyl) ethoxy) methyl) - 1H-pyrazolo [3， 4-b] pyridin-3-yl) -7-methyl-7H-pyrrolo [2， 3-d]pyrimidin-4- yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate

Similar to the synthesis of Example 34/step A， (+ or -) - (1R， 2S， 4R， 5S， 6S， 7S) -methyl 7- ( (2-chloro-7-methyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate (Intermediate B-11a， 300 mg， 831 μmol) was used instead to afford the title compound (50 mg， 13.4％ yield) after silica gel flash chromatography (0-80％ EtOAc-hexane gradient) purification as a yellow oil. MS： 609.2 [M+H] ⁺.

[B] (-) - (1R， 2S， 4R， 5S， 6S， 7S) -7- ( (2- (5-Chloro-1H-pyrazolo [3， 4-b] pyridin-3-yl) -7-methyl-7H- pyrrolo [2， 3-d]pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylic acid

Similar to the synthesis of Example 34/step B， (-or +) - (1R， 2S， 4R， 5S， 6S， 7S) -methyl 7- ( (2- (5-chloro-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3， 4-b] pyridin-3-yl) -7-methyl-7H-pyrrolo [2， 3-d] pyrimidin-4-yl) amino) tricyclo [3.2.2.02， 4] nonane-6-carboxylate (300 mg， 493 μmol) was used instead to afford the title compound (60 mg， 26.2％yield) after siiica gel flash chromatography purification as a white solid. MS： 464.1 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) δ 9.00 (d， J＝2.45 Hz， 1H) ， 8.43 (d， J＝2.45 Hz， 1H) ， 6.98 (d， J＝3.42 Hz， 1H) ， 6.61 (d， J＝3.42 Hz， 1H) ， 4.66 (br d， J＝6.36 Hz， 1H) ， 3.66-3.86 (m， 3H) ， 2.50-2.59 (m， 2H) ， 2.42 (br d， J＝2.20 Hz， 1H) ， 1.80-1.93 (m， 1H) ， 1.58-1.74 (m， 2H) ， 1.45-1.58 (m， 1H) ， 0.98-1.07 (m， 1H) ， 0.89-0.98 (m， 1H) ， 0.80 (td， J＝4.14， 7.98 Hz， 1H) ， 0.35 (q， J＝7.70 Hz， 1H) .

Example 36

(rac) - (2R， 3R) -3- ( (2- (5-Fluoro-1H-pyrrolo [2， 3-b] pyridin-3-yl) -7-oxo-6， 7-dihydro-5H-pyrrolo [3， 4-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

[A] 2， 4-Dihydroxyfuro [3， 4-d] pyrimidin-7 (5H) -one

A stirred mixture solution of 2， 6-dioxo-1， 2， 3， 6-tetrahydropyrimidine-4-carboxylic acid (20 g， 0.13 mol) and paraformaldehyde (30.8 g， 1.02 mol) in concentrated hydrochloric acid (400 mL) was heated to reflux at 85-95℃ for 1 8 h. After cooling to room temperature， the reaction mixture was concentrated in vacuo. The solid residue was washed with water (40 mL) ， filtered， and then dried under vacuum to give a crude product (10 g) as a yellow solid. ¹H NMR (400MHz， DMSO-d₆) δ ppm 12.09 (br. s.， 1H) ， 11.54 (s， 1H) ， 5.10 (s， 1H) . This crude product was used directly in the next step without further purification.

[B] 2， 4-Dihydroxy-6- (4-methoxybenzyl) -5H-pyrrolo [3， 4-d] pyrimidin-7 (6H) -one

A mixture solution of 2， 4-dihydroxyfuro [3， 4-d] pyrimidin-7 (5H) -one (5 g， 29.7 mmol) and PMB-NH₂ (8.16 g， 59.4 mmol) in 2-methoxyethanol (50 mL) was strried at 200 ℃ for 6 h. After cooling to room temperature， the reaction mixture was concentrated in vacuo. The solid residue was washed with water (40 mL) ， filtered， and then dried under vaccum to give a crude product (4.5 g) . The reaction was then cooled， concentrated to give a solid. The solid was washed with water (40 mL) and filtered to give the title compound (4.5 g) . This crude product was used directly in the next step without further purification.

[C] 4-Dichloro-6- (4-methoxybenzyl) -5H-pyrrolo [3， 4-d] pyrimidin-7 (6H) -one

To a stirred suspension of 2， 4-dihydroxy-6- (4-methoxybenzyl) -5H-pyrrolo [3， 4-d] pyrimidin-7 (6H) -one (4.5 g， 15.6 mmol) in POCl₃ (54.61 g) was slowly added N， N-dimethylaniline (3.8 g， 31.3 mmol) . After the addition， the resulting mixture solution was heated to 80 ℃ for 3 h. After cooling to room temperature， the reaction mixture was concentrated and poured into water (200 mL) and extracted with EtOAc (30 mL twice) . The organic layer was dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (petroleum ether∶EtOAc-10∶1) to afford the title compound (0.8 g) as a yellow oil. MS： 346.0 [M+23] ⁺.

[D] (rac) -Methyl (2S， 3S) -3- [ (6-benzyl-2-chloro-7-oxo-5H-pyrrolo [3， 4-d] pyrimidin-4 yl) amino] bicyclo [2.2.2] octane-2-carboxylate

A stirred mixture solution of 4-dichloro-6- (4-methoxybenzyl) -5H-pyrrolo [3， 4-d] pyrimidin-7 (6H) -one (0.7 g， 2.15 mmol) ， (rac) - (2R， 3R) -methyl 3-aminobicyclo [2.2.2] octane-2-carboxylate (0.39 g， 2.15 mmol) ， and DIPEA (0.83 g， 6.45 mmol) in THF (10 mL) was heated to 60 ℃ for 12 h before being cooled back to room temperature， After TLC (petroleum ether∶ EtOAc ＝ 5∶1) showed that the reaction was completed， the reaction mixture was concentrated in vacuo to give a crude product (0.8 g) as a yellow oil. MS： 471.2 [M+H] ⁺.

[E] (rac) -Methyl (2S， 3S) -3- [ [6-benzyl-2- [5-fluoro-1- (2-trimethylsilylethoxymethyl) pyrrolo [2， 3- b] pyridin-3-yl] -7-oxo-5H-pyrrolo [3， 4-d] pyrimidin-4-yl] amino] bicyclo [2.2.2] octane-2- carboxylate

To a stirred mixture solution of (rac) -methyl (2S， 3S) -3- [ (6-benzyl-2-chloro-7-oxo-5H-pyrrolo [3， 4-d] pyrimidin-4-yl) amino]bicyclo [2.2.2] octane-2-carboxylate (0.7 g， 1.5 mmol) ， 5-fluoro-3- (4， 4， 5， 5-tetramethyl-1， 3， 2-dioxaborolan-2-yl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2， 3-b] pyridine (0.58 g，1.5 mmol) in H₂O/THF (1/10 mL) were added K₃PO₄ (0.64 g， 3 mmol) and X-phos Biphenyl (0.072 g， 0.15 mmol) at room temperatue and the resulting reaction mixture was stirred at 60℃ for 2 h. After cooling to room temperature， solVent was removed under reduced pressure to give a crude product， which was purified by silica gel flash chromatography (petroleum ether∶EtOAc＝5∶1) to afford the title compound (0.3 g) as a yellow oil. MS： 701.3 [M+H] ⁺.

[F] (rac) - (2R， 3R) -3- ( (2- (5-Fluoro-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2， 3- b] pyridin-3-yl) -6- (4-methoxybenzyl) -7-oxo-6， 7-dihydro-5H-pyrrolo [3， 4-d] pyrimidin-4- yl) amino) bicyclo [2.2， 2] octane-2-carboxylic acid

To a stirred solution of (rac) -methyl (2S， 3S) -3- [ [6-benzyl-2- [5-fluoro-1- (2-trimethylsilylethoxymethyl) pyrrolo [2， 3-b] pyridin-3-yl] -7-oxo-5H-pyrrolo [3， 4-d] pyrimidin-4-yl] amino] bicyclo [2.2.2] octane-2-carboxylate (0.06 g， 0.085 mmol) in DCE (3 mL) was added (CH₃) ₃SnOH (0.082 g， 0.43 mmol) at room temperature and the resulting reaction mixture was heated at 90℃ for 12 h. After cooling to room temperature， the solvent was removed under reduced pressure to give a crude product (0.04 g) as a yellow solid. MS： 451.4 [M+H] ⁺. This crude product was used directly in the next step without further purification.

[G] (rac) - (2R， 3R) -3- ( (2- (5-Fluoro-1H-pyrrolo [2， 3-b] pyridin-3-yl) -7-oxo-6， 7-dihydro-5H- pyrrolo [3， 4-d] pyrimidin-4-yl) amino) bicyclo [2， 2， 2] octane-2-carboxylic acid

A mixture solution of (rac) - (2R， 3R) -3- ( (2- (5-fluoro-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2， 3-b] pyridin-3-yl) -6- (4-methoxybenzyl) -7-oxo-6， 7-dihydro-5H-pyrrolo [3， 4-d] pyrimidin-4-yl) amino) bicycio [2.2.2] octane-2-carboxylic acid (0.036 g， 0.052 mmol) ， MsOH (1 mL) in TFA (1 mL) was stirred at 80 ℃ for 8 h. After cooling to room temperature， the solVent was evaporated in vacuo to give a crude product， which was purified by prep-HPLC to afford the title compound (4 mg) as a white foam. MS： 437.3 [M+H] ⁺. ¹H NMR (400MHz， MeOH-d4) δ 8.82 (d， J＝9.8 Hz， 1H) ， 8.53 (s， 1H) ， 8.21 (s， 1H) ， 4.41 (s， 2H) ， 3.50 (s， 1H) ， 3.15 (s， 1H) ， 2.78 (d， J＝6.8 Hz， 1H) ， 2.68 (s， 1H) ， 2.20 -2.06 (m， 2H) ， 1.87 (br. s. ， 2H) ， 1.81 -1.65 (m， 3H) ， 1.64 -1.52 (m， 1H) ， 1.31 (s， 1H) .

Claims

A compound having the formula (I) ， optionally in the form of a pharmaceutically acceptable salt， solvate， polymorph， prodrug， codrug， cocrystal， tautomer， racemate， enantiomer， or diastereomer or mixture thereof，

wherein

is a single or double bond；

R¹ is selected from the group consisting of -H， -halogen， -CN， -C (O) R^＊＊， -COOR^＊＊， -C (O) NR^＊＊R^＊＊， -NR^＊＊R^＊＊， -NR^＊＊-C (O) R^＊＊， -N (R^＊＊) -C (O) -OR^＊＊， -N (R^＊＊) -C (O) -NR^＊＊R^＊＊， -N (R^＊＊) -S (O) ₂R^＊＊， - (optionally substituted C_1-6 alkyl) ， -OR^＊＊， - (optionally substituted heterocyclyl) ， - (optionally substituted C_1-4 alkylene) - (optionally substituted heterocyclyl) ， - (optionally substituted carbocyclyl) ， and - (optionally substituted C_1-4 alkylene) - (optionally substituted carbocyclyl) ， wherein R^＊＊is H， - (optionally substituted C_1-6 alkyl) ， - (optionally substituted heterocyclyl) ， or - (optionally substituted carbocyclyl) and

wherein the - (optionally substituted) can be independently-halogen， -CN， -NO₂， oxo， -C (O) R^＊＊＊， -COOR^＊＊＊， -C (O) NR^＊＊＊R^＊＊＊， -NR^＊＊＊R^＊＊＊， -NR^＊＊＊-C (O) R^＊＊＊， -N (R^＊＊＊) -C (O) -OR^＊＊＊， -N (R^＊＊＊) -C (O) -NR^＊＊＊R^＊＊＊， -N(R^＊＊＊) -S (O) ₂R^＊＊＊， -OR^＊＊＊， -O-C (O) R^＊＊＊， -O-C (O) -NR^＊＊＊R^＊＊＊， -SR^＊＊＊， -S(O) R^＊＊＊， -S (O) ₂R^＊＊＊， -S (O) ₂-NR^＊＊＊R^＊＊＊， -N (R^＊＊＊) -S (O) ₂-NR^＊＊＊R^＊＊＊， -P(O) (OR^＊＊＊) ₂， or -O-P (O) (OR^＊＊＊) ₂； wherein R^＊＊＊is H， C_1-6 alkyl， heterocyclyl or carbocyclyl； and wherein - (optionally substituted) can also be C_1-6 alkyl in the case of - (optionally substituted heterocyclyl) or - (optionally substituted carbocyclyl) ；

R² and R³ are linked together to form， with the carbon atoms to which they are attached， a carbocyclic or heterocyclic 5 to 7-membered ring which optionally comprises 0 to 3 heteroatoms in the ring and which may be substituted with one or more substituents independently selected from R⁶；

R⁴ is selected from the group consisting of -H and - (optionally substituted C_1-6 alkyl) ， - (optionally substituted carbocyclyl) ， and - (optionally substituted heterocyclyl) ， wherein the - (optionally substituted) can be independently -halogen， -CN， -NO₂， oxo， -C (O) R^＊＊， -COOR^＊＊， -C (O) NR^＊＊R^＊＊， -NR^＊＊R^＊＊， -NR^＊＊-C (O) R^＊＊， -N (R^＊＊) -C (O) -OR^＊＊， -N (R^＊＊) -C (O)-NR^＊＊R^＊＊， -N(R^＊＊) -S (O) ₂R^＊＊， -OR^＊＊， -O-C (O) R^＊＊-， -O-C (O) -NR^＊＊R^＊＊， -SR^＊＊， -S (O) R^＊＊， -S(O) ₂R^＊＊， -S (O) ₂-NR^＊＊R^＊＊， -N (R^＊＊) -S (O) ₂-NR^＊＊R^＊＊， -P (O) (OR^＊＊) ₂ or -O-P (O) (OR^＊＊) ₂； wherein R^＊＊is C_1-6 alkyl or C_3-6 cycloalkyl which can optionally be substituted with halogen； and wherein - (optionally substituted) can also be C_1-6 alkyl in the case of - (optionally substituted heterocyclyl) or - (optionally substituted carbocyclyl) ；

R^5a is selected from the group consisting of -halogen， -OR^＊， and -CN， wherein R^＊is - (optionally substituted C_1-6 alkyl) ， - (optionally substituted heterocyclyl) ， or - (optionally substituted carbocyclyl) ；

R^5b is selected from the group consisting of -H， - (optionally substituted C_1-6 alkyl) ， -(optionally substituted heterocyclyl) ， - (optionally substituted carbocyclyl) ， -(optionally substituted C_1-4 alkylene) - (optionally substituted heterocyclyl) and -(optionally substituted C_1-4 alkylene) - (optionally substituted carbocyclyl) ， wherein R^＊is - (optionally substituted C_1-6 alkyl) ， - (optionally substituted heterocyclyl) ， or - (optionally substituted carbocyclyl) ；

wherein the - (optionally substituted heterocyclyl) and - (optionally substituted carbocyclyl) in R^5a and R^5b may furthermore be bridged and the bridge may contain 0 to 2 carbonatoms and 0 to 2 heteroatoms， and wherein the -(optionally substituted) in R^5a and R^5b can be independently -halogen， -CN， -CF₃， -CHF₂， -CH₂F， -OCF₃， -OCHF₂， -OCH₂F， -NR^＊R^＊， -NR^＊COR^＊， -NR^＊C (O) NR^＊R^＊， -NR^＊S (O₂) NR^＊R^＊， -C (O) OR^＊， -C (O) NR^＊R^＊， -OH， or -O-C_1-6 alkyl， wherein each R^＊is H， C_1-6 alkyl or C_3-6 cycloalkyl； and wherein - (optionally substituted) can also be C_1-6 alkyl in the case of - (optionally substituted heterocyclyl) or - (optionally substituted carbocyclyl) ；

R⁶ is independently selected from the group consisting of -H， -Hal， -OR^＊＊， oxo， -CN， -NO₂， -C (O) R^＊＊， -COOR^＊＊， -C (O) NR^＊＊R^＊＊， -NR^＊＊R^＊＊， -NR^＊＊C (O) R^＊＊， -NR^＊＊C (O) NR^＊＊R^＊＊， -NR^＊＊S (O₂) NR^＊＊R^＊＊， - (CH₂) _pSR^＊＊， - (CH₂) _pS (O) R^＊＊， -(CH₂) _pSO₂R^＊＊， - (CH₂) _pSO₂NR^＊＊， - (optionally substituted C_1-6 alkyl) ， -O-(optionally substituted C_1-6 alkyl) ， - (optionally substituted carbocyclyl) and -(optionally substituted heterocyclyl) ， wherein R^＊＊is H， - (optionally substituted C_1-6 alkyl) ， - (optionally substituted C_1-4 alkylene) -O- (optionally substituted C_1-6 alkyl) and wherein the - (optionally substituted) can be independently -H， -halogen， -OH， and-CN；

R⁷ is selected from the group consisting of of -H and -C_1-6 alkyl；

R⁸ is independently selected from the group consisting of -H， -Hal， -CN， -NR^＊＊R^＊＊， - (optionally substituted C_1-6 alkyl) ， -OR^＊＊， - (optionally substituted heterocyclyl) ， and - (optionally substituted carbocyclyl) ， wherein R^＊＊is H， -(optionally substituted C_1-6 alkyl) ， - (optionally substituted heterocyclyl) ， or -(optionally substituted carbocyclyl) ， and wherein the - (optionally substituted) may be halogen；

R⁹ is independently selected from the group consisting of -H， -Hal， -C_1-6 alkyl， -OR^＊， -NR^＊R^＊， -CN and CF₃， wherein R^＊is -H or -C_1-6 alkyl；

R¹⁰ is independently selected from the group consisting of -H， -Hal， -CN， -NO₂， - (optionally substituted C_1-6 alkyl) ， -NR^＊R^＊， and -OR^＊， wherein R^＊is -H， or - (optionally substituted C_1-6 alkyl) and wherein the - (optionally substituted) may be halogen；

X¹ is selected from the group consisting of N and C；

X² is selected from the group consisting of N and CR⁹；

X³ is selected from the group consisting of N， NR⁹， CR⁹ and CR⁹ ₂， as valency permits；

X⁴ is selected from the group consisting of N and CR⁹；

X⁵ is selected from the group consisting of N and CR⁸；

X⁶ is selected from the group consisting of N and CR¹；

X⁷ is selected from the group consisting of N and CR⁸；

with the proviso that
is X¹-X²＝X³ if X¹ is N and

is X¹＝X²-X³ if X¹ is C； and with the further proviso that at least one of X¹，X²， and X³ is N or NR⁹；

X⁸ is selected from the group consisting of N and CR¹⁰；

T is selected from the group consisting of

the ring A is a saturated monocyclic carbocyclic ring having 5 to 8 ring carbon atoms or a saturated bridged carbocyclic ring having 5 to 8 ring carbon atoms and 1 to 3 carbon atoms in the bridge or a saturated bridged heterocyclic ring having 5 to 8 ring carbon atoms and 0 to 2 heteroatoms in the ring， and 0 to 2 carbon atoms and 0 to 2 heteroatoms in the bridge， wherein A can be substituted in any available position by one or two substituents which are selected from the group consisting of -L-R⁵；

the ring B， which is fused to the ring A， is a saturated monocyclic carbocyclic ring having 3 to 6 ring carbon atoms， wherein the ring B can be optionally substituted in any available position by one or more substituents which are selected from the group consisting of -L-R⁵；

-L-R⁵ is selected from -L^a-R^5a and -L^b-R^5b；

L^a is selected from the group consisting of - (CH₂) _p-C (O) -， - (CH₂) _p-CR⁷ (OR⁷) -， - (CH₂) _p-C (O) -N (R⁷) - (CH₂) _p-， - (CH₂) _p-N (R⁷) -C (O) - (CH₂) _p-， -(CH₂) _p-N (R⁷) -S (O) ₂-， - (CR⁷R⁷) _p-S (O) -， - (CR⁷R⁷) _p-S (O) ₂-， -(CR⁷R⁷) _p-S (O) - (CR⁷R⁷) _p-， - (CR⁷R⁷) _p-S (O) ₂- (CR⁷R⁷) _p-， - (CR⁷R⁷) _p- (optionally substituted heterocyclylene) -and a bond； the optional substituent of the heterocyclyene is independently selected from one or more groups selected from -Hal， -CN， -NO₂， -OH and -NH₂；

L^b is selected from the group consisting of - (CH₂) _p-C (O) -O-， - (CH₂) _p-C (O) -， -(CH₂) _p-CR⁷ (OR⁷) -， - (CH₂) _p-C (O) -N (R⁷) - (CH₂) _p-， - (CH₂) _p-N (R⁷) -， -(CH₂) _p-N (R⁷) -C (O) - (CH₂) _p-， - (CH₂) _p-N (R⁷) -C (O) -C (O) -， -(CH₂) _p-N (R⁷) -C (O) -O-， - (CH₂) _p-N (R⁷) -C (O) -N (R⁷) -， - (CH₂) _p-N (R⁷) -S (O) ₂-， -N(R⁷) -S (O) ₂-N (R⁷) -， - (CH₂) _p-O-C (O) -， - (CH₂) _p-O-C (O) -N (R⁷) -， -(CR⁷R⁷) _p-O-， - (CR⁷R⁷) _p-S (O) -， - (CR⁷R⁷) _p-S (O) ₂-， - (CR⁷R⁷) _p-S- (CR⁷R⁷) _p-， -(CR⁷R⁷) _p-S (O) - (C R⁷R⁷) _p-， - (CR⁷R⁷) _p-S (O) ₂- (CR⁷R⁷) _p-， -(C R⁷R⁷) _p-S (O) ₂-N (R⁷) -， - (CR⁷R⁷) _p-S (O) ₂-N (R⁷) -C (O) -， -(CR⁷R⁷) _p-P (O) (OR⁷) O-， -O-P (O) (OR⁷) O-， -P (O) ₂O-， - (CR⁷R⁷) _p- (optionally substituted heterocyclylene) - and a bond； the optional substituent of the heterocyclyene is independently selected from one or more groups selected from -Hal， -CN， -NO₂， -OH and -NH₂；

m is 1 to 3；

n is 1 to 4； and

p is 0 to 6；

with the proviso that the following compound is disclaimed：

cyclohexyl- (2-indazol-1-yl-quinazolin-4-yl) -amine.
The compound according to claim 1， wherein the ring A is selected from the group consisting of

wherein each W is independently selected from C， N， O and S， and wherein ring A can be substituted in any available position by one or two substituents which are selected from the group consisting of -L-R⁵.
The compound according to claim 1 or 2， wherein the ring B is
The compound according to any of the preceding claims， wherein R² and R³ are linked together to form， with the carbon atoms to which they are attached， a heterocyclic 5 or 6-membered ring which is unsaturated and which comprises 1 or 2 heteroatoms in the ring and which may be substituted with one or more substituents independently selected from R⁶.
The compound according to any of the preceding claims， wherein R¹ is selected from the group consisting of -H， -halogen， -CN， and -C_1-6 alkyl， which is optionally substituted by one or more selected from -halogen， -heterocyclyl and -carbocyclyl.
The compound according to any of the preceding claims， wherein R⁴ is -H and/or R⁶ is -H and/or R⁷ is -H.
The compound according to any of the preceding claims， wherein L is selected from the group consisting of -C (O) -O-， -O-C (O) -， -C (O) -N (R⁷) -， -N (R⁷) -C (O) -， and - (CR⁷R⁷) _p-O-.
The compound according to any of trhe preceding claims， wherein R⁵ is selected from the group consisting of -H， -C_1-6 alkyl， -heterocyclyl， and -carbocyclyl.
The compound according to any of the preceding claims， wherein X⁸ is N.
The compound according to any of the preceding claims， wherein the substructure
is selected from
wherein R⁶ and X⁸ are as defined in claim 1.
The compound according to any one of claims 1， 2 and 4 to 10， wherein T is selected from the group consisting of

wherein A and m are as defined in claim 1.
A pharmaceutical composition comprising：

a compound having the formula (I) as defined in any of claims 1 to 11， optionally in the form of a pharmaceutically acceptable salt， solvate， polymorph， prodrug， codrug， cocrystal， tautomer， racemate， enantiomer， or diastereomer or mixture thereof， and optionally one or more pharmaceutically acceptable excipient (s) and/or carrier (s) .
A compound having the formula (I) as defined in any of claims 1 to 11， optionally in the form of a pharmaceutically acceptable salt， solvate， polymorph， prodrug， codrug， cocrystal， tautomer， racemate， enantiomer， or diastereomer or mixture thereof， wherein the compound is for use in the treatment， amelioration or prevention of influenza； and

wherein the compound disclaimed in claim 1 is disclaimed or not disclaimed.
A method of treating， ameliorating or preventing influenza， the method comprising administering to a patient in need thereof an effective amount of a compound having the formula (I) as defined in any of claims 1 to 11， optionally in the form of a pharmaceutically acceptable salt， solvate， polymorph， prodrug， codrug， cocrystal， tautomer， racemate， enantiomer， or diastereomer or mixture thereof；

wherein the compound disclaimed in claim 1 is disclairned or not disclaimed.