WO2017133657A1

WO2017133657A1 - Pyridine and pyrimidine derivatives and their use in treatment, amelioration or prevention of influenza

Info

Publication number: WO2017133657A1
Application number: PCT/CN2017/072814
Authority: WO
Inventors: Xuefei Tan; Lisha Wang; John Graham Cumming; Yongfu Liu; Jun Wu; Dongbo Li; 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

Provided herein is a compound of 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, ameliorating or preventing influenza.

Description

[Title established by the ISA under Rule 37.2] PYRIDINE AND PYRIMIDINE DERIVATIVES AND THEIR USE IN 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 1 91 8， 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 1 968 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 highly 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. 1 977， 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 functionai 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 2013/1 84985 refer to specific compounds which are stated to be useful in inhibiting the replication of influenza viruses.

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

EP 2 397 479 relates to specific hetero ring derivatives and/or a salts thereof， which have certain pharmacological activities.

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 selected 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 monocyclic 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 azetidine， pyrrole， pyrrolidine， 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， 201 0， 571-588.

The term ″cocrystal″ refers to a multiple component crystal in which all components are solid under ambient conditions when intheir 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 sk illed 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 be 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

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) ， - (optionaliy substituted C_3-6 cycloalkyl， -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- (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. 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) -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. 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， -cyclopropyl， -CF₃， -CHF₂， and-CH₂F. Most preferably R¹ is selected from-H， -F， -Cl， -CN， -CH₃， and-cyclopropyl.

R² 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) ， - (optionally substituted C_3-6 cycloalkyl， -OR^＊＊， -SR^＊＊， -S (O) R^＊＊， -S (O) ₂R^＊＊， - (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- (optionally substituted) can be independently -halogen， -CN， -NO₂， oxo， -C (O) R^＊＊＊， -COOR^＊＊＊， -C (O) NR^＊＊＊R^＊＊＊， -NR^＊＊＊R^＊＊＊， -N R^＊＊＊-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， benzyl， heterocyclyl or carbocyclyl. Preferably R² 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) ， - (optionally substituted C_3- ₆ cycloalkyl， -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- (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. 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， R² is selected from the group consisting of-H， -halogen， -CN， -NR^＊＊R^＊＊， -NR^＊＊-C (O) R^＊＊， -N (R^＊＊) -C (O) -OR^＊＊， -N (R^＊＊) -C (O) -NR^＊＊R^＊＊， -N (R^＊＊) -S (O) ₂R^＊＊， -OR^＊＊， - (optionally substituted C_1-6 alkyl) ， - (optionally substituted C_3-6 cycloalkyl) ， - (optionally substituted C_1-4 alkylene) - (optionally substituted heterocyclyl) ， - (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- (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. 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. Even more preferably R² is-H.

R³ is selected from the group consisting of-H， -halogen， -CN， -NO₂， -C (O) R^＊＊， -COOR^＊＊， -C (O) NR^＊＊R^＊＊， -OR^＊＊， -SR^＊＊， -S (O) R^＊＊， -S (O) ₂R^＊＊， - (optionally substituted C_1-6 alkyl) ， - (optionally substituted C_3-6 cycloalkyl) ， - (optionally substituted C_1-4 alkylene) - (optionally substituted heterocyclyl) ， - (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- (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. 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， benzyl， heterocyclyl or carbocyclyl. Preferably， R³ is selected from the group consisting of-H， -halogen， -CN， -NO₂， -C (O) R^＊＊， -COOR^＊＊， -C (O) NR^＊＊R^＊＊， -OR^＊＊， - (optionally substituted C_1-6 alkyl) ， - (optionally substituted C_3-6 cycloalkyl) ， - (optionally substituted C_1-4 alkylene) - (optionally substituted heterocyclyl) ， - (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- (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. 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， R³ is selected from the group consisting of-H， -halogen， -CN， -OR^＊＊， - (optionally substituted C_1-6 alkyl) ， - (optionally substituted C_1-4 alkylene) - (optionally substituted heterocyclyl) ， - (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- (optionally substituted) can be independently-halogen， -CN， 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. Even more preferably R³ is-halogen.

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-H or-C_1-6 alkyl， 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 aikyl) ， - (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.

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.

R¹¹ is independently selected from the group consisting of-H， -CN， -NO₂， -OH， -NH₂， - (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 R¹¹ is -H.

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 and CR⁸.

X⁴ is selected from the group consisting of N and CR¹¹. In one embodiment， X⁴ is N. In further embodiment， X⁴ is CR¹¹.

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 group consisting 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.

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

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 monocyclic heterocyclic ring having 4 to 7 ring carbon atoms and 1 or 2 heteroatoms (e.g.， selected from N， O and S) in the ring， 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 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. More 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

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.

-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-， - (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 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.

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

In the present invention，

can be chosen from the following non-limiting examples：

Preferably，

is selected from the group consisting of

More preferably，

is selected from the group consisting of

It is to be understood that in any examples of

in which one or more of 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 X²， X³， and X⁴， and X⁶ may be replaced by C-R¹.

General 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 give the compound having the formula (Ia) ， as shown in Scheme A below.

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.

In one embodiment which illustrated in Scheme A， the compounds of formula (Ia) can be prepared by a method via reaction of azaindole or azaindole compound 1 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 (Ia) (step a) . The definitions of structural formula (Ia) and compounds 1 and 2 are independently as defined in any of the embodiments described above. Specific conditions are described in the Examples Section below.

Scheme A

G² is halogen.

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 for the 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 100 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 influenza. 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

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： trifiuoromethanesulfonic anhydride

SEM： 2- (trimethylsilyl) ethoxymethyl

SEMCI： 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 60

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 stated the 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 KJ， Balish AL， Katz JM. Curr Protoc Microbiol. influenza： propagation， quantification， and storage. 2006 Dec， Chapter 15： Unit 15G. 1. doi： 10.1002/0471729256. mc1 5g01 s3) 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 iuciferase 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 o the wells， and the plates were incubated for 24 h at 37 ℃， 5％CO₂.15 μl 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. mc15901s3) ， 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 (Miliipore) . 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 1 min/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.

Materiai 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 EXAMPLES USING THE BIO-ASSAYS

Table 1

Table 2.

Intermediate A-1

1H-Pyrazolo [4， 3-b] pyridine

A solution of 3-fluoropicolinaldehyde (12.5 g， 100 mmol) in N₂H₄. H₂O (80％， 200 mL) was stirred at 120 ℃ for 16 h. After TLC (petroleum ether∶EtOAc ＝ 5∶1) showed the reaction was completed， the mixture solution was poured into water (400 mL) and extracted by EtOAc (400 mL) . The organic layer was then washed with brine， dried over anhy. Na₂SO₄， filtered， and concentrated in vacuo to give a crude title compound (11 g， 96％yield) as yellow solid. MS： 120.3 [M+H] ⁺. ¹H NMR (400 MHz， CHCl₃-d1) ： δ 11.15 (br， 1H) ， 8.65-8.63 (m， 1H) ， 8.37 (s， 1H) ， 7.90 (d， J ＝ 11.6 Hz， 1H) ， 7.36-7.32 (m， 1H) .

Intermediate A-2

6-Fluoro-1H-pyrazolo [4， 3-b] pyridine

[A] 3， 5-Difluoropicolinaldehyde

To a stirred solution of 3， 5-difluoropicolinonitrile (30 g， 214 mmol) in THF (300 mL) was added DIBAL (235.7 mL， 235.7 mmol) and stirred at-20 ℃ for 2 h. After TLC (petroleum ether∶EtOAc＝ 5∶1， Rf ＝0.4) showed the starting material was consumed， the reaction was quenched with 1 N HCl to pH ＝ 5. The reaction mixture was extracted with EtOAc (500 mL x 3) and the combined organic layers were washed with brine， dried over anhy. Na₂SO₄， filtered， and concentrated in vacuo to give a crude title compound difluoropicolinaldehyde (25 g， 81.7％yield) as a yellow solid. It was used directly in the next step without further purification.

[B] 6-Fluoro-1H-pyrazolo [4， 3-b] pyridine

A mixture solution of 3， 5-difluoropicolinaldehyde (25 g， 175 mmol) and hydrazine (87.5 g， 1.75 mol) in n-BuOH (500 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 residule was re-dissolved in EtOAc (1 L) and washed with citric acid (200 mL x 5) ， water， and brine. The organic layer was dried over anhy. Na₂SO₄， filtered， and concentrated in vacuo to give a crude title compound (9.7 g， 41％yield) as a yellow solid. MS： 138.1 [M+H] ⁺. ¹H NMR (400 MHz， DMSO-d6) δ 7.94 (dd， J＝9.29， 1.63 Hz， 1 H) 8.34 (s， 1 H) 8.54 (dd， J＝2.26， 1.51 Hz， 1 H) 13.44 (brs， 1 H) .

Intermediate A-3

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

Intermediate A-4

1H-Pyrazolo [4， 3-b] pyridine-6-carbonitrile

[A] N- (5-Bromo-2-methylpyridin-3-yl) acetamide

To a solution of 5-bromo-2-methylpyridin-3-amine (20 g， 106 mmol) and Et₃N (11.7 g， 116 mmol) in DCM (200mL) was added Ac₂O (14.1 g， 139 mmol) and the resulting reaction mixture was stirred at 150 ℃ for 12 h. Afterwards， the mixture solution was concentrated under reduced pressure. The residule was diluted with water， basified with aq. NaHCO₃ solution (10 mL) ， and then extracted with EtOAc (10 mL x 3) . The combined organic layers were dried over anhy. Na2SO4， filtered， and concentrated in vacuo to giv a crude title compound (14 g， 66.3％yield) as a solid. MS： 231.7 [M+H] ⁺.

[B] 1- (6-Bromo-1H-pyrazolo [4， 3-b] pyridin-1-yl) ethanone

To a solution of N- (5-bromo-2-methylpyridin-3-yl) acetamide (14 g， 61.1 mmol) in toluene (200 mL) was added Ac₂O (21 mL， 183 mmol) ， AcOH (21 mL， 300 mmol) and KOAc (11.7 g， 120 mmol) . The resulting reaction mixture was warmed up to 90 ℃， added CHMe₂CH₂CH₂NO₂ (110 mL) and stirred at 90 ℃ for 5 h. After cooling to room temperature， the mixture was poured into water， basified with aq. NaHCO₃ solution， and extracted with EtOAc (50 mL x 6) . The combined organic layers were dried over anhy. MgSO₄， filtered， and concentrated in vacuo to give a crude title compound (6.5 g， 44.5％yield) as a solid. MS： 241.06 [M+H] ⁺.

[C] 1H-pyrazolo [4， 3-b] pyridine-6-carbonitrile

To a stirred solution of 1- (6-bromo-1H-pyrazolo [4， 3-b] pyridin-1-yl) ethanone (6.5 g， 27.04 mmol) in DMA (60 mL) was added Zn (0.416 g， 6.5 mmol) ， DPPF (1.19 g， 2.08 mmol) ， Zn (CN) 2 (2.08 g， 17.55 mmol) and Pd₂ (dba) ₃ (0.97 g， 0.78 mmol) . The reaction was warmed up to 90 ℃ before iPrNO₂ (19.5 mL) was added， and the resulting mixture was stirred at 120 ℃ for 5 h. After cooling to room temperature， the mixture was diluted with EtOAc (60 mL) and satd. aq. NaHCO₃ solution (100mL) . The combined organic layers were dried over anhy. MgSO4， filtered， and concentrated in vacuo to give a crude title compound (0.95 g， 24.4 ％yield) as a solid. MS： 145.1 [M+H] ⁺. ¹H NMR (400 MHz， DMSO-d6) ： δ 8.84 (d， J＝1.5 Hz， 1H) ， 8.74 (s， 1H) ， 8.51 (s， 1H) .

Intermediate A-5

6- (Trifluoromethyl) -1H-pyrazolo [4， 3-b] pyridine

[A] 2-Chloro-5- (trifluoromethyl) pyridin-3-amine

A mixture solution of 2-chloro-3-nitro-5- (trifluoromethyl) pyridine (80 g， 352.8 mmol) and SnCl₂. 2H₂O (320 g， 1.4 mol) in EtOAc (1 L) was stirred at 80 ℃ for 2 h. After TLC (petroleum ether∶EtOAc ＝ 5∶1) showed the reaction was completed， the reaction was quenched by pouring into ice cooled satd. aq. NaHCO₃ solution (200 mL) . The mixture was extracted with EtOAc (1500 mL) and the organic layer was dried over anhy. Na₂SO₄， filtered， and concentrated in vacuo to give desired crude title compound (75 g， 100％yield) as yellow oil. MS： 197.0 [M+H] ⁺. It was used directly in the next step without further purification.

[B] N- (2-Chloro-5- (trifluoromethyl) pyridin-3-yl) acetamide

A mixture solution of 2-chloro-5- (trifluoromethyl) pyridin-3-amine (75 g， 381.6 mmol) and Ac₂O (82.5 mg， 808.1 mmol) in pyridine (200 mL) was stirred at 80 ℃ for 16 h. After cooling to room temperature， it was diluted with EtOAc (500 mL) ， washed with water and brine. The organic layer was dried over anhy. Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was first purified by silica gel flash chromatography (petroleum ether∶EtOAc ＝ 5∶1) and then crystallization in petroleum ether (100 mL) to afford the title compound (65 g， mixture of mono-and bis-Ac protected product， 73％yield) as white solids. MS：239.0 [M+H] ⁺.

[C] N- (2-Methyl-5- (trifluoromethyl) pyridin-3-yl) acetamide

To a mixture of N- (2-chloro-5- (trifluoromethyl) pyridin-3-yl) acetamide and N-acetyl-N- (2-methyl-5- (trifluoromethyl) pyridin-3-yl) acetamide (35 g， 146.7 mmol) ， K₂CO₃ (62.2 g， 450 mmol) ， methyl boroxine (50％in ether， 70 g， 278.8 mmol) and X-phos (14.4 g， 43mmol) in MeCN (250 mL) and water (150 mL) was added Pd (OAc) ₂ (3.4 g， 15.1 mmol) And the resulting reaction mixture was stirred at 100 ℃ for 16 h. After cooling to room temperature， The reaction was diluted with EtOAc (300 mL) ， washed with water (300 mL) and brine (300 mL) . The organic layer was dried over anhy. Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was then purified by silica gel flash chromatography (petroleum ether∶EtOAc＝5∶1) to afford the title compound (20 g， 57％yield) as a gray solid. MS： 219.0 [M+H]⁺. ¹H NMR (400MHz， CHCl₃-d1) ： δ 8.62 (s， 1H) ， 8.54 (s， 1H) ， 7.11 (br， 1H) ， 2.60 (s， 3H) ， 2.28 (s， 3H) .

[D] 1- (6- (Trifluoromethyl) -1H-pyrazolo [4， 3-b] pyridin-1-yl) ethanone

To a mixture solution of N- (2-methyl-5- (trifluoromethyl) pyridin-3-yl) acetamide (25 g， 105 mmol) ， KOAc (22 g， 225 mmol) in toluene (280 mL) was added AcOH (35 mL) and Ac₂O (35 mL) . The reaction mixture was heated to reflux temperatue followed by the addition of CHMe₂CH₂CH₂NO₂ (430 mg， 3.6 mmol) . The mixture was stirred at 120 ℃ for additional 2 h. After cooling to room temperature， the reaction mixture was diluted with EtOAc (300 mL) ， washed with water and brine. The organic layer was dried over anhy. Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was first purified by silica gel flash chromatography (petroleum ether∶EtOAc ＝ 5∶1) and then crystallization in petroleum ether (100 mL) to give the title compound (12.5 g， 54％yield) as a gray solid. MS： 230.1 [M+H] ⁺.

[E] 6- (Trifluoromethyl) -1H-pyrazolo [4， 3-b] pyridine

To a stirred solution of 1- (6- (trifluoromethyl) -1H-pyrazolo [4， 3-b] pyridin-1-yl) ethanone (12.2 g， 53 mmol) in MeOH (100 mL) was added K₂CO₃ (8.8 g， 64 mmol) and the reaction mixture was heated to 90 ℃ for 5 min. After TLC (petroleum ether∶EtOAc ＝ 5∶1) showed the reaction was completed， the reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residule was re-dissolved in EtOAc (100 mL) ， washed with water and brine. The organic layer was dried over anhy. Na₂SO₄， filtered， and concentrated in vacuo to give product crude title compound (6.5 g， 65％yield) as a gray solid. MS： 188.1 [M+H] ⁺. ¹H NMR (400MHz， CHCl₃-d1) ： δ 11.2 (br， 1H) ， 8.89 (d， J＝ 1.6 Hz， 1H) ， 8.47 (s， 1H) ， 8.19 (s， 1H) .

Intermediate A-6

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

[A] 2， 6-Dimethyipyridin-3-amine

To a solution of 2， 6-dimethyl-3-nitropyridine (20g， 130 mmol) in MeOH (100 mL) was added Pd/C (2 g) and the reaction mixture was stirred at 150℃ under H₂ atomsphere (1 atm) for 3 h. Afterwards， the mixture was filtered and the filtrate was concentrated in vacuo to give a crude title compound (14.7 g， 91.8％yield) as an oil. It was used directly in the next step without further purification.

[B] N- (2， 6-Dimethylpyridin-3-yl) acetamide

To a solution of 2， 6-dimethylpyridin-3-amine (14.7 g， 0.12mol) ， Et₃N (13.3 g， 0.13 mol) in DCM (140 mL) was addedAc₂O (36.8 g， 0.36mol) and the resulting mixture solution was stirred at room temperature for 12 h. Afterwards， the reaction mixture was concentrated under reduced pressure， and the residule was diluted with water， basified with aq. NaHCO₃ solution (10 mL) ， and extracted with EtOAc (10 mL x 3) . The combined organic layers were dried over anhy. Na2SO4， filtered， and concentrated in vacuo to give a crude title compound acetamide (12 g， 60.9％yield) as a white solid. MS： 165.20 [M+H] ⁺

[C] 5-Methyl-1H-pyrazolo [4， 3-b] pyridine

To a solution of N- (2， 6-dimethylpyridin-3-yl) acetamide (12 g， 72.9 mmol) in toluene (200 mL) was added Ac₂O (32 mL， 292.3 mmol) ， AcOH (32 mL， 485 mmol) and KOAc (19 g， 194 mmol) . The misture solution was warmed up to 90 ℃ followed by the addition of iPrNO₂ (16 mL) . The resulting reaction mixture was the stirred at 90 ℃ for 4 h. After TLC (MeOH∶DCM＝1∶10) showed the reaction was completed， the mixture was concentrated under reduced pressure and the residule was re-dissolved in MeOH (200 mL) and added K₂CO₃ (93.7 g， 679 mmol) . The mixture was stirred at 90℃ for another 1 h before cooled back to room temperature. The reaction mixture was filtered and filtrate was concentrated in vacuo to give a crude title compound (2 g， 20.5％yield) as a solid. MS： 134.1 [M+H] ⁺. ¹HNMR (400MHz， CHCl₃-d1) ： δ 13.16 (br. s.， 1H) ， 8.14 (s， 1H) ， 7.89 (d， J＝8.5 Hz， 1H) ， 7.23 (d， J＝8.5 Hz， 1H) ， 2.57 (s， 3H) .

Intermediate A-7

1H-pyrazolo [3， 4-b] pyrazine

[A] 1H-Pyrazolo [3， 4-b] pyrazin-3-amine

To a stirred solution of 3-chloropyrazine-2-carbonitrile (5 g， 35.8 mmol) in EtOH (100 mL) was added N₂H₄. H₂O (85％aq.， 21 g， 360 mmol) dropwise at 15 ℃. After the addition， the reaction mixture was allowed to warm up and stirred at 110 ℃ for 16 h. After cooling to room temperature， the solvent was removed under reduced pressure and the residue solid was washed with EtOH (20 mL) to give a crude title compound (3 g， 62％yield) as a brown solid. MS： 136.1 [M+H] ⁺.

[B] 1H-pyrazolo [3， 4-b] pyrazine

To a stirred solution of 1H-pyrazolo [3， 4-b] pyrazin-3-amine (140.0 mg， 1.0 mmol) in EtOH (2 mL) was added AcOH (60 mg， 1 mmol) and isopentyl nitrite (235 mg， 2 mmol) dropwise at 15 ℃. Afterwards， the resulting reaction mixture was allowed to warm up and stirred at 80 ℃ for 1 h. After cooling to room temperature， the mixture was concentrated in vacuo to give a crude title compound (140 mg) as a yellow solid.. MS： 121.0 [M+H] ⁺. It was used directly in the next step without further purification.

Intermediate A-8

1H-Pyrazolo [4， 3-d] pyrimidine

[A] 1- (1H-Pyrazolo [4， 3-d] pyrimidin-1-yl) ethanone

To a stirred solution of 2， 4-dichloro-6-methyl-5-nitropyrimidine (42 g， 202 mmol) and AcOK (40g， 404mmol) in MeOH (900mL) was added Pd/C (18g) at room temperature and stirred for 16 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo and the residue was purified by silica gel flash chromatography (DCM/MeOH＝20∶1) to give a yellow solid intermediate (6 g) ， which was then re-dissolved in tiluene (110 mL) . To this solution was added AcOK (21.6 g， 220 mmol) ， AcOH (22 mL) and Ac₂O (22 mL) and the resulting reaction mixture was heated to reflux temperatue at 120 ℃. After the addtion of isopentyl nitrite (12.9 g， 110 mmol) was added， the heating continued for another 2 h at 120 ℃. After cooling to room temperature， the mixture was diluted with EtOAc (300 mL) ， washed with satd. aq. NaHCO₃ solution and brine. The organic layer was dried over anhy. Na2SO4， filtered， and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (DCM/MeOH ＝ 100％～1/100) to give the title compound (4.1 g， 62.1％yield) as a yellow solid. ¹HNMR (400 MHz， DMSO-d6) ： δ 9.73 (s， 1H) ， 9.29 (s， 1H) ， 8.43 (s， 1H) ， 2.75 (s， 3H) .

[B] 1H-Pyrazolo [4， 3-d] pyrimidine

To a stirred slution of 1- (1H-pyrazolo [4， 3-d] pyrimidin-1-yl) ethanone (3.9 g， 24 mmol) in MeOH (50 mL) was added K₂CO₃ (4.3 g， 31.2 mmol) and the resulting mixture was heated to reflux temperature at 90 ℃ for 5 min. After cooling to room temperature， the mixture was filtered and the filtrate was concentrated in vacuo to give a crude product， which was re-dissolved in EtOAc (100 mL) and washed with water and brine. The organic layer was dried over anhy. Na₂SO₄， filtered， and concentrated in vacuo to give a crude title compound (2.8 g， 97％yield) . MS： 121.0 [M+H] ⁺. It was used directly in the next step without further purification.

Example 1(rac) -N- [ (1R， 3S) -3- [ (5-Fluoro-2-pyrazolo [4， 3-b] pyridin-1-yl-pyrimidin-4-yl) amino] -cyclohexyl] benzamide

[A] (rac) -tert-butyl N- [ (1R， 3S) -3- [ (2-chloro-5-fluoro-pyrimidin-4- yl) amino] cyclohexyl] carbamate

To a stirred mixture solution of cyclohexane-1， 3-diamine (10.5 g， 92.2 mmol) in THF (100 mL) was added 2， 4-dichloro-5-fluro-pyrimidine (10 g， 60.1 mmol) at 0 ℃. The reaction mixture solution was allowed to warm up to room temperature and stirred for 12 h. The reaction mixture was then concentrated in vacuo and the residue was re-dissolved in DCM (100 mL) ， followed by the addition of Et₃N， (9.33 g， 92.2 mmol) and di-tert-butyl dicarbonate (20.1 g， 92.2 mmol) . The resulting mixture solution was stirred at room temperature for 3 h before it was diluted with DCM (1 L) and washed with brine. The organic layer was dried over anhy. 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 (600 mg， 6.6％yield) as a white solid. MS： 345.2 [M+H] ⁺.

[B] (rac) -tert-Butyl ( (1R， 3S) -3- ( (5-fluoro-2- (1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl) amino) cyclohexyl) carbamate

In a seal tube， to a stirred solution of (rac) -tert-butyl ( (1R， 3S) -3- ( (2-chloro-5-fluoropyrimidin-4-yl) amino) cyclohexyl) carbamate (2 g， 5.8 mmol) in dioxane (20 mL) was added 1H-pyrazolo [4， 3-b] pyridine (Intermediate A-1， 0.8 g， 7 mmol) ， (1S， 2S) -cyclohexane-1， 2-diamine (0.52 g， 4.6 mmol) ， Cul (1.32 g， 7 mmol) and K₃PO₄ (2.46 g， 11.6 mmol) at room temperature， and the resulting reaction mixture was stirred at 120℃ for 12 h. After cooling to room temperature， the reaction was was quenched with satd. aq. NH₄Cl solution (100 mL) and extracted with EtOAc (1 00 mL x 3) . The combined organic extracts were dried over anhy. Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purified by Prep-HPLC to afford the title compound (0.72 g， 29％yield) as a white solid. MS： 428.2 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) δ ppm 8.93 (br. s.， 1 H) ， 8.78 (br. s.， 1 H) ， 8.72 (br. s.， 1 H) ， 7.85 (br. s.， 1 H) ， 7.69 (br. s.， 1 H) ， 4.20 (br. s.， 1 H) ， 3.65 (br. s.， 1 H) ， 2.43 (d， J＝10.29 Hz， 1 H) ， 2.06～2.07 (m， 1 H) ， 2.11 (d， J＝12.05 Hz， 2 H) ， 1.89～2.02 (m， 2 H) ， 1.58 (br. s.， 1 H) ， 1.44 (s， 11 H) .

[C] (rac) - (1S， 3R) -N1- (5-Fluoro-2- (1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl) cyclohexane -1， 3-diamine

To a solution of (rac) -tert-butyl ( (1R， 3S) -3- ( (5-fluoro-2- (1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl) amino) cyclohexyl) carbamate (0.25 g， 0.58 mmol) in EtOAc (10 mL) was added 4 N HCl in dioxane (10 mL) at room temperature and stirred for 3 h. The solvent was removed under reduced pressure to afford a crude title compound (0.18 g， 94.7％yield) as a yellow solid. MS： 328.1 [M+H] ⁺. It was used directly in the next step without further purification.

[D] (rac) -N- [ (1R， 3S) -3- [ (5-Fluoro-2-pyrazoo [4， 3-b] pyridin-1-yl-pyrimidin-4-yl) amino] - cyclohexyl] benzamide

To a solution of (rac) - (1S， 3R) -N1- (5-fluoro-2- (1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl) cyclohexane-1， 3-diamine (100 mg， 0.31 mmol) in DCM (10 mL) was added Et₃N (62.8 mg， 0.62 mmol) and benzoyl chloride (65.4 mg， 0.47 mmol) at room temperature and stirred for 12 h. The reaction mixture solution was concentrated in vacuo to give a crude product， which was purified by Prep-HPLC to afford the title compound (60 mg， 44.9％yield) as a light-yellow solid. MS： 432.1 [M+H] ⁺. ¹HNMR (400HMz， MeOH-d4) δ 9.07 (d， J＝8.53 Hz， 1 H) ， 8.72 (d， J＝4.02 Hz， 1 H) ， 8.55 (br. s.， 1 H) ， 8.15 (br. s.， 1 H) ， 7.78～7.84 (m， 3 H) ， 7.51～7.58 (m， 1 H) ， 7.43～7.48 (m， 2 H) ， 4.20～4.41 (m， 2 H) ， 2.53 (d， J＝11.54 Hz， 1 H) ， 2.17 (d， J＝11.54 Hz， 1 H) ， 2.00～2.13 (m， 2 H) ， 1.71(q， J＝13.55Hz， 1 H) ， 1.45～1.63 (m， 3 H) .

Example 2 (rac) -N- [ (1R， 3S) -3- [ (5-Fluoro-2-pyrazolo [4， 3-b] pyridin-1-yl-pyrimidin-4-yl) amino] cyclohexyl] morpholine-4-carboxamide

To a stirred solution of (rac) - (1S， 3R) -N1- (5-fluoro-2- (1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl) cyclohexane-1， 3-diamine (Example 1/Step B， 50 mg， 0.15 mmol) in MeCN (10 mL) was added DIPEA (21.9 mg， 0.30 mmol) and morpholine-4-carbonyl chloride (34.3 mg， 0.23 mmol) at room temperatue and stirred for 12 h. After LCMC showed the reaction was completed， the reaction mixture was concentrated in vacuo and the residue was purified by Prep-HPLC to afford the title compound (20 mg， 30.3％yield) as a white solid. MS： 441.2 [M+H] ⁺. ¹H NMR (400MHz， MeOH-d4) δ 8.98 (d， J＝8.78Hz， 1H) ， 8.65 (d， J＝4.02 Hz， 1 H) ， 8.47 (s， 1 H) ， 8.07 (d， J＝2.76 Hz， 1 H) ， 7.67 (dd， J＝8.66， 4.39 Hz， 1 H) ， 4.14～4.30 (m， 1 H) ， 3.81～3.95 (m， 1 H) ， 3.62～3.67 (m， 4 H) ， 3.37 (t， J＝4.77 Hz， 4 H) ， 2.37～2.44 (m， 1 H) ， 2.13 (d， J＝12.05 Hz， 1 H) ， 1.92～2.04 (m， 2 H) ， 1.56～1.65 (m， 1 H) ， 1.29～1.49 (m， 3 H) .

Example 3

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

[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 reduced pressure and the residue was washed with cold MeOH (200 mL) . Vacuum filtration then afforded a crude title compound (30 g， 70％yield) as a white solid. It 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 anhy. Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (petroleum ether： EtOAc， 0～100％gradient) to afford a racemic mixture of title compounds (10 g， 67％yield) as a white solid. 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 hr. Benzyi alcohol (54.9 g， 508 mmol) was added and the resulting reaction mixture was stirred at 90 ℃ for 16 hr. 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 anhy. Na₂SO₄， filtered， and then concentrated in vacuo to give a crude product， which was then purified by slilical 9el column chromatography (EtOAc∶peterolium ether＝ 0 to 20％) to afford the title compound (58 g， 43.4％yield) as yellow oil. MS： 316.1 (M+1) ⁺.

[D] (rac) - (1S， 2S， 3S， 4R) -Methyl3-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 atmosphere (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] ⁺. It was used directly in the next step without further purification.

[E] (rac) -Methl (2S，3S) -3- [ (2-chloro-5-fluoro-pyrimidin-4-yl) amino] bicyclo [2.2.2] octane-2- carboxylate

A mixture solution of 2， 4-dichloro-5-fluoropyrimidine (870 mg， 5.25 mmol) ， (2S， 3S) -methyl 3-aminobicyclo [2.2.2] octane-2-carboxylate (800 mg， 4.37 mmol) and DIPEA (2 g， 15.75 mmol) in THF (20 mL) was stirred at 80 ℃ for 10 h before the solvent was removed under reduced pressure to give a crude product， which was purified by silica gel flash chromatography (petroleum ether∶EtOAc ＝ 3∶1) to give a racemic mixture of title compound (600 mg， 44 ％yield) as a yellow solid. MS： 314.2 (M+H⁺) . Under SFC chiral separation condition (AS-H， 250×20mmL.D， 20％Ethanol in CO₂) ， both enantiomers can be obtained as (+) - (1S， 2R， 3R， 4S) -methyl 3- ( (2-chloro-5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate and (-) - (1R， 2S， 3S， 4R) -methyl 3- ( (2-chloro-5-fluoropyrimidin-4-yl)amino) bicyclo [2.2.2] octane-2-carboxylate as white solids.

[F] (-) - (1R， 2S， 3S， 4R) -Methyl 3- ( (5-fluoro-2- (1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4- yl) amino) bicyclo [2.2.2] octane-2-carboxylate

To a stirred mixture solution of (-) - (1R， 2S， 3S， 4R) -methyl 3- ( (2-chloro-5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (200 mg， 637 μmol) ， and 1H-pyrazolo [4， 3-b]pyridine (Intermediate A-1， 137 mg， 1.15 mmol) in dioxane (6 mL) was added copper (I) iodide (48.6 mg， 255 μmol) ， (1R， 2S) -cyclohexane-1， 2-diamine (58.2 mg， 72.8 μL， 510 μmol) and potassium hydrogenphosphate (167 mg， 956 μmol) . The reaction mixture solution was stirred at 120 ℃ for 12 h， and after cooling to room temperature， the reaction mixture was poured into water (20 mL) and extracted with EtOAc (50 mL x 2) . The combined organic layers were washed with brine， dried over anhy. Na₂SO₄， filtered and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (0-50％ EtOAc-hexane gradient) to yield the title compound (100 mg， 39.6％yield) as a white solid. MS： 397.1 [M+H] ⁺.

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

To a stirred mixture solution of (-) - (1R， 2S， 3S， 4R) -methyl 3- ( (5-fluoro-2- (1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (130 mg， 328 μmol) in THF (4mL) and MeOH (2 mL) was added lithium hydroxide (39.3 mg， 1.64 mmol) pre-dissoved in water (1mL) . The reaction mixture solution was stirred at room temperature for 12 h before 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 ethyl acetate (40 mL x 3) . The combined organics were dried over anhy. Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purified by Prep-HPLC to afford the title compound (29 mg， 23 1％yield) as white foam. MS： 383.1 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) δ 9.17 (d， J＝8.53 Hz， 1 H) 8.67 (dd， J＝4.52， 1.25 Hz， 1 H) 8.49 (s， 1 H) 8.11 (d， J＝3.26 Hz， 1 H) 7.62 (dd， J＝8.66， 4.39 Hz， 1 H) 4.96 (d， J＝6.78 Hz， 1 H) 2.83 (d， J＝7.03 Hz， 1 H) 2.16 (br. s.， 1 H) 2.01 (br. s.， 1 H) 1.81 -1.95 (m， 3 H) 1.47 -1.80 (m， 5 H) .

Example 4

(rac) -N- ( (1R， 3S) -3- ( (5-Fluoro-2- (1 H-pyrazolo [4， 3-b] pyrid in-1-yl) pyrimidin-4-yl) amino) cyclohexyl) pyrrolidine-1-carboxamide

To a solution of (rac) - (1S， 3R) -N1- (5-fluoro-2- (1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl) cyclohexane-1， 3-diamine (Example 1/Step B， 180 mg， 0.55 mmol) in MeCN (10 mL) was added DIPEA (142.2 mg， 1.10 mmol) and pyrrolidine-1-carbonyl chloride (110.2 mg， 0.83 mmol) at room temperature and stirred for 12 h. After LCMS showed the reaction was complete， the reaction mixture was concentrated in vacuo to give a crude product， which was then purified by Prep-HPLC to afford the title compound (25 mg， 10.7％yield ) as a white solid. MS： 425.2 [M+H] ⁺. ¹HNMR (400MHz， MeOH-d4) δ 9.01 (d， J＝8.78 Hz， 1 H) ， 8.66 (d， J＝3.51 Hz， 1 H) ， 8.48 (s， 1 H) ， 8.09 (d， J＝3.51 Hz， 1 H) ， 7.70 (dd， J＝8.53， 4.52 Hz， 1 H) ， 4.20-4.32 (m， 1 H) ， 3.88 (ddd， J＝11.80， 8.16， 3.64 Hz， 1 H) ， 3.31 (s， 4 H) ， 2.39 (d， J＝11.80 Hz， 1 H) ， 2.14 (d， J＝12.05 Hz， 1 H) ， 1.94～2.06 (m， 2 H) ， 1.91 (t， J＝6.53 Hz， 4 H) ， 1.62 (q， J＝13.22 Hz， 1 H) ， 1.29～1.51 (m， 3 H) .

Example 5

N-Cyclohexyl-5-fluoro-2- (6-fluoropyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-amine

[A] 2-Chloro-N-cyclohexyl-5-fluoro-pyrimidin-4-amine

To a solution of 2， 4-dichloro-5-fluoro-pyrimidine (10 g， 60.0 mmol) in EtOH (100 mL) was added compound cyclohexanamine (26.7 g， 270.0 mmol) at 0℃. After the addition， the mixture solution was heated to 30 ℃ and stirred for 16 h. Afterwards， the reaction mixture was partitioned between DCM (300 mL) and H₂O (200 mL) . The organic layer was then washed with brine (100 mL) ， dried over anhy. Na₂SO₄， filtered， and concentrated in vacuo to give a crude product which was purified by silica gel flash chromatography (petroleum ether∶EtOAc ＝ 50∶1 to 10∶1) to afford the title compound (13 g， 94.3％yield) as a white solid. ¹H NMR (400HMz， CHCl₃-d1) δ 7.85 (d， J＝2.4 Hz， 1H) ， 5.05 (br. s.， 1H) ， 4.10-3.95 (m， 1H) ， 2.07-2.02 (m， 2H) ， 1.79-1.75 (m， 2H) ， 1.75-1.68 (m， 1H) ， 1.55-1.45 (m， 2H) ， 1.32-1.17 (m， 3 H) .

[B] N-Cyclohexyl-5-fluoro-2- (6-fluoropyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-amine

To a stirred solution of 6-fluoro-1H-pyrazolo [4， 3-b] pyridine (Intermediate A-2， 0.1 g， 0.73 mmol) in DMF (1 mL) was added 2-chloro-N-cyclohexyl-5-fluoro-pyrimidin-4-amine_ (0.17 g， 0.73 mmol) and Cs₂CO₃ (0.48 g 1.46 mmol) at room temperature. Afterwards， the resulting mixture solution was heated to 120 ℃ and stirred for 2 h. After TLC (petroleum ether∶EtOAc＝ 1∶1) showed the start material was consumed， the reaction mixture was concentrated in vacuo. The dark yellow residue was partitioned between DCM (6 mL) and water (5 mL) ， and extracted with DCM (5 mL × 2) . The organic layer was dried over anhy. Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purified by Prep-HPLC to afford the title compound (20 mg) as a white solid. ¹H NMR (400HMz， MeOH-d4) δ 8.73 (d， J＝8.8 Hz， 1H) ， 8.62 (s， 1H) ， 8.48 (s， 1H) ， 8.07 (d， J＝3.2 Hz， 1H) ， 4.15-4.08 (m， 1 H) ， 2.20-2.12 (m， 2H) ， 1.95-1.87 (m， 2H) 1.82-1.75 (m， 1H) ， 1.63-1.40 (m， 4H) ， 1.35-1.26 (m， 1 H) .

Example 6

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

[A] (-) -Methyl (2S， 3S) -3- [ [5-fluoro-2- (6-fluoropyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4- yl] amino] bicyclo [2.2.2] octane-2-carboxylate

To a stirred mixture solution of (-) - (1R， 2S， 3S， 4R) -methyl 3- ( (2-chloro-5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (Example 3/Step E， 120 mg， 382 μmol) ， and 6-fluoro-1H-pyrazolo [4， 3-b] pyridine (Intermediate A-2， 78.7 mg， 574 μmol) in dioxane (6 mL) was added copper (I) iodide (29.1 mg， 153 μmol) ， (1R， 2S) -cyclohexane-1， 2-diamine (34.9 mg， 43.7 μL， 306 μmol) and potassium phosphate (126 mg， 574 μmol) . The reaction mixture solution was stirred at 120 ℃ for 12 h before it was cooled back to room temperature， poured into water (20 mL) and extracted with EtOAc (50 mL x 2) . The combined organic layers were washed with brine， dried over anhy. Na₂SO₄， filtered and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (0-50％EtOAc-hexane gradient) to yield the title compound (110 mg， 70％yield) as white foam. MS： 415.2 [M+H] ⁺.

[B] (-) - (2S， 3S) -3- [ [5-Fluoro-2- (6 -fluoropyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl] amino] - bicyclo [2.2.2] octane-2-carboxylic acid

A mixture solution of (-) - (1R， 2S， 3S， 4R) -methyl 3- ( (5-fluoro-2- (6-fluoro-1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (110mg， 265 μmol) and lithium hydroxide monohydrate (100mg， 66.2 μl， 2.38 mmol) in THF (5 mL) and water (5 mL) was stirred at room temperature for 2 h. Afterwards， the mixture solution was acidified with 1N HCl aq. solution and concentrated in vacuo to give a crude product， which was purified by Prep-HPLC to afford the title compound (40 mg， 38％yield) as white foam. MS： 401.2 [M+H] ⁺. ¹H NMR (400 MHz， DMSO-d6) δ 12.45 (br. s.， 1 H) 8.73 (d， J＝2.51 Hz， 1 H) 8.59 -8.69 (m， 2 H) 8.28 (d， J＝3.26 Hz， 1 H) 8.16 (d， J＝7.28 Hz， 1 H) 4.69 (t， J＝6.90 Hz， 1 H) 2.90 (d， J＝6.78 Hz， 1 H) 2.03 (br. s.， 1 H) 1.92 (br. s.， 1 H) 1.29 -1.84 (m， 8 H) .

Example 7

(+) -N- [ (1S， 3R) -3- [ [5-Fluoro-2- (6-fluoropyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl] amino] cyclohexyl] morpholine-4-carboxamide

[A] (+) tert-Butyl N- [ (1S， 3R) -3- [ [5-fluoro-2- (6-fluoropyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4- yl] amino] cyclohexyl] carbamate

A mixture solution of copper (I) iodide (1 g， 5.25 mmol) ， (+) - (1R， 2R) -cyclohexane-1， 2-diamine (800 mg， 7.01 mmol) ， 6-fluoro-1H-pyrazolo [4， 3-b] pyridine (Intermediate A-2， 1.5 g， 10.9 mmol) ， (+) -tert-butyl ( (1S， 3R) -3- ( (2-chloro-5-fluoropyrimidin-4-yl) amino) cyclohexyl) carbamate (2 g， 5.8 mmoI) and potassium phosphate tribasic (2.2 g， 10.4 mmol) in dioxane (60 mL) was stirred at 130 ℃ for 12 h. After cooling to room temperature， the reaction mixture was poured into water (20 mL) and extracted with EtOAc (50 mL x 2) . The combined organic layers were washed with brine， dried over anhy. Na₂SO₄， filtered and concentrated in vacuo to give a crude product， which was purified by silica gel chromatography column (EtOAc∶petroleum ether ＝ 0 to 45％) to afford the title compound (1.3 g， 50％yield) as a solid. MS： 446.2 [M+H] ⁺.

[B] (+) - (1R， 3S) -N1- [5-Fluoro-2- (6-fluoropyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4- yl] cyclohexane-1， 3-diamine

A solution of (+) -tert-butyl ( (1S， 3R) -3- ( (5-fluoro-2- (6-fluoro-1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl) amino) cyclohexyl) carbamate (1.3 g， 2.92 mmol) and acetyl chloride (5.53 g， 70.4 mmol) in MeOH (20 mL) was stirred at room temperature for 14 h. Afterwards， the solvent was evaporated under reduced pressure to give a crude title compound (1 g， 90％yield) as yellow oil. MS： 346.2 [M+H] ⁺. It was used directly in the next step without further purification.

[C] (+) -N- [ (1S， 3R) -3- [ [5-Fluoro-2- (6-fluo ropyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4- yl] amino] cyclohexyl] morpholine-4-carboxamide

A mixture solution of (+) - (1R， 3S) -N1- (5-fluoro-2- (6-fluoro-1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl) cyclohexane-1， 3-diamine hydrochloride (100 mg， 262 μmol) ， morpholine-4-carbonyl chloride (78.4 mg， 524 μmol) ， morpholine-4-carbonyl chloride (78.4 mg， 524 μmol) and DIPEA (135 mg， 1.05 mmol) in DCM (5 mL) was stirred at room temperature for 16 h. Afterwards， the mixture was washed with satd. aq. NaHCO₃ solution， and the organic layer was dried over anhy. Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purifed by Prep-HPLC to afford the title compound (20 mg， 16.7 ％yield) as white foam. MS： 459.2 [M+H] ⁺. ¹HNMR (400 MHz， DMSO-d6) δ 8.72 (dd， J＝2.64， 0.88 Hz， 1 H) 8.56 -8.68 (m， 2 H) 8.26 (d， J＝3.26 Hz， 1 H) 8.08 (d， J＝7.78 Hz， 1 H) 6.36 (d， J＝7.53 Hz， 1 H) 3.94 -4.20 (m， 1 H) 3.55 -3.70 (m， 1 H) 3.42 -3.55 (m， 5 H) 3.17 -3.29 (m， 6 H) 2.09 (d， J＝12.05 Hz， 1 H) 1.98 (d， J＝11.54 Hz， 1 H) 1.83 (d， J＝10.54 Hz， 2 H) 1.25 -1.50 (m， 4 H) 1.11 -1.25 (m， 1 H) .

Example 8

(+) -N- ( (1S， 3R) -3- ( (5-Fluoro-2- (6-fluoro-1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl) amino) cyclohexyl) picolinamide

A mixture solution of (+) - (1R， 3S) -N1- (5-fluoro-2- (6-fluoro-1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl) cyclohexane-1， 3-diamine hydrochloride (Example 7/step B， 100 mg， 262 μmol) ， picolinic acid (64.5 mg， 524 μmol) ， HATU (199 mg， 524 μmol) and DIPEA (135 mg， 1.05 mmol) in DCM (5 mL) was stirred at room temperature for 16 h. Afterwards， the mixture solution was washed with satd. aq. NaHCO₃ solution， and the organic layer was dried over anhy. Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purifed by Prep-HPLC to afford the title compound (20 mg， 17％yield) as white foam. MS：451.2 [M+H] ⁺. ¹HNMR (400 MHz， DMSO-d6) δ 8.73 (dd， J＝2.51， 1.00 Hz， 1 H) 8.58 -8.71 (m， 3 H) 8.26 (d， J＝3.26 Hz， 1 H) 8.14 (d， J＝7.53 Hz， 1 H) 7.93 -8.08 (m， 3 H) 7.60 (ddd， J＝7.15， 4.77， 1.63 Hz， 1 H) 4.09 -4.25 (m， 1 H) 4.00 (d， J＝8.03 Hz， 1 H) 2.17 (d， J＝11.54 Hz， 1 H) 2.03 (d， J＝12.05 Hz， 1 H) 1.88 (d， J＝6.27 Hz， 3 H) 1.58 -1.78 (m， 2 H) 1.43-1.56 (m， 3 H) 1.39 (d， J＝12.30 Hz， 1 H) .

Example 9

(+) -2-Fluoro-N- ( (1S， 3R) -3- ( (5-fluoro-2- (6-fluoro-1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl) amino) cyclohexyl) benzamide

In analogy to the synthesis of Example 8， 2-fluorobenzoic acid (73.4 mg， 524 μmol) was used to obtain the title compound (20 mg， 16 ％yield) as white foam after Prep-HPLC purificaiton. _MS： 468.2 [M+H] ⁺. ¹HNMR (400 MHz， DMSO-d6) δ 8.71 -8.76 (m， 1 H) 8.60 -8.69 (m， 2 H) 8.35 (d， J＝7.78 Hz， 1 H) 8.27 (d， J＝3.51 Hz， 1 H) 8.12 (d， J＝7.78 Hz， 1 H) 7.42 -7.63 (m， 2 H) 7.18 -7.34 (m， 2 H) 4.17 (d， J＝8.28 Hz， 1 H) 3.81 -4.01 (m， 1 H) 2.20 (d， J＝11.80 Hz， 1 H) 2.02 (d， J＝11.80 Hz， 1 H) 1.83-1.96 (m， 2 H) 1.21 -1.60 (m， 4 H) .

Example 10

(+) -N- ( (1S， 3R) -3- ( (5-fluoro-2- (6-fluoro-1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl) amino) cyclohexyl) benzamide

In analogy to the synthesis of Example 7/step C， benzoyl chloride (73.6 mg， 524 μmol) was used to obtain the title compound (20 mg， 17 ％yield) as white foam after Prep-HPLC purificaiton. MS： 450.2 [M+H] ⁺. ¹HNMR (400 MHz， DMSO-d6) δ 8.72 (d， J＝1.76 Hz， 1 H) 8.58 -8.69 (m， 2 H) 8.37 (d， J＝7.78 Hz， 1 H) 8.23 -8.29 (m， 1 H) 8.13 (d， J＝8.03 Hz， 1 H) 7.79 -7.87 (m， 2 H) 7.41 -7.55 (m， 3 H) 4.10 -4.24 (m， 1 H) 3.91 -4.04 (m， 1 H) 2.18 (d， J＝11.80 Hz， 1 H) 2.03 (d， J＝11.04 Hz， 1 H) 1.84 -1.96 (m， 2 H) 1.29 -1.65 (m， 4 H) .

Example 11

(+) -N- ( (1S， 3R) -3- ( (5-Fluoro-2- (6-fluoro-1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl) amino) cyclohexyl) pyrrolidine-1-carboxamide

In analogy to the synthesis of Example 7/step C， pyrrolidine-1-carbonyl chloride (70 mg， 524 μmol) was used to obtain the title compound (20 mg， 17 ％) as white foam after Prep-HPLC purification. MS： 443.2 [M+H] ⁺. ¹HNMR (400 MHz， DMSO-d6) δ 8.72 (d， J＝1.76 Hz， 1 H) 8.65 (s， 1 H) 8.60 (d， J＝9.54 Hz， 1 H) 8.25 (d， J＝3.26 Hz， 1 H) 8.08 (d， J＝7.78 Hz， 1 H) 5.86 (d， J＝8.03 Hz， 1 H) 3.99 -4.16 (m， 1 H) 3.59 (dd， J＝7.91， 3.64 Hz， 1 H) 3.12 -3.26 (m， 4 H) 2.09 (d， J＝11.29 Hz， 1 H) 1.98 (d， J＝11.29 Hz， 1 H) 1.82 (d， J＝11.04 Hz， 2 H) 1.71 -1.79 (m， 3 H) 1.15 -1.52 (m， 4 H) .

Example 12

(-) -4-Fluoro-N- [ (1R， 3S) -3- [ [5-fluoro-2- (6-fluoropyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl] amino] cyclohexyl] benzamide

[A] (-) -tert-Butyl ( (1R， 3S) -3- ( (5-fluoro-2- (6-fluoro-1H-pyrazolo [4，3-b] pyridin-1-yl) pyrimidin-4- yl) amino) cyclohexyl) carbamate

A mixture solution of copper (I) iodide (1 g， 5.25 mmol) ， (-) - (1R， 2R) -cyclohexane-1， 2-diamine (800 mg， 7.01 mmol) ， 6-fluoro-1H-pyrazolo [4， 3-b] pyridine (Intermediate A-2， 1.5 g， 10.9 mmol) ， (-) -tert-butyl ( (1R， 3S) -3- ( (2-chioro-5-fluoropyrimidin-4-yl) amino) cyclohexyl) carbamate (2 g， 5.8 mmol) and potassium phosphate tribasic (2.2 g， 10.4 mmol) in dioxane (60 mL) was stirred at 125 ℃ for 12 h. After cooling to room temperature， the reaction mixture was poured into water (20 mL) and extracted with EtOAc (50 mL x 2) . The combined organic layers were washed with brine， dried over anhy. Na₂SO₄， filtered and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (EtOAc： petroleum ether ＝ 0 to 35％) to afford the title compound (1.1 g， 42％yield) as white foam. MS： 446.2 [M+H] ⁺.

[B] (-) - (1S， 3R) -N1- (5-fluoro-2- (6-fluoro-1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4- yl) cyclohexane-1， 3-diamine hydrochloride

A solution of (-) -tert-butyl ( (1R， 3S) -3- ( (5-fluoro-2- (6-fluoro-1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl) amino) cyclohexyl) carbamate (1.1 g， 2.47 mmol， ) and acetyl chloride (5.53 g， 70.4 mmol) in MeOH (20 mL) was stirred at room temperature for 14 h. Afterwards， the solvent was removed under reduced pressure to give a crude title compound (1 g， 96％yield) . MS： 346.2 [M+H] ⁺. It was used directly in the next step without further purification.

[C] (-) -4-Fluoro-N- [ (1R， 3S) -3- [ [5-fluoro-2- (6-fluoropyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4- yl] amino] cyclohexyl] benzamide

A mixture solution of (-) - (1S， 3R) -N1- (5-fluoro-2- (6-fluoro-1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl) cyclohexane-1， 3-diamine hydrochloride (100mg， 262 μ mol) ， 4-fluorobenzoic acid (44 mg， 314 μmol) ， HATU (129 mg， 340 μmol) and DIPEA (102 mg， 786 μmol) in DCM (5 mL) was stirred at room temperature for 16 h. The reaction mixture was then washed with satd. aq. NaHCO₃ solution， and the organic layer was dried over anhy. Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purifed by Prep-HPLC to afford the title compound (60 mg， 49％yield) as white foam. MS： 468.2 [M+H] ⁺. ¹HNMR (400 MHz， MeOH-d4) δ 8.71 (dd， J＝9.41， 2.13 Hz， 1 H) 8.63 (dd， J＝2.38， 1.13 Hz， 1 H) 8.51 (s， 1 H) 8.03 -8.16 (m， 1 H) 7.78 -7.93 (m， 2 H) 7.10 -7.24 (m， 2 H) 4.32 (ddd， J＝11.73， 7.97， 3.89 Hz， 1 H) 4.15 (tt， J＝11.86， 3.83 Hz， 1 H) 2.45 (d， J＝12.05 Hz， 1 H) 2.23 (d， J＝12.05 Hz， 1 H) 2.11 (d， J＝11.80 Hz， 1 H) 1.97-2.05 (m， 1 H) 1.53-1.77 (m， 2 H) 1.36-1.51 (m， 2 H) .

Example 13

(-) -N- ( (1R， 3S) -3- ( (5-Fluoro-2- (6-fluoro-1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl) amino) cyclohexyl) benzamide

A mixture solution of (-) - (1S， 3R) -N1- (5-fluoro-2- (6-fluoro-1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl) cyclohexane-1， 3-diamine hydrochloride (Example 12/Step B， 200 mg， 524 μmol) ， benzoyl chloride (88.4 mg， 629 μmol) ， and DIPEA (203 mg， 1.57 mmol) in DCM (5 mL) was stirred at room temperature for 16 h. Afterwards， the reaction mixture was washed with satd. aq. NaHCO₃ aq solution， and the organic layer was dried over anhy. Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purifed by Prep-HPLC to afford the title compound (110 mg， 47％yield) as white foam. MS： 450.2 [M+H] ⁺. ¹HNMR (400 MHz， MeOH-d4) δ 8.58-8.71 (m， 2 H) 8.49 (s， 1 H) 8.09 (d， J＝3.51 Hz， 1 H) 7.78-7.84 (m， 2 H) 7.48-7.56 (m， 1 H) 7.40-7.48 (m， 2 H) 4.22-4.35 (m， 1 H) 4.16 (tt， J＝11.86， 3.83Hz ，1H )2.40-2.5 0(m， 1H) 2.22 (d， J＝12.30Hz， 1H) 2.11 (d， J＝12.30Hz， 1 H) 1.96-2.06 (m， 1H) 1.54-1.77 (m， 2H) 1.36-1.52 (m， 2H) .

Example 14

(-) -N- ( (1R， 3S) -3- ( (5-Fluoro-2- (6-fluoro-1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl) amino) cyclohexyl) ethanesulfonamide

To a stirred solution of (-) - (1S， 3R) -N1- (5-fluoro-2- (6-fluoro-1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl) cyclohexane-1， 3-diamine hydrochloride (Example 12/Step B， 70 mg， 183 μmol) in DCM (5 mL) was added N-ethyl-N-isopropylpropan-2-amine (47.4 mg， 367 μmol) and ethanesulfonyl chloride (28.3 mg， 220 μmol) at room temperature and stirred for 16 h. Afterwards， the reaction mixture was washed with satd. aq. NaHCO₃ solution， and the organic layer was dried over anhy. Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purifed by Prep-HPLC to afford the title compound (7 mg， 8.7％yield) as white foam. MS： 438.1 [M+H] ⁺. ¹HNMR (400 MHz， MeOH-d4) δ 8.68 (dd， J＝9.41， 2.13 Hz， 1 H) 8.61 (dd， J＝2.51， 1.25 Hz， 1 H) 8.49 (s， 1 H) 8.09 (d， J＝3.26 Hz， 1 H) 4.18-4.28 (m， 1 H) 3.39-3.49 (m， 1 H) 3.05-3.12 (m， 2 H) 2.44-2.52 (m， 1 H) 2.04-2.17 (m， 2 H) 1.92-2.00 (m， 1 H) 1.54-1.67 (m， 1 H) 1.34-1.52 (m， 3 H) 1.31 (s， 3 H) .

Example 15

(-) - (2R) -1- [ [ (1R， 3S) -3- [ [5-Fluoro-2- (6-fluoropyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl] amino] cyclohexyl] carbamoyl] pyrrolidine-2-carboxylic acid

To a stirred mixture solution of (-) - (1S， 3R) -N1- (5-fluoro-2- (6-fluoro-1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl) cyclohexane-1， 3-diamine hydrochloride (Example 12/Step B， 100 mg， 262 μmol) and N-ethyl-N-isopropylpropan-2-amine (169 mg， 1.31 mmol) in DCM (20 mL) was added triphosgene (38.9 mg， 131 μmol) portionwise at room temperature and stirred for 1 h. The pyrrolidine-2-carboxylic acid hydrochloride (51.6 mg， 340 μmol) was added into the mixture and then the resulting reaction mixture solution was stirred for another 12 h. After the solvent was removed under reduced pressure， the residue was purified by silica gel flash chromatography to afford the title compound (10 mg， 8％yield) as white foam. MS： 486.2 [M+H] ⁺. ¹HNMR (400 MHz， MeOH-d4) δ 8.74 (d， J＝9.79 Hz， 1 H) 8.63 (dd， J＝2.51， 1.00 Hz， 1 H) 8.50 (s， 1 H) 8.10 (d， J＝3.51 Hz， 1 H) 4.18 -4.33 (m， 2 H) 3.80 (t， J＝1 1.80 Hz， 1 H) 3.44 -3.52 (m， 1 H) 2.33 (d， J＝10.04 Hz， 1 H) 2.20 (dd， J＝16.06， 12.05 Hz， 2 H) 1.89-2.11 (m， 3 H) 1.57-1.70 (m， 1 H) 1.44-1.55 (m， 1 H) 1.26-1.42 (m， 2 H) .

In analogy to the synthsis of Example 12/step C (method A) ， Example 13 (method B) ， Example 14 (method C) ， and Example 15 (method D) ， the following compounds were prepared by using appropriate reagents.

Table 3

Example 55

(rac) - (1R， 3S) -3- [ [5-Fluoro-2- (6-fluoropyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl] amino] -N- (4-pyridyl) cyclohexanecarboxamide

To a stirred solution of (1R， 3S) -3- ( (5-fluoro-2- (6-fluoro-1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl) amino) cyclohexanecarboxylic acid (Example 63/Step D， 150 mg， 0.4 mmol) in MeCN (20 mL) was added DIPEA (155.1 mg， 1.2 mmol) ， pyridin-4-amine (45.3 mg， 0.48 mmol) and HATU (152.1 mg， 0.4 mmol) at room temperature and stirred for 12 h. After TLC (DCM∶MeOH＝10∶1) showed the reaction was completed， the reaction mixture was concentrated in vacuo to give a crude product， which was purified by Prep-HPLC to afford the title compound (16 mg， 8.9％yield) as a white solid. MS： 451.1 [M+H] ⁺. ¹HNMR (400MHz， DMSO-d6) δ 10.35 (s， 1 H) ， 8.73 (d， J＝1.76 Hz， 1 H) ， 8.67 (s， 1 H) ， 8.60 (d， J＝9.54 Hz， 1 H) ， 8.40 (d， J＝6.27 Hz， 2 H) ， 8.26 (d， J＝3.51 Hz， 1 H) ， 8.13 (d， J＝7.78 Hz， 1 H) ， 7.57 (d， J＝6.27 Hz， 2 H) ， 4.10～4.23 (m， 1 H) ， 2.58～2.67 (m， 1 H) ， 2.08 (d， J＝10.79 Hz， 2 H) ， 1.93 (d， J＝11.04 Hz， 2 H) ， 1.73 (q， J＝12.13 Hz， 1 H) ， 1.28～1.55 (m， 3 H) .

Example 56

(rac) - (1R， 3S) -3- [ [5-Fluoro-2- (6-fluoropyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl] amino] -N- (3-pyridyl) cyclohexanecarboxamide

In analogy to the synthesis of Example 55， pyridin-3-amine (45.3 mg， 0.48 mmol) was used to obtain the title compound (25 mg， 13.9％yield) as a white solid after Prep-HPLC purification. MS： 451.2 [M+H] ⁺. ¹HNMR (400MHz， DMSO-d6) δ 10.17 (s， 1 H) ， 8.74 (t， J＝2.26 Hz， 2 H) ， 8.67 (s， 1 H) ， 8.61 (d， J＝9.54 Hz， 1 H) ， 8.23～8.28 (m， 2 H) ， 8.14 (d， J＝7.78 Hz， 1 H) ， 8.05 (d， J＝8.78 Hz， 1 H) ， 7.33 (dd， J＝8.16， 4.64 Hz， 1 H) ， 4.18 (d， J＝7.53 Hz， 1 H) ， 2.61 (t， J＝11.67 Hz， 1 H) ， 2.07 (br. s.， 2 H) ， 1.94 (d， J＝11.04 Hz， 2 H) ， 1.74 (q， J＝12.13 Hz， 1 H) ， 1.34～1.52 (m， 3 H) .

Example 57

(rac) -N- ( (1R， 3S) -3- ( (2- (6-Fluoro-1H-pyrazolo [4， 3-b] pyridin-1-yl) -5- (trifluoromethyl) pyrimidin-4-yl) amino) cyclohexyl) morpholine-4-carboxamide

[A] tert-Butyl ( (1R， 3S) -3- ( (2-chloro-5- (trifluoromethy) pyrimidin-4-yl) amino) cyclohexyl) - carbamate

To a stirred mixture solution of cyclohexane-1， 3-diamine (10.5 g， 92.2 mmol) in THF (100 mL) was added 2， 4-dichioro-5- (trifiuoromethyl) pyrimidine (10 g， 46.1 mmoi) at 0 ℃. The reaction mixture solution was allowed to warm up to room temperature and stirred for 13 h. The reaction mixture was then concentrated in vacuo， the residue was re-dissolved in DCM (100 mL) followed by the addition of Et₃N， (9.33 g， 92.2 mmol) and di-tert-butyl dicarbonate (20.1 g， 92.2 mmol) . The resulting mixture solution was stirred at room temperature for 3 h before was diluted with DCM (1 L) and washed with brine. The organic layer was dried over anhy. 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 (600 mg， 6.6％yield) as a white solid. MS： 395.1 [M+H] ⁺.

[B] tert-Butyl ( (1R， 3S) -3- ( (2- (6-fluoro-1H-pyrazolo [4， 3-b] pyridin-1-yl) -5- (trifluoromethyl) pyrimidin-4-yl) amino) cyclohexyl) carbamate

A mixture solution of 6-fluoro-1H-pyrazolo [4， 3-b] pyridine (417 mg， 3.04 mmol) ， tert-butyl ( (1R， 3S) -3- ( (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) cyclohexyl) carbamate (600 mg， 1.52 mmol) and Cs₂CO₃ (743 mg， 2.28 mmol) in DMF (10 mL) was stirred at 115 ℃ for 2 h. After cooling to room temperature， the reaction mixture was extracted with EtOAc (100 mL) and the organic layer washed with brine， dried over anhy. 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 (500 mg， 66.4％yield) as a white solid. MS： 496.1 [M+H] ⁺.

[C] (1S， 3R) -N1- (2- (6-fluoro-1H-pyrazolo [4， 3-b] pyridin-1-yl) -5- (trifluoromethyl) pyrimidin-4- yl) cyclohexane-1， 3-diamine

To a stirred mixture solution of tert-butyl ( (1R， 3S) -3- ( (2- (6-fluoro-1H-pyrazolo [4， 3-b] pyridin-1-yl) -5- (trifluoromethyl) pyrimidin-4-yl) amino) cyclohexyl) carbamate (500 mg， 1.01 mmol) in MeOH (5 mL) was added acetyl chloride (1.1 g， 14.1 mmol) at room temperature and stirred for 4 h. The reaction mixture was then concentrated in vacuo to give a crude title compound (400 mg， 100％yield) as yellow oil. MS： 396.1 [M+H] ⁺. It was used directly in the next step without further purification.

[D] N- ( (1R， 3S) -3- ( (2- (6-fluoro-1H-pyrazolo [4， 3-b] pyridin-1-yl) -5- (trifluoromethyl) pyrimidin-4- yl) amino) cyclohexyl) morpholine-4-carboxamide

To a stirred mixture solution of (1S， 3R) -N1- (2- (6-fluoro-1H-pyrazolo [4， 3-b] pyridin-1-yl) -5-(trifluoromethyl) pyrimidin-4-yl) cyclohexane-1， 3-diamine (150 mg， 379 μmol) and morpholine-4-carbonyl chloride (68.1 mg， 45.7 μl， 455 μmol， Eq： 1.2) in DCM (5 mL) was added and DIPEA (147 mg， 1.14 mmol) at room temperature and stirred for 16 h： Afterwards， the reaction mixture was washed with satd. aq. NaHCO₃ solution， dried over anhy. Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purifed by Prep-HPLC to afford the title compound (30 mg， 15.6％yield) as white foam. MS： 509.1 [M+H] ⁺. ¹HNMR (400 MHz， DMSO-d₆) δ 8.73 -8.78 (m， 2 H) 8.60 (s， 2 H) 7.39 -7.46 (m， 1 H) 6.31 -8.40 (m， 1 H) 4.25 -4.40 (m， 1 H) 3.55 -3.65 (m， 1 H) 3.46 -3.56 (m， 4 H) 3.18-3.27 (m， 4 H) 2.00-2.10 (m， 1 H) 1.87-1.95 (m， 1 H) 1.78-1.87 (m， 2 H) 1.32-1.62 (m， 3 H) 1.12-1.28 (m， 1 H) .

Example 58

(rac) -N- ( (1 R， 3S) -3- ( (2- (6-fluoro-1H-pyrazolo [4， 3-b] pyridin-1-yl) -5- (trifluoromethyl) pyrimidin-4-yl) amino) cyclohexyl) benzamide

In analogy to the synthesis of Example 57/step C， benzoyl chloride (64 mg， 455 μmol) was used to obtain the title compound (40 mg， 21.1％yield) as white foam after Prep-HPLC purification. MS： 500.1 [M+H] ⁺. ¹H NMR (400 MHz， DMSO-d₆) δ ppm 8.76 (s， 2 H) 8.58 -8.68 (m， 2 H) 8.37 (d， J＝7.53 Hz， 1 H) 7.80 -7.85 (m， 2 H) 7.48 -7.54 (m， 2 H) 7.40 -7.48 (m， 2 H) 4.41 (dd， J＝7.53， 3.51 Hz， 1 H) 3.88 -4.00 (m， 1 H) 2.08 -2.16 (m， 1 H) 1.85 -2.01 (m， 3 H) 1.66-1.80 (m， 1 H) 1.30 -1.62 (m， 3 H) .

Example 59

(rac) -N- ( (1R， 3S) -3- ( (2- (6-fluoro-1H-pyrazolo [4， 3-b] pyridin-1-yl) -5- (trifluoromethyl) pyrimidin-4-yl) arnino) cyclohexyl) pyrrolidine-1-carboxamide

To a stirred mixture solution of (1S， 3R) -N1- (2- (6-fluoro-1H-pyrazolo [4， 3-b] pyridin-1-yl) -5- (trifluoromethyl) pyrimidin-4-yl) cyclohexane-1， 3-diamine (Example 57/Step C， 150 mg， 379 μmol) and DIPEA (147 mg， 1.14 mmol) in DCM (5 mL) was added triphosgene (56.3 mg， 190 μmol) at room temperature and stirred for 30 min before pyrrolidine (35.1 mg， 493 μmol) was added to the above mixture solution and the resulting mixture solution was stirred at room temperature for another 16 h. Afterwards， the mixture solution was washed with satd. aq. NaHCO₃ solution， and the orgainc layer was dried over anhy. Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purifed by Prep-HPLC to afford the title compound (6 mg， 2.9％yield) as white foam. MS： 493.1 [M+H] ⁺. ¹HNMR (400 MHz， DMSO-d6) δ 8.74 -8.80 (m， 2 H) 8.59 -8.68 (m， 2 H) 7.46 (s， 1 H) 5.82 -5.88 (m， 1 H) 4.28 -4.41 (m， 1 H) 3.57 (d， J＝8.28 Hz， 1 H) 3.16 (br. s.， 4 H) 1.99 -2.09 (m， 1 H) 1.87 -1.95 (m， 1 H) 1.79-1.87 (m， 2 H) 1.76 (s， 4 H) 1.34-1.63 (m， 2 H) 1.14-1.29 (m， 2 H) .

Example 60

(rac) - (1R， 2R， 6S) -2-Benzamido-6- ( (5-fluoro-2- (6-fluoro-1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl) amino) cyclohexanecarboxylic acid

[A] (E) -tert-Butyl benzyl (3-oxobut-1-en-1-yl) carbamate

To a stirred solution of (E) -4-methoxybut-3-en-2-one (11 g， 110 mmol) in DCM (150 mL) was added phenylmethanamine (11.2 g， 104 mmol) dropwise at room temperature and stirred for 2 h. After removing the volatile under reduced pressure， the residue was re-dissolved in DCM (150 mL) and to this solution was added di-tert-butyl dicarbonate (24 g， 110 mmol) ， N， N-dimethylpyridin-4-amine (1.34 g， 11 mmol) and E_t3N (13.3 g， 132 mmol) at 0 ℃. After the addition， the reaction mixture was allowed to warm up to room temperature and stirred for another 2 h. Afterwards， the mixture solution was washed with satd. aq. NaHCO₃ solution， and the organic layer was dried over anhy. Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (EtOAc： petroleum ether ＝ 10∶1) to afford the title compound (23.7 g， 78.3％yield) as colorless oil. MS： 276.2 [M+H] ⁺.

[B] tert-Butyl N-benzyl-N- [ (E) -3-hydroxybut-1-enyl] carbamate

To a stirred solution of (E) -tert-butyl benzyl (3-oxobut-1-en-1-yl) carbamate (5 g， 18.2 mmol) in MeOH (80 mL) was added sodium borohydride (1.03 g， 27.2 mmol) at 0 ℃ portionwise. After the addition， the reaction mixture was allowed to warm up to room temperature andstirred for 1 h. The reaction was quencned by the addition of water (40 mL) at 0 ℃， and concentrated in vacuo to a volume of about 100 mL. It was then diluted with satd. aq. NH₄Cl and extracted with DCM. The organic layer was dried over anhy. Na₂SO₄， filtered， and concentrated in vacuo to give a crude title compound (4.6 g) as a yellow solid. MS： 278.2 [M+H] ⁺. It was used directly in the next step without further purification.

[C] tert-Butyl N-benzyl-N- [ (1E) -buta-1， 3-dienyl] carbamate

To a stirred mixture solution of (E) -tert-butyl benzyl (3-hydroxybut-1-en-1-yl) carbamate (16.4 g， 59.1 mmol) ， pyridine (7.02 g， 88.7 mmol) and N， N-dimethylpyridin-4-amine (722 mg， 5.91 mmol) in MeCN (150 mL) was added methanesulfonyl chloride (8.13 g， 71 mmol) dropwise at 0 ℃. After the addition， the reaction mxiture was allowed to warm up to room temperature and stirred for 2 h before cooling back to 0 ℃ and added Et₃N (8.97 g， 88.7 mmol) and the resulting reaction mixture was then heated at 100 ℃ for 2 h. After cooling to room temperature， the solution was concentrated in vacuo to about 50 mL of volume and quenched with the addition of satd. aq. NaHCO₃ solution and extracted with DCM. The organic layer was dried over anhy. Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (EtOAc： petroleum ether ＝ 0 to 10％) to afford the title compound (9.2 g， 60％yield) as yellow oil. MS： 260.2 [M+H] ⁺. It was used directly in the next step without further purification.

[D] (rac) -tert-Butyl N- [ (3aR， 4S， 7aR) -1， 3-dioxo-3a， 4， 7， 7a-tetrahydroisobenzofuran-4-yl] -N- benzyl-carbamate

To a stirred solution of (E) -tert-butyl benzyl (buta-1， 3-dien-1-yl) carbamate (12g， 46.3 mmol) in toluene was added furan-2， 5-dione (4.99 g， 50.9 mmol1) portionwise at room temperature and stirred for 4 h. Afterwards， the reacton mixture was concentrated in vacuo to give a crude title compound (18 g， 100％yield) as a white solid. MS： 358.2 [M+H] ⁺. It was used directly in the next step without further purification.

[E] (rac) - (1R， 5S， 6S) -5- [benzyl (tert-butoxycarbonyl) amino] -6-methoxycarbonyl-cyclohex-3- ene-1-carboxylic acid

A mixture solution of tert-butyl benzyl ( (3aR， 4S， 7aR) -1， 3-dioxo-1， 3， 3a， 4， 7， 7a-hexahydroisobenzofuran-4-yl) carbamate (11.4 g， 31.9 mmol) and sodium methoxide (5 N， 60 mL， 300 mmol) in MeOH (60 mL) was stirred at room temperature for 24 h before it was poured into 1 N aq. HCl solution (100 mL) at 0 ℃ and then extrated with EtOAc. The organic layer was dried over anhy. Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (MeOH： DCM ＝ 0 to 10％) to afford the title compound (4 g， 32％yield) as a white solid. Mass： 390.2 [M+H] ⁺.

[F] (rac) -Methyl (1S 2S， 6R) -2- [benzyl (tert-butoxycarbony) amino] -6- (benzyloxycarbonylamino) cyclohex-3-ene-1-carboxylate

A mixture solution of (rac) - (1R， 5S， 6S) -5- [benzyl (tert-butoxycarbonyl) amino] -6-methoxycarbonyl-cyclohex-3-ene-1-carboxylic acid (5 g， 12.8 mmol) ， Et₃N (3.38 g， 33.4 mmol) and diphenyl phosphorazidate (8.48 g， 30.8 mmol) was stirred at room temperature for 2 h before the temperature was raised to 90 ℃ for another hour of heating. After cooling to room temperature， phenylMeOH (5.55 g， 51.4 mmol) was added to the mixture and the resulting solution was stirred at room temperature for 1 h . Afterwards， the solvent was evaporated under reduced pressure， and the residue was redissolved in DCM (20 mL) and washed with satd. aq. NaHCO₃ solution. The organic layer was then dried over anhy. Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography to afford the title compound (4 g， 63％yield) as a solid. MS： 495.2 [M+H] ⁺.

[G] (rac) -Methyl (1S， 2S， 6R) -6-amino-2- [benzyl (tert-butoxycarbonyl) amino] cyclohex-3-ene-1- carboxylate and methyl (1R 2R 6S) -6-amino-2- [benzyl (tert-butoxycarbonyl) amino] - cyclohex-3-ene-1-carboxylate

A mixture solution of (rac) -methyl (1S， 2S， 6R) -2- [benzyl (tert-butoxycarbonyl) amino] -6-(benzyloxycarbonylamino) cyclohex-3-ene-1-carboxylate (4 g， 4.04 mmol) and dihydroxypalladium (1.0 g， 7.12 mmol) in MeOH (100 mL) was stirred under H₂ atmosphere (1 atm) for 16 h. Afterwards， the reaction mixture was filtered and the filtrate was concentrated in vacuo to give a crude title compound (1.5 g， 100％yield) as colorless oil. MS：363.2 [M+H] ⁺. It was used directly in the next step without further purification.

[H] (rac) -Methyl (1S， 2R， 6S) -2-benzamido-6- [benzyl (tert-butoxycarbonyl) amino] - cyclohexanecarboxylate and methyl (1R， 2S， 6R) -2-benzamido-6- [benzyl (tert- butoxycarbonyl) amino] cyclohexanecarboxylate

To a stirred mixture solution of (rac) -methyl (1S， 2S， 6R) -6-amino-2- [benzyl(tert-butoxycarbonyl) amino] cyclohex-3-ene-1-carboxylate (1.5 g， 4.14 mmol) and Et₃N (1.68 g， 16.6 mmol) in DCM (100 mL) was added benzoyl chloride (1.75 g， 12.4 mmol) dropwise at 0 ℃. After the addition， the reaction was allowed to warm up to room temperature and stirred for 4 h. The mixture solution was washed with satd. aq. NaHCO₃ solution， and the organic layer was dried over anhy. Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was then purified by silica gel flash chromatography (EtOAc： petroleum ether ＝ 0 to 30％) to afford the title compound (1.1 g， 57％yield) as a white solid. MS： 467.2 [M+H] ⁺.

[I] (rac) -Methyl (1R， 2R， 6S) -2-benzamido-6- (benzylamino) cyclohexanecarboxylate and methyl (1S， 2S， 6R)-2-benzamldo-6- (benzylamino) cyclohexanecarboxylate

A solution of (rac) -methyl (1S， 2R， 6S) -2-benzamido-6- [benzyl (tert-butoxycarbonyl) amino] -cyclohexanecarboxylate (1.1g， 2.35 mmol) in 4 N HCl in dioxane (50 mL) was stirred at room temperature for 4 h. Afterwards， the solvent was removed under reduced pressure to give a crude title compound (1 g， 100％yield) as a white solid. MS： 367.2 [M+H] ⁺. It was used directly in the next step without further purification.

[J] (rac) -Methyl (1R，2S， 6R) -2-amino-6-benzamido-cyclohexanecarboxylate and methyl (1S， 2R， 6S) -2-amino-6-benzamido-cyclohexanecarboxylate

A mixture solution of (rac) -methyl (1R， 2R， 6S) -2-benzamido-6- (benzylamino) cyclohexane-carboxylate

(1 g， 2.35 mmol) and dihydroxypalladium (100 mg， 712μmol) in MeOH (50 mL) was stirred under H₂ atmosphere (50 psi) at 30 ℃ for 16 h. Afterwards， the solvent was removed under reduced pressure to give a crude title compound (500 mg， 77％yield) as a white solid. MS： 277.2 [M+H] ⁺. It was used directly in the next step without further purification.

[K] (rac) - （1R， 2R， 6R) -Methyl 2-benzamido-6- ( (2-chloro-5-fluoropyrimidin-4- yl) amino) cyclohexanecarboxylate and (1S， 2S， 6R) -methyl 2-benzamido-6- ( (2-chloro-5- fluoropyrimidin-4-yi) amino) cyclohexanecarboxylate

A stirred mixture solution of (rac) -methyl (1R， 2S， 6R) -2-amino-6-benzamido-cyclohexanecarboxylate (2 g， 7.24 mmol) ， 2， 4-dichloro-5-fiuoropyrimidine (2.42 g， 14.5 mmol) and N-ethyl-N-isopropylpropan-2-amine (3.74 g， 29 mmol) in THF (100 mL) was heated at 60 ℃ for 10 h. After cooling to room temperature， the solvent was removed under reduced pressure， and the residue was re-dissolved in DCM and washed with satd. aq. NaHCO₃ solution. The organic layer was dried over anhy. Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (EtOAc： petroleum ether ＝ 0 to 30％) to afford the title compound (2.2 g， 75％yield) as a solid. MS： 407.2 [M+H] ⁺.

[L] (rac) - (1R， 2R， 6S) -Methy， l 2-benzamido-6- ( (5-fluoro-2- (6-fluoro-1H-pyrazolo [4， 3-b] pyridin- 1-yl) pyrimidin-4-yl) amino) cyclohexanecarboxylate and (1S， 2S， 6R) -methyl 2-benzamido-6- ( (5-fuoro-2- (6-fluoro-1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4- vl) amino) cyclohexanecarboxylate

To a stirred mixture solution of (rac) - (1R， 2R， 6S) -methyl 2-benzamido-6- ( (2-chloro-5-fluoropyrimidin-4-yl) amino) cyclohexanecarboxylate (200 mg， 492 μmol) and 6-fluoro-1H-pyrazolo [4， 3-b] pyridine (135 mg， 983 μmol) in DMF (6 mL) was added copper (I) iodide (37.4 mg， 197 μmol) ， (1R， 2S) -cyclohexane-1， 2-diamine (44.9 mg， 393 μmol) and potassium hydrogenphosphate (171 mg， 983 μmol) at room temperature. Then the reaction mixture solution was stirred at 120 ℃ for 12 h before cooling back to room temperature， poured into water (20 mL) and extracted with EtOAc (2 x 50 mL) . The combined organic layers were washed with brine， dried over anhy. Na₂SO₄， filtered and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography to afford the title compound (50 mg， 20％ yield) . MS： 508.2 [M+H] ⁺.

[M] (rac) - (1R， 2R， 6S) -2-Benzamido-6- ( (5-fluoro-2- (6-fluoro-1H-pyrazolo [4， 3-b] pyridin-1- yl) pyrimidin-4-yl) amino) cyclohexanecarboxylic acid

To a stirred mixture solution of (rac) - (1R， 2R， 6S) -methyl 2-benzamido-6- ( (5-fluoro-2- (6-fluoro-1H-pyrazolo [4， 3-b] pyridin-1 -yl) pyrimidin-4-yl) amino) cyclohexanecarboxylate (50mg， 98.5 μmol) in THF (4mL) and water (4mL) was added LiOH (11.8 mg， 493 μmoi) pre- dissoved in water (4mL) . The reaction mixture solution was stirred at room temperature for 48 h before it was diluted with water (10 mL) and then extracted with diethyl ether (20 mL) . The separated aqueous layer was acidified with concentrated HCl to pH 4 and extracted with ethyl acetate (3 x 40 mL) . The combined organics were dried over anhy. Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was then purified by Prep-HPLC to afford the title compound (8mg， 16.5％yield) as white foam . MS： 494.2 [M+H] ⁺. ¹HNMR (400 MHz， DMSO-d6) δ 12.12 (br. s.， 1 H) 8.70 -8.77 (m， 2 H) 8.67 (s， 1 H) 8.50 -8.58 (m， 1 H) 8.33 (d， J＝9.03 Hz， 1 H) 8.29 (d， J＝3.26 Hz， 1 H) 7.76 -7.85 (m， 2 H) 7.42 -7.56 (m， 3 H) 4.50 (br. s.， 1 H) 4.20 (d， J＝9.79 Hz， 1 H) 284 (t， J＝11.17 Hz， 1 H) 1.98 (br. s.， 1 H) 1.86 (d， J＝6.78 Hz， 2 H) 1.39 -1.56 (m， 3 H) .

Example 61

(+or-) - (S) -2- (3- (5-fluoro-2- (6-fluoro-1H-pyrazolo [4，3-b] pyridin-1-yl) pyrimidin-4-yl) amino) piperidin-1-yl) -1-morpholinoethanone

[A] (+ or-) - (S) -tert-Butyl 3 ( (2 chloro-5-fluoropyrimidin-4-yl)amino)piperidine-1-carboxylate

To a stirred a solution of 2， 4-dichloro-5-fluoropyrimidine (1.8 g， 10.8 mmol) in THF (30 mL) was added DIPEA (2.79 g， 21.6 mmol) and (S) -tert-butyl 3-aminopiperidine -1-carboxylate (2.59 g， 12.9 mmol) at room temperatue and the reaction mixture was stirred at 70 ℃ for 12 h. After TLC (petroleum ether∶EtOAc ＝ 3∶1) showed the reaction was completed， the reaction was quenched by the addition ot satd. aq. NH₄Cl solution (50 mL) and extracted with EtOAc (3 x 50) . The combined organic extracts were dried over anhy. Na₂SO₄， filtered， and concentrated in vacuo to give the title compound (3 g， 84.0% yield) as a yellow solid. MS： 331.2 [M+H] ⁺.

[B] (+ or -) - (S) -tert-Butyl-3- ( (5-fluoro-2- (6-fluoro-1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4- yl) amino) piperidine-1-carboxylate

In a seal tube， to a solution of (S) -tert-butyl 3- ( (2-chloro-5-fluoropyrimidin-4-yl) amino) piperidine-1- carboxylate (1 g， 3.04 mmol) in dioxane (20 mL) was added 6-fluoro-1H-pyrazolo [4， 3-b]pyridine (0.5 g， 3.65 mmol) ， (1S， 2S) -cyclohexane-1， 2-diamine (0.28 g， 2.43 mmol) ， Cul (0.69 g， 3.65 mmol) and K₃PO₄ (1.29 g， 6.08 mmol) . The reaction mixture was stirred at 120 °C for 12 h. After cooling to room temperature， the reaction was quenched by the addition of satd. aq. NH₄Cl solution(50 mL) and extracted with EtOAc (3 x 50) . The combined organic extracts were dried over anhy. Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromotography (petroleum ether∶EtOAc = 3∶1) to give the title compound (300 mg， 22.7%yield) as a red solid. MS： 432.3 [M+H] ⁺.

[C] (+ or -) - (S) -5-Fluoro-2- (6-fluoro-1H-pyrazolo [4， 3-b] pyridin-1-yl) -N- (piperidin-3- yl) pyrimidin-4-amine

To a stirred solution of (S) -tert-butyl-3- ( (5-fluoro-2- (6-fluoro-1H-pyrazolo [4， 3-b]pyridin-1-yl) pyrimidin-4-yl) amino) piperidine-1-carboxylate (300 mg， 0.70 mmol) in EtOAc (10 mL) was added 4N HCl/dioxane (10 mL) at room temperature， and stirred for 12 h. After TLC (DCM∶MeOH＝10∶1) showed the reaction was completed， the reaction mixture was concentrated in vacuo to give a crude title compound (220 mg， 95.5％yield) as a red solid. MS： 332.2 [M+H] ⁺. It was used directly in the next step without further purification.

[D] (+ or -) - (S) -2- (3- ( (5-Fluoro-2- (6-fluoro-1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4- yl) amino) piperidin-1-yl) -1-morpholinoethanone

To a solution of morpholine (31.4 mg， 0.36 mmol) in DMF (10 mL) was added DIPEA (116.3 mg， 0.9 mmol) and 2-chloroacetyl chloride (40.7 mg， 0.36 mmol) at 0℃ and after stirring for 30 min， to this solution was added (S) -5-fluoro-2- (6-fluoro-1H-pyrazolo [4， 3-b] pyridin-1-yl) -N- (piperidin-3-yl) pyrimidin-4-amine (100 mg， 0.3 mmol) . The resulting reaction mixture was stirred at 70℃ for 12 h. After cooling to room temperature， the reaction mixture was concentrated in vacuo to give a crude product， which was then purified by Prep-HPLC to afford the title compound (10 mg， 7.3％yield) as a yellow solid. MS： 459.2 [M+H] ⁺. ¹HNMR (400 MHz， MeOH-d4) δ 8.78 (d， J＝8.78 Hz， 1 H) ， 8.65 (s， 1 H) ， 8.56 (br. s.， 1 H) ， 8.25 (br. s.， 1 H) ， 4.77 (d， J＝14.56 Hz， 1 H) ， 4.28～4.44 (m， 2 H) ， 3.80 (br. s.， 2 H) ， 3.57～3.74 (m， 6 H) ， 3.43 (br. s.， 3 H) ， 3.02 (br. s.， 1 H) ， 2.23 (br. s.， 2 H) ， 2.08 (d， J＝11.54 Hz， 1 H) ， 1.71～1.97 (m， 1 H) .

Example 62

(+ or -) - (S) -1- (3- ( (5-Fluoro-2- (6-fluoro-1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl) amino) piperidin-1-yl) -2-morpholinoethanone

To a stirred solution of (S) -5-fluoro-2- (6-fluoro-1H-pyrazolo [4， 3-b] pyridin-1-yl) -N- (piperidin-3-yl) pyrimidin-4-amine (100 mg， 0.3 mmol) in MeCN (10 mL) was added DIPEA (116 mg， 0.9 mmol) ， 2-morpholinoacetic acid (52 mg， 0.36 mmol) and HATU (114 mg， 0.3 mmol) at room temperature and stirred for 12 h. After TLC (DCM∶MeOH ＝ 10∶1) showed the reaction was completed， the reaction mixture was concentrated in vacuo to give a crude product， which was then purified by Prep-TLC and Prep-HPLC to afford the title compound (10 mg， 7.24％yield) as a white solid. MS： 459.2 [M+H] ⁺. ¹HNMR (400 MHz， DMSO-d6) δ 8.58 (br. s.， 1 H) ， 8.50 (s， 1 H) ， 8.24～8.46 (m， 1 H) ， 8.04～8.19 (m， 1 H) ， 4.42～4.63 (m， 1 H) ， 4.12～4.34 (m， 2 H) ，3.87～4.03 (m， 1 H) ， 3.56～3.86 (m， 6 H) ， 3.09～3.26 (m， 1 H) ， 2.78～2.95 (m， 5 H) ， 2.23 (d， J＝13.55 Hz， 1 H) ， 1.89～2.03 (m， 1 H) ， 1.64～1.82 (m， 2 H) .

Example 63

(rac) - (1R， 3S) -3- ( (5-fluoro-2- (6-fluoro-1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl) amino) cyclohexanecarboxylic acid

[A (rac) - (1R， 3S) -Methyl 3-aminocyclohexanecarboxylate

To a solution of (1R， 3S) -3-aminocyclohexanecarboxylic acid (3 g， 20.95 mmol) in MeOH (10 mL) was added 4 N HCl/MeOH (20 mL) at room temperature and stirred for 12 h. After TLC (petroleum ether∶EtOAc ＝ 1∶1) showed the reaction was completed， the reaction mixture was concentrated in vacuo to afford the title compound (3.2 g， 97.3％yield) as colorless oil. MS： 158.1 [M+H] ⁺.

[B] (rac) - (1R， 3S) -Methyl 3-aminocyclohexanecarboxylate

To a solution of (1R， 3S) -methyl 3-aminocyclohexanecarboxylate (2 g， 12 mmol) in THF (30 mL) was added DIPEA (4.65 g， 36.0 mmol) and 2， 4-dichloro-5-fluoropyrimidine (2.88 g， 14.4 mmol) at room temperature and the resulting reaction mixture was stirred at for 12 h. TLC (PE∶EA＝3∶1) showed that the reaction was completed. Then the reaction was quenched by the addition of NH₄Cl aq. (50.0 mL) and extracted with EA (50 mL x 3) . The combined organic extracts were concentrated to give (1R， 3S) -methyl 3-aminocyclo hexanecarboxylate (3.2 g， 92.7％) as a yellow solid. MS： 288.1 [M+H] ⁺

[C] (rac) - (1R， 3S) -methyl 3- ( (5-fluoro-2- (6-fluoro-1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4- yl) amino) cyclohexanecarboxylate

In a seal tube， to a solution of (1R， 3S) -methyl 3-aminocyclo hexanecarboxylate (1.51 g， 5.25 mmol) in dioxane (20 mL) was added 6-fluoro-1H-pyrazolo [4， 3-b] pyridine (0.6 g， 4.38 mmol) ， (1S， 2S) -cyclohexane-1， 2-diamine (0.4 g， 3.5 mmol) ， Cul (1.0 g， 5.25 mmol) and K₃PO₄ (1.86 g， 8.76 mmol) at room temperature. The reaction mixture was then stirred at 120 ℃ for 12 h. After TLC (petroleum ether∶EtOAc ＝ 1∶1) showed that the reaction was completed， the reaction was quenched by the addition of satd. aq. NH₄Cl solution (50 mL) and extracted with EtOAc (3 x 50 mL) . The combined organic extracts were dried over anhy. Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (petroleum ether∶EtOAc ＝ 2∶1) to give the title compound (0.4 g， 23.5％yield) as a red solid. MS： 389.1 [M+H] ⁺. ¹HNMR (400MHz， DMSO-d6) δ 8.70 (s， 1 H) ， 8.64 (s， 1 H) ， 8.50～8.58 (m， 1 H) ， 8.24 (d， J＝2.01 Hz， 1 H) ， 8.06 (d， J＝7.78 Hz， 1 H) ， 3.96～4.15 (m， 1 H) ， 3.60 (s， 3 H) ， 2.53～2.62 (m， 1 H) ， 2.21 (d， J＝12.30 Hz， 1 H) ， 1.81～2.07 (m， 3 H) ， 1.24～1.59 (m， 4 H) .

[D] (rac) - (1R， 3S) -3- ( (5-Fluoro-2- (6-fluoro-1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4- yl) amino) cyclohexanecarboxylic acid

To a stirred solution of (1R， 3S) -methyl 3- ( (5-fluoro-2- (6-fluoro-1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl) amino) cyclohexanecarboxylate (0.4 g， 1.0 mmol) in THF (10 mL) and H₂O (10 mL) was added NaOH (0.12 g， 3 mmol) at room temperature and stirred for 12 h. After TLC (DCM∶MeOH＝10∶1) showed the reaction was completed， 1 N aq. HCl solution was added to the mixture to adjust pH to 3～4. The reaction mixture was then filtered， and the filtrate was concentrated in vacuo to afford a crude title compound (0.32 g， 86.5％yield) as a yellow solid. MS： 375.1 [M+H] ⁺. ¹HNMR (400 MHz， MeOH-d4) δ 8.63 (d， J＝9.54 Hz， 1 H) 8.60 (s， 1 H) 8.47 (s， 1 H) 8.07 (br. s.， 1 H) 4.18 (t， J＝11.42 Hz， 1 H) 2.54-2.66 (m， 1 H) 2.41 (d， J＝12.30 Hz， 1 H) 1.97-2.18 (m， 3 H) 1.52-1.67 (m， 2 H) 1.37-1.47 (m， 2 H) .

Example 64 (+ or -) - (2S， 3S) -3- [ [5-Fluoro-2- (6-fluoropyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl] amino] -N-phenyl-bicyclo [2.2.2] octane-2-carboxamide

A mixture solution of aniline (34.9 mg， 375 μmol) ， (2S， 3S) -3- [ [5-fluoro-2- (6-fluoropyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl] amino] bicyclo [2.2.2] octane-2-carboxylic acid (Example 6/Step B， 100 mg， 250 μmol) ， HATU (123 mg， 325 μmol) and DIPEA (96.8 mg， 749 μmol) in DCM (5 mL) was stirred at room temperature for 16 h. Afterwards， the reaction mixture was washed with satd. aq. NaHCO₃ solution. The organic layer was dried over anhy. Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purified by Prep-HPLC to afford the title compound (20 mg， 16.8 ％yield) as a white solid. MS： 476.3 [M+H⁺] . ¹H NMR (400 MHz， DMSO-d6) δ 9.97 (s， 1H) ， 8.70-8.81 (m， 2H) ， 8.65 (s， 1H) ， 8.26 (br d， J＝3.01 Hz， 1H) ， 8.19 (br d， J＝7.28 Hz， 1H) ， 7.60 (d， J＝7.78 Hz， 2H) ， 7.25 (t， J＝7.91 Hz， 2H) ， 6.88-7.06 (m， 1H) ， 4.99 (br t， J＝6.78 Hz， 1H) ， 2.94 (br d， J＝6.78 Hz， 1H) ， 2.06 (br s， 1H) ， 1.93 (br s， 1H) ， 1.73-1.91 (m， 3H) ， 1.49-1.67 (m， 3H) ， 1.35-1.49 (m， 2H) .

Example 65

(rac) - (2S， 3S) -3- [ [5-Fluoro-2- (6-fluoropyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl] amino] norbornane-2-carboxylic acid

[A] (1-Methoxy-3-nitro-1-oxopropan-2-yl) mercury (II) chloride

To a stirred mixture solution of HgCl₂ (92 g， 339 mmol) and NaNO₂ (47 g， 681 mmol) in H₂O (1 L) was added methyl acrylate (30.6 g， 355.0 mmol) slowly at 10 ℃， After the addition， the reaction mixture was stirred at room temperature for 12 h. The reaction solution was filtered， and the filter cake was washed with petroleum ether (100 mL) and water (500 mL) and then dried under vacuum to afford the title compound (114 g， 91.2％yield) as a white solid. It was used directly in the next step without further purification.

[B] Methyl 2-bromo-3-nitropropanoate

To a stirred solution of (1-methoxy-3-nitro-1-oxopropan-2-yl) mercury (II) chloride (90 g， 244 mmol) in Et₂O (800 mL) and H₂O (300 mL) was added Br₂ (78 g， 488 mmol) drop wise at 0 ℃. After the addition， the mixture solution was stirred at room temperature for 12 h and extracted with Et₂O (200 mL x 2) . The organic layer was washed with satd. aq. NaHCO₃ solution (200 mL x 3) ， dried over anhy. Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was then purified by silica gel flash chromatography (petroleum ether∶EtOAc ＝ 100∶1～5∶1) to afford the title compound (35 g， 67.7％yield) as yellow oil. ¹H NMR (400MHz， CHCl₃-d1) δ 5.11-5.05 (m， 1 H) ， 4.83-4.73 (m， 2H) ， 3.88 (s， 3H) .

[C] (E) -Methyl 3-nitroacrylate

To a stirred solution of methyl 2-bromo-3-nitropropanoate (1 g， 4.7 mmol) in Et₂O (20 mL) was added Et₃N (0.47 g， 4.7 mmol) slowly at 0 ℃ and stirred for 12 h. Afterwards， the mixture solution was filtered， and the filtrate was washed with brine (10 mL) ， 0.05 N aq. HCl solution (10 mL) and satd. aq. NaHCO₃ solution (10 mL) . The organic layer was dried over anhy. Na₂SO₄， filtered， and concentrated in vacuo to give a crude title compound (0.45 g， 73.7％yield) as an oil. It was used directly in the next step without further purification. ¹H NMR (400MHz CHCl₃-d1) δ 7.712-7.678 (d， 1H， J＝13.6Hz) ， 7.122-7.088 (d， 1H， J＝13.6Hz) ， 3.887 (s， 3H) .

[D] (rac) - (2S， 3S) -Methyl 3-nitrobicyclo [2.2.1] hept-5-ene-2-carboxylate

To a stirred solution of (E) -methyl 3-nitroacrylate (0.3 g， 2.3 mmol) in toluene (10 mL) was added cyclopenta-1， 3-diene (0.16 g， 2.4 mmol， freshly cracked) in one portion at 0 ℃ and the mixture was stirred first at 0 ℃ for 1 h and then at room temperature for 2 h. Afterwards， the mixture solution was concentrated in vacuo to give a crude title compound (0.42g， 93.3％yield) as yellow oil. It was used directly in the next step without further purification. ¹H NMR (400MHz， CHCl₃-d1) δ 6.50-6.48 (m， 1H) ， 6.10-6.08 (m， 1H) ， 5.42 (t， 1H) ， 3.78 (s， 1H) ， 3.62 (t， 1H) ， 3.25 (t， 1H) ， 3.07 (t， 1H) ， 1.72-1.69 (m， 1H) ， 1.65-1.64 (m， 1H) .

[E] (rac) - (2S， 3S) -Methyl 3-aminobicyclo [2.2.1] hept-5-ene-2-carboxylate

To a stirred solution of HgCl₂ (1.1 g， 4 mmol) in H₂O (50 mL) was added alumina (0.7 g， 26 mmol) and the mixture was stirred under N₂ protection at room temperature for 15 min. The resulting solid was washed with MeOH (20 mL x 2) and Et₂O (20 mL) before being suspended in THF/H₂O (30 mL/3 mL) . To the above suspension was then added (rac) - (2S， 3S) -methyl 3-nitrobicyclo [2.2.1] hept-5-ene-2-carboxylate (0.2 g， 1.0 mmol) at 0 ℃ in one portion， and the resulting mixture was stirred first at 0 ℃ for 2 h and then at room temperature for 10 h under N₂ protection. The reaction mixture solution was filtered and extracted with EtOAc (200 mL) . The organic phase was washed with satd. aq. NaHCO₃ solution， dried over anhy. Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was then purified by silica gel flash chromatography (DCM∶MeOH＝100∶1～30∶1) to afford the title compound (40 mg， 25％yield) as yellow oil. ¹H NMR (400MHz， CHCl₃-d1) δ 6.39-6.37 (m， 1H) ， 6.17-6.15 (m， 1H) ， 3.96 (t， 1H) ， 3.73 (s， 1H) ， 3.14 (t， 1H) ， 3.05 (t， 1H) ， 1.81-1.80 (m， 1H) ， 1.76-1.73 (m， 1H) ， 1.58-1.56 (m， 1H) .

[F] (rac) - (2S， 3S) -Methyl 3- ( (tert-butoxycarbonyl) amino) bicyclo [2.2.1] hept-5-ene-2- carboxylate

To a stirred solution of (rac) - (2S， 3S) -methyl 3-aminobicyclo [2.2.1] hept-5-ene-2-carboxylate (0.8 g， 4.8 mmol) in DCM (30 mL) was added Et₃N (0.72 g， 7.2 mmol) and Boc₂O (1.27 9， 5.8 mmol) in one portion and the resulting mixture solution was stirred at room temperature for 12 h. After TLC (petroleum ether∶EtOAc ＝ 5∶1) showed that starting material was consumed， the reaction mixture was diluted with DCM (50 mL) and washed with citric acid solution (20 mL x 2) . After concentrating the mixture solution under reduced pressure， the residue was purified by silica 9el flash chromatography (petroleum ether∶EtOAc ＝ 10∶1) to afford the title compound (1 g) as a white solid. ¹H NMR (400MHz， CHCl₃-d1) δ 6.43-6.41 (m， 1H) ， 6.19-6.15 (m， 1H) ， 3.72 (s， 1H) ， 3.04 (t， 1H) ， 2.99 (t， 1H) ， 1.88-1.83 (m， 1H) ， 1.83-1.80 (m， 1H) ， 1.58-1.50 (m， 2H) ， 1.45 (s， 9H) .

[G] (rac) - (2S， 3S) -Methyl 3-aminobicyclo [2.2.1] heptane-2-carboxylate

To a solution of (rac) - (2S， 3S) -methyl 3-aminobicyclo [2.2.1] hept-5-ene-2-carboxylate (2.0 g， 10.0 mmol) in MeOH (40 mL) was added Pd/C (0.5 g) and the mixture was stirred under H2 (50 Psi) at 25℃ for 72h. The reaction mixture was filtered and concentrated to give a yellow oil as title compound (1.6 g， 97％) .

[H] (rac) - (2S， 3S) -Methyl， 3- ( (2-chloro-5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.1] heptanes-2- carboxylate

To a stirred solution of (rac) - (2S， 3S) -methyl 3-aminobicyclo [2.2.1] heptane-2-carboxylate (0.7 g， 4.1 mmol) in THF (30 mL) was added DIPEA (1 g， 8.2 mmol) and 2， 4-dichloro-5-fluoropyrimidine (0.82 g， 4.9 mmol) at room temperature and the resulting reaction mixture was stirred at 70 ℃ for 12 h. After cooling to room temperature， the reaction was quenched by the addition of satd. aq. NH₄Cl solution (50 mL) and extracted with EtOAc (3 x 50 mL) . The combined organic extracts were dried over anhy. Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was then purified by silica gel flash chromatography (petroleum ether∶EtOAc ＝ 10∶1) to afford the title compound (1.1 g， 91.6％yield) as a light-yellow solid. MS： 300.2 [M+H] ⁺.

[I] (rac) - (2S， 3S) -Methyl， 3- ( (5-fluoro-2- (6-fluoro-1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl) amino) bicyclo [2.2.1] heptane-2-carboxylate

In a sealed tube， to a stirred solution of 6-fluoro-1H-pyrazolo [4， 3-b] pyridine (Intermediate A-2， 200 mg， 1.45 mmol) in dioxane (30 mL) was added (2S， 3S) -methyl 3- ( (2-chloro-5-fluoropyrimidin-4-yl) amino) bicycle [2.2.1] heptane-2-carboxylate (521.5 mg， 1.74 mmol) ， (1S， 2S) -cyclohexane-1， 2-diamine (137.0 mg， 1.2 mmol) ， Cul (331.4 mg， 1.74 mmol) and K₃PO₄ (615.6 mg， 2.9 mmol) and the resulting reaction mixture was stirred at 120 ℃ for 12 h. After cooling to room temperature， the reaction mixture was concentrated in vacuo to give a crude product， which was then purified by silica gel flash chromatography (petroleum ether∶EtOAc ＝ 3∶1) to afford the title compound (120 mg， 20.7％yield) as a red solid. MS： 401.1 [M+H] ⁺.

[J] (rac) - (2S， 3S) -3- [ [5-Fluoro-2- (6-fluoropyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl] amino] norbornane-2-carboxylic acid

To a stirred solution of (2S， 3S) -methyl 3- ( (5-fluoro-2- (6-fluoro-1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl) amino) bicyclo [2.2.1] heptane-2-carboxylate (110 mg， 0.27 mmol) in THF (10 mL) was added 8N aq. NaOH solution (10 mL) at room temperature and stirred for 12 h. After TLC (petroleum ether∶EtOAc ＝ 1∶1) showed the reaction was completed， the mixture solution was extracted with EtOAc (50 mL x 3) . The separated aqueous layer was adjusted to pH 4～5 by the addition of 6N aq. HCl solution and then extracted with EtOAc (50 mL x 3) . The combined organic extracts were dried over anhy. Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purified by Prep-HPLC to afford the title compound (9.2 mg， 8.7％yield) as a white solid. MS 387.1 [M+H] ⁺. ¹HNMR (400MHz， MeOH-d4) δ ppm 9.40 (br. s.， 1 H) ， 8.61 (br. s.， 1 H) ， 8.17 (br. s.， 1 H) ， 7.89 (d， J＝8.28 Hz， 1 H) ， 4.74 (br. s.， 1 H) ， 2.77 (br. s.， 1 H) ， 2.58 (br. s.， 1 H) ， 2.38 (d， J＝4.27 Hz， 1 H) ， 1.88 (d， J＝10.04 Hz， 1 H) ， 1.66～1.81 (m， 2 H) ， 1.40～1.60 (m， 3 H) .

Example 66

(rac) - (6S， 7S) -6- [ [5-Fluoro-2- (6-fluoropyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl] amino] bicyclo [3.2.2] nonane-7-carboxylic acid

[A] (3aR， 4S， 8R， 8aS) -4， 5， 6， 7， 8， 8a-hexahydro-1H-4， 8-ethenocyclohepta [c] furan-1， 3 (3aH) - dione and (3aR， 4S， 8R， 8aS) -4， 5， 6， 7， 8， 8a-hexahydro-1H-4， 8-ethenocyclohepta [c] furan- 1， 3 (3aH) -dione

A stirred solution of cyclohepta-1， 3-diene (15 g， 159 mmol) and maleic anhydrid (15.6 g， 159 mmol) in toluene (50 mL) was heated at 120 ℃ for 16 h. After cooling to room temperature， the solvent was evaporated under reduced pressure to give a crude title compound (29.4 g， 96％yield) as a white solid. It was used directly in the next step without further purification. MS： 225.1 [M+H⁺] .

[B] (1R， 5S， 8S， 9S) -9- (Methoxycarbonyl) bicyclo [3.2.2] non-6-ene-8-carboxylic acid and (1S， 5R， 8R， 9R) -9- (methoxycarbonyl) bicyclo [3.2.2] non-6-ene-8-carboxylic acid

(3aR， 4S， 8R， 8aS) -4， 5， 6， 7， 8， 8a-hexahydro-1H-4， 8-ethenocyclohepta [c] furan-1， 3 (3aH) -dione and (3aR， 4S， 8R， 8aS) -4， 5， 6， 7， 8， 8a-hexahydro-1H-4， 8-ethenocyclohepta [c] furan-1， 3 (3aH) -dione (50 g， 260 mmol) was treated with sodium methoxide (70.3 g， 1.3 mol) in MeOH (500 mL) at room temperature. After the reaction mixture was stirred at room temperature for 24 h， it was acidified with 2 N HCl solution (300 mL) and extracted with EtOAc (300 mL x 3) . The combined organic layers were dried over anhy. Na₂SO₄， filtered， and concentrated in vacuo to give a crude title compound (50 g， 85.7％yield) as a yellow solid. MS： 344.2 [M+H⁺] . It was used directly in the next step reaction without further purification.

[C] (1S， 5R， 8S， 9S) -Methyl 9- ( ( (benzyloxy) carbonyl) amino) bicyclo [3.2.2] non-6-ene-8- carboxylate and (1R， 5S， 8R， 9R) -methyl 9- ( ( (benzyloxy) carbonyl) amino) bicyclo [3.2.2] -non-6- ene-8-carboxylate

To a stirred solution of (1R， 5S， 8S， 9S) -9- (methoxycarbonyl) bicyclo [3.2.2] non-6-ene-8-carboxylic acid and (1S， 5R， 8R， 9R) -9- (methoxycarbonyl) bicyclo [3.2.2] non-6-ene-8-carboxylic acid (17.3 g， 77.1 mmol) and Et₃N (23.4 g， 231 mmol) in toluene (100 mL) was added diphenylphosphoryl azide (25.5 g， 92.6 mmol) dropwise at room temperature. After the addition， the reaction mixture was heated at 100 ℃ for 1 h before benzyl alcohol (16.7 g， 154 mmol) was added. The resulting mixture solution was heated at 100 ℃ for another 1 h. After cooling to room temperature， the solvent was evaporated under reduced pressure to give a crude product， which was purified by silica gel flash chromatography (EtOAc： petroleum ether ＝ 0 to 40％) to afford the title compound (13 g， 52％yield) as yellow oil. MS： 330.2 [M+H⁺] .

[D] (rac) - (1R， 5S， 6S， 7S) -Methyl 7-aminobicyclo [3.2.2] nonane-6-carboxylate

A mixture solution of (rac) - (1S， 5R， 8S， 9S) -methyl 9- ( ( (benzyloxy) carbonyl) amino) bicyclo-[3.2.2] non-6-ene-8-carboxylate (20 g， 60.7 mmol) and palladium hydroxide on carbon (800 mg， 5.7 mmol) in MeOH (100 mL) was stirred at room temperature under H₂ atmosphere (1 atm) for 5 h. Afterwards， the reaction mxiture was filtered and the filtrate was concentrated under vacuum to give a crude title compound (9 g， 75.1％yield) as a white solid. MS： 198.2 [M+H] ⁺. It was used directly in the next step without further purificaiton.

[E] (rac) - (6S， 7S-Methyl， 7- ( (5-fluoro-2- (6-fluoro-1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4- yl) amino) bicyclo [3.2.2] nonane-6-carboxylate

In analogy to the synthesis of Example 65/Step B， (rac) - (1R， 5S， 6S， 7S) -methyl 7-aminobicyclo [3.2.2] nonane-6-carboxylate (570 mg， 1.74 mmol) was used to obtain the title compound (180 mg， 29.2％yield) as a red solid after silica gel flash chromatography (petroleum ether∶EtOAc ＝ 3∶1) purification. MS： 429.1 [M+H] ⁺.

[F] (rac) - (6S， 7S) -6- [ [5-Fluoro-2- (6-fluoropyrazolo [4， 3-b] pyridin-1 -yl) pyrimidin-4-yl] amino] bicyclo [3.2.2] nonane-7-carboxylic acid

A solution of (6S， 7S) -methyl， 7- ( (5-fluoro-2- (6-fluoro-1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl) amino) bicyclo [3.2.2] nonane-6-carboxylate (160 mg， 0.37 mmol) in 12 N HCl solution (20 mL) was stirred at room temperature for 12 h. After TLC (petroleum ether∶EtOAc ＝ 1∶1) showed the reaction was completed， the reaction mixture was concentrated in vacuo to give a crude product， which was then purified by Prep-HPLC to afford the title compound (5 mg， 3.3％ yield) as a white solid. MS： 415.2 [M+H] ⁺. ¹HNMR (400MHz， MeOH-d4) δ 8.97 (d， J＝9.03 Hz， 1 H) ， 8.64 (br. s.， 1 H) ， 8.50 (br. s.， 1 H) ， 8.11 (br. s.， 1 H) ， 5.22 (d， J＝7.03 Hz， 1 H) ， 2.87 (dd， J＝7.53， 3.51 Hz， 1 H) ， 2.56 (br. s.， 1H) ， 2.11 (br. s.， 1 H) ， 1.93～2.08 (m， 3 H) ， 1.80～1.92 (m， 3 H) ， 1.73～1.79 (m， 2 H) ， 1.67 (d， J＝8.53 Hz， 2 H) .

Example 67

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

[A] (-) - (1R， 2S， 3S， 4R) -Methyl 3- ( (5-fluoro-2- (6-fluoro-1H-pyrrolo [3， 2-b] pyridin-1-yl) pyrimidin- 4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate

In analogy to the synthesis of Example 65/Step B， (-) - (1R， 2S， 3S， 4R) -methyl 3- ( (2-chloro-5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (Example 3/Step E， 120 mg， 382 μmol) and 6-fluoro-1H-pyrrolo [3， 2-b] pyridine (120 mg， 882 μmol) were used as coresponding reagents to obtain the title compound (80 mg， 50％yield) as a yellow solid after silica gel flash chromatography (0-50％EtOAc-hexane gradient) purification. MS： 414.2 [M+H] ⁺.

[B] (-) - (2S， 3S) -3- ( (5-Fluoro-2- (6-fluoro-1H-pyrrolo [3， 2-b] pyridin-1-yl) pyrimidin-4- yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

To a stirred mixture solution of (-) - (1R， 2S， 3S， 4R) -methyl 3- ( (5-fluoro-2- (6-fluoro-1H-pyrrolo [3， 2-b] pyridin-1-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (80 mg， 194 μmol) in THF (4mL) and MeOH (2 mL) was added LiOH. H₂O (40.6 mg， 968 μmol) pre-dissoved 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 HCl to pH 4 and extracted with ethyl acetate (3 x 40 mL) . The combined organics were dried over anhy. Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was then purified by Prep-HPLC to afford the title compound (22 mg， 28％yield) as white foam. MS： 400.2 [M+H] ⁺. ¹HNMR (400 MHz， MeOH-d4) δ 8.87 (dd， J＝10.29， 2.26 Hz， 1 H) 8.45-8.52 (m， 1 H) 8.29-8.38 (m， 1 H) 7.98-8.08 (m， 1 H) 6.77 (d， J＝3.76 Hz， 1 H) 4.81 (d， J＝6.78 Hz， 1 H) 2.78 (d， J＝6.53 Hz， 1 H) 2.12 (d， J＝2.01 Hz， 1 H) 1.79-2.03 (m， 4 H) 1.63-1.78 (m， 3 H) 1.47-1.62 (m， 2 H) .

Example 68

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

[A] (-) - (1R， 2S， 3S， 4R) -Methyl 3- ( (2- (6-chloro-1H-pyrazolo [ 4， 3-b] pyridin-1-yl) -5- fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate

In analogy to the synthesis of Example 65/Step B， (-) - (1R， 2S， 3S， 4R) -methyl 3- ( (2-chloro-5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (Example 3/Step E， 150 mg， 478μmol) and 6-chloro-1H-pyrazolo [4， 3-b] pyridine (Intermediate A-3， 147 mg， 956 μmol) were used to obtain the title compound (140 mg， 68％yield) as light yellow foam after silica gel flash chromatography (0-50％EtOAc-hexane gradient) purification. MS： 431.2 [M+H] ⁺.

[B] (-) - (2S， 3S) -3- ( (2- (6-Chloro-1H-pyrazolo [4， 3-b] pyridin-1-yl) -5-fluoropyrimidin-4- yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

In analogy to the synthesis of Example 67/step B， (-) - (1R， 2S， 3S， 4R) -methyl 3- ( (2- (6-chloro-1H-pyrazolo [4， 3-b] pyridin-1-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (140mg， 325 μmol) was used to obtain the title compound (40 mg， 30％yield) as white foam after Prep-HPLC purification. MS： 417.2 [M+H] ⁺. ¹HNMR (400 MHz， MeOH-d4) δ 9.18 (d， J＝1.51 Hz， 1 H) 8.64 (d， J＝2.01 Hz， 1 H) 8.49 (s， 1 H) 8.10 (d， J＝3.51 Hz， 1 H) 4.95 (d， J＝7.03 Hz， 1 H) 2.85 (d， J＝7.03 Hz， 1 H) 2.17 (br. s.， 1 H) 1.95-2.11 (m， 2H) 1.81-1.94 (m， 2 H) 1.64-1.80 (m， 3 H) 1.48-1.63 (m， 2 H) .

Example 69

(-) - (2S， 3S) -3- ( (2- (6-Chloro-1H-pyrrolo [3， 2-b] pyridin-1-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

[A] (-) - (1R， 2S， 3S， 4R) -Methyl 3- ( (2- (6-chloro-1H-pyrrolo [3， 2-b] pyridin-1-yl) -5-fluoropyrimidin- 4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate

In analogy to the synthesis of Example 65/Step B， (-) - (1R， 2S， 3S， 4R) -methyl 3- ( (2-chloro-5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (200 mg， 637 μmol) and 6-chloro-1H-pyrrolo [3， 2-b] pyridine (154 mg， 1.01 mmol) were used to obtain the title compound (120 mg， 43.8％yield) as a yellow solid after silica gel flash chromatography (0-50％EtOAc-hexane gradient) purification. MS： 430.2 [M+H] ⁺.

[B] (-) - (2S， 3S) -3- ( (2- (6-Chloro-1H-pyrrolo [3， 2-b] pyridin-1-yl) -5-fluoropyrimidin-4- yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

In analogy to the synthesis of Example 67/step B， (1R， 2S， 3S， 4R) -methyl 3- ( (2- (6-chloro-1H-pyrrolo [3， 2-b] pyridin-1-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (100 mg， 233 μmol) was used to obtain the title compound (40 mg， 41％yield) as white foam after Prep-HPLC purification. MS： 416.2 [M+H⁺] . ¹HNMR (400 MHz， MeOH-d4) δ 9.16 (d， J＝1.76 Hz， 1 H) 8.53 (d， J＝3.76 Hz， 1 H) 8.40 (d， J＝2.01 Hz， 1 H) 8.08 (d， J＝3.51 Hz， 1 H) 4.85 (d， J＝6.78 Hz， 1 H) 2.79 (d， J＝6.78 Hz， 1 H) 2.13 (br. s.， 1 H) 1.98 (br. s.， 2 H) 1.82 -1.90 (m， 2 H) 1.63-1.78 (m， 3 H) 1.49-1.61 (m， 2H) .

Example 70

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

[A] (-) - (1R， 2S， 3S， 4R) -Methyl 3- ( (2- (6-cyano-1H-pyrazolo [4， 3-b] pyridin-1-yl) -5- fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate

In analogy to the synthesis of Example 65/Step B， (-) - (1R， 2S， 3S， 4R) -methyl 3- ( (2-chloro-5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (Example 3/Step E， 313 mg， 998 μmol) and 1H-pyrazolo [4， 3-b] pyridine-6-carbonitrile (Intermediate A-4， 187 mg， 1.3 mmol) were used to obtain the title compound (170 mg， 40.4％yield) as a white solid after silica gel flash chromatography (0-80％ EtOAc-hexane gradient) purification. MS： 422.1 [M+H] ⁺.

[B] (-) - (2S， 3S) -3- ( (2- (6-Cyano-1H-pyrazolo [4， 3-b] pyridin-1-yl) -5-fluoropyrimidin-4- yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

In analogy to the synthesis of Example 67/step B， (-) - (1R， 2S， 3S， 4R) -methyl 3- ( (2- (6-cyano-1H-pyrazolo [4， 3-b] pyridin-1-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (170 mg， 403 μmol) was used to obtain the title compound (26 mg， 15.8％yield) as white foam after Prep-HPLC purification. MS： 408.1 [M+H] ⁺. ¹HNMR (400 MHz， MeOH-d4) δ 9.52-9.56 (m， 1 H) 8.91-8.96 (m， 1 H) 8.60-8.67 (m， 1 H) 8.10-8.17 (m， 1 H) 4.95 -5.02 (m， 1 H) 2.77-2.82 (m， 1 H) 2.13-2.21 (m， 1 H) 1.99-2.05 (m， 2 H) 1.85-1.91 (m， 2 H) 1.50-1.84 (m， 5 H) .

Example 71 (rac) -N- ( (1R， 3S) -3- ( (2- (6-cyano-1H-pyrazolo [4， 3-b] pyridin-1-yl) -5-fluoropyrimidin-4-yl) amino) cyclohexyl) benzamide

[A] (rac) -tert-Butyl ( (1R， 3S) -3- ( (2- (6-cyano-1H-pyrazolo [4 3-b] pyridin-1-yl) -5-fluoropyrimidin- 4-yl) amino) cyclohexyl) carbamate

In a seal tube， to a stirred solution of (rac) -tert-butyl N- [ (1R， 3S) -3- [ (2-chloro-5-fluoro-pyrimidin-4-yl) amino] cyclohexyl] carbamate (Example 1/Step A， 2 g， 5.8 mmol) in dioxane (30 mL) was added 1H-pyrazolo [4， 3-b] pyridine-6-carbonitrile (Intermediate A-4， 1.25 g， 8.7 mmol) ， (1R， 2R) -cyclohexane-1， 2-diamine (0.79g， 6.9 mmol) ， Cul (1.31 g， 6.9 mmol) and K₃PO₄ (1.84 g， 8.7 mmol) and the resulting reaction mixture was stirred at 120℃ for 12 h. After cooling to room temerature， the reaction was quenched by the addition of satd. aq. NH₄Cl solution (100 mL) and extracted with EtOAc (3 x 100) . The combined organic extracts were concentrated in vacuo to give a crude product， which was the purified by Prep-HPLC to give the title compound (0.5 g， 2.7％yield) as an orange solid. MS： 453.3 [M+H] ⁺.

[B] (rac) -1- (4- ( ( (1S， 3R) -3-Aminocyclohexyl) amino) -5-fluoropyrimidin-2-yl) -1H-pyrazolo [4， 3- b] pyridine-6-carbonitrile

A mixture solution of tert-butyl ( (1R， 3S) -3- ( (2- (6-cyano-1H-pyrazolo [4， 3-b] pyridin-1-yl) -5-fluoropyrimidin-4-yl) amino) cyclohexyl) carbamate (0.48 g， 1.06mmol) in DCM (5 mL) and TFA (5 mL) was stirred at room temperature for 3 h. After TLC (MeOH∶DCM ＝ 1∶10) showed the reaction was completed， the reaction mixture was concentrated in vacuo to giva a crude title compound (0.32 g， 88.9％yield) . MS： 353.3 [M+H] ⁺. It was used directly in the next step without further purification.

[C] (rac) -N- ( (1R， 3S) -3- ( (2- (6-cyano-1H-pyrazolo [4， 3-b] pyridin-1-yl) -5-fluoropyrimidin-4- yl) amino) cyclohexyl) benzamide

To a stirred solution of 1- (4- ( ( (1 S， 3R) -3-aminocyclohexyl) amino) -5-fluoropyrimidin-2-yl) -1H-pyrazolo [4， 3-b] pyridine-6-carbonitrile (120 mg， 0.34 mmol) in MeCN (10 mL) was added DIPEA (87.9 mg， 0.68 mmol) and benzoyl chloride (71.8 mg， 0.51 mmol) at room temperature and stirred for 12 h. After LCMS indicatedthe reaction was completed， the reaction mixture was concentrated in vacuo to give a crude product， which was then purified by Prep-HPLC to afford the title compound (15 mg， 9.7％yield) as a white solid. MS： 457.2 [M+H] ⁺. ¹HNMR (400MHz， MeOH-d4) δ 9.41 (s， 1 H) ， 8.93 (d， J＝1.25 Hz， 1 H) ， 8.64 (s， 1 H) ， 8.12 (d， J＝2.76 Hz， 1 H) ， 7.80 (d， J＝7.28 Hz， 2 H) ， 7.49～7.55 (m， 1 H) ， 7.42～7.47 (m， 2 H) ， 4.32 (t， J＝11.67 Hz， 1 H) ， 4.13～4.24 (m， 1 H) ， 2.52 (d， J＝12.05 Hz， 1 H) ， 2.25 (d， J＝12.55 Hz， 1 H) ， 2.01～2.14 (m， 2 H) ， 1.77 (q， J＝13.47 Hz， 1 H) ， 1.42～1.62 (m， 3 H) .

Example 72

(rac) -N- ( (1R， 3S) -3- ( (2- (6-cyano-1H-pyrazolo [4， 3-b] pyridin-1-yl) -5-fluoropyrimidin-4-yl) amino) cyclohexyl) pyrrolidine-1-carboxamide

In analogy to the synthesis of Example 71/step C， pyrrolidine-1-carbonyl chloride (68.1 mg， 0.51 mmol) was used to obtain the title compound (60 mg， 39.3％yield) as a white solid after Prep-HPLC purification. MS： 450.2 [M+H] ⁺. ¹HNMR (400MHz， MeOH-d4) δ 9.30 (br. s.， 1 H) ， 8.93 (br. s.， 1 H) ， 8.66 (d， J＝4.27 Hz， 1 H) ， 8.14 (br. s.， 1 H) ， 4.24 (br. s.， 1 H) ， 3.79～3.91 (m， 1 H) ， 3.28～3.32 (m， 4 H) ， 2.39 (d， J＝11.80 Hz， 1 H) ， 2.22 (d， J＝11.29 Hz， 1 H) ， 2.01 (d， J＝10.29 Hz， 2 H) ， 1.91 (t， J＝6.40 Hz， 4 H) ， 1.61～1.79 (m， 1 H) ， 1.4～1.54 (m， 1 H) ， 1.34～1.45 (m， 2 H) .

Example 73

(rac) -N- ( (1R， 3S) -3- ( (2- (6-cyano-1H-pyrazolo [4， 3-b] pyridin-1-yl) -5-fluoropyrimidin-4-yl) amino) cyclohexyl) morpholine-4-carboxamide

In analogy to the synthesis of Example 71/step C， morpholine-4-carbonyl chloride (76.3 mg， 0.51 mmol) was used to obtain the title compound (30 mg， 18.9％yield) as a yellow solid after Prep-HPLC purification. MS： 466.2 [M+H] ⁺. ¹HNMR (400HMz， MeOH-d4) δ 9.28 (s， 1 H) ， 8.92 (d， J＝1.51 Hz， 1 H) ， 8.64 (s， 1 H) ， 8.12 (d， J＝3.26 Hz， 1 H) ， 4.22 (t， J＝11.67 Hz， 1 H) ， 3.80～3.88 (m， 1 H) ， 3.64 (t， J＝4.64 Hz， 4 H) ， 3.36 (d， J＝5.02 Hz， 3 H) ， 2.40 (d， J＝11.80 Hz， 1 H) ， 2.21 (d， J＝12.05 Hz， 1 H) ， 1.97～2.05 (m， 2 H) ， 1.69 (q， J＝13.47 Hz， 1 H) ， 1.34～1.49 (m， 3 H) ， 1.13 (t， J＝7.03 Hz， 1 H) .

Example 74 (-) - (2S， 3S) -3- ( (2- (6-Cyano-1H-pyrrolo [3， 2-b] pyridin-1-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

[A] (-) - (1R， 2S， 3S， 4R) -Methyl 3- ( (2- (6-cyano-1H-pyrrolo [3， 2-b] pyridin-1-yl) -5-fluoropyrimidin- 4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate

In analogy to the synthesis of Example 65/Step B， (-) - (1R， 2S， 3S， 4R) -methyl 3- ( (2-chloro-5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (120 mg， 382μmol) and 1H-pyrrolo [3， 2-b] pyridine-6-carbonitrile (Example 3/Step E， 120 mg， 838 μmol) were used to obtain the title compound (60 mg， 37％yield) as a white solid after silica gel flash chromatography (0-50％EtOAc-hexane gradient) purification. MS： 421.2 [M+H] ⁺.

[B] (-) (2S， 3S) -3- ( (2- (6-Cyano-1H-pyrrolo [3， 2-b] pyridin-1-yl) -5-fluoropyrimidin-4- yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

In analogy to the synthesis of Example 67/step B， (1R， 2S， 3S， 4R) -methyl 3- ( (2- (6-cyano-1H-pyrrolo [3， 2-b] pyridin-1-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (80 mg， 190 μmol) was used to obtain the title compound (12 mg， 15％yield) as white foam after Prep-HPLC purification. MS： 407.2 [M+H] ⁺. ¹HNMR (400 MHz， MeOH-d4) δ ppm 9.28 (s， 1 H) 8.57-8.72 (m， 2 H) 8.03 (d， J＝3.26 Hz， 1 H) 7.68 (d， J＝6.53 Hz， 1 H) 6.83 (d， J＝3.26 Hz， 1 H) 4.80 (d， J＝5.52 Hz， 1 H) 2.78 (d， J＝5.77 Hz， 1 H) 2.13 (br. s.， 1 H) 1.63-2.00 (m， 7 H) 1.50-1.63 (m， 2 H)

Example 75

(rac) -N- ( (1R， 3S) -3- ( (5-Fluoro-2- (6- (trifluoromethyl) -1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl) amino) cyclohexyl) morpholine-4-carboxamide

[A] (rac) -tert-Butyl ( (1R， 3S) -3- ( (5-fluoro-2- (6- (trifluoromethyl) -1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl) amino) cyclohexyl) carbamate

To a stirred solution of (rac) -tert-butyl N- [ (1R， 3S) -3- [ (2-chloro-5-fluoro-pyrimidin-4-yl) amino] cyclohexyl] carbamate (Example 1/Step A， (1 g， 3 mmol) in dioxane (15 mL) was added 6- (trifluoromethyl) -1H-pyrazolo [4， 3-b] pyridine (Intermediate A-5， 940 mg， 5 mmol) ， (1R， 2R) -cyclohexane-1， 2-diamine (400 mg， 3.5 mmol) ， Cul (685 mg， 3.5 mmol) and K₃PO₄ (1.1 g， 5 mmol) at room temperature. After the addition， the reaction mixture was allowed to warm up and stirred at 120℃ for 12 h. After cooling to room temperature， the reaction mixture was filtered to remove salt， and the filtrate was concentrated in vacuo to give a crude product， which was then purified by silica gel flash chromatography (DCM/MeOH ＝100∶1～40∶1) to give the title compound (630 mg， 41.7％yield) as a yellow solid. MS： 496.0 [M+H] ⁺.

[B] (rac) - (1S， 3R) -N1- (5-fluoro-2- (6- (trifluoromethyl) -1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl) cyclohexane-1， 3-diamine

To a stirred solution of tert-butyl ( (1R， 3S) -3- ( (5-fluoro-2- (6- (trifluoromethyl) -1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl) amino) cyclohexyl) carbamate (250 mg， 0.5 mmol) in DCM (10 mL) was added TFA (1 mL) at 15℃ and stirred at 15℃ for 1 h. Afterwards， the reaction mixture was concentrated in vacuo to give a crude title compound (200 mg) . MS： 396.0 [M+H] ⁺. It was used directly in the next step reaction without further purification.

[C] (rac) -N- ( (1R， 3S) -3- ( (5-Fluoro-2- (6- (trifluoromethyl) -1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl) amino) cyclohexyl) morpholine-4-carboxamide

In analogy to the synthesis of Example 71/step C， (1S， 3R) -N1- (5-fluoro-2- (6- (trifluoromethyl) -1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl) cyclohexane-1， 3-diamine (100 mg， 0.25 mmol) and morpholine-4-carbonyl chloride (75 mg， 0.5 mmol) were used to obtain the title compound (42.4 mg， 32.6％yield) as a white solid after Prep-HPLC purification. MS： 509.2 [M+H] ⁺. ¹H NMR (400 MHz， DMSO-d6) ： δ 9.21 (s， 1H) ， 9.05 (s， 1H) ， 8.84 (s， 1H) ， 8.31 (s， 1H) ， 8.14 (d， J ＝ 7.6 Hz， 1H) ， 6.36 (d， J ＝ 7.6 Hz， 1H) ， 4.11～4.08 (m， 1H) ， 3.56-3.50 (m， 5H) ， 3.24～3.21 (m， 4H) ， 2.07～1.80 (m， 4H) ， 1.45～1.15 (m， 4H) .

Example 76

(rac) -N- ( (1R， 3S) -3- ( (5-fluoro-2- (6- (trifluoromethyl) -1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl) amino) cyclohexyl) pyrrolidine-1-carboxamide

In analogy to the synthesis of Example 71/step C， (1S， 3R) -N1- (5-fluoro-2- (6- (trifluoromethyl) -1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl) cyclohexane-1， 3-diamine (Example 75/Step B， 100 mg， 0.25 mmol) and pyrrolidine-1-carbonyl chloride (75.0 mg， 0.5 mmol) were used to obtain the title compound (65.5 mg， 53％yield) as a white solid after Prep-HPLC purification. MS： 493.2 [M+H] ⁺. ¹HNMR (400MHz， MeOH-d4) ： δ 9.32 (s， 1H) ， 8.94 (s， 1H) ， 8.21 (s， 1H) ， 8.10 (d， J ＝ 3.2 Hz， 1H) ， 4.28～4.25 (m， 1H) ， 2.29～1.96 (m， 2H) ， 1.93～1.87 (m， 6H) ， 1.49～1.28 (m， 4H) .

Example 77 (rac) -N- [ (1R， 3S) -3- [ [5-Fluoro-2- [6- (trifluoromethyl) pyrrolo [3， 2-b] pyridin-1-yl] pyrimidin-4-yl] amino] cyclohexyl] morpholine-4-carboxamide

To a stirred solution of N- ( (1S， 3R) -3- ( (2-chloro-5-fluoropyrimidin-4-yl) amino) cyclohexyl) morpholine-4-carboxamide (192 mg， 537 μmol) in dioxane (15 mL) was added K₃PO₄ (281 mg， 1.32 mmol) ， copper (I) iodide (20.5 mg， 107 μmol) ， 6- (trifluoromethyl) -1H-pyrrolo [3， 2-b] pyridine (100 mg， 537 μmol) and (1R， 2S) -cyclohexane-1， 2-diamine (24.5 mg， 215 μmol) and the resulting reaction mixture was heated to reflux overnight. After cooling to room temperature， the mixture soiution was concentrated in vacuo and the residue was partitioned between satd. aq. NH₄Cl solution and EtOAc. The separated organic layer was then dried over anhy. Na₂SO₄， filteres， and concentrated in vacuo to give a crude product， which was purified by Prep-HPLC to afford the title compound (1 mg， 0.4％yield) as a white powder. MS： 508.3 [M+H] ⁺. ¹HNMR (400 MHz， MeOH-d4) δ 9.36 (s， 1 H) ， 8.75 (d， J ＝ 4 Hz， 1 H) ， 8.12 (d， J ＝ 4 Hz， 1 H) ， 6.94 (d， J ＝ 4 Hz， 1 H) ， 6.32 (d， J ＝ 8 Hz， 1 H) ， 4.62 (s， 1 H) ， 4.28-4.20 (m， 1 H) ， 3.84-3.77 (m 1 H) ， 3.65 (t， J ＝ 4 Hz， 2 H) ， 3.38-3.35 (m， 3 H， partially overlapped with MeOH) ， 2.36-1.92 (m， 5 H) ， 1.66-1.56 (m， 1 H) ， 1.44-1.27 (m， 4 H) .

Example 78 (rac) -N- [ (1S， 3R) -3- [ [5-fluoro-2- [6- (trifluoromethyl) pyrrolo [3， 2-b] pyridin-1-yl] pyrimidin-4-yl] amino] cyclohexyl] morpholine-4-carboxamide

In analogy to the synthsis of Example 78， N- ( (1R， 3S) -3- ( (2-chloro-5-fluoropyrimidin-4-yl) amino) cyclohexyl) morpholine-4-carboxamide (192 mg， 537 μmol) was used to obtain the title compound (0.5 mg， 0.2％yield) as a white powder after Prep-HPLC purification. MS： 508.3 [M+H] ⁺. ¹HNMR (400 MHz， MeOH-d4) δ 9.36 (s， 1 H) ， 8.75 (d， J＝4 Hz， 1 H) ， 8.73 (s， 1 H) ， 8.12 (d， J ＝ 4 Hz， 1 H) ， 6.94 (d， J ＝ 4 Hz， 1 H) ， 4.62 (s， 1 H) ， 4.30-4.20 (m， 1 H) ， 3.84 -3.76 (m， 1 H) ， 3.65 (t， J＝4 Hz， 2 H) ， 3.38-3.35 (m， 3 H， partially overlapped with MeOH) ， 2.38-2.32 (m， 1 H) ， 2.23-1.91 (m， 3 H) ， 1.66-1.57 (m， 1 H) ， 1.44-1.31 (m， 4 H) ， 0.95-0.90 (m， 1 H) .

Example 79

(+ or -) - (2S， 3S) -3- [ [5-Fluoro-2- [6- (trifluoromethyl) pyrrolo [3， 2-b] pyridin-1-yl] pyrimidin-4-yl] amino] bicyclo [2.2.2] octane-2-carboxylic acid

[A] (+ or -) -Methyl (2S， 3S) -3- [ [5-fluoro-2- [6- (trifluoromethyl) pyrrolo [3， 2-b] pyridin-1- yl] pyrimidin-4-yl] amino] bicyclo [2.2.2] octane-2-carboxylate

In analogy to the synthesis of Example 65/Step B， (-) - (1R， 2S， 3S， 4R) -methyl 3- ( (2-chloro-5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (Example 3/Step E， 169 mg， 537 μmol) and 6- (trifluoromethyl) -1H-pyrrolo [3， 2-b] pyridine (100 mg， 537 μmol) were used to obtain a crude title compound (100 mg， 34％yield) as brown oil. MS： 464.1 [M+H] ⁺. It was used directly in the next step without further purification.

[B] (+ or -) - (2S， 3S) -3- [ [5-Fluoro-2- [6- (trifluoromethyl) pyrrolo [3， 2-b] pyridin-1-yl] pyrimidin-4- yl] amino] bicyclo [2.2.2] octane-2-carboxylic acid

In analogy to the synthesis of Example 67/step B， (+ or -) -methyl (2S， 3S) -3- [ [5-fluoro-2- [6- (trifluoromethyl) pyrrolo [3， 2-b] pyridin-1-yl] pyrimidin-4-yl] amino] bicyclo [2.2.2] octane-2-carboxylate (249 mg， 537 μmol) was used to obtain the title compound (7.2 mg， 3％yield) as a white powder after Prep-HPLC purification. MS： 450.3 [M+H] ⁺. ¹HNMR (400 MHz， MeOH-d4) δ 9.39 (s， 1 H) ， 8.72 (d， J ＝ 4 Hz， 1 H) ， 8.11 (d， J ＝ 4 Hz， 1 H) ， 7.65 (d， J ＝ 8 Hz， 1 H) ， 6.91 (d， J ＝ 4 Hz， 1 H) ， 2.76 (d， J ＝ 8 Hz， 1 H) ， 2.12 (brs， 1 H) ， 1.92-1.81 (m， 3 H) ， 1.75-1.65 (m， 3 H) ， 1.57-1.51 (m， 2 H) ， 1.35-1.30 (m， 2 H) .

Example 80

(+ or -) - (2R， 3R) -3- [ [5-fluoro-2- [6- (trifluoromethyl) pyrrolo [3， 2-b] pyridin-1-yl] pyrimidin-4-yl] amino] bicyclo [2.2.2] octane-2-carboxylic acid

[A] (- or +) -Methyl (2R， 3R) -3- [ [5-fluoro-2- [6- (trifluoromethyl) pyrrolo [3， 2-b] pyridin-1- yl] pyrimidin-4-yl] amino] bicyclo [2.2.2] octane-2-carboxylate

In analogy to the synthesis of Example 65/Step B， (+) - (1S， 2R， 3R， 4S) -methyl 3- ( (2-chloro-5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (Example 3/Step E， 169 mg， 537 μmol) and 6- (trifluoromethyl) -1H-pyrrolo [3， 2-b] pyridine (100 mg， 537 μmol) were used to obtain a crude title compound (100 mg， 34％yield) as brown oil. MS： 464.1 [M+H] ⁺. It was used directly in the next step without further purification.

[B] (-or +) - (2R， 3R) -3- [ [5-fluoro-2- [6- (trifluoromethyl) pyrrolo [3， 2-b] pyridin-1-yl] pyrimidin-4- yl] amino] bicyclo [2.2.2] octane-2-carboxylic acid

In analogy to the synthesis of Example 68/Step B， (-or +) -methyl (2R， 3R) -3- [ [5-fluoro-2- [6- (trifluoromethyl) pyrrolo [3， 2-b] pyridin-1-yl] pyrimidin-4-yl] amino] bicyclo [2.2.2] octane-2-carboxylate (249 mg， 537 μmol) was used to obtain the title compund (3.5mg， 1.5％yield) as a white powder after Prep-HPLC purification. MS： 449.7 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d1) δ 9.40 (s， 1 H) ， 8.73 (d， J ＝ 4 Hz， 1 H) ， 8.11 (d， J ＝ 4 Hz， 1 H) ， 7.66 (d， J ＝ 4 Hz， 1 H) ， 6.91 (d， J ＝ 4 Hz， 1 H) ， 2.76 (d， J ＝ 8 Hz， 1 H) ， 2.12 (brs， 1 H) ， 1.92 -1.81 (m， 3 H) ， 1.75-1.65 (m， 3H) ， 1.57-1.51 (m， 2H) ， 1.35-1.30 (m， 2H) .

Example 81

(rac) -N- ( (1R， 3S) -3- ( (5-Fluoro-2- (5-methyl-1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl) amino) cyclohexyl) picolinamide

[A] (rac) -tert-Butyl ( (1R， 3S) -3- ( (5-fluoro-2- (5-methyl-1H-pyrazolor4， 3-b] pyridin-1-yl) pyrimidin- 4-yl) amino) cyclohexyl) carbamate

In a sealed tube， to a solution of (rac) -tert-butyl N- [ (1R， 3S) -3- [ (2-chloro-5-fluoro-pyrimidin-4-yl) amino] cyclohexyl] carbamate (Example 1/Step A， 0.92 g， 3.7 mmol) in dioxane (20 mL) was added 5-methyl-1H-pyrazolo [4， 3-b] pyridine (Intermediate A-8， 0.6 g， 4.5 mmol) ， (1S， 2S) -cyclohexane-1， 2-diamine (034 g， 2.96 mmol) ， Cul (0.86 g， 4.5 mmol) and K₃PO₄ (1.57 g， 7.4 mmol) and the resulting reaction mixture was stirred at 120 ℃ for 12 h. After cooling to room temperature， the reaction was quenched by the addition of satd. aq. NH₄Cl solution (100 mL) and extracted with EtOAc (100 mL x 3) . The combined organic extracts were dried over anhy. Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was then purified by Prep-HPLC to the title compound (320 mg， 19.6％yield) as a white solid. MS： 442.3 [M+H] ⁺.

[B] (rac) - (1S， 3R) -N1- (5-fluoro-2- (5-methyl-1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4- yl) cyclohexane-1， 3-diamine

To a stirred solution of tert-butyl ( (1R， 3S) -3- ( (5-fluoro-2- (5-methyl-1H-pyrazolo [4， 3-b] pyridine-1-yl) pyrimidin-4-yl) amino) cyclohexyl) carbamate (0.32 g， 0.72 mmol) in EtOAc (10 mL) was added HCl/dioxane (10 mL) at room temperature and stirred for 3 h. After LCMS showed the reaction was completed， the mixture was concentrated in vacuo to give a crude title compound (0.24 g， 96.0％yield) as a grey solid. MS： 342.1 [M+H] ⁺. ¹HNMR (400MHz， DMSO-d6) δ ppm 8.89 (br. s.， 1 H) ， 8.45 (br. s， 1 H) ， 8.37 (br. s.， 3 H) ， 7.77 (br. s.， 1 H) ， 4.12 (br. s.， 1 H) ， 3.22 (br. s.， 1 H) ， 2.70～ 2.82 (m， 3 H) ， 2.24～2.37 (m， 1 H) ， 1.92～2.08 (m， 2 H) ， 1.84 (d， J＝13.05 Hz， 1 H) ， 1.61 (q， J＝11.46 Hz， 1 H) ， 1.40～1.53 (m， 1 H) ， 1.21～1.39 (m， 2H) .

[C] (rac) -N- ( (1R， 3S) -3- ( (5-fluoro-2- (5-methyl-1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4- yl) amino) cyclohexyl) picolinamide

To a stirred solution of (1S， 3R) -N1- (5-fluoro-2- (5-methyl-1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl) cyclohexane-1， 3-diamine (120mg， 0.35 mmol) in MeCN (10mL) was added Et₃N (106.4 mg， 1.05 mmol) ， picolinic acid (51.7 mg0.42 mmol) and HATU (133.1 mg， 0.35 mmol) at room temperature and stirred for 12 h. After LCMS showed the reaction was completed， the reaction mixture was concentrated in vacuo to give a crude product， which was purified by Prep-HPLCto afford the title compound (50 mg， 32％yield) as a yellow solid. MS： 447.2 [M+H] ⁺. ¹H NMR (400MHz， DMSO-d6) δ 8.73 (t， J＝7.65 Hz 2 H) ， 8.64 (d， J＝4.52 Hz， 1 H) ， 8.48 (s， 1 H) ， 8.23 (d， J＝3.01 Hz， 1 H) ， 8.02～8.12 (m， 2 H) ， 7.94～8.02 (m， 1 H) ， 7.57～7.64 (m， 1 H) ， 7.54 (d， J＝8.53 Hz， 1 H) ， 3.90～4.28 (m， 2 H) ， 2.64 (s， 3 H) ， 2.21 (d， J＝11.80 Hz 1 H) ， 1.98 (d， J＝11.54 Hz， 1 H) ， 1.86 (br. s.， 2 H) ， 1.64 (q， J＝11.80 Hz， 1 H) ， 1.27～1.58 (m， 3 H) .

Example 82

(rac) -N- ( (1R， 3S) -3- ( (5-fluoro-2- (5-methyl-1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl) amino) cyclohexyl) morpholine-4-carboxamide

To a stirred solution of (1S， 3R) -N1- (5-fluoro-2- (5-methyl-1H-pyrazolo [4， 3-b] pyridin-1-yl) pyrimidin-4-yl) cyclohexane-1， 3-diamine (Example 81/Step B， 120 mg， 0.35 mmol) in MeCN (10 mL) was added DIPEA (51.2 mg， 0.70 mmol) and morpholine-4-carbonyi chloride (78.5 mg， 0.53 mmol) at room temperature and stirred for 12 h. After LCMS showed the reaction was completed， 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， 12.6％yield) as a white solid. MS： 455.3 [M+H] ⁺. ¹ HNMR (400HMz， DMSO-d6) δ 8.70 (d， J＝8.78 Hz， 1 H) ， 8.47 (s， 1 H) ， 8.22 (d， J＝3.01 Hz， 1 H) ， 8.00 (d， J＝7.78 Hz， 1 H) ， 7.49 (d， J＝8.78 Hz， 1 H) ， 6.38 (d， J＝7.78 Hz， 1 H) ， 4.04～4.11 (m， 1H) ， 3.62～3.72 (m， 1 H) ， 3.49～3.55 (m， 4 H) ， 3.25 (t， J＝4.52 Hz， 4 H) ， 2.62 (s， 3 H) ， 2.14 (d， J＝11.54 Hz， 1 H) ， 1.93 (d， J＝11.29 Hz， 1 H) ， 1.81 (d， J＝10.29 Hz， 2 H) ， 1.29～1.48 (m， 3 H) ， 1.16～1.26 (m， 1 H) .

Example 83

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

To a stirred mixture solution of (-) - (1R， 2S， 3S， 4R) -methyl 3- ( (2- (6-cyano-1H-pyrazolo [4， 3-b] pyridin-1-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (Example 70/Step A， 170 mg， 403 μmol， Example 71) in THF (4mL) and MeOH (2 mL) was added LiOH (48.3 mg， 2.02 mmol) pre-dissoved in water (1mL) . 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 acidified with concentrated HCl to pH 4 and then extracted with ethyl acetate (3 x 40 mL) . The combined organics were dried over anhy. Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purified by Prep-HPLC to afford the title compound (38.7 mg， 21.8％yield) as white foam. MS： 441.1 [M+H] ⁺. ¹HNMR (400 MHz， MeOH-d4) δ 9.65 -9.69 (m， 1 H) 9.21 -9.25 (m， 1 H) 8.55 -8.59 (m， 1 H) 8.08 -8.15 (m， 1 H) 4.98 -5.07 (m， 1 H) 4.03 (s， 3 H) 2.79 -2.84 (m， 1 H) 2.15 -2.21 (m， 1 H) 1.95 -2.03 (m， 2 H) 1.76-1.90 (m， 3 H) 1.42 -1.71 (m， 5 H) .

Example 84

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

The title compound (12 mg， 6.7％yield) was obtained as another product during the synthesis of Example 83 white foam. MS： 426.1 [M+H] ⁺. ¹HNMR (400 MHz， MeOH-d4) δ9.66 (d， J＝1.00 Hz， 1 H) 9.10 -9.14 (m， 1 H) 8.56 (s， 1 H) 8.09 -8.14 (m， 1 H) 5.11 -5.18 (m， 1 H) 2.72 -2.77 (m， 1 H) 2.11 -2.17 (m， 1 H) 1.80 -1.96 (m， 4 H) 1.60 -1.79 (m， 3 H) 1.47 -1.59 (m， 2 H) .

Example 85 (rac) -N- ( (1R， 3S) -3- ( (5-Fluoro-2- (1 H-pyrazolo [3， 4-b] pyrazin-1-yl) pyrimidin-4-yl) amino) cyclohexyl) pyrrolidine-1 -carboxamide

[A] (rac) -tert-Butyl ( (1R， 3S) -3- ( (5-fluoro-2- (1H-pyrazolo [3， 4-b] pyrazin-1-yl) pyrimidin-4- yl) amino) cyclohexyl) carbamate

To a solution of (rac) -tert-butyl N- [ (1R， 3S) -3- [ (2-chloro-5-fluoro-pyrimidin-4-yl) amino] cyclohexyl] carbamate (Example 1/Step A， 610 mg， 2 mmol) in dioxane (10 mL) was added 1H-pyrazolo [3， 4-b] pyrazine (Intermediate A-7， 600 mg， 5 mmol) ， (1R， 2R) -cyclohexane-1， 2-diamine (350 mg， 3 mmol) ， Cul (600 mg， 3.0 mmol) and K₃PO₄ (1.05 g， 5 mmol) . The resuting reaction mixture was stirred at 120 ℃ for 12 h. After cooling to room temperature， the reaction mixture was filtered， and the filtrate was concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (DCM/MeOH ＝50∶1) to afford the title compound (420 mg， 39％yield) as a brown solid. MS： 429.0 [M+H] ⁺.

[B] (rac) - (1S， 3R) -N1- (5-fluoro-2- (1H-pyrazolo [3， 4-b] pyrazin-1-yl) pyrimidin-4-yl) cyclohexane- 1， 3-diamine

To a stirred solution of (rac) -tert-butyl ( (1R， 3S) -3- ( (5-fluoro-2- (1H-pyrazolo [3， 4-b] pyrazin-1-yl) pyrimidin-4-yl) amino) cyclohexyl) carbamate (150 mg， 0.33 mmol) in DCM (10 mL) was added TFA (1 mL) at room temperature and stirred for 1 h. The reaction mixture was then concentrated in vacuo to give a crude title compound (200 mg) as yellow gum. MS： 329.0 [M+H] ⁺. It was used directly in the next step without further purification.

[E] (rac) -N- ( (1R， 3S) -3- ( (5-fluoro-2- (1H-pyrazolo [3， 4-b] pyrazin-1-yl) pyrimidin-4-yl) amino) - cyclohexyl) pyrrolidine-1 -carboxamide

To a mixture solution of (rac) - (1S， 3R) -N1- (5-fluoro-2- (1H-pyrazolo [3， 4-b] pyrazin-1-yl) pyrimidin-4-yl) cyclohexane-1， 3-diamine (200 mg， 0.25 mmol) in DCM (2.5 mL) was added TEA (0.5 mL) and pyrrolidine-1-carbonyl chloride (66 mg， 0.5 mmol) at room temperature and stirred for 24 h. After LCMS showed the reaction was completed， the mixture solution was concentrated in vacuo to give a crude product， which was then purified by Prep-HPLC to afford the title compound (5.1 mg， 4.2％yield) as a white solid. MS： 426.0 [M+H]⁺ . ¹HNMR (400MHz， MeOH-d4) ： δ8.75 (d， J＝2.0Hz， 1H) 8.71 (d， J＝2.0Hz， 1H) ， 8.56 (s， 1H) ， 8.10 (d， J＝ 3.6 Hz， 1H) ， 4.34-4.30 (m， 1H) ， 3.81-3.77 (m， 1H) ， 2.41-2.39 (m， 1H) ， 2.13-2.08 (m， 1H) ， 1.90-1.86 (m， 6H) ， 1.44-1.23 (m， 4H) .

Example 86

(rac) -N- ( (1R， 3S) -3- ( (5-Fluoro-2- (1H-pyrazolo [3， 4-b] pyrazin-1-yl) pyrimidin-4-yl) amino) cyclohexyl) benzamide

In analogy to the synthesis of Example 85， benzoyl chloride (281 mg， 2 mmol) was used to obtain the title compound (12.2 mg， 9.8％yield) as a white solid. MS： 433.0 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) ： δ 8.76 (d， J＝ 2.4 Hz， 1H) ， 8.71 (d， J ＝ 2.4 Hz， 1H) ， 8.57 (s， 1H) ， 8.11 (d， J ＝ 3.2 Hz， 1H) ， 7.82-7.80 (m， 2H) ， 7.53-7.42 (m， 3H) ， 4.37-4.36 (m， 1H) ， 4.18-4.12 (m， 1H) ， 2.57-2.54 (m， 1H) ， 2.14-1.93 (m， 3H) ， 1.60-1.40 (m， 4H)

Example 87

(rac) -N- ( (1R， 3S) -3- ( (5-Fluoro-2- (1 H-pyrazolo [4， 3-d] pyrimidin-1-yl) pyrimidin-4-yl) amino) cyclohexyl) pyrrolidine-1-carboxamide

[A] (rac) -tert-Butyl ( (1R， 3S) -3- ( (5-fluoro-2- (1H-pyrazolo [4， 3-d] pyrimidin-1-yl) pyrimidin-4- yl) amino) cyclohexyl) carbamate

To a stirred solution of (rac) -tert-butyl N- [ (1R， 3S) -3- [ (2-chloro-5-fluoro-pyrimidin-4-yl) amino] cyclohexyl] carbamate (Example 1/Step A， 1 g， 3 mmol) in dioxane (15 mL) was added 1H-pyrazolo [4， 3-d] pyrimidine (Intermediate A-8， 940 mg， 5 mmol) ， (1R， 2R) -cyclohexane-1， 2-diamine (400 mg， 3.5 mmol) ， Cul (685 mg， 3.5 mmol) and K₃PO₄ (1.1g， 5 mmol) and the resulting reaction mixture was stirred at 120 ℃ for 12 h. After cooling to room temperature， the mixtute solution was filtered to remove salt， and the filtrate was concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (DCM/MeOH＝100∶1 ～40∶1) to give the title compound (150 mg， 8.3％yield) as a yellow solid. MS： 429.0 [M+H] ⁺.

[B] (rac) - (1S， 3R) -N1- (5-fluoro-2- (1H-pyrazolo [4， 3-d] pyrimidin-1-yl) pyrimidin-4- yl) cyclohexane-1， 3-diamine

To a solution of tert-butyl ( (1R， 3S) -3- ( (5-fluoro-2- (1H-pyrazolo [4， 3-d] pyrimidin-1-yl) pyrimidin-4-yl) amino) cyclohexyl) carbamate (250 mg， 0.5 mmol) in DCM (10 mL) was added TFA (1 mL) and the resuting reaction mixture was stirred at room temperature for 1 h. After LCMS showed the reaction was completed， the mixture was concentrated in vacuo to give a crude title compound (200 mg) as yellow oil. MS： 329.0 [M+H] ⁺. It was used directly in the next step without further purification.

[C] (rac) -N- ( (1R， 3S) -3- ( (5-fluoro-2- (1H-pyrazolo [4， 3-d] pyrimidin-1-yl) pyrimidin-4- yl) amino) cyclohexyl) pyrrolidine-1-carboxamide

To a stirred solution of (1S， 3R) -N1- (5-fluoro-2- (1H-pyrazolo [4， 3-d] pyrimidin-1-yl) pyrimidin-4-yl) cyclohexane-1， 3-diamine (200 mg， 0.25 mmol) in DCM (2.5 mL) was added TEA (0.5 mL) and pyrrolidine-1-carbonyl chloride (66 mg， 0.5 mmol) at room temperature and stirred for 12 h. Afterwards， the reaction was concentrated in vacuo to give a crude product， which was purified by Prep-HPLC to afford the title compound (36.8 mg， 30.4％yield) as a white solid. MS： 426.2 [M+H] ⁺. ¹HNMR (400 MHz， DMSO-d6) ： δ 9.96 (s， 1H) ， 9.19 (s， 1H) ， 8.76 (s， 1H) ， 8.27 (d， J＝ 3.6 Hz， 1H) ， 8.13 (d， J＝ 8.0 Hz， 1H) ， 5.86 (d， J＝ 7.6 Hz， 1H) ， 4.11 (d， J＝8.0 Hz， 1H) ， 3.60-3.58 (m， 1H) ， 3.16-3.19 (m， 4H) ， 2.07-1.95 (m， 2H) ， 1.83-1.74 (m， 6H) ， 1.47-1.22 (m， 4H)

Example 88

(rac) -N- ( (1R， 3S) -3- ( (5-Fluoro-2- (1H-pyrazolo [4， 3-c] pyridazin-1-yl) pyrimidin-4-yl) amino) cyclohexyl) pyrrolidine-1-carboxamide

[A] (rac) -tert-Butyl ( (1R， 3S) -3- ( (5-Fluoro-2- (1H-pyrazolo [4， 3-c] pyridazin-1-yl) pyrimidin-4-yl) amino) cyclohexyl) carbamate

In a sealed tube， to a mixture solution of (rac) -tert-butyl N- [ (1R， 3S) -3- [ (2-chloro-5-fluoro-pyrimidin-4-yl) amino] cyclohexyl] carbamate (Example 1/Step A， 517.2 mg， 1.5 mmol) in dioxane (10 mL) was added 1H-pyrazolo [4， 3-c] pyridazine (150 mg， 1.25 mmol) ， (1S， 2S) -cyclohexane-1， 2-diamine (114.2 mg， 1 mmol) ， Cul (285.7 mg， 1.5 mmol) and K₃PO₄ (530.6 mg， 2.5 mmol) . The resulting reaction mixture was stirred at 120 ℃ for 12 h. After TLC (petroleum ether ∶EtOAc ＝ 1∶1) showed the reaction was completed， the reaction was quenched by the addition of satd. aq. NH₄Cl solution (50 mL) and extracted with EtOAc (3 x50.0mL) . The combined organic extracts were dried over anhy. Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was then purified by silica gel flash chromatography (petroleumether∶EtOAc ＝ 1∶1) to give the title compound (125 mg， 23.3％yield) as a red solid. MS： 429.1 [M+H] ⁺.

[B] (rac) - (1S， 3R) -N1- (5-Fluoro-2- (1H-pyrazolo [4， 3-c] pyridazin-1-yl) pyrimidin-4- yl) cyclohexane-1， 3-diamine

To a solution of tert-butyl ( (1R， 3S) -3- ( (5-fluoro-2- (1H-pyrazolo [4， 3-c] pyridazin-1-yl) pyrimidin-4-yl) amino) cyclohexyl) carbamate (250 mg， 0.583 mmol) in DCM (5 mL) was added TFA (5mL) at room temperature and the resulting reaction mixture was stirred for 12 h. Afterwards， the reaction mixture was concentrated in vacuo to give a crude title compound (190 mg， 99.2％yield) as red oil. MS： 329.2 [M+H] ⁺.

[C] (rac) -N- ( (1R， 3S) -3- ( (5-Fluoro-2- (1H-pyrazolo [4， 3-c] pyridazin-1-yl) pyrimidin-4- yl) amino) cyclohexyl) pyrrolidine-1-carboxamide

To a solution of (1S， 3R) -N1- (5-fluoro-2- (1H-pyrazolo [4， 3-c] pyridazin-1-yl) pyrimidin-4 -yl) cyclohexane-1， 3-diamine (180 mg， 0.55 mmol) in MeCN (20.0 mL) was added DIPEA (213.2 mg， 1.65 mmol) and pyrrolidine-1-carbonyl chloride (147 mg， 1.1 mmol) and the resulting reaction mixture was stirred at 50 ℃ for 12 h. After TLC (DCM∶MeOH＝10∶1) showed the reaction was completed， the mixture solution was concentrated in vacuo to give a crude product， which was purified by Prep-HPLC to afford the title compound (25 mg， 19.2％yield) as a yellow solid. MS： 426.2 [M+H] ⁺. ¹HNMR (400MHz， MeOH-d4) δ 9.52 (d， J＝6.27 Hz， 1 H) ， 9.09 (s， 1 H) ， 8.91 (d， J＝6.27 Hz， 1 H) ， 8.16 (d， J＝2.76 Hz， 1 H) ， 4.19～4.31 (m， 1 H) ， 3.84～3.95 (m， 1 H) ， 3.31 (br. s.， 3 H) ， 2.45 (d， J＝12.05 Hz， 1 H) ， 2.10 (d， J＝12.30 Hz， 1 H) ， 1.88～2.02 (m， 7 H) ， 1.64 (q， J＝13.22 Hz， 1 H) ， 1.33～1.50 (m， 3 H)

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

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 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^＊＊， -SR^＊＊， -S (O) R^＊＊， -S (O) ₂R^＊＊， - (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， benzyl， 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) ；

R³ is selected from the group consisting of -H， -halogen， -CN， -NO₂， -C (O) R^＊＊， -COOR^＊＊， -C (O) NR^＊＊R^＊＊， -OR^＊＊， -SR^＊＊， -S (O) R^＊＊， -S (O) ₂R^＊＊， - (optionally substituted C_1-6 alkyl) ， - (optionally substituted C_3-6 cycloalkyl) ， - (optionally substituted C_1-4 alkylene) - (optionally substituted heterocyclyl) ， 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， benzyl， 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) ；

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) - (optionaily 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) ；

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) ， - (optionally substituted carbocyclyl) ， wherein R^＊＊ is H， - (optionally substituted C_1-6 alkyl) ， - (optionally substituted heterocyclyl) ， or - (optionally substituted carbocyclyl) ， wherein the - (optionally substituted) may be halogen；

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；

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；

R¹¹ is independently selected from the group consisting of -H， -CN， -NO₂， -OH， -NH₂， - (optionally substituted C_1-6 alkyll) ， -NR^＊R^＊， and -OR^＊， wherein R^＊ is -H， or - (optionally substituted C_1-6 alkyl) and wherein the - (optionally substituted) may be halogen；

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

X³ is selected from the group consisting of N and CR⁸；

X⁴ is selected from the group consisting of N and CR¹¹；

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；

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 satu rated monocyclic heterocyclic ring having 4 to 7 ring carbon atoms and 1 or 2 heteroatoms in the ring， 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 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；

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

L^a is selected from the group cons isting 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) - (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 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； and

p is 0 to 6；

with the proviso that the following compounds are disclaimed：

cyclohexyl- (2-indazol-1-yl-pyrimidin-4-yl) -amine；

cyclohexyl- (2-indazol-1-yl-6-methyl-pyrimidin-4-yl) -amine；
The compound according to claim 1， wherein R² is selected from the group consisting of -H and C_1-6 alkyl， and R³ is selected from the group consisting of -H， -halogen， -CN， -NO₂ and -C_1-6 alkyl.
The compound according to claim 2， wherein R² is -H and/or R³ is -halogen.
The compound according to any of the preceding claims， wherein the ring A is selected from the group consisting of

wherein each W is independently selected from C， N， O and S， 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 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 R⁷ is -H.
The compound according to any of the preceding claims， wherein L^b 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 the preceding claims， wherein R^5b 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 L^b is -N (R⁷) -C (O) -and R^5b is - (optionally substituted heterocyclyl) or - (optionally substituted carbocyclyl) ， wherein the optional substituent of the- (optionally substituted heterocyclyl) and - (optionally substituted carbocyclyl) can be halogen， CN， CF₃， CHF₂， CH₂F， OCF₃， OCHF₂， OCH₂F， OH or NH₂.
The compound according to any of the preceding claims， wherein X⁴ and/or X⁸ is N.
A pharmaceutical composition comprising：

a compound having the formula (I) as defined in any of claims 1 to 10， 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 10， 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；

wherein the compounds disclaimed in claim 1 are 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 10， optionally in the form of a pharmaceutically acceptable salt， solvate， polymorph， prodrug， codrug， cocrystal， tautomer， racemate， enantiomer， or diastereomer or mixture thereof；

wherein the compounds disclaimed in claim 1 are disclaimed or not disclaimed.