WO2017133670A1

WO2017133670A1 - Pyridine and pyrimidine derivatives and their use in treatment, amelioration or prevention of influenza

Info

Publication number: WO2017133670A1
Application number: PCT/CN2017/072840
Authority: WO
Inventors: Xuefei Tan; Yongfu Liu; Jun Wu; Katrin Groebke Zbinden; Bernd Kuhn; Guozhi Tang; Guolong Wu; Lisha Wang; Hong Shen; Tianlai SHI; Zongxing Qiu
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 (l) ， optionally in the form of a pharmaceutically acceptable salt， solvate， polymorph， prodrug， codrug， cocrystal， tautomer， racemate， enantiomer， or diastereomer or mixture thereof，

which is useful in treating， ameloriating or preventing influenza.

Background of the invention

Influenza viruses belong to the Orthomyxoviridae family of RNA viruses. Based on antigenic differences of viral nucleocapsid and matrix proteins， influenza viruses are further divided into three types named influenza A， B， and C viruses. All influenza viruses have an envelope， and their genomes are composed of eight or seven single-stranded， negative-sensed RNA segments. These viruses cause respiratory diseases in humans and animals with a significant morbidity and mortality. The influenza pandemic of 1918， Spanish flu， is thought to have killed up to 100 million people. The reassortment of avian flu RNA fragments with circulating human viruses caused the other two pandemics in 1957 H2N2 ″Asian influenza″ and 1968 H3N2 ″Hong Kong influenza″ . Now， people around the world face the challenges of influenza from various angles： seasonal influenza epidemics affect about 5-15％of the world′spopulation 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 reiativeiy 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 structurai data include zanamivir (Glaxo) and oseltamivir (Rcche) . However， although these medicaments maylead to a reduction of the duration of the disease， there remains an urgent need for improved medicaments which may also be used for cuhng these diseases.

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

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

Influenza viruses being Orthomyxoviridae， as described above， are negative-sense ssRNA viruses. Other examples of viruses of this group include Arenaviridae， Bunyaviridae， Ophioviridae， Deltavirus， Bornaviridae， Filoviridae， Paramyxoviridae， Rhabdoviridae and Nyamiviridae. These viruses use negative-sense RNA as their genetic material. Single-stranded RNA viruses are classified as positive or negative depending on the sense or polanty of the RNA. Before transcnption， the action of an RNA polymerase is necessary to produce posltive RNA fromthe 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 replicativemachinery 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) repiication intermediate， a fuii-iength 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 Th s 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 nuc eoprotein 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 v ral mRNAs is thus a promising starting points for developing new classes of compounds which may be used in order to treat influenza (Fodor， Acta virologica 2013， 57， 113-122) This finding is augmented by the fact that the polymerase complex contains a number of functional active sites which are expected to differ to a considerable degree from functional sites present in proteins of cells functioning as hosts for the virus (Magden et al. ， Appl. Microbiol. Biotechnol. 2005， 66， 612-621) . As one example， a substituted 2.6-diketopiperazine has been identified which selectively inhibits the cap-dependent transcriptase of influenza A and B viruses without having an effect on the activities of other polymerases (Tomassini et al .， Antimicrob. Agents Chemother. 1996， 40， 1189-1193). In addition， it has been reported that phosphorylated 2′-deoxy-2′-fluoroguanosine reversibly inhibits influenza virus replication in chick embryo cells. While primary and secondary transcrlption of influenza virus RNA were blocked even at low concentrations of the compound，noinhibition of cell protein synthesis was observed even at high com pound concentrations (Tisdale et al. ， Antimicrob. Agents Chemother. 1995， 39， 2454-2458) .

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

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

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 embod ment， the present invention prov. des a compound having the formula (I) .

It is understood that throughout the present specification the term ″acompound having the formula (l) ″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 ″Amultilingual 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′sspecifications， 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 bicyciic 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 ″heterocyciyl″ covers any mono-， bi- or polycyciic 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， pyrazoie， oxazo d ne， 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 bicyciic 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 C3-6 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 rlng h-aving 5 to 8 ring carbon atoms which does not include heteroatoms in the ring， wiherein tWo carbon atoms of the ring are connected to each other by an alkylene bridge havlng 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 (eg， 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， glycolyiarsanilate， hemisulfate， heptanoate， hexanoate， hexylresorcinate， hydrabamine， hydrobromide， hydrochloride， hydroiodide， 2-hydroxy-ethanesulfonate， hydroxynaphthoate， iodide， isothionate， lactate， iactobionate， laurate， lauryi suifate， malate， maleate， maionate， 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 thhe 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-propanoiates.

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

The term ″cocrystal″refers to a multiple component crystal in which all components are solid under ambient conditions when in their pure form. These components co-exist as a stoichiometric or non-stoichometric ratio of a target molecule or ion (ie， compound of the present invention) and one or more neutral molecular cocrystal formers A detailed discussion can be found， for example， in Nih9 Shah et al. ， Drug Discovery Today， 13 (9/10) ， 2008， 440-446 and in D. J. Good et al. ， Cryst Growth Des. ， 9 (5) ， 2009， 2252-2264.

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

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

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

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

Thiol functionalities can be converted into thioesters or thioethers.

Amino functionalities can be converted into amides， carbamates， N-mannich bases， oximes， imines or phosphates. The phosphates may also be attached via C_1-4-alkyienegiycol 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

is a single or double bond；

R¹ is selected from the group consisting of-H， -halogen， -CN， -C(O)R^＊＊， -COOR^＊＊， -C (O) NR^＊＊R^＊＊，-NR^＊＊R^＊＊，-NR^＊＊-C (O) R^＊＊，-N (R^＊＊) -C (O) -OR^＊＊，-N (R^＊＊) -C (O) -NR^＊＊R^＊＊，-N (R^＊＊) -S (O) ₂R^＊＊，- (optionally substituted C_1-6 aikyl) ， -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) ， whereln 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. ln the case of- (optionally substituted heterocyclyl) or- (optionally substituted carbocyclyl) the- (optionaiiy substituted) canl be any of the aforementioned substituents or can be C_1-6 alkyl. Preferably R¹ is selected from the g roup consisting of-H， -halogen，-CN，- (optionally substituted C_1-6 alkyl)，- (optionally substituted C_3-6 cycloalkyl， and-OR^＊＊， whereln 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， -cyciopropyi， -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) ， -OR^＊＊， -SR^＊＊， -S (O) R^＊＊， -S (O) ₂R^＊＊， - (optionally substituted heterocyclyl) ，- (optionally substituted C_1-4 alkyiene) - (optionally substituted heterocyclyl) ， - (optionally substituted carbocyclyl) ， and- (optionally substituted C_1-4 alkylene) - (optionally substituted carbocyclyl) ， whereln R^＊＊is H， - (optionally substituted C_1-6 alkyl) ， - (optionally substituted heterocyclyl) ， or- (optionally substituted carbocyclyl) . The- (optionally substltuted) 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. Inthe case of- (optionaliy 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^＊＊， - (optionaliy substituted C_1-6 alkyl) ， -OR^＊＊， - (optionally substituted heterocyclyl) ， -(optionally substituted C_1-4 alkylene) - (optionally substituted heterocyclyl) ， - (optionally substituted carbocyclyl) ， and - (optionally substituted C_1-4 alkylene) - (optionally substituted carbocyclyl) ， wherein R^＊＊ is H， - (optionally substituted C_1-6 alkyl)， - (optionally substituted heterocyclyl) ， or- (optionally substituted carbocyclyl) . The - (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) ， -(optionaily substituted C_1-4 aikylene) - (optionally substituted heterocyclyi) ， - (optionally substituted C_1-4 alkylene) - (optiornally substituted carbocyclyl) ， wherem R^＊＊i s 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) (ORw^＊＊) ₂，or-O-P (O) (OR^＊＊＊) ₂. In the case of- (optionally substituted heterocyclyl) or- (optionally substituted caibocyclyl) the- (optionally substituted) can be any of the aforementioned substituents or can be C_1-6 alkyl. R^＊＊＊ is H， C_1-6 alkyi， 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 heterocyciyl) ， 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. ln 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) ， 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-N R^＊＊＊R^＊＊＊， -P (O) (OR^＊＊＊) 2_， or -O-P (O) (OR^＊＊＊) ₂. in the case of- (optionally substituted heterocyclyi) 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 carbocyciyl) 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， 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 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 aikyl) ， - (optionally substituted heterocyclyl) ， - (optionally substituted carbocyclyl) ， - (optionally substituted C_1-4 alkylene) - (optionally substituted heterocyclyl) and - (optionally substituted C_1-4 alkylene) - (optionally substituted carbocyclyl) ， wherein R^＊ is - (optionally substituted C_1-6 alkyl) ， - (optionally substituted heterocyclyl) ， or- (optionally substituted carbocyciyl) . 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 - (optionaliy 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 cycloaikyi. 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 R⁸is-H.

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

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

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

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

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

any compound containing the tautomer thereof having the following partial structure

is also comprised.

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

X³″ is ″X²-X³″， then X³is NR⁹. In another embodiment， if X²

X³″is ″X²＝X³″then X³ is CR⁹ .

X⁴ is selected from the group consisting of C-Hal， wherein Hal may be any halogen isotope. In a preferred embodiment， X⁴ is C-F.

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， -CH₂ CH₃， -CH (CH₃) ₂， -cyclopropyl， -CF₃， -CHF₂， and-CH₂F..

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

The above definitions apply with the proviso that X¹

X²

X³ is X¹ -X² ＝ X³ if X¹ is N and X¹

X²

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

X⁸ is selected from the group consisting of N and CR¹⁰ . In one embodiment， X⁸ is N. In another embodiment， X⁸ is C R¹⁰ .

T is selected from the group consisting of

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

-L-R⁵ is seIected 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 to4 heteroatoms independently selected from N， O and S. Specific examples of substituted heterocycly lenes 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 contaiing 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 carbocyciyi) ， more preferably R^5b is selected from the group consisting of-H， -C_1-6 alkyl， - (optionally substituted heterocyclyl) ， and- (optionaliy 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：

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

Preferably，

is selected from the group consisting of

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

More preferably，

is selected from

wherein each X⁶ is CR¹. Preferably， R¹ is selected from

-H， -halogen， -CN， -CH₃， -CH₂CH₃， -CH (CH₃) ₂， -cyclopropyl， -CF₃， -CHF₂，and-CH₂F.

In these examples of

R⁶ is preferably the same as R⁹.

It is to be understood that in any examples of

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

Generic Synthesis / Assay Description

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

Scheme A

G¹ is halogen or boronic ester； G² is halogen or trialkylstannane；

Azaindole or azaindazole compounds 1 with G¹＝halogen (preferabiy iodme) are known. They can be prepared by methods described in the exemplary synthesis of intermediates A or by methods known to a person skilled in the art. If desired， the amine group of the compounds 1 can be protected by an amine protecting group， PG. Any known amine protecting group such as THP， SEM， Ts， or Boc can be employed.

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

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

Scheme B

In another embodiment which illustrated in Scheme C， the compounds of formula (lb) can be prepared by a method via reaction of 4-halogen substituted indole/azaindole or indazole/azaindazole compound 8 with a suitable heteroaryl halide， compound 2 (G² ＝ halogen， bromine and chlorine preferred) in a solvent like dioxane， in the presence of a catalyst like Cul， a ligand like (1R， 2S) -cyclohexane-1， 2-dioamine， and a base like potassium phosphate at elevated temperature about 120 ℃ to give a Ullman couping reaction product， compound (lc) (step h) . The definitions of structural formula (lb) and compounds 2 and 8 are independently as defined in any of the embodiments described above. Specific conditions are described in the Examples Section below.

Scheme C

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， potyol， 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 eontainer， 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 s 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

TIPSCl： 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： trifluoromethanesulfonic anhydride

SEM： 2- (trimethylsilyl) ethoxymethyl

SEMCl： 2- (trimethylsilyl) ethoxymethyl chloride

Pd₂ (dba) ₃： tris (dibenzylideneacetone) dipalladium

General Experimental Conditions

Intermediates and final compounds were purified by flash chromatography using one of the following instruments： i) Biotage SP1 system and the Quad 12/25 Cartridge module. ii) ISCO combi-flash chromatography instrument. Silica gel Brand and pore size： i) KP-SIL 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. mc15g01s3) and contains the extremely bright luciferase variant， NanoLuc (Promega) ， which has been appended to the C-terminus of the polymerase subunit， PA. The reporter virus replicates with near native properties both in cell culture and in vivo. Thus， NanoLuc luciferase activity can be used as a readout of viral infection.

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

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

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

Virus and cell culture methods

A/WSN/33 influenza virus containing the NanoLuc reporter construct was obtained from the laboratory of Andrew Mehle (University of Wisconsin) . A549 human lung carcinoma cells were purchased (ATCC) . All studies were performed with A549 cells cultured in complete DMEM. Influenza virus stocks were propagated in MDBK cells (ATCC) using standard methods (Szretter KJ， Balish AL， Katz JM. Curr Protoc Microbiol. Influenza： propagation， quantification， and storage. 2006 Dec； Chapter 15： Unit 15G. 1. doi： 10. 1002/0471729256. mc15g01s3) ， and stocks frozen at -80℃. Viral infections were carried out using DMEM Glutamax supplemented with 0.3％BSA (Sigma) ， 25mM Hepes (Sigma) ， and 1X penicillin/streptomycin (Invitrogen) .

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

Preparation of virus lysate containing native influenza vRNP complex

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

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

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

Material and methods for Filter RNP transcription assay：

Virus lysate (H1N1 Influenza strain A/PR/8/34， Charles River， Cat #10100374； Influenza B\Lee\40， Charles River， Cat# 10100379) was pre-incubated with compounds for 30 min at 30℃ in the reaction buffer containing 24 mM HEPES (pH 7.5) ， 118 mM NaOAC， 1 mM Mg (OAC) ₂， 0.1 mM Mn (OAC) ₂， 0.1 mM EDTA， 2 mM DTT， 0.3 U RNase inhibitor (Riboguard) ， 70 mM ATP/CTP/UTP， 14 mM GTP and 0.175 μCi ³³P-GTP. Then capped RNA substrate was added to the reaction at 0.07 uM (5’ m⁷G-ppp-GAA UAC UCA AGC UAU GCA UC-3′， 5’ -triphosphorylated RNA was purchased from Fidelity Systems and the capping reaction was performed using the ScriptCap Capping System from CellScript) . The Cap-snatching and subsequent mRNA synthesis reactions were performed for 90 min at 30℃ before the reactions were terminated by EDTA addition. Synthesized mRNA products were precipitated on the filter plate (Millipore) using 20％TCA at 4 ℃ for 35 min and followed by three times wash with 10％TCA and 1 time with 70％ethanol on the vacuum manifold system (Millipore) . After complete dry of the filter plate， Microsint 20 solution was added to the wells and scintillation counting was performed on the TopCount equipment for 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， itis possible to inhibit replication by either directly blocking the polymerase active site of PB1 or by preventing the conformational changes of RNP that is required for the realignment of polymerase complex on the vRNA template. Therefore this assay is able to determine IC50 values of replication inhibitors.

Material and methods for replication assay：

The concentrations refer to final concentrations unless mentioned otherwise. Cap-binding inhibitors were serially diluted 4 fold in 40％DMSO and 2ul of diluted compound was added to 17 ul reaction mix containing 0.35 nM vRNP enzyme， 20 mM HEPES (pH 7 5) ， 100 mM NaOAC， 1 mM Mg (OAC) ₂， 0 1 mM Mn (OAC) ₂， 0.1 mM EDTA， 2 mM DTT， 0.25 U RNase inhibitor (Epicentre) ， 70 uM ATP/CTP/UTP， 1.4 uM GTP and 0.175 μCi ³³P-GTP for 30 minutes at 30℃. pppApG dinucleotide was added to the reaction at 75 uM as final concentration. Reactions were performed for 3 hours at 30℃ and then stopped by adding EDTA to a final concentration of 56 mM. Synthesized cRNA products from the replication reaction were precipitated on the filter plate (Millipore) using 20％TCA at 4 ℃ for 35 minutes and followed by three times wash with 10％TCA and 1 time with 70％ethanol on the vacuum manifold system (Millipore) . After complete air dry of the filter plate， Microsint 20 solution was added to the wells and scintillation counting was performed on the TopCount equipment for 1 min/well. Dose-response curves were analyzed using 4-parameter curve fitting methods. The concentration of test compound resulting in 50％ inhibition to that of the control wells were reported as IC50.

Results Obtained For The Examples Using The Bio-Assays

Table 1.

Table 2.

Intermediate A-1

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

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

Intermediate A-2a

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

[A] 5， 7-Difluoro-1H-indazol-3-amine

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

[B] 5， 7-Difluoro-3-iodo-1H-indazole

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

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

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

Intermediate A-2b

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

A mixture solution of 5， 7-difluoro-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (2 g， 5.5 mmol) ， Sn₂Bu₆ (4.8 g， 8.3 mmol) and Pd (PPh₃) ₄ (634 mg， 0.55mmol) in dioxane (20 mL) was stirred at 120 ℃ for 3 h. After cooling to the room temperature， the solvent was removed under reduced pressure and the crude product was then purified by silica gel flash chromatography (petroleum ether∶EtOAc ＝20∶1) to afford the title compound (1.1 g， 38 ％) as colorless oil.

Intermediate A-3a

5-Chloro-7-fluoro-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole

[A] 5-Bromo-2， 3-difluorobenzaldehyde

To a stirring solution of 2， 3-difluorobenzaldehyde (35 g， 246 mmol) in H₂SO₄ (100 mL) was added NBS (60 g， 337 mmol) in portions at 50 ℃. After the addition， the reaction mixture was stirred at 60 ℃ for 12 h After cooling to room temperature， the reaction was quenched with ice-water (800 mL) and extracted with EtOAc (800 mL three times) . The combined organic layers were then washed with satd. aq. NaHCO₃ solution (200mL twice) ， and the organic layer was dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (petroleum ether ∶EtOAc ＝ 100∶1～10∶1) to afford the title compound (30 g， 55.2％yield) as yellow oil.

[B] (E) -5-Bromo-2， 3-difluorobenzaldehyde O-methyi oxime

To a solution of 5-bromo-2， 3-difiuorobenzaldehyde (30 g， 135 mmol) in DME (100 mL) was added NH₂OMe. HCl (12.7 g， 152 mmol) and K₂CO₃ (22.2 g， 160 mmol) and the resulting mixture was stirred at 60 ℃ for 12 h. After TLC (petroleum ether∶EtOAc ＝ 5∶1) showed the consumption of the starting material， the solvent was removed under reduced pressure to give a crude product， which waspurified by silica gel flash chromatography (petroleum ether∶EtOAc＝500∶1～20∶1) to afford the title compound (15 g， 44.5％yield) as a white solid. MS： 250.1， 252.1 [M+H] ⁺. ¹H NMR (400MHz， CHCl₃-d1) δ 8.21 (s， 1H) ， 7.76-7.75 (m， 1H) ， 7.35-7.30 (m， 1H) ， 4.02 (s， 1H) .

[C] 5-Bromo-7-fluoro-1H-indazole

To a solution of (E) -5-bromo-2， 3-difluorobenzaldehyde O-methyl oxime (15 g， 60 mmol) in THF (60 mL) was added NH₂NH₂ (60 mL， 1170 mmol) and the reaction mixture was stirred at 90 ℃ for 48 h. After TLC (petroleum ether∶EtOAc ＝ 3∶1) showed the complete consumption of starting material， the solvent was removed under reduced pressure， The residue was re-dissolved in EtOAe (1 00 mL) and washed with water (50 mL twice) . The orgamc layer was then dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was recrystallizad from EtOAc to afford the title compound (6 g， 46.5 ％yield) as a white solid. MS： 213.1&215.1 [M+H] ⁺.

[D] 5-Bromo-7-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole

To a stirred solution of 5-bromo-7-fluoro-1H-indazole (6 g， 27.9 mmol) and 3， 4-dihydro-2H-pyran (2.82 g， 33.5 mmol) in DCM (100 mL) was added TsOH (2 g， 11.2 mmol) at room temperature and stirred for 2 h. The reaction mixture was neutralized with satd. aq. NaHCO₃ solution (100 mL) and extracted with EtOAc (200 mL three times) . The combined organic layers were dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purified by silica gai flash chromatography (petroleum ether∶EtOAc＝20∶1～5∶1) to afford title compound (8 g， 76.9％yield) as a white solid. ¹H NMR (400MHz， CHCl₃-d1) δ 8.00-7.99 (m， 1H) ， 7.65 (s， 1H) ， 7.24-7.22 (m， 1H) ， 5.87-5.84 (m， 1H) ， 4.07-4.04 (m， 1H) ， 3.78-3.73 (m， 1H) ， 2.60-2.57 (m， 1H) ， 2.17-2.09 (m， 2H) ， 1.79-1.74 (m， 2H) ， 1.63-1.55 (m， 1H) .

[E] 5-Chloro-7-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole

To a mixture solution of 5-bromo-7-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H--indazole (3 g， 10 mmol) ， Cu₂O (0.29 g， 2 mmol) and s-proline (0.46 g， 4 mmol) in n-BuOH (10 mL) was added Me₄NCl (2.2 g， 20 mmol) . The resulting reaction mixture was stirred at 150℃ for 2 h under microwave heating. After cooling to room temperature， the soiution was diluted with EtOAc (150 mL) and washed with brine (50 mL twice) . The organic layer was dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purified by Prep-HPLC to afford the title compound (1g， 39.7％yield) as a white solid.

[F] 5-Chloro-7-fluoro-1H-indazole

To a stirred solution of 5-chloro-7-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (3.56 g， 14 mmol) in DCM (100 mL) was added TFA (31.9 g， 280 mmol) in portions. After the addition， the reaction mixture was stirred at room temperature for 12 h. After TLC showed the complete consumption of starting material， the reaction mixture was concentrated in vacuo. The residue was re-dissolved in EtOAc (200 mL) and washed with satd. aq. NaHCO₃ solution (100 mL) and water. The organic layer was dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， whcih was purified by silica gel flash chromatography (petroleum ether∶EtOAc＝20∶1～1∶1) to afford the title compound (2.1 g， 88.2％yield) as a white solid.

[G] 5-Chloro-7-fluoro-3-iodo-1H-indazole

To a stirred solution of 5-chloro-7-fluoro-1H-indazole (2.1 g， 12.3 mmol) and KOH (2.76 g， 49.2 mmol) in DMF (70 mL) was added I₂ (6.24 g， 24.6 mmol) in portions and after the addition， the mixture was stirred at room temperature for 12 h. The reaction was quenched with aq. Na₂SO₃ solution (100 mL) ， acidified with 1 N HCl to pH＝7 and extracted with EtOAc (500 mL three times) . The combined organic layers were dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (petroleum ether∶EtOAc ＝ 10∶1～1∶1) to afford title compound (3.1 g， 85.1％yield) as a white solid. MS： 297.0 [M+H] ⁺. ¹H NMR (400MHz， CHCl₃-d1) δ7.525-7.520 (m， 1H) ， 7.49 (s， 1H) ， 7.36 (s， 1H) .

[H] 5-Chloro-7-fluoro-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole

To a solution of 5-chloro-7-fluoro-3-iodo-1H-indazole (9g， 30 mmol) and 3， 4-dihydro-2H-pyran (3 g， 36 mmol) in DCM (80 mL) was added TsOH (2.06 g， 12 mmol) in portions， and the resulting mixture solution was stirred at room temperature for 12 h. After TLC showed the complete consumption of starting material， the solution was neutralized with satd. aq. NaHCO₃ solution (100 mL) and extracted with EtOAc (200 mL three times) . The combined organic layers were dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was then purified by silica gel flash chromatography (petroleum ether∶EtOAc＝20∶1～5∶1) to afford the title compound (9.8 g， 85.9％yield) as a white solid. ¹H NMR (400MHz， CHCl₃-d1) δ 7.30-7.28 (m， 1H) ， 7.21-7.18 (m， 1H) ， 5.83 (t， 1H) ， 4.07-4.05 (m， 1H) ， 3.74 (t， 1H) ， 2.61-2.58 (m， 1H) ， 2.18-2.09 (m， 2H) ， 1.78-1.74 (m， 2H) ， 1.64-1.62 (m， 1H) .

Intermediate A-3b

5-Chloro-7-fluoro-1- (tetrahydro-2H-pyran-2-yl) -3- (tributylstannyl) -1H-indazole

To a stirred solution of 5-chloro-7-fluoro-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (500 mg， 1.3 mmol) and Sn₂Bu₆ (930 mg， 1.6 mmol) in dioxane (30 mL) was added Pd (PPh₃) ₄ (150 mg， 0.13 mmol) and the mixture solution was stirred at 140 ℃ for 6 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 (petroleum ether∶DCM ＝ 50∶1) to afford the title compound (350 mg， 50％yield) as colorless oil. MS： 545.3 {M+H) ⁺.

Intermediate A-4a

7-Fluoro-3-iodo-1-tetrahydropyran-2-yl-indazole-5-carbonitrile

[A] 7-Fluoro-1H-indazole-5-carbonitrile

To a soiution of 5-bromo-7-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (7.2 g， 24.0 mmol) and Pd (PPh₃) ₄ (2.7 g， 2.4 mmol) in DMF (50 mL) was added Zn (CN) ₂ (5.6 g， 48 mmol) in one portion and the reaction mixture was stirred at 120 ℃ for 12 h. After cooling to room temperature， the reaction mixture was filtered， and the filtrate was quenched with water (200 mL) and extracted with EtOAc (500 mL three times) . The combined organic layers were dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give acrude product， which was purified by silica gel flash chromatography (petroleum ether∶ EtOAc＝10∶1～1∶1 then DCM∶MeOH＝100∶1～10∶1) to afford title compound (1.3 g， 34.2％yield) as a white solid. MS： 162.2 [M+H] ⁺.

[B] 7-Fluoro-3-iodo-1H-indazole-5-carbonitrile

To a stirred solution of 7-fluoro-1H-indazole-5-carbonitrile (1.28 g， 8 mmol) and KOH (1.8 g， 32 mmol) in DMF (20 mL) was added I₂ (4 g， 16.0 mmol) in portions， and after the addition， the reaction mixture was stirred at room temperature for 12 h. After TLC showed the compiete consumption of starting material， the reaction was quenched with aq. Na₂SO₃ solution (200 mL) ， acidified with 1 N HCI to pH ＝ 7， and extracted with EtOAc (300 mL three times) . The combined organic layers were dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was then purified by silica gel flash chromatography (petroieum ether∶EtOAc ＝ 10∶1～1∶1) to afford title compound (2 g， 89.3％yield) as a yellow solid. ¹H NMR (300MHz， CHCl₃-d1) δ 14.63 (s， 1H) ， 7.98 (s， 1H) ， 7.85-7.82 (d， 1H， J＝10.8Hz) .

[C] 7-Fluoro-3-iodo-1-tetrahydropyran-2-yl-indazole-5-carbonitrile

To a stirred mixture solution of 7-fluoro-3-iodo-1H-indazole-5-carbonitrile (2 g， 6.97 mmol) and DHP (4.69 g， 5.1 mL， 55.7 mmol) in toluene (150 mL) was added 2， 2， 2-trifluoroacetic acid (159 mg， 1.39 mmol) at room temperature and the resulting reaction mixture solution was heated at 100℃ for 12 h. After cooling to room temperature， the reaction mixture was poured into water (20 mL) and extracted with EtOAc (50 mL twice) . The combined organic layers were washed with brine， dried over anhydrous Na₂SO₄， filtered and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (0-30％EtOAc-hexane gradient) to afford the title compound (1.6 g， 61.9％yield) as a white solid. MS∶ 372.1 [M+H] ⁺.

Intermediate A-4b

7-Fluoro-1- (tetrahydro-2H-pyran-2-yl) -3- (tributylstannyl) -1 H-indazole-5-carbonitrile

To a stirred solution of 7-fluoro-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole-5-carbonitrile (0.4 g， 1.08 mmol) in dioxane (10 mL) was added Bu₆Sn₂ (1.13 g， 1.94 mmol) and Pd (PPh₃) ₄ (0.12 g， 0.1 mmol) and the resulting reaction mixture was stirred at 100 ℃for 3 h. After cooling to room temperature， the reaction was quenched by the addition of satd aq. NH₄Cl solution (50 mL) and extracted with EtOAc (50 mL three times) . The combined organic extracts were concentrated in vacuo and the residule was purified by silica gel flash chromatography (peterolium ether ∶EtOAc ＝ 100∶1) to afford the title compound (0.4 g， 51.7％yield) as light yellow oil. MS： 536.3 [M+H]⁺. ¹H NMR (400 MHz， CHCl₃-d1) δ 0.93 (t， J＝7.28 Hz， 9 H) ， 1.28～1.42 (m， 10 H) ， 1.57～1.70 (m， 9 H) ， 1.79 (t， J＝10.16 Hz， 2 H) ， 2.09～2.19 (m， 1 H) ， 2.20～2.30 (m， 1 H) ， 2.63～2.77 (m， 1 H) ， 3.75～3.83 (m， 1 H) ， 4.05 (d， J＝10.04 Hz， 1 H) ， 5.96 (dd， J＝9.29， 2.51 Hz， 1 H) ， 7.30 (s， 1 H) ， 7.83 (s， 1 H) .

Intermediate A-5

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

[A] 4-Chloro-5-fluoronicotinaldehyde

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

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

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

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

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

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

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

Intermediate A-6a

7-Chloro-3-iodo-1-tetrahydropyran-2-yl-indazole

[A] 7-Chloro-3-iodo-1H-indazole

To a stirred solution of 7-chloro-1H-indazole (3.5 g， 23.0 mmol) and KOH (3.2 g， 57.6 mmol) in DMF (50 mL) was added I₂ (14.6 g， 57.6 mmol) in an ice-water bath. The reaction mixture was allowed to warm up to room temperature and stirred for 0.5 h. After TLC (petroleum ether∶EtOAc ＝ 5∶1) showed the complete comsuption of starting material， the reaction was quenched with satd. aq. NH₄Cl solution and extracted with EtOAc (100 mL) . The organic layer was then washed with water， brine， dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to afford the title compound (5 g， 79.4％yield) as a yellow solid. MS∶279.1 [M+H] ⁺.

[B] 7-Chloro-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole

A mixture solution of 7-chloro-3-iodo-1H-indazole (5 g， 18.0 mmol) ， DHP (7.6 g， 90 mmol) and TsOH. H₂O (310 mg， 1.8 mmol) in THF (50 mL) was stirred at 80℃ for 10 h. After TLC (petroleum ether∶EtOAc ＝ 5∶1) showed the complete comsuption of starting material， the solvent was removed under reduced pressure to give a crude product， which was purified by silica gel flash chromaography (petroleum ether∶EtOAc＝20∶1) to afford the title compound (3.5 g， 54％yield) as a yellow solid. MS： 363.1 [M+H]⁺.

Intermediate A-6b

7-Chloro-1- (tetrahydro-2H-pyran-2-yl) -3- (tributylstannyl) -1H-indazole

A mixture solution of 7-chloro-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (1 g， 2.76 mmol) ， Sn₂Bu₆ (2.4 g， 4.14 mmol) and Pd (PPh₃) ₄ (470 mg， 0.414 mmol) in dioxane (20 mL) was stirred at 11 0℃ for 1 h. After cooling to room temperature， the solvent was removed under reduced pressure to give a crude product， which was purified by silica gel fiash chromatography (petroleum ether∶EtOAc＝50∶1) to afford the title comppund (600 mg， 42％ yield) as colorless oil.

Intermediate A-7a

7-Fluoro-3-iodo-5-methyl-1 - (tetrahydro-2H-pyran-2-yl) -1 H-indazole

[A] 7-Fluoro-5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole

To a solution of 5-bromo-7-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (10 g， 33.3 mmol) and 2， 4， 6-trimethyl-1， 3， 5， 2， 4， 6-trioxatriborinane (5 g， 40 mmol) in DMF (30 mL) was added Pd (PPh₃) ₄ (1.92 g， 1.67 mmol) and K₂CO₃ (13.8 g， 100 mmol) in one portion and the resulting reaction mixture was stirred at 120℃ for 4 h. After cooling to room temperature， the mixtute solution was diluted with EtOAc (300 mL) and washed with brine (100 mL three times) . The orgamc layer was dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to giye a cride product， which was purified by silica gel flash chromatography (petroleum ether∶EtOAc＝20∶1～5∶1) to afford title compound (4.5 g， 57.7％yield) as a white solid. MS： 235.3 [M+H]⁺.

[B] 7-Fluoro-5-methyl-1H-indazole

To astirred solution of 7-fluoro-5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (5.8 g， 24.7 mmol) in DCM (50 mL) was added TFA (28 g， 247 mmol) and the reaction mixture was stirred at room temperature for 12 h. After TLC showed the complete consumption of starting material， the reaction mixture was concentrated in vacuo and the residue was re-dissolved in EtOAc (200 mL) . The organic phase was washed with satd. aq. NaHCO₃ solution (100 mL) dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude title compound (4.5 g) as a white solid. MS： 151.1 [M+H] ⁺.

[C] 7-Fluoro-3-iodo-5-methyl-1H-indazole

To a stirred solution of 7-fluoro-5-methyl-1H-indazole (4.5 g 24.7 mmol) and KOH (5.5 g， 98.8 mmol) in DMF (50 mL) was added I₂ (12.5 g， 49.4 mmol) in portions at room temperature and stirred for 12 h. After TLC showed the complete consumption of the starting matenal， the reaction was quenched with aq. Na₂SO₃ solution (200 mL) ， acidified with 1 N HCl to pH＝7， and extracted with EtOAc (500 mL three times) . The combined orgamc layers were dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude title compound (5.2 g) as a white solid. MS： 277.2 [M+H] ⁺.

[D] 7-Fluoro-3-iodo-5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole

To a stirred solution of 7-fluoro-3-iodo-5-methyl-1H-indazole (5.2 g 15.0 mmol) and 3， 4-dihydro-2H-pyran (1.51 g， 18 mmol) in DCM (60 mL) was added TsOH (1.03 g， 6 mmol) at room temperature and stirred for 3 h. After TLC showed the complete consumption of the starting material， the mixture was neutralized with satd. aq. NaHCO₃ solution (100 mL) and extracted with EtOAc (300 mL three times) . The combined organic layers were dried over anhydrous Na₂SO₄， filtered， and concertrated in vacuo to give a crude product， which was then purified first by silica gel flash chromatography (petroleum ether∶EtOAc＝20∶1～5∶1) and then Prep-HPLC to give title compound (3.2g， 59.2％ yield) as a white solid. MS： 361.2 [M+H] ⁺. ¹HNMR (400MHz， CHCl₃-d1) δ ppm 7.04-7.00 (m， 2H) ， 5.84-5.81 (m， 1H) ， 4.09-4.06 (m， 1H) ， 3.77-3.72 (m， 1H) ， 2.63-2.59 (m，1H) ， 2.47 (s， 3H) ， 2.19-2.11 (m， 2H) ， 1.79-1.76 (m， 2H) ， 1.74-1.62 (m， 1H) .

Intermediate A-7b

7-Fluoro-5-methyl-1- (tetrahydro-2H-pyran-2-yl) -3- (tributylstannyl) -1H-indazole

To a mixture solution of 7-fluoro-3-iodo-5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (1g， 3mmol) and Sn₂Bu₆ (2.1g， 3.6mmol) in dioxane (30mL) was added Pd (PPh₃) ₄ (350mg， 0.3mmol) and the resulting reaction mixture was stirred at 140℃ for 2h. After TLC showed the complete comsuption of the starting material， the mixture solution was concentrated in vacuo. The residule was purifiied by silica gel flash chromatography (petroleum ether∶ DCM ＝ 50∶ 1) to afford the title compound (750mg， 51.7％ yield) as colorless oil.

Example 1

(-) -N- [(1R， 3S) -3- [ [ 5-fluoro-2- (7-fluoro-1H-indazol-3-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 (1 0.5g， 92.2mmol) in THF (100mL) was added 2，4-dichloro-5-fluro-pyrimidine (10g， 60.1mmol) at 0℃. The reaction mixture solution was allowedto warm up to room temperature and srirred 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， (9.33g， 92.2mmol) and di-tert-butyl dicarbonate (20.1g， 92.2mmol) . The resulting mixture solution was stirred at room temperature for 3h before being diluted with DCM (1L) and washed with brine. The organic layer was dried over anhydrous Na₂SO₄， filtered and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (0-80％ EtOAc-hexane gradient) to afford the title compound (600mg， 6.6％ yield) as a white solid. MS： 345.2 [M+H] ⁺.

[B] (-) -tert-Butyl N- [ (1R， 3S) -3- [ [5-fluoro-2- (7-fluoro-1-tetrahydropyran-2-yl-indazol-3- yl) pyrimidin-4-yl] amino] cyclohexyl] carbamate

To a stirred mixture solution of (-) -tert-butyl ( (1R， 3S) -3- ( (2-chloro-5-fluoropyrimidin-4-yl) amino) cyclohexyl) carbamate (220mg， 638μmol) and Pd (PPh₃) ₄ (111mg， 95.7μmol) in dioxane (4mL) was added 1， 1， 1， 2， 2， 2-hexabutyldistannane (502μL， 957μmol) at room temperature. The resulting mixture solution was heated at 125℃ for 2h before it was cooled back to the room temperature follwed by the addition of 7-fluoro-3-iodo-1-(tetrahydro-2H-pyran-2-yl) -1H-indazole (Intermediate A-1， 442mg， 1.28mmol) and Pd (PPh₃) ₄ (111mg， 95.7μmol) in dioxane (16mL) . The resulting reaction mixture solution was then re-heated at 145℃ for 1h under microwave heating. After cooling to room temperature， the reaction mixture was poured into water (20mL) and extracted with EtOAc (2 x 50mL) . The combined orgamc layers were washed with brine， dried over anhydrous Na₂SO₄， filtered and concentrated in vacuo to give a crude product， which was purified by first silica gel flash chromatography (0-100％ petroleum ether / EtOAc) and then chiral SFC purification to afford the title compound (90mg， 27％ yield) as a while solid. MS： 529.2 [M+H] ⁺.

[B] (-) - (1S， 3R) -N1- [5-fluoro-2- (7-fluoro-1H-indazol-3-yl) pyrimidin-4-yl] cyclohexane-1， 3- diamine

A mixture solution of (rac-) -tert-butyl ( (1R， 3S) -3- ( (5-fluoro-2- (7-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) pyrimidin-4-yl) amino) cyclohexyl) carbamate (370mg， 0.7mmol) and acetyl chloride (1.1g， 14mmol) in MeOH (20mL) was stirred at room temperature for 16h before the solvent was evaporated under reduced pressure to afford the crude title compound (330mg， 1 00％ yield) as yellow oil. MS： 345.2 [M+H] ⁺. it was used directly in the next step reaction without further purification.

[C] (-) -N- [ (1R， 3S) -3- [ [5-fluoro-2- (7-fluoro-1H-indazol-3-yl) pyrimidin-4-yl] amino] cyclohexyl] - benzamide

A mixture solution of (-) - (1S， 3R) -N1- (5-fluoro-2- (7-fluoro-1H-indazol-3-yl) pyrimidin-4-yl) cyclohexane-1， 3-diamine hydrochloride (60mg， 158μmol) ， benzoyl chloride(26.6mg， 189μmol)， and N， N-diisopropylethylamine (61.1mg， 473μmol) in DCM (5mL) was stirred at room temperature for 16h before it was washed with stad. aq. NaHCO₃ solution， dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purifed by Prep-HPLC to afford the title compound (10mg， 14％ yield) as white foam. MS： 449.2 [M+H] ⁺. ¹H NMR (400MHz， DMSO-d6) □ ppm 1.27-1.44 (m，2H) 1.45-1.61 (m，2H) 1.82-1.94 (m， 2H) 1.99 (d， J＝10.29Hz， 1H) 2.24 (d， J＝11.29Hz， 1H) 4.06 (br.s.， 1H) 4.27 (br.s.， 1H) 7.14-7.32 (m， 2H) 7.39-7.48 (m， 2H) 7.48-7.55 (m， 1H) 7.77 (d， J＝7.03Hz， 1H) 7.81-7.89 (m， 2H) 8.1 7-8.32 (m， 2H) 8.38 (d， J＝8.28Hz， 1H) 13.57-14.42 (m， 1H)

Example 2

(-) -N- [ (1R， 3S) -3- [ [5-fluoro-2- (7-fluoro-1H-indazol-3-yl) pyrimidin-4-yl] armirno] cyclohexyl] morpholine-4-carboxamide

A mixture solution of (-) - (1S， 3R) -N1- (5-fluoro-2- (7-fluoro-1H-indazol-3-yl) pyrimidin-4-yl) cyclohexane-1，3-diamine hydrochloride (Example 1/Step B， 60mg， 1 58μmol) ， morpholine-4-carbonyl chloride (28.3mg， 189μmol) and N，N-diisopropylethylamine (61.1mg， 473μmol) in DCM (5mL) was stirred at room temperature for 16h before it was washed with satd.aq. NaHCO₃ solution， dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude product，which was purified by Prep-HPLC to afford the title compound (11mg， 14％ yield) as white foam. MS： 458.2 [M+H] ⁺. ¹H NMR (400MHz， DMSO-d6) □ 1.14-1.26 (m， 1H) 1.28-1.53 (m， 3H) 1.82 (d， J＝11.29Hz， 2H) 1.95 (d， J＝1 1.04Hz， 1H) 2.15 (d， J＝12.05Hz， 1H) 3.19-3.27 (m， 4H) 3.47-3.57 (m， 4H) 3.68 (br.s.， 1H) 4.18 (br.s.， 1H) 6.37 (d， J＝7.78Hz， 1H) 7.22 (d， J＝6.53Hz， 2H) 7.71 (br.s.， 1H) 8.17-8.32 (m， 2H)

Example 3

(-) -N- [ (1R， 3S) -3- [ [5-fluoro-2- (7-fluoro-1H-indazol_3-yl) pyrimidin-4-yl] amino] cyclohexyl] pyridine-2-carboxamide

A mixture solution of (-) - (1S， 3R) -N1- (5-fluoro-2- (7-fluoro-1H-indazol-3-yl) pyrimidin-4-yl) cyclohexane-1， 3-diamine hydrochloride (Example 1/Step B， 60mg， 158μmol) ， picolinic acid (23.3mg， 1 89μmol) ， 2- (3H- [1， 2， 3] triazolo [4， 5-b]pyridin-3-yl) -1， 1， 3， 3-tetramethylisouronium hexafluorophosphate (V) (77.9rng， 205μmol) and and N， N-diisopropylethylamine (61.1mg， 473μmol) in DCM (5mL) was stirred at room temperature for 16h before it was washed with satd. aq. NaHCO₃ solution， dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purifed by Prep-HPLC to afford the title compound (9mg， 14％) as white foam. MS： 450.2 [M+H] +. ¹H NMR (400MHz， DMSO-d6) □ □ 1.36-1.58 (m， 3H) 1.65 (q， J＝11.88Hz， 1H) 1.81-1.93 (m， 2H) 1.94-1.94 (m， 1H) 1.99 (d， J＝11.29Hz， 1H) 2.24 (d， J＝11.54Hz， 1H) 4.10 (d， J＝8.28Hz， 1H) 4.27 (br.s.， 1H) 7.15-7.38 (m， 2H) 7.60 (ddd， J＝7.47， 4.83， 1.25Hz， 1H) 7.86-8.08 (m， 3H) 8.26 (d， J＝8.03Hz， 1H) 8.31 (d， J＝3.51Hz， 1H) 8.64 (dd， J＝4.3g， 1.13Hz， 1H) 8.70 (d， J＝8.78Hz， 1H) 14.06 (br.s.，1H)

Example 4

(-) -2-Fluoro-N- [ (1R， 3S) -3- [ [5-fluoro-2- (7-fluoro-1H-indazol-3-yl) pyrimidin-4-yl] amino] cyclohexyl] benzamide

In analogy to the synthesis of Example 3， 2-fluorobenzoic acid (26.5mg， 189μmol) was used to afford the title compound (10mg， 12％ yield) as white foam. MS： 450.2 [M+H] ⁺. ¹H NMR (400MHz， DMSO-d6) □ 1.36-1.58 (m， 3H) 1.65 (q， J＝11.88Hz， 1H) 1.81-1.93 (m， 2H) 1.94-1.94 (m， 1H) 1.99 (d， J＝11.29Hz， 1H) 2.24 (d， J＝11.54Hz， 1H) 4.10 (d， J＝8.28Hz， 1H) 4.27 (br.s.， 1H) 7.15-7.38 (m， 2H) 7.60 (ddd， J＝7.47， 4.83， 1.25Hz， 1H) 7.86-8.08 (m， 3H) 8.26 (d， J＝8.03Hz， 1H) 8.31 (d， J＝3.51Hz， 1H) 8.64 (dd， J＝4.39， 1.13Hz， 1H) 8.70 (d， J＝8.78Hz， 1H) 14.06 (br.s.， 1H)

Example 5

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

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

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

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

To a stirred solution of sodium methoxide (40g， 0.74mol) in MeOH (250mL) was added meso-endo-tetrahydro-4， 7-ethanoisobenzofuran-1， 3-dione (15g， 84.6mmol) portion-wise at 0℃. After the addition， the reaction mixture was allowed to slowly warm up to room temperature and stirred for 60h The solvent was removed under reduced pressure and the residue was poured into 1N HCl solution， and extracted with EtOAc. The organic layer was dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (petroleum ether： EtOAc， 0～100％ gradient) to afford a racemic mixture of title compounds (10g， 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 (89g， 423mmol) ， diphenylphosphoryl azide (151g， 119ml， 550mmol) and Et₃N (60g， 593mmol) in toluene (700mL) was stirred at room temperature for 30min and then at 90℃ for additonal 2hr. Benzyl alcohol (54.9g， 508mmol) was added and the resulting reaction mixture was stirred at 90℃ for 1 6hr. 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 1N aq. NaOH solution (300mL three times) . The organic layer was dried over anhydrous Na₂SO₄， filtered， and then concentrated in vacuo to give a crude product， which was then purified by silica gel column chromatography (EtOAc： peterolium ether＝0 to 20％) to afford the title compound (58g， 43.4％ yield) as yellow oil. MS： 316.1 (M+1) ⁺.

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

A mixture solution of (rac) - (1S， 2S， 3S， 4R) -methyl 3- ( ( (benzyloxy) carbonyl) amino) bicyclo- [2.2.2] oct-5-ene-2-carboxylate (17g， 53.9mmol) and palladium on carbon (1g， 53.9mmol) in MeOH (100mL) was stirred at room temperature under H₂ atmosphere (1atm) for 1 5h. Afterwards， the reaction mixture was filtered and the filtration was concentrated in vacuo to give a crude title compound (10g， 100％ yield) as light yellow oil. MS： 184.1 [M+H] ⁺. This crude product was used directly in the nextstep withoutfurther purification.

[E] (rac) -Methyl (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 (870mg， 5.25mmol) ， (2S， 3S) -methyl 3-aminobicyclo [2.2.2] octane-2-carboxylate (800mg， 4.37mmol) and DlPEA (2g， 15.75mmol) in THF (20mL) was stirred at 80℃ for 10h before the solvent was removed under reduced pressure to give a crude product， which was purified by silica gel flash chromotography (petroleum ether∶EtOAc＝3∶1) to give a racemic mixture of title compound (600mg， 44％ yield) as a yellow solid. MS： 31 4.2 (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] (rac) - (2S， 3S) -methyl3- ( (2- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -5- fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate

A mixture solution of 5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -3- (tributylstannyl) -1H-indazole (Intermediate A-2b， 200mg， 0.39mmol) ， (rac) - (2S， 3S) -methyl 3- ( (2-chloro-5-fluoropyrimidin-4-yl) amino) bicycle [2.2.2] octane-2-carboxylate (178mg， 0.56mmol) ， Pd₂ (dba) ₃ (43mg， 0.059mmol) and Xphos (28mg， 0.059mmol) in dioxane (4mL) was heated at 1 20℃ under microwave heating. After TLC (petroleum ether∶EtOAc＝3∶1) showed all the starting material was consumed， the solvent was removed under reduced pressure to give a crude product， which was purified by silica gel flash chrmotography (petroleum ether∶EtOAc＝5∶1 to 3∶1) to afford the title compound (100mg， 51％ yield) as a yellow solid. MS： 516.3 [M+H] ⁺.

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

A solution of (rac) - (2S， 3S) -methyl 3- ( (2- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (80mg， 0.039mmol) in 4N HCl (2mL) was stirred at 100℃ for 10h before solvent was removed under reduced pressure to give a crude product， which was purified by Prep-HPLC to afford the title compound (18mg， 28％ yield) as a white solid. MS： 41 8.2， [M+H] ⁺. ¹H NMR (400MHz， DMSO-d6) □ 1.34-1.45 (m， 1H) 1.46-1.58 (m， 4H) 1.64 (d， J＝5.77Hz， 1H) 1.71-1.86 (m， 4H) 1.96(br.s.， 1H) 2.04(br.s.， 1H) 2.92 (d， J＝6.90Hz， 2H) 4.78 (t， J＝6.78Hz， 1H) 7.41 (t， J＝9.85Hz， 1H) 8.00 (d， J＝9.29Hz， 1H) 8.17 (br.s.， 1H) 8.35 (d， J＝3.64Hz， 1H) .

Examdle 6

(rac) -N- ( (1R， 3S) -3- ( (2- (5， 7-Difluoro-1H-indazol-3-yl) -5-fluoropyrimidin-4-yi) amino) cyclohexyl) morpholine-4-carboxamide

[A] (rac) -tert-Butyl ( (1R， 3S) -3- ( (2- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) - 5-fluoropyrimidin-4-yl) amino) cyclohexyl) carbamate

A mixture solution of 5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -3- (tributylstannyl) -1H-indazole (lntermediate A-2b， 200mg， 0.38mmol) ， (rac) -tert-butyl N- [ (1R， 3S) -3- [(2-chloro-5-fluoro-pyrimidin-4-yl) amino] cyclohexyl] carbamate (Example 1/Step A， 196mg， 0.57mmol) ， Pd₂ (dba) ₃ (42mg， 0.057mmol) and Xphos (27mg， 0.057mmol) in dioxane (5mL) was heated at 125℃ urder microwave heating for 2h. After cooling to room temperature， the solvent was removed under reduced pressure to give a crude product， which was purified by silica gel flash chromatography (petroleum ether∶EtOAc＝3∶1) to afford the title compound (100mg， 48.3％ yield) as a yellow solid. [M+H] ⁺＝547.3.

[B] (rac) - (1S， 3R) -N1- (2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoropyrimldin-4-yl) cyclohexane- 1， 3-diamine

To a stirred solution of (rac) -tert-butyl ( (1R， 3S) -3- ( (2- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) cyclohexyl) carbamate (100mg， 0.18mmol) in EtOAc (5mL) was added HCl/dtoxane (5mL) and the reaction mixture was stirred at 50℃ for 1 2h. After cooling to room temperature， the mixture was concentrated in vacuo to give a crude title compound (60mg， 90.5％ yield) as a yellow solid. It was used directly in teh next step reaction without further purification.

[C] (rac) -N- ( (1R， 3S) -3- ( (2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoropyrimidin-4- yl) amino) cyclohexyl) morpholine-4-carboxamide

To a stirred solution of (rac) - (1S， 3R) -N1- (2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) cyclohexane-1， 3-diamine (60mg， 0.16mmol) in MeCN (10mL) was added DIPEA (43.9mg， 0.32mmol) and morpholine-4-carbonyl chloride (35.9mg， 0.24mmol) and the resulting reaction mixture was stirred at room temperature for 12h. After TLC indicated the completion of reaction， the reaction mixture was concentrated in vacuo and the crude product was then purified by Prep-HPLC to afford the desired title compound (18mg， 22.9％ yield) as a yellow solid. MS： 476.2 [M+H] ⁺. ¹H NMR (400MHz， MeOH-d4) δ 8.32 (d， J＝5.02Hz， 1H) ， 7.77 (d， J＝7.78Hz， 1H)， 7.22-7.30 (m， 1H) ， 4.35 (t， J＝11.67Hz， 1H) ， 3.77～3.93 (m， 1H) ， 3.63～3.69 (m， 4H) ， 3.36～3.41 (m， 4H) ， 2.38 (d， J＝11.29Hz， 1H)， 2.23 (d， J＝11.80Hz， 1H) ， 1.99～2.08 (m， 2H) ， 1.55～1.70 (m， 2H) ， 1.34～1.51 (m， 2H) .

Example 7

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

[A] (-) - (1R， 2S， 3S， 4R) -Methyl 3- ( (5-fluoro-2- (7-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H- pyrazolo [4， 3-c] pyridin-3-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) ammo) bicyclo [2.2.2] octane-2-carboxylate (Exampie 5/Step E， 220mg， 701μmol) and Pd (PPh₃) ₄ (81mg， 70.1μmol) in dioxane (4mL) was added 1， 1， 1， 2， 2， 2-hexabutyldistannane (610mg， 552μL， 1.05mmol) at room temperature The reaction mixture solution was then stirred at 125℃ for 2h before being cooled back to the room temperature and followed by the addition of 7-fluoro-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [4， 3-c] pyridine (Intermediate A-5， 365mg， 1.05mmol) and Pd (PPh₃) ₄ (81mg， 70.1μmol) in dioxane (16mL) . The resulting reaction mixture solution was stirred at 145℃ for 1h under microwave heating. After cooling to room temperature， the reaction mixture was poured into water (20mL) and extracted with EtOAc (2 x 50mL) . The combined organic layers were washed with brine， dried over anhydrous Na₂SO₄， filtered and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography(0-80％ EtOAc-hexane gradient) to afford the title compound (70mg， 20％ yield) as yellow oil. MS： 499.1 [M+H]⁺

[B] (-) - (1R， 2S， 3S， 4R) -3- ( (5-Fluoro-2- (7-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [4， 3- c] pyridin-3-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- (7-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [4， 3-c] pyridin-3-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (65mg， 130μmol) in THF (4mL) and MeOH (2mL) was added LiOH (15.6mg， 652μmol) pre-dissolved in water (1mL) . The reaction mixture solution was stirred at room temperature for 12h before being diluted with water (10mL) and extracted with diethyl ether (20mL) . The separated aqueous iayer was acidified with concentrated hydrochloric acid to pH＝4 and extracted with EtOAc (40mL three times) . The combined organics were dned over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude product (60mg， 95％ yield) as yellow oil. MS： 485.1 [M+H] ⁺. it was used directly in the next step reaction without further purification.

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

To a stirred mixture solution of (-) - (1R， 2S， 3S， 4R) -3- ( (5-fluoro-2- (7-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [4， 3-c] pyridin-3-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (60mg， 124μmol) in DCM (3mL) was added 2， 2， 2-trifluoroacetic acid (4.44g， 38.9mmol) at room temperature and the reaction mixture was stirred at room temperature for 12h before it was concentrated in vacuo to give a crude product，which was punfied by Prep-HPLC to afford the title compound (8mg， 16.1％ yield) as white foam. MS： 401.1 [M+H] +. ¹H NMR (400MHz， MeOH-d4) □ 9.72 (br.s.， 1H) 8.28-8.33 (m， 1H) 8.14-8.20 (m， 1H) 4.97-5.06 (m， 1H) 2.79-2.86 (m， 1H) 2.15 (br.s.， 1H) 1.93-2.06 (m， 1H) 1.80-1.92 (m， 2H) 1.48-1.79 (m， 6H) .

Example 8

(rac) -N- ( (1R， 3S) -3- ( (2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) cyclohexyl) piperazine-1-carboxamide

[A] (rac) -tert-Butyl 4- ( ( (1R， 3S) -3- ( (2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) cyclohexyl) carbamoyl) piperazine-1-carboxylate

To a solution of (rac) - (1S， 3R) -N1- (2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) cyclohexane-1， 3-diamine (Example 6/Step B， 50mg， 0.14mmol) in MeCN (10mL) was added DIPEA (36.2mg， 0.28mmol) and tert-butyl 4- (chlorocarbonyl) piperazine-1-carboxylate (52.2mg， 0.21mmol) at roomtemperature and the reaction mixture was stirred for 1 2h. The reaction was quenched by the addition of satd. aq. NH₄Cl solution (20mL) and extracted with EtOAc (20mL three times) . The combined organic extracts were concentrated in vacuo to give a crude title compound (80 mg) as a yellow solid. It was used directly in the next step reaction without further purification.

[B] (rac) -N- ( (1R， 3S) -3- ( (2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoropyrimidin-4- yl) amino) cyclohexyl) piperazine-1-carboxamide

To a solution of (rac) -tert-butyl 4- ( ( (1R， 3S) -3- ( (2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) cyclohexyl) carbamoyl) piperazine-1-carboxylate (100 mg， 0.174 mmol) in DCM (5 mL) was added TFA (5 mL) at room temperature and the reaction mixture was stirred for 12 h. After the reaction mixture was concentrated in vacuo， the crude product was subject to purification by Prep-HPLC to afford the title compound (10 mg， 12.1％yield) as a white solid. MS： 475.2 [M+H] ⁺. ¹H NMR (400MHz， MeOH-d4) δ 8.09 (d， J＝3.76 Hz， 1 H) ， 7.93 (d， J＝8.03 Hz， 1 H) ， 7.07 (t， J＝9.29 Hz， 1 H) ， 4.22～4.31 (m， 1 H) ， 3.78～3.86 (m， 1 H) ， 3.42～3.50 (m， 4 H) ， 2.88～2.98 (m， 4 H) ， 2.33 (d， J＝11.54 Hz， 1 H) ， 2.21 (d， J＝11.54 Hz， 1 H) ， 1.91～2.06 (m， 2 H) ， 1.44～1.67 (m， 2 H) ， 1.27～1.36 (m， 2 H) .

Example 9

(rac) -N- ( (1R， 3S) -3- ( (2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) cyclohexyl) -4-methylpiperazine-1-carboxamide

To a solution of (rac) - (1S， 3R) -N1- (2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) cyclohexane-1， 3-diamine (Example 6/Step B， 50 mg， 0.14 mmol) in MeCN (10 mL) was added DIPEA (36.2 mg， 0.28 mmol) and 4-methylpiperazine-1-carbonyl chloride (34.2 mg， 0.21 mmol) at room temperature and the reaction mixture was stirred for 12 h. After the reaction mixture was concentrated in vacuo， the crude product was subject to purification by Prep-HPLC to afford the title compound (6 mg， 12.1％yield) as a white solid. MS： 489.2 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) δ 8.12 (d， J＝2.76 Hz， 1 H) ， 7.98 (d， J＝8.78 Hz， 1 H) ， 7.10 (t， J＝9.41 Hz， 1 H) ， 4.63 (br. s.， 1 H) ， 4.32 (br. s.， 1 H) ， 3.81 (t， J＝11.67 Hz， 1 H) ， 3.41～3.48 (m， 4 H) ， 2.47 (br. s.， 4 H) ， 2.34 (s， 3 H) ， 2.23 (d， J＝12.30 Hz， 1 H) ， 1.94～2.10 (m， 2 H) ， 1.63 (q， J＝13.22 Hz， 1 H) ， 1.21～1.38 (m， 3 H) .

Example 10

(-) -N- ( (1R， 3S) -3- ( (5-Fluoro-2- (7-fluoro-1H-pyrazolo [4， 3-c] pyridin-3-yl) pyrimidin -4-yl) amino) cyclohexyl) benzamide

[A] (-) -N- ( (1R， 3S) -3- ( (2-chloro-5-fluoropyrimidin-4-yl) amino) cyclohexyl) benzamide

To a stirred solution of (-) -tert-butyl ( (1R， 3S) -3- ( (2-chloro-5-fluoropyrimidin-4-yl) amino) cyclohexyl) carbamate (1.5 g， 4.35 mmol) in MeOH (10 mL) was added acetyl chloride (3.41g， 43.5 mmol) at room temperature and the reaction mixture was stirred for 3 h. After the solvent was removed under reduced pressure， the residue was re-dissolved in DCM (10 mL) followed by the addition of benzoyl chloride (673 mg， 4.79 mmol) and DIPEA (562 mg， 4.35 mmol) . The reaction mixture solution was stirred at room temperature for 1 h before it was poured into water (20 mL) and extracted with EtOAc (50 mL twice) . The combined organic layers were washed with brine， dried over anhydrous Na₂SO₄， filtered and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (0-80％EtOAc-hexane gradient) to afford the title compound (1 g， 65.9％yield) as a white solid. MS： 349.1 [M+H] ⁺

[B] (-) -N- ( (1R， 3S) -3- ( (5-Fluoro-2- (7-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [4， 3- c] pyridin-3-yl) pyrimidin-4-yl) amino) cyclohexyl) benzamide

To a stirred mixture solution of (-) -N- ( (1R， 3S) -3- ( (2-chloro-5-fluoropyrimidin-4-yl) amino) cyclohexyl) benzamide (348 mg， 998 μmol) and Pd (PPh₃) ₄ (115 mg， 99.8 μmol) in dioxane (4 mL) was added 1， 1， 1， 2， 2， 2-hexabutyldistannane (868 mg， 1.5 mmol) at room temperature. The reaction mixture solution was then stirred at 125 ℃ for 2 h before was cooled back to room temperature and re-dissolved in dioxane (16 mL) and followed by the addition of 7-fluoro-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [4， 3-c] pyridine (Intermediate A-5， 519 mg， 1.5 mmol) and Pd (PPh₃) ₄ (115 mg， 99.8 μmol) . The resulting mixture solution was stirred at 145 ℃ for 1 h under microwave heating. After cooling to room temperature， the reaction mixture was poured into water (20 mL) and extracted with EtOAc (2 x 50 mL) . The combined organic layers were washed with brine， dried over anhydrous Na₂SO₄， filtered and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (0-80％EtOAc-hexane gradient) to afford the title compound (130 mg， 24.4％yield) as yellow foam. MS： 534.1 [M+H] ⁺

[C] (-) -N- ( (1R， 3S) -3- ( (5-fluoro-2- (7-fluoro-1H-pyrazolo [4， 3-c] pyridin-3-yl) pyrimidin-4- yl) amino) cyclohexyl) benzamide

To a stirred solution of (-) -N- ( (1R， 3S) -3- ( (5-fluoro-2- (7-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [4， 3-c] pyridin-3-yl) pyrimidin-4-yl) amino) cyclohexyl) benzamide (130 mg， 244 μmol) in DCM (3 mL) was added 2， 2， 2-trifluoroacetic acid (4.44 g， 38.9 mmol) at room temperature and stirred for 12 h. After the reaction mixture was concentrated in vacuo， the crude residule was subject to purifccation by Prep-HPLC to afford the title compound (9 mg， 8.22％) as white foam. MS： 450.1 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) □□ 9.62 (s， 1 H) 8.30-8.33 (m， 1 H) 8.15-8.20 (m， 1 H) 7.79-7.84 (m， 2 H) 7.50-7.55 (m， 1 H) 7.42-7.48 (m， 2 H) 4.40-4.49 (m， 1 H) 4.12-4.22 (m， 1 H) 2.40-2.46 (m， 1 H) 2.20-2.27 (m， 1 H) 2.07-2.14 (m， 1 H) 1.97-2.04 (m， 1 H) 1.70-1.78 (m， 1 H) 1.55-1.66 (m， 1 H) 1.36-1.54 (m， 2 H) .

Example 11

(rac) - (2S， 3S) -3- ( (2- (5-Cyano-7-fluoro-1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo- [2.2.2] octane-2-carboxylic acid

[A] (rac) - (2S， 3S) -Methyl3- ( (2- (5-cyano-7-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3- yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate

To a stirred solution of 7-fluoro-1- (tetrahydro-2H-pyran-2-yl) -3- (tributylstannyl) -1H-indazole-5-carbonitrile (Intermediate A-4b， 0.25 g， 0.47 mmol) in dioxane (5 mL) was added (rac) - (2S， 3S) -methyl 3- ( (2-chloro-5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (Example 5/Step E， 0.17 g， 0.56 mmol ) ， Pd₂ (dba) ₃ (45.8 mg， 0.05 mmol) and X-phos (71.5 mg， 0.15mmol) at room tenperature. The resulting reaction mixture was stirred at 140 ℃ for 2 h under microwave heating. After cooling to the room temperature， the reaction was quenched by the addition of satd. aq. NH₄Cl solution (50 mL) and extracted with EtOAc (50 mL three times) . The combined organic extracts were dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (petroleum ether∶EtOAc ＝ 3∶1～1∶1) to afford the title compound (150 mg， 41.8％yield) as a red solid. MS： 523.2 [M+H] ⁺.

[B] (rac) (2S， 3S) -Methyl3- ( (2- (5-cyano-7-fluoro-1H-indazol-3-yl) -5-fluoropyrimidin-4- yl) amino) bicyclo [2.2.2] octane-2-carboxylate

To a stirred solution of (rac) - (2S， 3S) -methyl 3- ( (2- (5-cyano-7-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (250 mg， 0.478 mmol) in DCM (5 mL) was added TFA (5 mL) at room temperature and stirred for 12 h. Afterwards， the solvent was removed under reduced pressure to give a crude title compound (200 mg， 95.7％yield) as a grey solid. MS： 439.1 [M+H] ⁺. It was used directly in the next step reaction without further purificaition.

[C] (rac) - (2S， 3S) -3- ( (2- (5-Cyano-7-fluoro-1H-indazol-3-yl) -5-fluoropyrimidin-4- yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

To a stirred solution of (rac) - (2S， 3S) -methyl 3- ( (2- (5-cyano-7-fluoro-1H-indazol-3-yl) -5 -fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (200 mg， 0.456 mmol) in THF (5 mL) and H₂O (5 mL) was added NaOH (54.7 mg， 1.368 mmol) at room temperature and stirred for 12 h. After solvent was removed under reduced pressure， the residue was subject to Prep-HPLC purification to afford the title compound (15 mg， 7.7％yield) as a white solid. MS： 425.1 [M+H] ⁺ . ¹H NMR (400 MHz， DMSO-d6) δ 1.37～1.59 (m， 4 H) ， 1.60～1.70 (m， 1 H) ， 1.77 (d， J＝7.03 Hz， 2 H) ， 1.84 (d， J＝11.80Hz， 1 H) ， 1.93 (br. s.， 1H) ， 2.01～2.08 (m， 1H) ， 2.90 (d， J＝6.78 Hz， 1 H) ， 4.78 (t， J＝6.53 Hz， 1 H) ， 7.77 (d， J＝8.78 Hz， 1 H) ， 7.96 (d， J＝6.27 Hz， 1 H) ， 8.33 (d， J＝3.26 Hz， 1 H) ， 8.79 (s， 1 H) .

Example 12

(-) -N- ( (1R， 3S) -3- ( (2- (5， 7-Difluoro-1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) cyclohexyl) -5-hydroxypicolinamide

To a stirred mixture solution of (-) - (1S， 3R) -N1- (2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) cyclohexane-1， 3-diamine (Example 8/Step B， 105 mg， 290 μmol) in DCM (5 mL) was added 2- (3H- [1， 2， 3] triazolo [4， 5-b] pyridin-3-yl) -1， 1， 3， 3-tetramethylisouronium hexafluorophosphate (V) (143 mg， 377 μmol) ， 5-hydroxypicolinic acid (44.4 mg， 319 μmol) and N， N-diisopropylethylamine (112 mg， 870 μmol) at room temperature and stirred for 16 h. The reaction mixture was then washed with satd. aq. NaHCO₃ solution， dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purifed by Prep-HPLC to afford the title compound (18 mg， 12.8％yield) as white foam. MS： 484.1 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) □ 8.15 (d， J＝2.45 Hz， 2 H) 7.92-8.03 (m， 2 H) 7.21-7.30 (m， 1 H) 7.05-7.17 (m， 1 H) 4.34-4.48 (m， 1 H) 4.07-4.19 (m， 1 H) 2.35-2.46 (m， 1 H) 2.22-2.31 (m， 1 H) 2.06-2.17 (m， 1 H) 1.95-2.05 (m， 1H) 1.57-1.79 (m， 2 H) 1.35-1.51 (m， 2 H) .

Example 13

(-) -N- ( (1R， 3S) -3- ( (2- (5， 7-Difluoro-1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) cyclohexyl) picolinamide

In analogy to the synthesis of Example 12， picolinic acid (39.3 mg， 319 μmol) was used to afford the title compound (20 mg， 14.8％yield) as white foam after Prep-HPLC purification. MS： 468.1 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) □ 8.62-8.67 (m， 1 H) 8.07-8.22 (m， 2 H) 7.94-8.05 (m， 2 H) 7.52-7.62 (m， 1 H) 7.10-7.21 (m， 1 H) 4.41-4.51 (m， 1 H) 4.13-4.25 (m， 1 H) 2.40-2.46 (m， 1H) 2.24-2.32 (m， 1 H) 2.11-2.20 (m， 1 H) 1.98-2.09 (m， 1 H) 1.62-1.80 (m， 2 H) 1.38-1.57 (m， 2 H) .

Example 14

(-) -N- ( (1R， 3S) -3- ( (2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) cyclohexyl) morpholine-4-carboxamide

To a stirred mixture solution of (-) - (1S， 3R) -N1- (2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) cyclohexane-1， 3-diamine (Example 8/Step B， 560mg， 1.55 mmol) in DCM (5 mL) was added DIPEA (599 mg， 810 μl， 4.64 mmol) and morpholine-4-carbonyl chloride (277 mg， 1.85 mmol) at room temperature and stirred for 16 h. The reaction mixture was then washed with satd. aq. NaHCO₃ solution， dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purifed by Prep-HPLC to afford title compound (150 mg， 20.4％yield) as white foam. MS： 476.1 [M+H] ⁺. ¹H NMR (400 MHz， DMSO-d6) □□ 8.21-8.30 (m， 1 H) 7.90-7.99 (m， 1 H) 7.69-7.82 (m， 1 H) 7.26 -7.43 (m， 1 H) 6.24-6.45 (m， 1 H) 4.09-4.30 (m， 1 H) 3.56-3.73 (m， 1 H) 3.51 (s， 4 H) 3.21-3.27 (m， 4 H) 2.64-2.69 (m， 1 H) 2.04-2.10 (m， 1 H) 1.93-2.02 (m， 1 H) 1.76-1.87 (m， 2 H) 1.35-1.49 (m， 2 H) 1.10-1.34 (m， 2 H) .

Example 15

(-) -N- ( (1R， 3S) -3- ( (2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) cyclohexyl) benzamide

[A] (-) -N- ( (1R， 3S) -3- ( (2- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -5- fluoropyrimidin-4-yl) amino) cyclohexyl) benzamide

To a stirred mixturesolution of (-) -N- ( (1R， 3S) -3- ( (2-chloro-5-fluoropyrimidin-4-yl) amino) cyclohexyl) benzamide (Example 10/Step A， 348 mg， 998 μmol) and Pd (PPh₃) ₄ (115 mg， 99.8 μmol) in dioxane (4 mL) was added 1， 1， 1， 2， 2， 2-hexabutyldistannane (868 mg， 786 μL， 1.5 mmol) at room temperature. The resulting reaction mixture solution was stirred at 125 ℃ for 2 h before being cooled back to room temperature and re-dissolved in dioxane (16 mL) and followed by the addition of 5， 7-difluoro-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (Intermediate A-2a， 436 mg， 1.2 mmol) and Pd (PPh3) 4 (115 mg， 99.8 μmol) . The reaction mixture solution was stirred at 145 ℃ for 1 h under microwave heating. After cooling to room temperature， the reaction mixture was poured into water (20 mL) and extracted with EtOAc (50 mL twice) . The combined organic layers were washed with brine， dried over anhydrous Na₂SO₄， filtered and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (0-80％EtOAc-hexane gradient) to afford the title compound (100 mg， 18.2％yield) as yellow foam. MS： 551.1 [M+H] ⁺

[B] (-) -N- ( (1R， 3S) -3- ( (2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoropyrimidin-4- yl) amino) cyclohexyl) benzamide

To a stirred mixture solution of (-) -N- ( (1R， 3S) -3- ( (2- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) cyclohexyl) benzamide (100 mg， 182 μmol) in DCM (3 mL) was added 2， 2， 2-trifluoroacetic acid (4.44 g， 3 mL， 38.9 mmol) at room temperature and stirred for 12 h. After solvent was removed under reduced pressure， the residue was subject to Prep-HPLC purification to afford the title compound (10 mg， 11.8％yield) as white foam. MS： 467.1 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) □ 8.11-8.17 (m， 1 H) 8.01-8.08 (m， 1 H) 7.80-7.88 (m， 2 H) 7.50-7.57 (m， 1 H) 7.42-7.50 (m， 2 H) 7.07-7.18 (m， 1 H) 4.37-4.48 (m， 1 H) 4.10-4.24 (m， 1 H) 2.39-2.48 (m， 1 H) 2.20-2.32 (m， 1 H) 2.08-2.18 (m， 1 H) 1.94-2.06 (m， 1 H) 1.56-1.78 (m， 2 H) 1.32-1.53 (m， 2 H) .

Example 16

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

[A] (-) - (1R， 2S， 3S， 4R) -Methyl 3- ( (2- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3- yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate

In analogy to the synthesis of Example 7/Step A， 5， 7-difluoro-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (Intermediate A-2a， 1.15 g， 3.16 mmol) was used to afford the title compound (200 mg， 18.4％yield) after silica gel flash chromatography (0-80％EtOAc-hexane gradient) purification as yellow foam. MS： 516.1 [M+H] ⁺.

[B] (-) - (1R， 2S， 3S， 4R) -3- ( (2- (5， 7-Difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -5- fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

In analogy to the synthesis of Example 7/Step B， (-) - (1R， 2S， 3S， 4R) -methyl 3- ( (2- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (200 mg， 388μmol) was used to give a crude title compound (200 mg， 100％yield) as yellow oil. MS： 502.1 [M+H] ^+. It was used directly in the next step reaction without further purification.

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

In analogy to the synthesis of Example 7/Step C， (-) - (1R， 2S， 3S， 4R) -3- ( (2- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (200 mg， 399μmol) was used to afford the title compound (49 mg， 29 4％yield) as white foam after Prep-HPLC purification. MS： 418.1 [M+H] ⁺. ¹H NMR (400 MHz， DMSO-d6) □ 8.23-8.31 (m， 1 H) 7.96-8.05 (m， 1 H) 7.72-7.81 (m， 1 H) 7.29-7.40 (m， 1 H) 4.67-4.79 (m， 1 H) 2.78-2.88 (m， 1 H) 1.98-2.06 (m， 1 H) 1.90-1.97 (m， 1 H) 1.67-1.87 (m， 3 H) 1.30-1.66 (m， 5H) .

Example 17

(-) - (2S， 3S) -3- ( (5-Fluoro-2- (7-fluoro-1H-indazol-3-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

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

In analogy to the synthesis of Example 7/Step A， 7-fluoro-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (Intermediate A-1， 728 mg， 2.1 mmoi) was used to afford the title compound (140 mg， 20.1％yield) after silica gel flash chromatography (0-80％EtOAc-hexane gradient) purification as yellow oil. MS： 498.2 [M+H] ⁺.

[B] (-) - (2S， 3S) -3- ( (5-Fluoro-2- (7-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3- yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

In analogy to the synthesis of Example 7/Step B， (-) - (2S， 3S) -methyl 3- ( (5-fluoro-2- (7-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (100 mg， 201 μmol) was used to give a crude title compound (100 mg， 100％yield) . MS： 484.2 [M+H] ⁺. It was used directly in the next step reaction without further purification.

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

In analogy to the synthesis of Example 7/Step C， (-) - (2S， 3S) -3- ( (5-fluoro-2- (7-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (100 mg， 207 μmol) was used to afford the title compound (30 mg， 36.3％yield) as a white solid after Prep-HPLC purification. MS： 400.2 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) δ 8.30 (br d， J＝7.46 Hz， 1H) ， 8.04 (br s， 1H) ， 6.95-7.25 (m， 2H) ， 4.92 (br s， 1H) ， 2.74 (br d， J＝5.50 Hz， 1H) ， 2.04 (br s， 1H) ， 1.95 (br s， 1H) ， 1.78-1.90 (m， 1H) ， 1.68-1.77 (m， 2H) ， 1.52-1.68 (m， 3H) ， 1.37-1.52 (m， 2H) .

Example 18

(-) -N- ( (1R， 3S) -3- ( (2- (5， 7-Difluoro-1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) cyclohexyl) pyrrolidine-1-carboxamide

To a stirred solution of (-) - (1S， 3R) -N1- (2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) cyclohexane-1， 3-diamine ( (-) -enantiomer from SFC chiral separation of Example 6/Step C， 105 mg， 290 μmol) and N-ethyl-N-isopropylpropan-2-amine (112 mg， 870 μmol) in DCM (20 mL) was added di (1H-imidazol-1-yl) methanone (94 mg， 580 μmol) and pyrrolidine (30.9 mg， 435 μmol) at room temperature. The resulting mixture solution was stirred at room temperature for 16 h before solvent was evaporated under reduced pressure. The residue crude product was then purified by Prep-HPLC to afford the title compound (1 mg， 1％yield) as white foam. MS： 460.1 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) □ 8.12-8.15 (m， 1 H) 8.00-8.06 (m， 1 H) 7.08-7.16 (m， 1 H) 4.31-4.42 (m， 1 H) 3.78-3.88 (m， 1 H) 2.21-2.36 (m， 3 H) 1.88-2.08 (m， 8 H) 1.59-1.71 (m， 1 H) 1.45-1.57 (m， 1 H) 1.25-1.41 (m， 3 H) .

Example 19

(+ or -) ) -N- [ (1R， 3S) -3- [ [5-fluoro-2- (7-fluoro-1H-pyrazolo [4， 3-c] pyridin-3-yl) pyrimidin-4-yl] amino] cyclohexyl] pyridine-2-carboxamide

[A] (+ or -) ) -tert-Butyl N- [ (1R， 3S) -3- [ [5-fluoro-2- (7-fluoro-1-tetrahydropyran-2-yi-pyrazolo [4， 3- c] pyridin-3-yl) pyrimidin-4-yl] amino] cyclohexyl] carbamate

To a stirred mixture solution of (+ or -) -tert-butyl ( (1S， 3R) -3- ( (2-chloro-5-fluoropyrimidin-4yl) amino) cyclohexyl) carbamate ( ( (+ or -) -enantiomer from SFC chiral separation of Example 1/Step A， 220 mg， 638 μmol) and Pd (PPh₃) ₄ (100 mg， 86.5 μmol) in dioxane (4 mL) was added 1， 1， 1， 2， 2， 2-hexabutyldistannane (740 mg， 1.28 mmol) and the resulting mixture solution was stirred at 125 ℃ for 2 h. After cooling to the room temperature， to the above solution was added 7-fluoro-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [4， 3-c] pyridine (Intermediate A-5， 288 mg， 829 μmol) and Pd (PPh₃) ₄ (100 mg， 86.8 μmol) in dioxane (16 mL) ， and the reaction mixture solution was stirred at 145 ℃ for 1 h under microwave heating. After cooling to room temperature， the reaction mixture was poured into water (20 mL) and extracted with EtOAc (50 mL twice) . The combined organic layers were washed with brine， dried over anhydrous Na₂SO₄， filtered and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (0-80％EtOAc-hexane gradient) to afford the title compound (47mg， 13.9 ％yield) as yellow oil. MS： 530.2 [M+H+] .

[B] (+ or -) ) - (1S， 3R) -N1- [5-fluoro-2- (7-fluoro-1H-pyrazolo [4， 3-c] pyridin-3-yl) pyrimidin-4- yl] cyclohexane-1， 3-diamine hydrochloride

To a stirred solution of (+ or -) -tert-butyl N- [ (1R， 3S) -3- [ [5-fluoro-2- (7-fluoro-1-tetrahydropyran-2-yl-pyrazolo [4， 3-c] pyridin-3-yl) pyrimidin-4-yl] amino] cyclohexyl] carbamate (470 mg， 887 μmol) in MeOH (20 mL) was added acetyl chloride (697 mg， 8.87 mmol) dropwise at room temperature and stirred for 14 h. Afterwards， the solvent was removed under reduced pressure to give a crude title compound (340 mg， 100％yieid) . MS： 346.1 [M+H+] . It was used directly in the next step reaction without further purification.

[C] (+ or -) -N- [ (1R， 3S) -3- [ [5-fluoro-2- (7-fluoro-1H-pyrazolo [4， 3-c] pyridin-3-yl) pyrimidin-4- yl] amino] cyclohexyl] pyridine-2-carboxamide

A mixture solution of (+ or -) - (1S， 3R) -N1- (5-fluoro-2- (7-fluoro-1H-pyrazolo [4， 3-c] pyridin-3-yl) pyrimidin-4-yl) cyclohexane-1， 3-diamine hydrochloride (40 mg， 105 μmol) ， picolinic acid (15.5 mg， 126 μmol) ， HATU (51.8 mg， 136 μmol) and N， N-diisopropylethylamine (40.6 mg， 314 μmol) in DCM (5 mL) was stirred at room temperature for 16 h. Afterwards， the mixture solution was partitioned between DCM and satd. aq. NaHCO₃ solution. The separated organic layer was dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purified by Prep-HPLC to afford the title compound (10 mg， 21％yield) as a white solid. MS： 451.2 [M+H+] . ¹H NMR (400 MHz， MeOH-d4) δ 9.52 (d， J＝1.83 Hz， 1H) ， 8.52 (d， J＝4.28 Hz， 1H) ， 8.20 (d， J＝2.81 Hz， 1H) ， 8.07 (d， J＝3.67 Hz， 1H) ， 7.97 (d， J＝7.82 Hz， 1H) ， 7.84 (dt， J＝1.65， 7.73 Hz， 1H) ， 7.43 (ddd， J＝1.10， 4.77， 7.58 Hz， 1H) ， 4.30-4.42 (m， 1H) ， 4.00-4.14 (m， 1H) ， 2.31 (br d， J＝11.74 Hz， 1H) ， 2.13 (br d， J＝12.10 Hz， 1H) ， 2.00 (br d， J＝12.84 Hz， 1H) ， 1.84-1.94 (m， 1H) ， 1.58-1.70 (m， 1H) ， 1.53 (q， J＝11.86 Hz， 1H) ， 1.24-1.44 (m， 2H) .

Example 20

(rac) - (2S， 3S) -3- ( (2- (7-Chloro-1 H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] -octane-2-carboxylic acid

[A] (rac) - (2S， 3S) -Methyl-3- ( (2- (7-chloro-1 - (tetrahydro-2H-pyran-2-yl) ， -1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) bicycio [2.2.2] octane-2-carboxylate

In analogy to the synthesis of Example 11/Step A， 7-chloro-1- (tetrahydro-2H-pyran-2-yl) -3-(tributylstannyl) -1H-indazole (Intermediate A-6b， 200 mg， 0.38 mmol) was used to afford the title compound (60 mg， 30 ％yield) after silica gel flash chromatography (petroleum ether： EtOAc ＝ 3∶1 to DCM∶ MeOH ＝ 30∶1) purification as a yellow solid. MS： 514.1 [M+H] ⁺.

[B] (rac) - (2S， 3S) -3- ( (2- (7-Chloro-1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) bicycle [2.2.2] octane-2-carboxylic acid

A solution of (rac) - (2S， 3S) -methyl 3- ( (2- (7-chloro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (130 mg， 0.253 mmol) in 4 N HCl (10 mL) was stirred at 100 ℃ for 3 h. After cooling to room temperature， the solvent was removed under reduced pressure to give a crude product， which was purified by Prep-HPLC to afford the title compound (18 mg， 17.2％yield) as a white solid. MS： 416.1 [M+H] ⁺. ¹H NMR (300 MHz， DMSO-d6) δ 8.43 (d， J＝8.3 Hz， 1H) ， 8.37 (d， J＝4.1 Hz， 1H) ， 8.29 (br. s. ， 1H) ， 7.54 (d， J＝7.3 Hz， 1H) ， 7.28 (t， J＝7.8 Hz， 1H) ， 4.79 (br. s. ， 1H) ， 2.99 -2.85 (m， 2H) ， 2.08-1.92 (m， 2H) ， 1.83-1.30 (m， 8H) .

Example 21

(+ or -) -N- [ (1R， 3S) -3- [ [5-Fluoro-2- (7-fluoro-1H-pyrazolo [4， 3-c] pyridin-3-yl) pyrimidin-4-yl] amino] cyclohexyl] morpholine-4-carboxamide

In analogy to the synthesis of Example 19/step C， morpholine-4-carbonyl chloride (18.8 mg， 126 μmol was used to afford the title compound (2 mg， 4.2％yield) as a white solid after Prep-HPLC purification. MS： 459.2 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) δ 9.61 (d， J＝1.96 Hz， 1H) ， 8.32 (br s， 1H) ， 8.18 (d， J＝3.67 Hz， 1H) ， 4.32-4.47 (m， 1H) ， 3.76-3.90 (m， 1H) ， 3.61-3.68 (m， 4H) ， 3.37 (br d， J＝4.89 Hz， 4H) ， 2.32 (br d， J＝1 1.74 Hz， 1 H) ， 2.21 (br d， J＝12.96 Hz， 1H) ， 1.90-2.07 (m， 2H) ， 1.60-1.75 (m， 1H) ， 1.48 (q， J＝12.31 Hz， 1H) ， 1.26-1.41 (m 2H) .

Example 22

(+ or-) -N- [ (1R， 3S) -3- [ [5-Fluoro-2- (7-fluoro-1H-pyrazolo [4， 3-c] pyridin-3-yl) pyrimidin-4-yl] amino] cyclohexyl] pyrrolidine-1-carboxamide

In analogy to the synthesis of Example 19/step C， pyrrolidine-1-carbonyl chloride (16.8 mg， 126 μmol) was used to afford the title compound (2 mg， 4.3％yield) as a white solid after Prep-HPLC purification. MS： 443.2 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) δ 9.61 (br s， 1H) ， 8.32 (br s， 1H) ， 8.17 (br s， 1H) ， 5.86 (br d， J＝6.24 Hz， 1H) ， 4.39 (br s， 1H) ， 3.82 (br s， 1H) ， 2.30 (br s， 1H) ， 2.23 (br s， 1H) ， 1.79-2.08 (m， 8H) ， 1.68 (br d， J＝14.92 Hz， 1H) ， 1.50 (br d， J＝11.86 Hz， 1H) ， 1.34 (br d， J＝11.86 Hz， 3H) .

Example 23

(+ or -) -N- [ (1R， 3S) -3- [ [5-Fluoro-2- (7-fluoro-1H-pyrazolo [4， 3-c] pyridin-3-yl) pyrimidin-4-yl] amino] cyclohexyl] -5-hydroxy-pyridine-2-carboxamide

In analogy to the synthesis of Example 19/step C， 5-hydroxypicolinic acid (17.5 mg， 126 μmol) was used to afford the title compound (3 mg， 6.2％yield) as a white solid after Prep-HPLC purification. MS： 467.2 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) δ9.65 (d， J＝1.96 Hz， 1H) ， 8.33 (br s， 1H) ， 8.17 (dd， J＝3.18， 13.33 Hz， 2H) ， 7.93 (d， J＝8.56 Hz， 1H) ， 7.26 (dd， J＝2.69， 8.68 Hz， 1H) ， 4.40-4.56 (m， 1H) ， 4.15 (br t， J＝11.37 Hz， 1H) ， 2.40 (br d， J＝10.39 Hz， 1H) ， 2.25 (br d， J＝12.72 Hz， 1H) ， 2.10 (br d， J＝14.43 Hz， 1H) ， 2.01 (br d， J＝13.69 Hz， 1H) ， 1.75 (q， J＝13.94 Hz， 1H) ， 1.62 (q， J＝12.23 Hz， 1H) ， 1.35-1.54 (m， 2H) .

Example 24

(-) - (2S， 3S) -3- ( (2- (5-Cyano-7-fluoro-1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

[A] (-) - (1R， 2S， 3S， 4R) -Methyl 3- ( (2- (5-cyano-7-fluoro-1 - (tetrahydro-2H-pyran-2-yl) -1H- indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate

In analogy to the synthesis of Example 7/Step A， (-) - (1R， 2S， 3S， 4R) -methyl 3- ( (2-chloro-5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (Example 5/Step E， 250 mg， 797 μmol) and 7-fluoro-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole-5-carbonitrile (Intermediate A-4a， 384 mg， 1.04 mmol) were used to afford the title compound (100 mg， 24％yield) after silica gel flash chromatography (0-80％EtOAc-hexane gradient) purification as yellow oil. MS： 523.1 [M+H] ⁺.

[B] (-) - (2S， 3S) -3- ( (2- (5-cyano-7-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -5- fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

ln analogy to the synthesis of Example 7/Step B， (-) - (1R， 2S， 3S， 4R) -Methyl 3- ( (2- (5-cyano-7-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] -octane-2-carboxylate (100 mg， 191 μmol) was used to give a crude title compound (100 mg， 1 00％yield) . MS： 509.1 [M+H] ⁺. It was used directly in the next step reaction without further purification

[C] (-) - (2S， 3S) -3- ( (2- (5-Cyano-7-fluoro-1H-indazol-3-yl) -5-fluoropyrimidin-4- yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

In analogy to the synthesis of Example 7/Step C， (-) - (2S， 3S) -3- ( (2- (5-cyano-7-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (97 mg， 191 μmol) was used to afford the title compound (5 mg， 6.2％yield) as white foam after Prep-HPLC purification. MS： 424.1 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) □ 8.95 (s， 1 H) 8.12 -8.16 (m， 1 H) 7.45 -7.53 (m， 1 H) 4.99-5.05 (m， 1 H) 2.68 -2.74 (m， 1 H) 2.13-2.19 (m， 1 H) 2.04-2.11 (m， 2 H) 1.75 -1.91 (m， 4H) 1.62-1.71 (m， 1H) 1.49-1.61 (m， 2H) .

Example 25

(-) -N- ( (1R， 3S) -3- ( (2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) cyclohexyl) pyrimidine-2-carboxamide

In analogy to the synthesis of Example 12， pyrimidine-2-carboxylic acid (37.7 mg， 304 μmol) was used to afford the title compound (7 mg， 5.4％yield) as white foam after Prep-HPLC purification. MS： 469.1 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) □ 8.80 -8.85 (m， 2 H) 7.88 -8.05 (m， 2 H) 7.48 -7.54 (m， 1 H) 6.94 -7.04 (m， 1 H) 4.24 -4.39 (m， 1 H) 4.03 -4.16 (m， 1 H) 2.29-2.36 (m， 1 H) 2.10-2.19 (m， 1 H) 1.98-2.07 (m， 1 H) 1.85-1.94 (m， 1 H) 1.50-1.64 (m， 2 H) 1.26 -1.44 (m， 2 H) .

Example 26

(-) -N- [ (1R， 3S) -3- [ [5-fluoro-2- (7-fluoro-1H-indazol-3-yl) pyrimidin-4-yl] amino] cyclohexyl] pyrimidine-2-carboxamide

In analogy to the synthesis of Example 3， pyrimidine-2-carboxylic acid (23.5 mg， 189 μmol) was used to afford the title compound (3 mg， 4.2％yield) as a white solid after Prep-HPLC purification. MS： 451.2 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) δ 8.94 (d， J＝4.89Hz， 2H) ， 8.36 (br d， J＝8.56 Hz， 1H) ， 8.14 (d， J＝3.67 Hz， 1H) ， 7.63 (t， J＝4.89 Hz， 1H) ， 7.33 (br d， J＝4.77 Hz， 1H) ， 7.09-7.22 (m， 1H) ， 4.39-4.54 (m， 1H) ， 4.27 (br t， J＝11.86 Hz， 1H) ， 2.53 (br d， J＝11.49 Hz， 1H) ， 2.21 (br d， J＝14.06 Hz， 1H) ， 2.12 (br d， J＝12.72 Hz， 1H) ， 1.98-2.08 (m， 1H) ， 1.68-1.79 (m， 1H) ， 1.59-1.67 (m， 1H) ， 1.42-1.56 (m， 2H) .

Example 27

(rac) - (2S， 3S) -3- ( (2- (5-Chloro-7-fluoro-1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxyiic acid

[A] (rac) - (1S， 2R， 3R， 4S) -Methyl 3- ( (2- (5-chloro-7-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H- indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate

In analogy to the synthesis of Example 11/Step A， 5-chloro-7-fluoro-1- (tetrahydro-2H-pyran-2-yl) -3- (tributylstannyl) -1H-indazole (Intermediate A-3b， 108 mg， 0.2 mmol) was used to afford the title compound (20 mg， 33％yield) after silica gel flash chromatography (DCM∶MeOH ＝ 100∶1～20∶1) purification as a white solid MS： 532.4 [M+H] ⁺.

[B] (rac) - (1S， 2R， 3R， 4S) -3- ( (2- (5-chloro-7-fluoro-1 H-indazol-3-yl) -5-fluoropyrimidin-4- yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

A suspended solution of (rac) - (1S， 2R， 3R， 4S) -methyl 3- ( (2- (5-chloro-7-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (80 mg， 0.15 mmol) in 4 N HCl (5 mL) was stirred at 80 ℃ for 4 h. After cooling to room temperature， the solvent was removed under reduced pressure to give a crude product， which was purified by Prep-HPLC to afford the title compound (6 mg， 9.2％yield) as a white solid. MS： 434.2 [M+H] ⁺. ¹H NMR (400MHz， CHCl₃-d1) δ 8.45 (s， 1H) ， 8.24 (s， 1H) ， 7.34-7.32 (d， 1H， 10.4Hz) ， 5.10-5.09 (d， 1H， 6.8Hz) ， 2.91-2.89 (d， 1H， 6.4Hz) ， 2.19-2.07 (m， 3H) ， 1.88-1.57 (m， 7H) .

Example 28

(rac) - (2S， 3S) -3- ( (2- (5， 7-Difluoro-1H-indol-3-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] -octane-2-carboxylic acid

[A] 5， 7-Difluoro-3- (4， 4， 5， 5-tetramethyl-1， 3， 2-dioxaborolan-2-yl) -1- ( (2- (trimethylsilyl) ethoxy) - methyl) -1 H-indole

To a stirred solution of 5， 7-difluoro-3-iodo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-indole (0.82 g， 2 mmol) in THF (10 mL) was added i-PrMgCl (1.5 mL， 3 mmol) and 2-isopropoxy-4， 4， 5， 5-tetramethyl-1， 3， 2-dioxaborolane (550 mg， 3 mmol) at 0 ℃. After the reaction mixture was stirred at 0℃ for 2 h， the reaction was quenched with satd. aq. NH₄Cl solution (30 mL) ， extracted with EtOAc (100 mL) ， and washed with water (50 mL) and brine (50 mL) . The organic layer was then dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (petroleum ether∶EtOAc ＝ 100∶1 to 10∶1) to afford the title compound (0.8 g， 97％yield) as yellow oil. ¹H NMR (400 MHz， CHCl₃-d1) ： δ 7.64 (s， 1 H) ， 7.51 (dd， J＝2.0， 9.2 Hz， 1H) ， 6.79-6.74 (m， 1H) ， 5.58 (s， 2H) ， 3.51 (t， J ＝ 8.0 Hz， 2H) ， 1.38 (s， 12H) ， 0.89 (t， J ＝ 8.0 Hz， 2H) ， 0.04 (s， 9H) .

[B] (rac) - (2S. 3S) -Methyl 3- ( (2- (5， 7-difluoro-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-indol-3- yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate

To a stirred mixture solution of 5， 7-difluoro-3- (4， 4， 5， 5-tetramethyl-1， 3， 2-dioxaborolan-2-yl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-indole (500 mg， 1.25 mmol) and (2S， 3S) -methyl 3- ( (2-chloro-5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (Example 5/Step A， 350 mg， 1.2 mmol) in dioxane (5 mL) was added Pd₂ (dba) ₃ (100 mg， 0.11 mmol) ， X-phos (50 mg， 0.1 mmol) ， K₃PO₄ (510 mg， 2 mmol) and H₂O (two drops) at room temperature and then the reaction mixture was stirred at 100 ℃ for 16 h. After cooling to the room temperature， the mixture was diluted with EtOAc (100 mL) and washed with water (50 mL) and brine (50 mL) . The organic layer was dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (peterolium ether∶EtOAc ＝ 100∶1 to 10∶ 1) to afford the title compound (300 mg， 44.7％yield) as white foam. MS： 561 . 0 [M+H] ⁺.

[C] (rac) - (2S， 3S) -Methyl 3- ( (2- (5， 7-difluoro-1H-indol-3-yl) -5-fluoropyrimidin-4- yl) amino) bicyclo [2.2.2] octane-2-carbexylate

A solution of (rac) - (2S， 3S) -methyl 3- ( (2- (5， 7-difluoro-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-indol-3-yl) -5-fluoropyrimidin-4-yl) ammo) bicyclo [2.2.2] octane-2-carboxylate (290 mg， 0.5 mmol) in TFA/DCM (1/3， 2 mL) was stirred at 100 ℃ for 2 h. After cooling to room temperature， the solvent was removed under reduced pressure to give a crude title compound (300 mg) as colorless oil. MS： 431.2 [M+H] ⁺. It was used directly in the next step reaction without further purification.

[D] (rac) - (2S， 3S) -3- ( (2- (5， 7-difluoro-1H-indol-3-yl) -5-fluoropyrimidin-4- yl) amino) bicyclo [2.2.2] -octane-2-carboxylic acid

To a stirred solution of (rac) - (2S， 3S) -methyl 3- ( (2- (5， 7-difluoro-1H-indol-3-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (300 mg， 0.5 mmol) in THF/water (1/1， 10 mL) was added NaOH (40 mg， 1mmol) at room temperature and stirred for 2 h. After TLC indicated the complete consumption of starting material， the reaction mixture was neutralized by the addition of aq. HCl solution to pH ＞ 5. The reaction mixture was then concentrated in vacuo to give a crude product， which was purified by Prep-HPLC to afford the title compound (20 mg， 9.6％yield) as a white solid. MS： 417.1 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) ： δ 8.31 (s， 1H) ， 8.22 (d， J ＝ 5.2 Hz， 1H) ， 8.05 (dd， J ＝ 2.0， 9.6 Hz， 1H) ， 7.00-6.94 (m， 1H) ， 5.11 (d， J＝6.8 Hz， 1H) ， 2.91 (d， J＝7.2 Hz， 1H) ， 2.18-1.56 (m， 10H) .

Example 29

(rac) - (6S， 7S) -7- ( (2- (5， 7-Difluoro-1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [3.2.2] nonane-6-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 reaction without further purification. MS： 225.1 [M+H⁺] .

[R] (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-1 H-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 three times) . The combined organic layers were dried over anhydrous 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- ( (2- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -5- fluoropyrimidin-4-yl) amino) bicyclo [3.2.2] nonane-6-carboxylate

A stirred mixture solution of 5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -3- (tributylstannyl) -1H-indazole (Intermediate A-2b， 200 mg， 0.379 mmol) ， (rac) - (1R， 5S， 6S， 7S) -Methyl 7-aminobicyclo [3.2.2] nonane-6-carboxylate (149 mg， 0.455 mmol) ， Pd₂ (dba) ₃ (42 mg， 0.057 mmol) and Xphos (27 mg， 0.057 mmol) in dioxane (5 mL) was heated at 120 ℃ for 2 h under microwave heating. After cooling to room temperature， the solvent was removed under reduced pressure to give a crude product， which was purified by silica gel flash chromatography (petroleum ether∶EtOAc＝3∶1 to DCM： MeOH＝30∶1) to afford the tltle compound (180 mg， 45％yield) as a yellow solid. MS： 530.2 [M+H] ⁺.

[F] (rac) - (6S， 7S) -7- ( (2- (5， 7-Difluoro-1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [3.2.2] nonane-6-carboxylic acid

A stirred solution of (rac) - (6S， 7S) -methyl 7- ( (2- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [3.2.2] nonane-6-carboxylate (180 mg， 0.34 mmol) in 4 N HCl (10 mL) was stirred at 100C for 12 h. After cooling to the room temperature， the solvent was removed under reduced pressure to give a crude product， which was purified by Prep-HPLC to afford the title compound (66 mg， 45％yield) as a white solid. MS： 432.1， [M+H] ⁺. ¹H NMR (300 MHz， DMSO-d6) δ 8.34 (d， J＝4.1 Hz， 1H) ， 8.21 (br. s.， 1H) ， 8.12-8.04 (m， 1H) ， 7.40 (t， J＝9.2 Hz， 1H) ， 5.06 (t， J＝7.2 Hz， 1H) ， 2.92 (dd， J＝3.8， 7.5 Hz， 1H) ， 2.41 (br. s. ， 1H) ， 2.05-1.81 (m， 3H) ， 1.77-1.44 (m， 5H) .

Example 30

(rac) - (2S， 3S) -3- [ [2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoro-pyrimidin-4-yl] amino] norbornane-2-carboxyiic 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. This crude product 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 twice) . The organic layer was washed with satd. aq. NaHCO₃ solution (200 mL three times) ， dried over anhydrous 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， 1H) ， 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 Et₂0 (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 anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude title compound (0.45 g， 73.7％yield) as an oil. This crude product 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. This crude product 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 twice) and Et₂O (20 mL) before 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 anhydrous 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 9， 7.2 mmol) and Boc₂O (1.27 g， 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 twice) . After concentrating the mixture solution under reduced pressure， the residue was purified by silica gel 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 72 h. 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 anhydrous 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- ( (2- (5，7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -5- fluoropyrimidin-4-yl) amino) bicyclo [2.2.1] heptane-2-carboxylate

A stirred mixture solution of 5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -3- (tributylstannyl) -1H-indazole (Intermediate A-2b， 250 mg， 0.47 mmol) ， Pd₂ (dba) ₃ (52 mg， 0.071 mmol) ， (rac) -(2S， 3S) -methyl， 3- ( (2-chloro-5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.1] heptanes -2-carboxylate (169 mg， 0.57 mmol) and Xphos (34 mg， 0.071 mmol) in dioxane (5 mL) was heated at 120 ℃ for 2 h under microwave heating. After cooling to room temperature， the solvent was removed under reduced pressure to give a crude product， which was purified by silica gel flash chromatography (petroleum ether∶EtOAc ＝ 5∶1 to DCM∶MeOH ＝ 30∶1) to afford the title compound (150 mg， 31.6％yield) as yellow oil.

[J] (rac) - (2S， 3S) -3- [ [2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoro-pyrimidin-4-yl] amino] norbornane-2-carboxylic acid

A solution of (rac) - (2S， 3S) -methyl 3- ( (2- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.1] heptane-2-carboxylate (150 mg， 0.3 mmol) in 4 N HCl (10 mL) was stirred at 100 ℃ for 12 h. After cooling to room temperature， the solvent was removed under reduced pressure to give a crude product， which was purified by Prep-HPLC to afford the title compound (10 mg， 8.4％yield) as a white solid. MS： 404.1， [M+H] ⁺. ¹H NMR (400 MHz， DMSO-d6) δ 8.27 (s， 1 H) 7.97-7.99 (d， J＝8.4 Hz， 1 H) 7.88 (s， 1 H) 7.31 (m， 1 H) 4.72 (s， 1 H) 2.68 (s， 1 H) 2.47 (s， 1 H) 2.34 (s， 1 H) 1.71-1.73 (d， J＝8 Hz， 1 H) 1.47-1.54 (m， 3 H) 1.25-1.28 (m， 2 H) .

Example 31

(+) - (1S， 5R， 6S， 7S) -6- [ [5-fluoro-2- (7-fluoro-1H-indazol-3-yl) pyrimidin-4-yl] amino] bicyclo [3.2.2] nonane-7-carboxylic acid

[A] (-) -Methyl (1S， 5R， 6S， 7S)-6- [ (2-chloro-5-fluoro-pyrimidin-4-yl) amino] bicyclo [3.2..2] - nonane-7-carboxylate and (+) -methyl (1R， 5S， 6R， 7R) -6- [ (2-chloro-5-fluoro-pyrimidin-4- yl) amino] bicyclo [3.2.2] nonane-7-carboxylate

A stirred mixture solution of 2， 4-dichloro-5-fluoropyrimidine (6.09 g， 36.5 mmol) ， (rac) -(1R， 5S， 6S， 7S) -methyl 7-aminobicyclo [3.2.2] nonane-6-carboxylate (9 g， 18.2 mmol) ， and N， N-diisopropylethylamine (4.72 g， 36.5 mmol) in THF (150 mL) was heated at 60 ℃ for 16 h. After cooling to room temperature， the solvent was evaporated under reduced pressure and the residue was purified by silica gel flash chromatography (petroleum ether∶EtOAc ＝ 0 to 30％gradient) to afford the title mixture of racemic compounds (6.4 g， 85.6％yield) . It was then subject to SFC separation (IC， 250 × 30 mm I. D.， mobile phase A/CO₂， B/MeOH， 30％B gradient) to afford both enantiomers， (-) -methyl (1S， 5R， 6S， 7S) -6- [ (2-chloro-5-fluoro-pyrimidin-4-yl) amino] bicyclo [3.2.2] nonane-7-carboxylate (2 g， 31％yield) and (+) -methyl (1R， 5S， 6R， 7R) -6- [ (2-chloro-5-fluoro-pyrimidin-4-yl) amino] bicyclo [3.2.2] nonane-7-carboxyiate (2 g， 31％yield) as white solids. MS： 328.2 [M+H] ⁺..

[B] (+) -Methyl (1S， 5R， 6S， 7S) -6- [ [5-fluoro-2- (7-fluoro-1-tetrahydropyran-2-yl-indazol-3- yl) pyrimidin-4-yl] amino] bicyclo [3.2.2] nonane-7-carboxylate

To a stirred mixture solution of (-) -methyl (1S， 5R， 6S， 7S) -6- [ (2-chloro-5-fluoro-pyrimidin-4-yl) amino] bicyclo [3.2.2] nonane-7-carboxylate (220 mg， 671 μmol) and Pd (PPh₃) ₄ (100 mg， 86.5 μmol) in dioxane (4 mL) was added 1， 1， 1， 2， 2， 2-hexabutyldistannane (552 mg， 0.5 ml， 952 μmol) and the resulting reaction mixture solution was stirred at 125 ℃ for 2 h before being cooled back to room temperature. To the above solution was then added 7-fluoro-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (Intermediate A-1， 348 mg， 1.01 mmol) and Pd(PPh₃) ₄ (100 mg， 86.5 μmol) in dioxane (16 mL) . The resulting reaction mixture was stirred at 145 ℃ for 1 h under microwave heating. After cooling to room temperature， the reaction mixture was poured into water (20 mL) and extracted with EtOAc (50 mL twice) . The combined organic layers were washed with brine， dried over anhydrous Na₂SO₄， filtered and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (0-80％EtOAc-hexane gradient) to afford the title compound as a yellow solid (95 mg， 27.7％yield) . MS： 512.2 [M+H] ⁺.

[C] (+) - (1S， 5R， 6S， 7S) -6- [ [5-Fluoro-2- (7-fluoro-1H-indazol-3-yl) pyrimidin-4-yl] amino] bicyclo- [3.2.2] nonane-7-carboxylic acid

A solution of +) -methyl (1S， 5R， 6S， 7S) -6- [ [5-fluoro-2- (7-fluoro-1-tetrahydropyran-2-yl-indazol-3-yl) pyrimidin-4-yl] amino] bicyclo [3.2.2] nonane-7-carboxylate (95mg， 186 μmol) in 37％aq. HCl solution (10 mL) and dioxane (10 ml) was stirred at 60 ℃ for 6 h. After cooling to room temperature， the solvent was removed under reduced pressure and the residue was purified by Prep-HPLC to afford the title compound (35 mg， 45.6％yield) as a white solid. MS： 414.2 [M+H] ⁺. ¹H NMR (400 MHz， DMSO-d6) δ 14.00 (br s， 1H) ， 12.30 (br s， 1H) ， 8.36 (d， J＝7.82 Hz， 1H) ， 8.25 (d， J＝3.67 Hz， 1H) ， 7.70 (br d， J＝7.21 Hz， 1H) ， 7.07-7.30 (m， 2H) ， 4.97 (br t， J＝7.21 Hz， 1H) ， 2.82 (br dd， J＝3.30， 7.46 Hz， 1H) ， 2.39 (br s， 1H) ， 1.91-2.05 (m， 2H) ， 1.84 (br d， J＝8.07 Hz， 2H) ， 1.58-1.74 (m， 5H) ， 1.42-1.56 (m， 2H) .

Example 32

(-) - (1R， 5S， 6R， 7 R) -6- [ [5-Fluoro-2- (7-fluoro-1H-indazol-3-yl) pyrimidin-4-yl] amino] bicyclo- [3.2.2] nonane-7-carboxylic acid

[A] (-) -Methyl (1R， 5S， 6R， 7R) -6- [ [5-fluoro-2- (7-fluoro-1-tetrahydropyran-2-yl-indazol-3- yl) pyrimidin-4-yl] amino] bicyclo [3.2.2] nonane-7-carboxylate

In analogy to the synthesis of Example 31/Step B， (+) -methyl (1R， 5S， 6R， 7R) -6- [ (2-chloro-5-fluoro-pyrimidin-4-yl) amino] bicyclo [3.2.2] nonane-7-carboxylate (220 mg， 671 μmol) was used to afford the title compound (95 mg， 27.7％yield) as a yellow solid after silica gel flash chromatography (0-80％EtOAc-hexane gradient) purification. MS： 512.2 [M+H] +.

[B] (-) - (1R， 5S， 6R， 7R) -6- [ [5-Fluoro-2- (7-fluoro-1H-indazol-3-yl)pyrimidin-4- yl] amino] bicyclo [3.2.2] nonane-7-carboxylic acid

In analogy to the synthesis of Example 31/Step C， (-) -methyl (1R， 5S， 6R， 7R) -6- [ [5-fluoro-2-(7-fluoro-1-tetrahydropyran-2-yl-indazol-3-yl) pyrimidin-4-yl] amino] bicyclo [3.2.2] nonane-7-carboxylate (95 mg， 186 μmol) was used to afford the title compound (30 mg， 39.1％yield) as a yellow solid after Prep-HPLC separation. MS： 414.2 [M+H] ⁺. 1H NMR (400 MHz， DMSO-d6) δ 14.00 (br s， 1H) ， 12.30 (br s， 1H) ， 8.36 (d， J＝7.82 Hz， 1H) ， 8.25 (d， J＝3.67 Hz， 1H) ， 7.70 (br d， J＝7.21 Hz， 1H) ， 7.07-7.30 (m， 2H) ， 4.97 (br t， J＝7.21 Hz， 1H) ， 2.82 (br dd， J＝3.30， 7.46 Hz， 1H) ， 2.39 (br s， 1H) ， 1.91-2.05 (m， 2H) ， 1.84 (br d， J＝8.07 Hz， 2H) ， 1.58-1.74 (m， 5H) ， 1.42-1.56 (m， 2H) .

Example 33

(-) - (2S， 3S) -3- [ [5-fluoro-2- (7-fluoro-1H-indazol-3-yl) pyrimidin-4-yl] amino] -N-methyl-bicyclo [2.2.2] octane-2-carboxamide

To a stirred solution of (-) - (2S， 3S) -3- ( (5-Fluoro-2- (7-fluoro-1H-indazol-3-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-car boxylic acid (Example 17， 193 mg， 483 μmol) in DCM (5 mL) was added 2- (3H- [1， 2， 3] triazolo [4， 5-b] pyridin-3-yl) -1， 1， 3， 3-tetramethylisouronium hexafluorophosphate (V) (239 mg， 628 μmol) ， methanamine hydrochloride， and N， N-diisopropylethylamine (187 mg， 1.45 mmol) at room temperature and stirred for 16 h. Afterwards， the reaction mixture was washed with satd. aq. NaHCO₃ solution， dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purifed by Prep-HPLC to afford the title compound (112 mg， 56.2％yield) as white foam. MS： 413.1 [M+H] ⁺. ¹H NMR (400 MHz， DMSO-d6) □ 8.29 -8.38 (m， 2 H) 8.06 -8.23 (m， 1 H) 7.77 (d， J＝4.65 Hz， 1 H) 7.24 (br. s.， 2 H) 4.88 -5.01 (m， 1 H) 2.66 -2.74 (m， 1 H) 2.57 (d， J＝4.52 Hz， 3 H) 1.86 -1.96 (m， 2 H) 1.72 -1.85 (m， 3 H) 1.53 -1.66 (m， 2 H) 1.44 -1.53 (m， 1 H) 1.29-1.43 (m， 2 H) .

Example 34

-) - (6S， 7R) -9-chloro-6- [ [5-fluoro-2- (7-fluoro-1H-indazol-3-yl) pyrimidin-4-yl] amino] -8-methyl-bicyclo [3.2.2] nonane-7-carboxylic acid

A solution of (-) - (1R， 2S， 4R， 5S， 9R， 10R) -methyl 10- ( (2- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) tricyclo [3.3.2.02， 4] decane-9-carboxylate (120 mg， 229 μmol) in 37％aq. HCl solution (10 mL) and dioxane (10 mL) was stirred at 60 ℃ for 6 h. After cooling to room temperature， the solvent was removed under reduced pressure and the residue was purified by Prep-HPLC to afford the title compound (20 mg， 19％yield) as a yelow solid. MS： 462.2 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) δ 8.37 (br d， J＝7.58 Hz， 1H) ， 8.03 (br s， 1H) ， 6.92-7.16 (m， 2H) ， 5.41 (br d， J＝9.78 Hz， 1H) ， 4.54 (dd， J＝2.75， 7.89 Hz， 1H) ， 2.56 (s， 1H) ， 2.43 (quin， J＝7.24 Hz， 1H) ， 2.06-2.18 (m， 1H) ， 2.03 (br d， J＝3.06 Hz， 1H) ， 1.77-1.97 (m， 2H) ， 1.37-1.70 (m， 4H) ， 1.21 (d， J＝6.97 Hz， 3H) .

Example 35

(-) - (6R， 7S) -9-chloro-6- [ [5-fluoro-2- (7-fluoro-1H-indazol-3-yl) pyrimidin-4-yl] amino] -8-methyl-bicyclo [3.2.2] nonane-7-carboxylic acid

In analogy to the synthesis of Example 34， (+) - (1S， 2R， 4S， 5R， 9S， 10S) -methyl 10- ( (2- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) tricyclo [3.3.2.02， 4] decane-9-carboxylate (120 mg， 229 μmol) was used to afford the title compound (20 mg， 19％yield) as a yellow solid after Prep-HPLC purification. MS： 462.2 [M+H] ⁺， ¹H NMR (400 MHz， MeOH-d4) δ 8.37 (br d， J＝7.70 Hz， 1H) ， 7.98-8.10 (m， 1H) ， 6.94-7.11 (m， 2H) ， 5.41 (br d， J＝9.90 Hz， 1H) ， 4.55 (dd， J＝2.87， 7.76 Hz， 1H) ， 2.56 (s， 1H) ， 2.38-2.49 (m， 1H) ， 2.07-2.20 (m， 1H) ， 2.04 (br d， J＝3.30 Hz， 1H) ， 1.76-1.98 (m， 2H) ， 1.41-1.72 (m， 4H) ， 1.16-1.26 (m， 3H) . MS： 462.2 [M+H] ⁺.

Example 36

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

[A] (rac) - (2S， 3S) -Methyl 3- ( (2- (5， 7-dimethyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -5- fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate

To a mixture solution of 7-fluoro-5-methyl-1- (tetrahydro-2H-pyran-2-yl) -3- (tributylstannyl) -1H-indazole (Intermediate A-7b， 156 mg， 0.3 mmol) and (rac) - (2S， 3S) -methyl 3- ( (2-chloro-5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (145 mg， 0.45 mmol) in dioxane (1 mL) was added Pd₂ (dba) ₃ (27 mg， 0.03 mmol) and X-Phos (15 mg， 0.03 mmol) . The resulting mixture solution was stirred at 140 ℃ for 2 h under microwave heating. 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 ＝ 100∶1～20∶1) to afford the title compound (25 mg， 16.3％yield) as as white solid. MS： 512.2 [M+H] ⁺.

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

A suspension of (rac) - (2S， 3S) -methyl 3- ( (2- (5， 7-dimethyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (20 mg， 0.04 mmol) in 4 N HCl (2 mL) was stirred at 80 ℃ for 4 h. After LC-MS showed the completion of reaction， the mixture was concentrated in vacuo to give a crude product， which was purified by Prep-HPLC to afford the title compound (22.8 mg， 38％yield) as a white solid. MS： 414.2 [M+H] ⁺. ¹H NMR (400MHz， CHCl₃-d1) δ 8.21 (m， 2H) ， 7.12-7.09 (m， 1H) ， 5.20 (m， 1H) ， 2.91- 2.90 (m， 2H) ， 2.54 (s， 3H) ， 2.18 (m， 2H) ， 2.06-2.00 (m， 2H) ， 1.88 (m， 2H) ， 1.77-1.73 (m， 2H) ， 1.60-1.57 (m， 2H) .

Example 37

(+ or -) - (2S， 3S) -3- [ [2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoro-pyrimidin-4-yl] amino] -N-methyl-bicyclo [2.2.2] octane-2-carboxamide

To a stirred solution of (-) - (1R， 2S， 3S， 4R) -3- ( (2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (Example 16， 202mg， 484 μmol) in DCM (5 mL) was added 2- (3H- [1， 2， 3] triazolo [4， 5-b] pyridin-3-yl) -1， 1， 3， 3-tetramethylisouronium hexafluorophosphate (V)(239 mg， 629 μmol) ， and N， N-diisopropylethylamine (188 mg， 1.45 mmol) at room temperature and stirred for 16 h. Afterwards， the reaction mixture was washed with satd. aq. NaHCO₃ solution， dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purifed by Prep-HPLC to afford the title compound as a white solid. MS： 431.1 [M+H] ⁺. ¹H NMR (400 MHz， DMSO-d6) δ 14.03-14.23 (m， 1H) ， 8.24-8.29 (m， 1H) ， 8.07-8.15 (m， 1H) ， 7.62-7.80 (m， 2H) ， 7.32-7.46 (m， 1H) ， 4.84-4.94 (m， 1H) ， 2.63-2.70 (m， 1H) ， 2.54-2.61 (m， 3H) ， 1.71-1.94 (m， 5H) ， 1.28-1.67 (m， 5H) .

Example 38

(+ or -) - (2R， 3R) -2- [ [5-Fluoro-2(7-fluoro-1H-indazol-3-yl) pyrimidin-4-yl] amino] -5-methyl-bicyclo [2.2.2] octane-3-carboxylic acid

In analogy to the synthesis of example 39， (+ or -) -methyl (2R， 3R) -2-amino-5-methyl-bicyclo [2.2.2] octane-3-carboxylate was used in step A， and following the same steps B and C， the title compound (12 mg， 12.7％yield) was obtained as a yellow solid after Prep-HPLC purification. MS： 414.1 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) δ 0.98 -1.08 (m， 3 H) 1.09 -1.50 (m， 3 H) 1.67 (d， J＝10.04 Hz， 1 H) 1.74 -1.99 (m， 4 H) 2.04 -2.28 (m， 3 H) 2.58 -2.72 (m， 1 H) 5.03 (d， J＝7.40 Hz， 2 H) 7.16 (br. s.， 2 H) 7.91 -8.19 (m， 1 H) 8.28 -8.55 (m， 1 H) .

Example 39

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

[A] Methyl (2S， 3S) -2- [ [5-fluoro-2- (7-fluoro-1-tetrahydropyran-2-yl-indaxol-3-yl) pyrimidin-4- yl] amino] -5-methyl-bicyclo [2.2.2] octane-3-carboxylate

To a stirred solution of 7-fluoro-3- (5-fluoro-4- (methylsulfinyl) pyrimidin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (Example 42/Step C， 50 mg， 0.132 mmol) in THF (10 mL) was added methyl (2S， 3S) -2-amino-5-methyl-bicyclo [2.2.2] octane-3-carboxylate (26.1mg， 0.132 mmol) and DIPEA (17.1 mg， 0.132 mmol) and the resulting reaction mixture was stirred at 70 ℃ for 12 h. After cooling to room temperature， the mixture was concentrated in vacuo to give a crude product， which was purified by Prep-TLC (petroleum ether∶EtOAc ＝ 1∶1) to give the title compound (50 mg， 74.1％yield) as a yellow solid. MS： 512.3 [M+H] ⁺

[B] (+ or-) -Methyl (2S， 3S) -2- [ [5-fluoro-2- (7-fluoro-1H-indazol-3-yl) pyrimidin-4-yl] amino] -5- methyl-bicyclo [2.2.2] octane-3-carboxylate

To a stirred solution of (+ or -) -methyl (2S， 3S) -2- [ [5-fluoro-2- (7-fluoro-1-tetrahydropyran-2-yl-indazol-3-yl) pyrimidin-4-yl] amino] -5-methyl-bicyclo [2.2.2] octane-3-carboxylate (100 mg， 0.2 mmol) in DCM (10 mL) was added TFA (10 mL) at room temperature and stirred for 12 h. After TLC (petroleum ether∶EtOAc ＝ 1∶1) showed that the reaction was completed， the reaction mixture was concentrated in vacuo to give a crude title compound (80 mg， 95.7％yield) as a red solid. MS： 428.3 [M+H] ⁺. It was used directly in the next step reaction without further purification.

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

To a solution of (+ or-) -methyl (2S， 3S) -2- [ [5-fluoro-2- (7 -fluor o-1H-indazol-3-yl) pyrimidin-4-yl] amino] -5-methyl-bicyclo [2.2.2] octane-3-carboxylate (70 mg， 0.16 mmol) in MeOH (10 mL) was added 4 N NaOH solution (10 mL) ) at room temperature. The reaction mixture was stirred at room temperature for 3 h. After TLC (petroleum ether∶EtOAc ＝ 1∶1) showed that the reaction was completed， methanol was removed under reduced pressure. After acidification with 4 N HCl to adjust pH ＝ 6～7， the mixture solution was extracted with DCM (20 mL three times) . The organic extracts were concentrated in vacuo to give a crude product， which was then purified by Prep-HPLC to afford the title compound (20 mg， 29％yield) as a white solid. MS： 414.1 [M+H] ⁺. ¹H NMR (400MHz， MeOH-d4) δ 8.35 (d， J＝8.28 Hz， 1 H) ， 8.29 (d， J＝3.76 Hz， 1 H) ， 7.32～740 (m， 1 H) ， 7.23～7.31 (m 1 H) ， 5.15 (d， J＝6.78 Hz， 1 H) ， 2.97 (d， J＝7.28 Hz， 1 H) ， 2.15～2.25 (m， 1 H) ， 1.88～2.13 (m， 4 H) ， 1.81 (br. s.， 1 H) ， 1.71 (d， J＝10.79 Hz， 1 H) ， 1.46～1.56 (m， 1 H) ， 1.21 (dd， J＝12.67， 7.65 Hz， 1 H) ， 1.00～1.15 (m， 3 H) .

Example 40

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

In analogy to the synthesis of example 39， (+ or -) -methyl (2R， 3R) -3-amino-5-methyl-bicyclo [2.2.2] octane-2-carboxylate was used in step A， and following the same steps B and C， the title compound (20 mg， 27.7％yield) was obtained as a yellow solid after Prep-HPLC purification. MS： 414.1 [M+H] ⁺. ¹H NMR (400Mhz， MeOH-d4) δ 8.20～8.39 (m， 2 H) ， 7.20～7.37 (m， 2 H) ， 5.11 (d， J＝5.52 Hz， 1 H) ， 2.92 (d， J＝6.02 Hz， 1 H) ， 2.20 (br. s.， 2 H) ， 1.93～2.05 (m， 2 H) ， 1.59～1.89 (m， 4 H) ， 1.31 (br. s.， 1 H) ， 1.05～1.18 (m， 3 H) .

Example 41

(+ or -) - (2R， 3R) -3- [ [5-fluoro-2- (7-fluoro-1H-indazol-3-yl) pyrimidin-4-yl] amino] -5-methyl-bicyclo [2.2.2] octane-2-carboxylic acid

In analogy to the synthesis of example 39， (+ or -) -methyl (2S， 3S) -3-amino-5-methyl- bicyclo [2.2.2] octane-2-carboxylate was used in step A， and following the same steps B and C， the title compound (20 mg， 27.8％yield) was obtained as a yellow solid after Prep-HPLC purification. MS： 414.1 [M+H] ⁺. ¹H NMR (400MHz， MeOH-d4) δ 8.25～8.41 (m， 2 H) ， 7.23～7.38 (m， 2 H) ， 5.12 (d， J＝4.77 Hz， 1 H) ， 2.92 (d， J＝5.77 Hz， 1 H) ， 2.21 (br. s.， 2 H) ， 2.00 (br. s.， 2 H) ， 1.62～1.89 (m， 4 H) ， 1.28～1.44 (m， 1 H) ， 1.07～1.17 (m， 3 H) .

Example 42

(rac) - (1R， 2S， 3S， 4S) -3- [ [5-fluoro-2- (7-fluoro-1H-indazol-3-yl) pyrimidin-4-yl] amino] norbornane-2-carboxylic acid

[A] 5-Fluoro-4- (methylthio) -2- (tributylstannyl) pyrimidine

A mixture solution of 2-chloro-5-fluoro-4- (methylthio) pyrimidine (619 mg， 3.46 mmol) ， Sn₂Bu₆ (2.21 g， 3.82 mmol) ， Pd₂ (dba) ₃ (380 mg， 0.52 mmol) and X-Phos (250 mg， 0.52 mmol) in methyl-THF (10 mL) was stirred at 100 ℃ for 2 h. Aftr TLC (petroleum ether∶EtOAc ＝40∶1) showed that the reaction was completed， the reaction mixture was used directly in the next step without further purification. MS： 435.1 [M+H] ⁺.

[B] 7-Fluoro-3- (5-fluoro-4- (methylthio) pyrimidin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H- indazole

A mixture solution of 7-fluoro-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (Intermediate A-1， 900 mg， 2.6 mmol) ， 5-fluoro-4- (methylthio) -2- (tributylstannyl) pyrimidine (3.46 mmol) ， Pd₂ (dba) ₃ (480 mg， 0.42 mmol) ， X-Phos (200 mg， 0.42 mmol) ， and Cul (80 mg， 0.42 mmol) in methyl-THF (5 mL) was stirred at 92 ℃ for 24 h. After TLC (petroleum ether∶EtOAc ＝ 40∶1) showed that half of the start material was consumed， the reaction mixture was concentrated under reduced presure to give a crude product， which was purified by silica gel flash chromatography (petroleum ether∶EtOAc ＝ 20∶1 to 6∶1) to afford the title compound (0.37 g， 39％yield) as a solide. MS： 279.0 [M+H] ⁺.

[C] 7-Fluoro-3- (5-fluoro-4- (methylsulfinyl) pyrimidin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H- indazole

To a stirred solution of 7-fluoro-3- (5-fluoro-4- (methylthio) pyrimidin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (1.5 g， 4.44 mmol) in DCM (30 mL) was added m-CPBA (0.92 g， 4.55 mmol) with ice-water bath cooling. Afterwards， the reaction was stirred at 5 ℃ for 1 h and quenched by the addition of satd. Na₂SO₃ solution after TLC (petroleum ether∶EtOAc ＝10∶1) showed the start material was consumed. The mixture solution was then extracted with DCM (30 mL twice) and the organic layer was washed with brine， dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (petroleum ether∶EtOAc ＝ 2∶1 to DCM∶EtOAc ＝ 1∶1) to afford the title compound (0.5 g， 13.6％yield) as a solid. MS： 379.0 [M+H] ⁺.

[D] (rac) -Methyl (1R， 2S， 4S) -3- [ [5-fluoro-2- (7-fluoro-1-tetrahydropyran-2-yl-indazol-3- yl) pyrimidin-4-yl] amino] norbornane-2-carboxylate

To a solution of 7-fluoro-3- (5-fluoro-4- (methylsulfinyl) pyrimidin-2-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (400 mg， 1.08 mmol) in THF(30 mL) was added (rac) - (1R， 2S， 3S， 4S) -methyl 3-aminobicyclo [2.2.1] heptane-2-carboxylate (Example 30/Step H， 201.4 mg， 1.19 mmol) and DIPEA (139.6 mg， 1.08 mmol) at room temperature. The resulting reaction mixture was stirred at 70 ℃ for 12 h before being cooled back to room temperature and concentrated in vacuo. The crude product was then purified by Prep-TLC (petroleum ether∶EtOAc ＝ 1∶1) to afford the title compound (230 mg， 45.1％ yield) as a yellow solid. MS： 484.2[M+H] ⁺

[E] (rac) - (1R， 2S， 3S， 4S) -Methyl. 3- ( (5-fluoro-2- (7-fluoro-1H-indazol-3-yl) pyrimidin-4-yl) amino) bicyclo [2.2.1] heptane-2-carboxylate

To a solution of (rac) - (1R， 2S， 3S， 4S) -methyl 3- ( (5-fluoro-2- (7-fluoro-1- (tetrahydro-2H-pyran-2- yl) -1H-indazol-3-yl) pyrimidin-4-yl) amino) bicyclo [2.2.1] heptane-2-carboxylate (230 mg， 0.475 mmol) in DCM (10 mL) was added TFA (10 mL) at room temperature and stirred for 12 h. After TLC (petroleum ether∶EtOAc＝1∶1) showed that the reaction was completed， the mixture solution was concentrated in vacuo to give a crude title compound (170 mg， 89.9％yield) as a red solid. MS： 400.2 [M+H] ⁺. This crude product was used directly in the next step without further purification.

[F] (rac) - (1R， 2S， 3S， 4S) -3- [ [5-fluoro-2- (7-fluoro-1H-indazol-3-yl) pyrimidin-4-yl] amino] norbornane-2-carboxylic acid

To a solution of (rac) - (1R， 2S， 3S， 4S) -methyl 3- ( (5-fluoro-2- ( (7-fluoro-1H-indazol-3-yl) pyrimidin -4-yl) amino) bicyclo [2.2.1] heptane-2-carboxylate (170 mg， 0.427 mmol) in MeOH (10 mL) was added 4N NaOH solution (10 mL) ) at room temperature and stirred for 3 h. After TLC (petroleum ether∶EtOAc ＝ 1∶1) showed that the reaction was completed， the reaction mixture was concentrated to remove MeOH and then acidified with 4N HCl to pH ＝6～7， and extracted with DCM (20 mL three times) . The organic extracts were concentrated in vacuo to give a crude product， which was purified by Prep-HPLC to give title compound (35 mg， 23.3％yield) as a yellow solid. MS： 386.1 [M+H] ⁺. ¹H NMR (400MHz， MeOH-d4) δ8.21～8.41 (m， 2 H) ， 7.32～7.41 (m， 1 H) ， 7.23～7.30 (m， 1 H) ， 5.13 (br. s.， 1 H) ， 2.86 (br. s.， 1 H) ， 2.68 (br. s.， 1 H) ， 2.56 -2.64 (m， 1 H) ， 1.88 (d， J＝10.29 Hz， 1 H) ， 1.60～1.80 (m， 3 H) ， 1.45～1.57 (m， 2H) .

Example 43

(rac) - (1R， 2R， 3R， 4S) -3- [ [5-Fluoro-2- (7-fluoro-1H-indazol-3-yl) pyrimidin-4-yl] amino] -7-oxabicyclo [2.2.1] heptane-2-carboxylic acid

[A] (rac) - (1R， 2S， 3S， 4S) -3-Methoxycarbonyl-7-oxabicyclo [2.2.1] heptane-2-carboxylic acid

A mixture solution of exo-7-oxabicyclo [2.2.1] heptane-2， 3-dicarboxylic anhydride (5 g， 29.7 mmol) and sodium methoxide (8.03 g， 149 mmol) in MeOH (20 mL) was stirred at room temperature for 16 h.Afterwards， the mixture was treated with 1 N HCl solution (160 mL) slowly and then extracted with EtOAc (50 mL x 4) . The combined organic layers were dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude title compound (3.9 g) as a white solid. This crude product was used directly in the next step without further purification.

[B] (rac) -Methyl (1S， 2S， 3S， 4R) -3- (benzyloxycarbonylamino) -7-oxabicyclo [2.2.1] heptane-2- carboxylate

A mixture solution of (rac) - (1R， 2S， 3S， 4S) -3-methoxycarbonyl-7-oxabicyclo [2.2.1] heptane-2-carboxylic acid (3.85 g， 19.2 mmol) ， diphenyl phosphorazidate (6.35 g， 23.1 mmol) and Et₃N (3.89 g， 38.5 mmol) was stirred at room temperature for 1 h. After the reaction temperature was raised up to 100℃ and heated for 1 h， benzyl alcohol (4.16 g， 38.5 mmol) was added to the mixture and the resulting solution was heated at 100 ℃ for another 1 h. After cooling to room temperature， the solvent was removed under reduced pressure and the residue was purified by silica gel flash chromatography to afford the title compound (3.9 g， 66％ yield) as a yellow solid. MS： 306.1 [M+H] ⁺

[C] (rac) -Methyl (1S， 2S， 3S， 4R) -3-amino-7-oxabicyclo [2.2.1] heptane-2-carboxylate

A mixture solutiorl of (rac) -methyl (1S， 2S， 3S， 4R) -3- (benzyloxycarbonylamino) -7-oxabicyclo [2.2.1] heptane-2-carboxylate (3.9 g， 12.8 mmol) and palladium hydroxide on carbon (179 mg， 1.28 mmol) in MeOH (100 ml) was stirred at room temperature under H₂ (1atm) atmosphere for 16 h. Afterwards， the reaction mixture was filtered， and the filtrate was concentrated in vacuo to give a crude title compound (2 g， 91.5％ yield) as yellow gum. MS：172.1 [M+H+] . This crude product was used directly in the next step without further purification.

[D] (rac) -Methyl (1S， 2S， 3S， 4R) -3- [ (2-chloro-5-fluoro-pyrimidin-4-yl) amino] -7- oxabicyclo [2.2.1] heptane-2-carboxylate

A stirred mixture solution of (rac) -methyl (1S， 2S， 3S， 4R) -3-amino-7-oxabicyclo [2.2.1] -heptane-2-carboxylate (2 g， 11.7 mmol) ， 2， 4-dichloro-5-fluoropyrimidine (2.93 g， 17.5 mmol) and DIPEA (2.26 g， 17.5 mmol) in THF (40 mL) was heated at 60 ℃ for 16 h. After cooling to room temperature， the solvent was removed under reduced pressure， and the residue was purified by silica gel flash chromatography (petroleum ether： EtOAc ＝ 0 to 40％) to afford the title compound (3 g， 85.1％ yield) as a white solid. MS： 302.2 [M+H+] .

[E] (rac) -Methyl (1R， 2R， 3R. 4S) -3- [ [5-fluoro-2- (7-fluoro-1-tetrahydropyran-2-yl-indazol-3- yl)pyrimidin-4-yl]amino] -7-oxabicyclo [2.2.1] heptane-2-carboxylate

A stirred mixture solution of (rac) -methyl (1S， 2S， 3S， 4R) -3- [ (2-chloro-5-fluoro-pyrimidin-4-yl) amino] -7-oxabicyclo [2.2.1] heptane-2-carboxylate (250 mg， 829 μmol) ， 1， 1， 1， 2， 2， 2-hexabutyldistannane (577 mg， 994 μmol) and Pd (PPh₃) ₄ (100 mg， 86.5 μmol) in dioxane (10 mL) was heated at 125 ℃ for 3 h. After cooling to room temperature， 7-fluoro-3-iodo-1-(tetrahydro-2H-pyran-2-yl) -1H-indazole (intermediate A-1， 373 mg， 1.08 mmol) ， Pd (PPh₃) ₄ (100 mg， 86.5 μmol) in dioxane (10 mL) was added and the resulting reaction mixture was heated at 145 ℃ under microwave heating for 1 h. After cooling to room temperature， the solvent was removed under reduced pressure， and the residue was purified by silica gel flash chromatography (petroleum： EtOAc ＝ 0 to 80％) to afford the title compound (80 mg， 19.9％ yield) as a white solid. MS： 486.2 [M+H+] .

[F] (rac) - (1R， 2R， 3R， 4S) -3- [ [5-Fluoro -2- (7-fluoro-1 H-indazol-3-yl) pyrimidin-4-yl] amino] -7- oxabicyclo [2.2.1] heptane-2-carboxylic acid

A mixture solution of (rac) -methyl (1R， 2R， 3R， 4S) -3- [ [5-fluoro-2- (7-fluoro-1-tetrahydropyran-2-yl-indazol-3-yl) pyrimidin-4-yl] amino] -7-oxabicyclo [2.2.1] heptane-2-carboxylate (80 mg， 165 umol) and lithium hydroxide monohydrate (69.1 mg， 1.65 mmol) in THF (5 mL) and water (5 mL) was stirred at room temperature for 16 h. Afterwards， the solvent was removed under reduced pressure， and the residue was re-dissolved in TFA (10 mL) and stirred at room temperature for 16 h. The reaction mixture solution was then concentrated in vacuo to

give a crude product， which was purified by Prep-HPLC to afford the title compound (20mg， 31.3％yield) as a white solid. MS： 388.2 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) δ 8.25 (d， J＝8.07 Hz， 1H) ， 8.08 (br s， 1H) ， 6.86-7.25 (m， 2H) ， 4.75-4.76 (m， 3H) ， 4.52 (d， J＝4.40 Hz， 1H) ， 1.53-1.82 (m， 4H) .

Example 44

(rac) - (1R， 2R， 3R， 4S) -3- [ [2- (5， 7-Difluoro-1H-indazol-3-yl) -5-fluoro-pyrimidin-4-yl] amino] -7-oxabicyclo [2.2.1] heptane-2-carboxylic acid

In analogy to the synthesis of Example 46， 5， 7-difluoro-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (Intermediate A-2a， 350 mg， 961 μmol) was used in step E， and after following the same step F， the title compound (20 mg， 31.3％yield) was obtained as a white solid after Prep-HPLC purification. MS： 406.2 [M+H⁺] . ¹H NMR (400 MHz， MeOH-d4) δ 8.09 (br d， J＝3.42 Hz， 1H) ， 7.88-8.00 (m， 1H) ， 6.93-7.10 (m， 1H) ， 4.78 (br s， 1H) ， 4.73 (br d， J＝3.79 Hz， 2H) ， 4.53 (br s， 1H) ， 1.74-1.86 (m， 2H) ， 1.56-1.73 (m， 2H) .

Example 45

(rac) - (2S， 3S) -3- ( (2- (4， 6-difluoro-1H-indazol-1-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] -octane-2-carboxylic acid

[A] (2S， 3S) -methyl-3- ( (2- (4， 6-difluoro-1H-indazol-1-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate

In a seal tube， to a stirred solution of 4， 6-difluoro-1H-indazole (70 mg， 0.45 mmol) in dioxane (10 mL) was added (rac) - (2S， 3S) -methyl 3- ( (2-chloro-5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (Example 5/Step E， 120 mg， 0.38 mmol) ， (1S， 2S) -cyclohexane-1， 2-diamine (35 mg， 0.3 mmol) ， Cul (86 mg， 0.45 mmol) and K₃PO₄ (161 mg， 0.76 mmol) ， and the resulting reaction mixture was heated at 120 ℃ 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 (50 mL three times) . The combined organic extracts were dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (petroleum ether∶EtOAc ＝ 3∶1～1∶1) to afford the title compound (35 mg， 21.3％yield) as red oil. MS： 432.2 [M+H] ⁺.

[B] (rac) - (2S， 3S) -3- ( (2- (4， 6-difluoro-1H-indazol-1-yl) -5-fluoropyrimidin-4- yl) amino) bicyclo [2.2.2] -octane-2-carboxylic acid

A solution of (rac) - (2S， 3S) -methyl-3- ( (2- (4， 6-difluoro -1H-indazol-1-yl) -5-fluoropyrimidin-4-yl) amino) bicycle [2.2.2] octane-2-carboxylate (65 mg， 0.15 mmol) in HCl (20.0 mL) was stirred at 80 ℃ for 12h. After cooling to room temperature， the reaction mixture was concentrated in vacuo to give a crude product， which was purified by Prep-HPLC to afford the title compound (13 mg， 20.8％yield) as a white solid. MS： 418.1 [M+H] ⁺. ¹H NMR (400MHz， MeOH-d4) δ 8.44 (br. s.， 1 H) ， 8.35 (d， J＝9.54 Hz， 1 H) ， 8.13 (br. s.， 1 H) ， 7.02 (t， J＝9.03 Hz， 1 H) ， 4.95 (br. s.， 1 H) ， 2.87 (d， J＝6.78 Hz， 1 H) ， 2.17 (br. s.， 1 H) ， 1.95～2.06 (m， 2 H) ， 1.81～1.92 (m， 2 H) ， 1.64～1.79 (m， 3 H) ， 1.50～1.63 (m， 2H) .

Example 46

(+) - (1S， 5R， 6S， 7S) -6- [ [2- (5， 7-Difluoro-1H-indazol-3-yl) -5-fluoro-pyrimidin-4-yl] amino] bicyclo [3.2.2] nonane-7-carboxylic acid

[A] (+ or -) - (1R， 5S， 6S， 7S) -Methyl 7- ( (2- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H- indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [3.2.2] nonane-6-carboxylate

Similar to the synthesis of Example 29/step E， (+) - (1R， 5S， 6S， 7S) -methyl 7- ( (2-chloro-5-fluoropyrimidin-4-yl) amino) bicyclo [3.2.2] nonane-6-carboxylate (250mg， 763 μmol) was used to afford the title compound (73 mg， 18.1％yield) after silica gel flash chromatography purification (0-80％EtOAc-petroleum ether gradient) as a yellow oil. MS： 530.1 [M+H] ⁺.

[B] (+) - (1S， 5R， 6S， 7S) -6- [ [2- (5， 7-Difluoro-1H-indazol-3-yl) -5-fluoro-pyrimidin-4- yl] amino] bicyclo [3.2.2] nonane-7-carboxylic acid

Similar to the synthesis of Example 29/step F， (+ or -) - (1R， 5S， 6S， 7S) -methyl 7- ( (2- (5， 7-difluoro-1 - (tetrahydro-2H-pyran-2-yl) -1H-indazoi-3-yl) -5-fiuoropyrimidin-4-yl) amino) bicyclo [3.2.2] nonane-6-carboxylate (1.4 g， 2.64 mmol) was used to afford the title compound (595 mg， 52％yield) after prep-HPLC purification as a white solid. MS: 432.1 [M+H] ⁺. ¹H NMR (400 MHz， DMSO-d6) δ 10.52-12.88 (m， 2H) ， 8.26 (d， J＝3.79 Hz， 1H) ， 8.09 (dd， J＝2.08， 9.17 Hz， 1H) ， 7.78 (br d， J＝7.58 Hz， 1H) ， 7.27-7.42 (m， 1H) ， 5.00 (brt， J＝7.34 Hz， 1H) ， 2.86 (dd， J＝3.67， 7.46 Hz， 1H) ， 2.40 (br s， 1H) ， 2.00 (br s， 2H) ， 1.86 (br d， J＝8.31 Hz， 2H) ， 1.57-1.73 (m， 5H) ， 1.44-1.57 (m， 2H) .

Example 47

(trans) -2- [6- [ [ (1S， 3R) -3-Benzamidocyclohexyl] amino] -2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoro-pyrimidin-4-yl] acetic acid

To a stirred solution of (trans) -N- ( (1R， 3S) -3- ( (2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoro-6- (2-hydroxyethyl) pyrimidin-4-yl) amino) cyclohexyl) benzamide (25 mg， 49 μmol) in acetone (2 mL) was added Jones reagent (1.36 M， 20 μl) and the resulting reaction mixture was stirred at room temperature for 1 h before filtration. The filtrate was then concentrated in vacuo to give a crude product， which was purified by prep-HPLC to afford the title compound (2.5 mg， 9.3％yield) as as a light yellow solid. MS: 525.5 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) δ ppm 8.28 (br s， 1 H) 7.88 (br s， 1 H) 7.71 (br d， J＝7.46 Hz， 2 H) 7.39 -7.45 (m， 1 H) 7.30 -7.38 (m， 2 H) 7.07 (br s， 1 H) 4.32 (br s， 1 H) 4.05 (br s， 1 H) 2.31 (br s， 1 H) 2.14 (br d， J＝12.47 Hz， 1 H) 2.00 (br d， J＝10.88 Hz， 1 H) 1.86-1.93 (m， 1 H) 1.47 -1.66 (m， 2 H) 1.27 -1.41 (m， 2H) 1.13 -1.25 (m， 2H) .

Example 48

(-) - (1S， 5R， 6R， 7R) -7- ( (2- (5， 7-Difluoro-1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [3.2.2] nonane-6-carboxylic acid

[A] (+ or -) -(1S， 5R， 6R， 7R) -Methyl 7- ( (2- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H- indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [3.2.2] nonane-6-carboxylate

Similar to the synthesis of Example 29/step E， (+) - (1S， 5R， 6R， 7R) -methyl 7- ( (2-chloro-5-fluoropyrimidin-4-yl) amino) bicyclo [3.2.2] nonane-6-carboxylate (250 mg， 763 μmol) was used to afford the title compound (120 mg， 29.7％yield) after silica gel flash chromatography (0-80％EtOAc-hexane gradient) purification as a yellow oil. MS： 530.1 (M+H) ⁺.

[B] (+ or -) - (1S， 5R， 6R， 7R) -7- ( (2- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) - 5-fluoropyrimidin-4-yl) amino) bicyclo [3.2.2] nonane-6-carboxylic acid

To a stirred mixture solution of (+ or-) - (1S， 5R， 6R， 7R) -methyl 7- ( (2- (5， 7-difluoro-1-(tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [3.2.2] nonane-6-carboxylate (600 mg， 1.13 mmol) in THF (6 mL) and MeOH (3 mL) was added LiOH (136 mg， 5.67 mmol) pre-dissolved in water (3 mL) . The reaction mixture solution was stirred at room temperature for 12 h before being diluted with water (10 mL) and extracted with diethyl ether (20 mL) . The organic layer was discarded and the aqueous layer was acidified with concentrated hydrochlorid acid to pH 4 and extracted with EtOAc (40 mL three times) . Combined organics were dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude product (585 mg， 100％yield) as a yellow solid. MS： 516.1 (M+H) ⁺. This crude product was used directly in the next step without further purification.

[C] (-)- (1S， 5R， 6R， 7R) -7- ( (2- (5， 7-Difluoro-1H-indazol-3-yl) -5-fluoropyrimidin-4- yl) amino) bicyclo [3.2.2] nonane-6-carboxylic acid

To a stirred mixture solution of (+ or-) - (1S， 5R， 6R， 7R) -7- ( (2- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [3.2.2] nonane-6-carboxylic acid (600 mg， 1.16 mmol) in DCM (3 mL) was added 2， 2， 2-trifluoroacetic acid (5.92 g， 4 mL， 51.9 mmol) and the resulting reaction mixture was stirred at room temperature for 12 h. After solvent was removed in vacuo， the crude product was purified by prep-HPLC to afford the the title compound (138 mg， 27.5％yield) as a white foam. MS： 432.1 (M+H) ⁺. ¹H NMR (400 MHz， DMSO-d₆) δ 8.27 (br d， J＝3.55 Hz， 1H) ， 8.05-8.15 (m， 1H) ， 7.72-7.87 (m， 1H) ， 7.25-7.45 (m， 1H) ， 4.95-5.07 (m， 1H) ， 2.83-2.95 (m， 1H) ， 2.35-2.45 (m， 1H) ， 1.40-2.06 (m， 11H) .

Example 49

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

[A] (rac) - (2S， 3S) -Methyl 3- ( (2-chloro-5-methylpyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2- carboxylate

A stirred mixture solution of (rac) - (2S， 3S) -methyl 3-aminobicyclo [2.2.2] octane-2-carboxylate (1 g， 5.46 mmol) ， 2， 4-dichloro-5-methylpyrimidine (1.07 g， 6.55 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.06 g， 1.42 ml， 8.19 mmol) in THF (150 ml) was heated at 60 ℃for 16 h. After cooling to room temperature， the reaction mixture was poured into water (100 mL) and extracted with EtOAc (150 mL twice) . The combined organic layers were washed with brine， dried over anhydrous Na₂SO₄， filtered and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (0-100％EtOAc-hexane gradient) to afford the title compound (0.77 g， 45.5％yield) as a white solid. MS： 310.0 [M+H] ⁺.

[B] (rac) - (2S， 3S) -Methyl 3- ( (2- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -5- methylpyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate

To a stirred mixture solution of (rac) - (2S， 3S) -methyl 3- ( (2-chloro-5-methylpyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (250 mg， 807 μmol) and Pd (PPh₃) ₄(110 mg， 95.2 μmol) in dioxane (5 mL) was added 1 ，1 ，1， 2， 2， 2-hexabutyldistannane (562 mg， 508 μL， 968 μmol) and the resulting reaction mixture solution was stirred at 125℃ for 2 h before it was cooled back to room temperature. To the above mixture， were then added 5， 7-difluoro-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (441 mg， 1.21 mmol) and Pd (PPh₃) ₄(110 mg， 95.2μmol) in dioxane (10 mL) . The resulting reaction mixture was stirred at 145℃ for 1 h under microwave heating. After cooling to room temperature， the reaction mixture was poured into water (20 mL) and extracted with EtOAc (50 mL twice) . The combined organic layers were washed with brine， dried over anhydrous Na₂SO₄， filtered and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (0-100％ EtOAc-hexane gradient) to afford the title compound (50 mg， 12.1％ yield) as a yellow solid. MS： 512.1 [M+H] ⁺.

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

A mixture solution of (rac) - (2S， 3S) -methyl 3- ( (2- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -5-methylpyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (150 mg， 293μmol) and lithium hydroxide hydrate (24.6 mg， 586 μmol) in THF/H₂O (20 mL， 1∶1) wasstirred at room temperature for 16 h. And then， solvent was evaporated under reduced pressure and the residue was re-dissolved in TFA (10 mL) and stirred at room temperature for another 16 h. After LC-MS showed that the reaction was completed， the solvent was evaporated and the residue was purified by prep-HPLC to afford the title compound (28 mg， 21.9％ yield) as a white solid. MS： 414.2 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) δ 7.96-8.02 (m， 1H) ， 7.88 (s， 1H) ， 7.09-7.17 (m， 1H) ， 5.09 (d， J＝6.97 Hz， 1H) ， 2.92 (d， J＝6.85 Hz， 1H) ， 2.16 (s， 3H) ， 2.10 (s， 1H) ， 1.87-1.98 (m， 2H) ， 1.69-1.82 (m， 2H) ， 1.56-1.67 (m， 2H) ， 1.38-1.54 (m， 3H) .

Example 50

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

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

Similar to the synthesis of Example 68/step F， 2- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -5-fluoro-6-methylpyrimidin-4-yl trifluoromethanesulfonate (100 mg， 0.2 mmol) was used instead to afford the title compound (75 mg， 63.3％ yield) after silica gel flash chromatography purification (petroleum ether∶EtOAc＝100∶10 to 100∶50 gradient) as a light yellow solid. MS： 530.5 [M+H] ⁺.

[B] (rac) - (2S， 3S) -Methyl 3- ( (2- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -5- fluoro-6-methylpyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate

Similar to the synthesis of Example 68/step G， (rac) - (2S， 3S) -methyl 3- ( (2- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -5-fluoro-6-methylpyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (75 mg， 0.13 mmol) was used instead to afford the title compound (10 mg， 19.9％ yield) after preparative HPLC purification as a light yellow solid. MS： 432.4 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) δ ppm 8.01 (br d， J＝8.44 Hz， 1H) 6.98 (br t， J＝9.84 Hz， 1H) 2.69 (br s， 1H) 2.31 (br s， 3H) 2.02 (br s， 1H) 1.84-1.94 (m， 2H) 1.70-1.80 (m， 2H) 1.35-1.67 (m， 6H) .

Example 51

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

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

To a stirred mixture solution of 5， 7-difluoro-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (15 g， 41.2 mmol) and Pd (PPh₃) ₄ (4.7 g， 4.1 mmol) in DMF (300 mL) was added Zn (CN) ₂ (9.7 g， 82.4 mmol) in one portion and the resulting mixture solution was stirred at 150℃ for 2 h. After TLC (petroleum ether∶EtOAc＝5∶1) showed that the reaction was completed， the reaction mixture was filtered， and the filtrate was quenched with water (150 mL) and extracted with EtOAc (150 mL three times) . Combined organics were dried over anhydrous Na₂SO₄， filtered， and concentrated in vacauo to give a crude product， which was purified by silica gel flash chromatog raphy (petroleum ether∶EtOAc＝50∶1～10∶1 gradient) to afford the title compound (5 g， 46.2％ yield) as a white solid. MS：263.9 [M+H] ⁺.

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

To a stirred solution of 5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbonitrile (5 g， 1 9 mmol) in MeOH (50 mL) was added NaOMe (0.5 g， 9.5 mmol) at 15℃ and stirred at 15℃ for 12 h before NH₄Cl (1.5 g， 28.5 mmol) and AcOH (1.2 g， 19.0 mmol) were added. The resulting mixture soiution was then heated at 50℃ for 6 h before being cooied back to room temperature. Solvent was removed under reduced pressure to give a crude product， which was purified by silica gelflash chromatography (DCM∶MeOH＝20∶1) to afford (3.5 g， 66％ yield) as a yellow solid. MS： 280.9 [M+H] ⁺.

[C] 2- (5， 7-Difiuoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -5-fluoropyrimidine-4， 6-diol

To a stirred solution of MeOH (50 mL) was added MeONa (5 N solution in MeOH， 5 mL， 25 mmol) followed by the addition of 5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole-3-carboximidamide (3.5 g， 12.5 mmol) and diethyl 2-fluoromalonate (4.5 g， 25.0 mmol) and the resulting reaction mixture was then stirred at 15℃ for 2 h.Solvent was removed under reduced pressure to give the crude product (4 g) as a yellow solid. MS： 389.2 [M+H] ⁺. This crude product was used directly in the next step without further purification.

[D] 3- (4， 6-Dichloro-5-fluoropyrimidin-2-yl) -5， 7-difluoro-1H-indazole

To a suspension of 2- (5，7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -5-fluoropyrimidine-4， 6-diol (4 g， 11 mmol) in POCl₃ (57.31 g) was slowly added N， N-dimethylaniline (2.7 g， 22 mmol). After the addition， the reaction mixture was heated to 80℃ for 12 h before being cooled back to room temperature.After TLC (DCM∶MeOH＝20∶1) showed completion of the reaction， the reaction mixture was concentrated and poured into water (100 mL) and extracted with EtOAc (100 mL twice) . Combined organics were dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromotography (petroleum ether∶EtOAc＝10∶1) to afford the title compound (0.73 g， 34.8％ yield) as a yellow solid. MS： 319.0 [M+H] ⁺.

[E] (rac) - (1R， 2S， 3S， 4R) -Methyl 3- ( (6-chloro-2- (5， 7-difluoro-1H-indazol-3-yl) -5- fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate

To a stirred mixture solution of 3- (4， 6-dichloro-5-fluoropyrimidin-2-yl) -5， 7-difluoro-1H-indazole (0.65 g， 2 mmol) and (rac) -(1R， 2S， 3S， 4R) -methyl 3-aminobicyclo [2.2.2] octane-2-carboxylate (0.4 g， 2.2 mmol) in THF (20 mL) was added DIPEA (0.52 g， 4 mmol) at 15℃. After the addition， the reaction mixture was stirred at 70℃ for 1 2 h before being cooled back to room temperature. Solvent was removed under reduced pressure and the crude product was purified by silica gel flash chromatography (petroleum ether∶EtOAc＝5∶1) to afford the title compound (0.8 g， 84.2％ yield) as a yellow solid. MS： 466.3 [M+H] ⁺.

[F] (rac) - (1R， 2S， 3S， 4R) -3- ( (2- (5， 7-Difluoro-1H-indazol-3-yl) -6-ethoxy-5-fluorooyrimidin-4- yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

To a stirred solution of (rac) -(1R， 2S， 3S， 4R) -methyl， 3- ( (6-chloro-2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (100 mg， 0.21 mmol) in EtOH (3 mL) was added EtONa (2 N solution in EtOH， 0.84 mL， 2.1 mmol) at 15℃. The reaction mixture was allowed to warm up and was heated at 80℃ for 48 h. After cooling to room temperature， the mixture solution was concentrated in vacuo. The residue was re-dissolved in MeCN and AcOH was added to adjust pH to 5～6. The mixture solution was then concentrated in vacuo to give a crude product， which was purified by prep-HPLC to afford the title compound (32 mg， 28.3％ yield) as a white solid. MS： 462.2 [M+H] ⁺.¹H NMR (400 MHz， MeOH-d4) δ ppm 8.10 (d， J＝8.28 Hz， 1H) 7.09 (t， J＝9.54 Hz， 1H) 4.61 (q， J＝7.03 Hz， 2H) 3.37 (br.s.， 1H) 2.73 (d， J＝6.53 Hz， 1H) 2.11 (br.s.， 1H) 1.93～2.05 (m， 2H) 1.80～1.92 (m， 2H) 1.60～1.78 (m， 3H) 1.49～1.58 (m， 2H) 1.46 (t， J＝7.03 Hz， 3H) .

Example 52

(1R， 2S， 3S， 4R) -3- ( (2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoro-6- ( (2-hydroxyethyl) (methyl) amino) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

[A] (rac) - (1R， 2S， 3S， 4R) -Methyl， 3- ( (2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoro-6- ( (2- hydroxyethyl) (methyl) amino) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate

To a stirred mixture solution of (rac) -(1R， 2S， 3S， 4R)-methyl 3- ( (6-chloro-2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (100 mg， 0.21 mmol) and 2- (methylammo) ethanol (157 mg， 2.1 mmol) in THF (5 mL) was added DIPEA (54.3 mg， 0.42 mmol) at 15℃. The reaction mixture was allowed to warm up and heated at 70℃ for 48 h.After cooling to room temperature， solvent was removed in vacuo to giye a crude product (106 mg). MS： 505.4 [M+H] ⁺. This crude product was used directly in the next step without further purification.

[B] (rac) - (1R， 2S， 3S， 4R) -3- ( (2- (5， 7-Difluoro-1H-indazol-3-yl)-5-fluoro-6- ( (2- hydroxyethyl) (methyl) amino) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

To a stirred solution of (rac) -(1R， 2S， 3S， 4R) -methyl， 3- ( (2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoro-6- ( (2-hydroxyethyl) (methyl) amino) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (128 mg， 0.25 mmol) in MeOH (3 mL) was added 4N aq. NaOH solution (1 mL) and the resulting reaction mixture was stirred at 15℃ for 6 h.After TLC (petroleum ether∶EtOAc＝1∶1) showed that the reaction was completed， the reaction mixture was concentrated under reduced pressure. The residue was re-dissolved in MeCN (5 mL) and AcOH was added to adjust pH to 5～6. The resulting mixture solution was then concentrated in vacuo to give a crude product， which was purified by prep-HPLC to afford the title compound (8.6 mg， 6.9％ yield) as a white solid. MS： 491.2 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) δ ppm 8.11 (br.s.， 1H) 7.06 (t， J＝9.29 Hz， 1H) 4.85 (br.s.， 3H) 3.81 (d， J＝10.04 Hz， 4H) 3.50 (br.s.， 1H) 2.70 (br.s.， 1H) 1.27～2.31 (m， 10H) .

Example 53

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

[A] (rac) - (1R， 2S， 3S， 4R) -Methyl-3- ( (2- (5， 7-difiuoro-1H-indazol-3-yl) -5-fluoro-6- ( (2- hydroxyethyl) amino) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate

To a stirred solution of (rac) -(1R， 2S， 3S， 4R) -methyl 3- ( (6-chloro-2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (100 mg， 0.21 mmol) and 2-aminoethanol (128 mg， 2.1 mmol) in THF (5 mL) was added DIPEA (54.3 mg， 0.42 mmol)at 15℃. The reaction mixture was allowed to warm up and heated at 70℃ for 48 h before being cooled back to room temperature. After TLC (petroleum ether∶EtOAc＝3∶1) showed that the reaction was completed， the reaction mixture was concentrated in vacuo to give a crude product (100 mg) as a yellow oil. MS： 491.2 [M+H] ⁺. This crude product was used directly in the next step without further purification.

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

To a stirred solution of (rac) - (1R， 2S， 3S， 4R) -methyl-3- ( (2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoro-6- ( (2-hydroxyethyl) amino) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (1 22 mg， 0.25 mmol) in MeOH (3 mL) was added 4N aq. NaOH solution (1 mL) and the resulting reaction mixture was stirred at 15℃ for 6 h. After TLC (petroleum ether∶EtOAc＝1∶1) showed that the reaction was completed， the reaction mixture was concentrated under reduced pressure. The residue was re-dissolved in MeCN (5 mL) and AcOH was added to adjust pH to 5～6. The resulting mixture solution was then concentrated in vacuo to give a crude product，which was purified by prep-HPLC to afford the title compound (2 mg， 1.7％ yield) as a white solid.MS：477.2 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) δ ppm 8.51 (br.s.， 1H) 8.12 (br.s.， 1H) 7.07 (br.s.， 1H) 4.65(br.s.， 1H) 3.60～3.95(m， 4H) 3.50 (br.s.， 1H) 2.59 (br.s.， 1H) 1.91～2.13 (m， 3H) 1.77～1.89 (m， 2H) 1.66 (d， J＝17.07 Hz， 2H) 1.49 (d， J＝11.80 Hz， 2H) 1.24～1.41 (m， 1H) .

Example 54

(1R， 2S， 3S， 4R) -3- ( (2- (5， 7-Difluoro-1H-indazol-3-yl) -6- (dimethylamino) -5-fluoropyrimidin-4-yl) amino) bicyc lo [2.2.2] octane-2-carboxylic acid

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

To a stirred solution of (rac) -(1R， 2S， 3S， 4R) -methyl 3- ( (6-chloro-2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (300 mg， 0.64 mmol) in MeOH (15 mL) was added 4N aq. NaOH solution and the resulting reaction mixture was stirred at 15℃ for 12 h. After TLC (petroleum ether∶EtOAc＝1∶1) showed that the reaction was completed， the reaction mixture was concentrated under reduced pressure. The residue was re-dissolved in MeCN(20 mL) and AcOH was added to adjustpH to 5～6. The resulting mixture solution was filtered and then concentrated in vacuo to give a crude product， TLC (PE∶EA＝1∶1) showed that the reaction was completed， the reaction mixture was concentrated and MeCN (20.0 mL) added. AcOH was added to adjust pH to 5～6， the mixture was filtered and concentrated to give a crude product (300 mg， 82.2％ yield) as a yellow solid. MS： 455.2 [M+H] ⁺. This crude product was used directly in the next step without further purification.

[B] (rac) - (1R， 2S， 3S， 4R)-3- ( (2- (5， 7-Difluoro-1H-indazol-3-yl) -6- (dimethylamino) -5- fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

To a stirred solution of (rac) - (1R， 2S， 3S， 4R) -3- ( (2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoro-6- ( (2-hydroxyethyl) amino) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (100 mg， 0.2 mmol) and dimethylamine hydrochioride (82 mg， 1 mmol) in dioxane (5 mL) was added Cs₂CO₃ (130 mg， 0.4 mmol) at 15℃. The reaction mixture was allowed to warm up and heated at 90℃ for 12 h before being cooled back to room temperature. After TLC (DCM∶MeOH＝20∶1) showed that 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 (9.7 mg， 10.5％ yield) as a white solid. MS： 461.2 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) δ ppm 7.98 (d，J＝8.78 Hz， 1H) 7.14 (t， J＝10.04 Hz， 1H) 4.75 (d， J＝6.27 Hz， 1H) 3.31 (br.s.， 6H) 2.73 (d， J＝6.78 Hz， 1H) 2.14 (br.s.， 1H) 1.50～2.06 (m， 9H) .

Example 55

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

To a stirred solution of (rac) -(1R， 2S， 3S， 4R) -3- ( (6-chloro-2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (Example 54/step A， 100 mg， 0.2 mmol) in 2-methoxyethanol (2 mL) was added t-BuOK (45 mg， 0.4 mmol) at 15℃. The reaction was allowed to warm up and heated at 90℃ for 12 h before being cooled back to room temperature. After TLC (DCM∶MeOH＝20∶1) showed that 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 (12.8 mg， 13.1％ yield) as a white solid. MS： 492.2 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) δ ppm 8.01～8.12 (m， 1H) 7.02～7.12 (m， 1H) 4.88 (br.s.， 1H) 4.68 (br.s.， 2H) 3.81 (t， J＝3.89 Hz， 2H) 3.46 (s， 3H) 2.77 (d， J＝6.90 Hz， 1H) 2.12 (br.s.， 1H) 1.37～2.07 (m， 9H) .

Example 56

(rac) - (6S， 7S) -6- [ [6-Chloro-2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoro-pyrimidin-4-yl] amino] bicyclo [3.2.2] nonane-7-carboxylic acid

[A] (rac) - (6S， 7S) -Methyl 7- ( (6-chloro-2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoropyrimidin-4- yl) amino) bicyclo [3.2.2] nonane-6-carboxylate

To a stirred solution of (rac) -(6R， 7R) -methyl 7-aminobicyclo [3.2.2] nonane-6-carboxylate (167 mg， 846μmol) in THF (50 mL) was added 3- (4， 6-dichloro-5-fluoropyrimidin-2-yl) -5， 7-difluoro-1H-indazole (450 mg， 846μmol) and N-ethyl-N-isopropylpropan-2-amine (164 mg， 221 μl， 1.27 mmol) at room temperature andthe resulting reaction mixture solution was stirred at 60℃ for 1 6 h.After cooling to room temperature， the reaction mixture was poured into water (100 mL) and extracted with EtOAc (150 mL twice) . The combined organic layers were washed with brine， dried over anhydrous Na₂SO₄，filtered and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (0-100％ EtOAc-hexane gradient) to afford the title compound (350 mg， 86.2％ yield) as a light yellow solid. MS： 480.0 [M+H] ⁺.

[B] (rac) - (6S， 7S) -7- ( (6-Chloro-2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoropyrimidin-4- yl) amino) bicyclo [3.2.2] nonane-6-carboxylic acid

A mixture solution of (rac) - (6S， 7S) -methyl 7- ( (6-chloro-2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [3.2.2] nonane-6-carboxylate (200 mg， 417 μmol) and lithium hydroxide hydrate (35 mg， 0.83 mmol) in THF/H₂O (10 mL， 1∶1) was stirred at room temperature for 16 h. Solvent was removed in vacuo and the residue was re-dissolved in TFA (10 mL) and stirred at room temperature for another 16 h.After LC-MS showed that the reaction was completed，the reaction mixture was acidified with 2 N HCl to pH 6 and concentrated in vacuo to afford the title compound (190 mg， 97.9％ yield) as a white solid. MS： 466.0 [M+H] ⁺. ¹H NMR (400 MHz， DMSO-d6) δ 12.36 (s， 1H)， 8.09 (dd， J＝8.25， 17.79 Hz， 2H)， 7.40 (t， J＝9.23 Hz， 1H)， 4.96-5.06 (m， 1H)， 2.87-2.93 (m， 1H)， 2.41 (s， 2H)， 1.93-2.02 (m， 2H)， 1.86 (d， J＝6.97 Hz， 2H) ， 1.47-1.71 (m， 7H) .

Example 57

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

To a solution of (1R， 2S， 3S， 4R) -3- ( (6-chloro-2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (Example 54/step A， 100 mg， 0.2 mmol) in ethane-1， 2-diol (2 mL) was added t-BuOK (45 mg， 0.4 mmol) at 15℃. The reaction was allowed to warm up and heated at 90℃ for 24 h before being cooled back to room temperature. After TLC (DCM∶MeOH＝20∶1) showed that 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 (13.2 mg， 13.9％ yield) as a white solid. MS： 478.2 [M+H] ⁺. ¹H NMR (400 MHz， DMSO-d6) δ ppm 8.11 (dd， J＝9.03， 2.13 Hz， 1H) 7.05～7.15 (m， 1H) 4.89 (br.s.， 1H) 4.62～4.67 (m， 2H) 3.91～3.98 (m， 2H) 2.78 (d， J＝7.03 Hz， 1H) 2.12 (br.s.， 1H) 1.48～2.02 (m， 9H) .

Example 58

(rac) - (2S，3S) -3- [ [6-Cyclopropyl-2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoro-pyrimidin-4-yl] amino] bicyclo [2.2.2] octane-2-carboxylic aced

[A] Methyl 3-cyclopropyl-2-fluoro-3-oxopropanoate

Similar to the synthessis of Example 68/step C， methyl 3-cyclopropyl-3-oxopropanoate (2.13 g， 15 mmol) was used instead to afford the title compound (2.0 g， 97.1％ yield) after silica gel flash chromatography purification (petroleum ether∶EtOAc＝100∶10 to 100∶50 gradient) as a colorless oil. MS： 161.1 [M+H] ⁺.

[B] 6-Cyclopropyl-2- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -5- fluoropyrimidin-4-ol

Similar to the synthesis of Example 68/step E， methyl 3-cyclopropyl-2-fluoro-3-oxopropanoate (76 mg， 0.46 mmol) was used instead to afford the title compound (80 mg， 38.9％ yield) after precipitating from MeOH/water as a white solid. MS： 391.4 [M+H] ⁺.

[C] 6-Cyclopropyl-2- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -5- fluoropyrimidin-4-yl trifluoromethanesulfonate

Similar to the synthesis of Example 68/step E， 6-Cyclopropyl-2- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -5-fluoropyrimidin-4-ol(80 mg， 0.18 mmol) was used instead to afford the title compound (96.4 mg， 97.1％ yield) after silica gel flash chromatography purification (petroleum ether∶EtOAc＝100∶10 to 100∶50 gradient) as a light yellow solid. MS： 523.4 [M+H] ⁺.

[D] (rac) -Methyl (2S， 3S) -3- [ [6-cyclopropyl-2- (5， 7-difluoro-1-tetrahydropyran-2-yl-indazol-3- yl) -5-fluoro-pyrimidin-4-yl] amino] bicyclo [2.2.2] octane-2-carboxylate

Similar to the synthesis of Example 68/step F， 6-cyclopropyl-2- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -5-fluoropyrimidin-4-yl trifluoromethanesulfonate (110 mg， 0.18 mmol) was used instead to afford the title compound (72.1 mg， 72.2％ yield) after silica gel flash chromatography purification (petroleum ether∶EtOAc＝100∶10to 100∶50 gradient) as a light yellow solid. MS： 556.2 [M+H] ⁺.

[E] (rac) - (2S， 3S) -3- [ [6-Cyclopropyl-2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoro-pyrimidin-4- yl] amino] bicyclo [2.2.2] octane-2-carboxylic acid

Similar to the synthesis of Example 68/step G， (rac) -methyl (2S， 3S) -3- [ [6-cyclopropyl-2- (5， 7-difluoro-1-tetrahydropyran-2-yl-indazol-3-yl) -5-fluoro-pyrimidin-4-yl] amino] bicyclo [2.2.2] octane-2-carboxylate (72 mg， 0.13 mmol) was used instead to afford the title compound (9 mg， 16.8％yield) after preparative HPLC purification as a light yellow solid. MS： 458.2 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) δ ppm 7.93 (br d， J＝8.56 Hz， 1 H) 6.95 (br t， J＝9.66 Hz， 1 H) 2.68 (br s， 1 H) 2.19 (br s， 1 H) 2.01 (br s， 1 H) 1.83 -1.94 (m， 2 H) 1.76 (br s， 2 H) 1.51 -1.69 (m， 3 H) 1.36-1.49 (m， 2 H) 1.20 (br d， J＝7.58 Hz， 3 H) 0.96 (br dd， J＝7.89， 2.51 Hz， 2 H) .

Example 60

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

[A] Ethyl 2-fluoro-5-methoxy-3-oxo-pentanoate

Similar to the synthesis of Example 68/step C， ethyl 5-methoxy-3-oxo-pentanoate (801 mg， 5 mmol) was used instead to afford the title compound (368 mg， 41.3％yield) after silica gel flash chromatography purification (petroleum ether∶EtOAc ＝ 100∶10 to 100∶50 gradient) as a colorless oil. MS： 179.2 [M+H] ⁺.

[B] 2- (5， 7-Difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -5-fluoro-6- (2- methoxyethyl) pyrimidin-4-ol

Similar to the synthesis of Example 68/step E， ethyl 2-fluoro-5-methoxy-3-oxo-pentanoate (102 mg， 0.57 mmol) was used instead to afford the title compound (140 mg， 72.4％yield) after precipitating from MeOH/water as a white solid. MS： 409.4 [M+H] ⁺.

[C] 2- (5， 7-Difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -5-fluoro-6- (2- methoxyethyl) pyrimidin-4-yl trifluoromethanesulfonate

Similar to the synthesis of Example 68/step E， 6-cyclopropyl-2- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -5-fluoropyrimidin-4-ol (140 mg， 0.34 mmol) was used instead to afford the title compound (148.8 mg， 81％yield) after silica gel flash chromatography purification (petroleum ether∶EtOAc ＝ 100∶10 to 100∶50 gradient) as a light yellow solid. MS： 541.4 [M+H] ⁺.

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

Similar to the synthesis of Example 68/step F， 2- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -5-fluoro-6- (2-methoxyethyl) pyrimidin-4-yl trifluoromethanesulfonate (148 mg， 0.27 mmol) was used instead to afford the title compound (85 mg， 53.4％yield) after silica gel flash chromatography purification (petroleum ether∶EtOAc ＝ 100∶10 to 100∶50 gradient) as a light yellow solid. MS： 574.7 [M+H] ⁺.

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

Similar to the synthesis of Example 68/step G， (rac) - (2S， 3S) -methyl 3- ( (2- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -5-fluoro-6- (2-methoxyethyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (85 mg， 0.15 mmol) was used instead to afford the title compound (25 mg， 34.8％yield) after preparative HPLC purificaiton as a light yellow solid. MS： 458.2 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) δ ppm 8.02 (br d， J＝8.68 Hz， 1 H) 6.91 -7.02 (m， 1 H) 3.74 (t， J＝6.48 Hz， 2 H) 3.26 (s， 3 H) 2.92 (br t， J＝6.24 Hz， 2 H) 2.62 (br d， J＝6.24 Hz， 1 H) 2.01 (brs， 1 H) 1.85 -1.93 (m， 2 H) 1.37-1.79 (m， 7 H) 1.13 -1.27 (m， 1 H) .

Exampie 61

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

[A] (rac) - (1R， 2S， 3S， 4R) -Methyl 3- ( (5-fluoro-2- (7-fluoro-1H-pyrazolo [3， 4-c] pyridin-3- yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate

To a stirred mixture solution of 7-fluoro-3- (5-fluoro-4- (methylsulfinyl) pyrimidin-2-yl) -1H-pyrazolo [3， 4-c] pyridine (200 mg， 677 μmol) in THF (35 mL) was added (rac) - (1R， 2S， 3S， 4R) -methyl 3-aminobicyclo [2.2.2] octane-2-carboxylate (124 mg， 677 μmol) and DIPEA (263 mg， 355 μL， 2.03 mmol) and the resulting reaction mixture solution was stirred at 70 ℃ for 12 h. After cooling to room temperature， the reaction mixture was poured into water (100 mL) and extracted with EtOAc (150 mL twice) . The combined organic layers were washed with brine， dried over anhydrous Na₂SO₄， filtered and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (0-40％EtOAc-hexane gradient) to afford the title compound (160 mg， 57％yield) as a yellow oil. MS： 415.1 (M+H) ⁺.

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

To a stirred mixture solution of (rac) - (1R， 2S， 3S， 4R) -methyl 3- ( (5-fluoro-2- (7-fluoro-1H-pyrazolo [3， 4-c] pyridin-3-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (150 mg， 362 μmol) in THF (5 mL) and MeOH (5 mL) was added lithium hydroxide (86.7 mg， 3.62 mmol) pre-dissolved in water (5 mL) . The reaction mixture solution was stirred at room temperature for 12 h before being diluted with water (10 mL) and extracted with diethyl ether (20 mL) . The organic layer was discarded and the aqueous layer was acidified with concentrated hydrochlorid acid to pH 4 and extracted with EtOAc (40 mL three times) . Combined organics were dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was then purified by prep-HPLC to afford the the title compound (70 mg， 48.3％yield) as a white foam. MS： 401.1 (M+H) ⁺. ¹H NMR (400 MHz， MeOH-d₄) δ 8.35-8.45 (m， 1H) ， 8.16 (s， 1H) ， 7.79-7.89 (m， 1H) ， 4.97-5.05 (m， 1H) ， 2.78-2.86 (m， 1H) ， 2.11-2.17 (m， 1H) ， 1.99-2.05 (m， 1H) ， 1.82-1.95 (m， 3H) ， 1.46-1.80 (m， 5H) .

Example 62

(rac) - (6S， 7S) -6- [ [2- (5， 7-Difluoro-1H-indazol-3-yl) -5-fluoro-6- (2-hydroxyethoxy) pyrimidin-4-yl] amino] bicyclo [3.2.2] nonane-7-carboxylic acid

A mixture solution of (rac) - (6S， 7S) -7- ( (6-chloro-2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [3.2.2] nonane-6-carboxylic acid (50 mg， 107 μmol) and potassium tert-butoxide (36.1 mg， 322 μmol) in ethylene glycol (5 ml) was stirred at 95 ℃for 4 h. After cooling to room temperature， the reaction mixture was concentrated in vacuo to give a crude title compound， which was purified by prep-HPLC to afford the title compound (23 mg， 42.7％yield) as a white solid. MS： 492.2 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) δ 8.23 (dd， J＝2.08， 9.05 Hz， 1H) ， 7.08-7.14 (m， 1H) ， 5.20 (d， J＝7.58 Hz， 1H) ， 4.62-4.67 (m， 2H) ， 3.94 (dd， J＝4.03， 5.50 Hz， 2H) ， 2.80 (dd， J＝3.67， 7.83 Hz， 1H) ， 2.52 (s， 1H) ， 2.10-2.16 (m， 2H) ， 1.94-2.01 (m， 2H) ， 1.61-1.89 (m， 7H) .

Example 63

(rac) - (6S， 7S) -6- [ [2- (5， 7-Difluoro-1H-indazol-3-yl) -5-fluoro-6- (2-methoxyethoxy) pyrimidin-4-yl] amino] bicyclo [3.2.2] nonane-7-carboxylic acid

A mixture of (rac) - (6S， 7S) -7- ( (6-chloro-2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [3.2.2] nonane-6-carboxylic acid (200 mg， 429 μmol) and potassium tert-butoxide (145 mg， 1.29 mmol) in 2-methoxyethanol (5 mL) was stirred at 95 ℃ for 4 h. After cooling to room temperature， the reaction mixture was concentrated in vacuo to give a crude product， which was purified by prep-HPLC to afford the title compound (170 mg， 65.7％yield) as a white solid. MS： 506.1 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) δ 8.09 (d， J＝8.80 Hz， 1H) ， 6.93-7.01 (m， 1H) ， 5.06 (d， J＝7.82 Hz， 1H) ， 4.56-4.60 (m， 2H) ， 3.68-3.72 (m， 2H) ， 3.33 (s， 3H) ， 2.66 (dd， J＝3.67， 7.83 Hz， 1H) ， 2.40 (s， 1H) ， 1.96-2.05 (m， 2H) ， 1.86 (dd， J＝5.69， 8.25 Hz， 2H) ， 1.49-1.77 (m， 7H) .

Example 64

(rac) - (6S， 7S) -6- [ [2- (5， 7-Difluoro-1H-indazol-3-yl) -5-fluoro-6-methoxy-pyrimidin-4-yl] amino] bicyclo [3.2.2] nonane-7-carboxylic acid

A mixture solution of (rac) - (6S， 7S) -7- ( (6-chloro-2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [3.2.2] nonane-6-carboxylic acid (50 mg， 107 μmol) and sodium methoxide (29 mg， 537 μmol) in MeOH (5 mL) was stirred at 95 ℃ for 16 h. After cooling to room temperature， the reaction mixture was concentrated in vacuo to give a crude product， which was purified by prep-HPLC to afford the title compound (23 mg， 44.1％yield) as a white solid. MS： 462.2 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) δ8.23 (d， J＝8.44 Hz， 1H) ， 7.06-7.16 (m， 1H) ， 5.18 (d， J＝7.83 Hz， 1H) ， 4.13 (s， 3H) ， 2.79 (dd， J＝3.48， 7.89 Hz， 1H) ， 2.51 (s， 1H) ， 2.08-2.17 (m， 2H) ， 1.93-2.01 (m， 2H) ， 1.60-1.88 (m， 7H) .

Example 65

(rac) - (6S， 7S) -6- [ [2- (5， 7-Difluoro-1H-indazol-3-yl) -5-fluoro-6-oxo-1H-pyrimidin-4-yl] amino] bicyclo [3.2.2] nonane-7-carboxylic acid

A mixture solution of (rac) - (6S， 7S) -7- ( (6-chloro-2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [3.2.2] nonane-6-carboxylic acid (50 mg， 107 μmol) in 2 M sodium hydroxide (5 mL， 10 mmol) was stirred at 95 ℃ for 64 h. After cooling to room temperature， the reaction mixture was acidified with concentrated hydrochlorid acid to pH 4 and concentrated in vacuo to give a crude product， which was purified by prep-HPLC to afford the title compound (7 mg， 13.8％yield) as a white solid. MS： 448.2 [M+H] ⁺. ¹H NMR (400 MHz， DMSO-d6) δ 8.05 (d， J＝7.21 Hz， 1H) ， 7.45 (t， J＝9.23 Hz， 1H) ， 7.10 (d， J＝7.82 Hz， 1H) ， 4.96 (s， 1H) ， 2.85 (dd， J＝3.42， 7.46 Hz， 1H) ， 2.37 (s， 1H) ， 1.79-1.97 (m， 4H) ， 1.42-1.70 (m， 8H) .

Example 66

(trans) -N- [ (1R， 3S) -3- [ [2- (5， 7-Difluoro-1H-indazol-3-yl) -5-fluoro-6- (2-hydroxyethyl) pyrimidin-4-yl] amino] cyclohexyl] benzamide

[A] (trans) -tert-Butyl ( (1R， 3S) -3- ( (6- (2- (benzyloxy) ethyl) -2- (5， 7-difluoro-1- ( (trifluoromethyl) sulfonyl) -1H-indazol-3-yl) -5-fluoropyrimidin-4- yl) amino) cyclohexyl) carbamate

Similar to the synthesis of Example 68/step F， 6- (2- (benzyloxy) ethyl) -2- (5， 7-difluoro-1- ( (trifluoromethyl) sulfonyl) -1H-indazol-3-yl) -5-fluoropyrimidin-4-yl trifluoromethanesulfonate (320 mg， 0.48 mmol) and (trans) -tert-butyl ( (1R， 3S) -3-aminocyclohexyl) carbamate (121 mg， 0.48 mmol) were used instead to afford the title compound (80 mg， 22.8％yield) after silica gel flash chromatography (petroleum ether∶EtOAc ＝ 100∶10 to 100∶50 gradient) as a light yellow solid. MS： 729.7 [M+H] ⁺.

[B] (trans) - (3R) -N1- [6- (2-benzyloxyethyl) -2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoro-pyrimidin- 4-yl] cyclohexane-1， 3-diamine hydrochloride

Similar to the synthesis of Example 74/step D， (trans) -tert-butyl ( (1R， 3S) -3- ( (6- (2- (benzyloxy) ethyl) -2- (5， 7-difluoro-1- ( (trifluoromethyl) sulfonyl) -1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) cyclohexyl) carbamate (80 mg， 0.11 mmol) was used instead to afford the crude title compound (55 mg， 100％yield) after evaporating the solvent in vacuo as a light yellow solid. MS： 497.2 [M+H] ⁺.

[C] (trans) -N- ( (1R， 3S) -3- ( (6- (2- (benzyloxy) ethyl) -2- (5， 7-difluoro-1H-indazol-3-yl) -5- fluoropyrimidin-4-yl) amino) cyclohexyl) benzamide

Similar to the synthesis of Example 74/step E， (trans) - (3R) -N1- [6- (2-benzyloxyethyl) -2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoro-pyrimidin-4-yl] cyclohexane-1， 3-diamine trihydrochloride (130 mg， 0.24 mmol) and benzoic acid (30 mg， 0.24 mmol) were used instead to afford the title compound (70 mg， 47.8％yield) after silica gel flash chromatography purification (petroleum ether∶EtOAc ＝ 100∶10 to 0∶100gradient) as a light yellow solid. MS： 601.6 [M+H] ⁺.

[D] (trans) -N- [ (1R， 3S) -3- [ [2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoro-6- (2- hydroxyethyl) pyrimidin-4-yl] amino] cyclohexyl] benzamide

A stirred mixture solution of (trans) -N- ( (1R， 3S) -3- ( (6- (2- (benzyloxy) ethyl) -2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) cyclohexyl) benzamide (70 mg， 117 μmol) and Pd/C (5 mg， 47 μmol) in MeOH (5 mL) was hydrogenated using a hydrogen balloon for 1 week. After filtering off the catalyst， the filtrate was concentrated in vacuo to give a crude product， which was then purifed by silica gel flash chromatography (EtOAc∶MeOH ＝ 100∶10 to 100∶30 gradient) to afford the title compound (29 mg， 47.3％yield) as a light yellow solid. MS： 511.5 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) δ ppm 7.97-8.13 (m， 1 H) 7.73-7.87 (m， 2 H) 7.38-7.59 (m， 3 H) 7.12 (br t， J＝8.68 Hz， 1 H) 4.32-4.50 (m， 1 H) 4.13-4.21 (m， 1 H) 4.02 (br t， J＝6.30 Hz， 2 H) 2.96 -3.16 (m， 2 H) 2.42 (br d， J＝12.23 Hz， 1 H) 2.24 (br d， J＝10.39 Hz， 1 H) 2.11 (br d， J＝12.10 Hz， 1 H) 1.93-2.02 (m， 1 H) 1.53-1.76 (m， 2 H) 1.33 -1.50 (m， 2 H) .

Example 67

(rac) - (1S， 5R， 6S， 7S) -6- [ [5-Fluoro-2- (7-fluoro-1H-pyrazolo [3， 4-c] pyridin-3-yl) pyrimidin-4-yl] amino] bicyclo [3.2.2] nonane-7-carboxylic acid

[A] (rac) - (1R， 5S， 6S， 7S) -Methyl7- ( (5-fluoro-2- (7-fluoro-1H-pyrazolo [3， 4-c] pyridin-3- yl) pyrimidin-4-yl) amino) bicyclo [3.2.2] nonane-6-carboxylate

To a stirred mixture solution of 7-fluoro-3- (5-fluoro-4- (methylsulfinyl) pyrimidin-2-yl) -1H-pyrazolo [3， 4-c] pyridine (150 mg， 508 μmol) in THF (35 mL) was added rac- (1R， 5S， 6S， 7S) -methyl 7-aminobicyclo [3.2.2] nonane-6-carboxylate (120 mg， 610 μmol) and DIPEA (197 mg， 266 μL， 1.52 mmol) and the resulting reaction mixture solution was stirred at 70℃ for 12 h. After cooling to room temperature， the reaction mixture was poured into water (100 mL) and extracted with EtOAc (150 mL twice) . The combined organic layers were washed with brine， dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (EtOAc∶petroleum ether ＝ 0 to 40％gradient) to afford the title compound (100 mg， 45.9％yield) as a yellow oil. MS： 429.1 [M+H] ⁺. This crude product was used directly in the next step without further purification.

[B] (rac) - (1S， 5R， 6S， 7S) -6- [ [5-Fluoro-2- (7-fluoro-1H-pyrazolo [3， 4-c] pyridin-3-yl) pyrimidin-4- yl] amino] bicyclo [3.2.2] nonane-7-carboxylic acid

A mixture solution of rac- (1R， 5S， 6S， 7S) -methyl 7- ( (5-fluoro-2- (7-fluoro-1H-pyrazolo [3， 4-c] pyridin-3-yl) pyrimidin-4-yl) amino) bicyclo [3.2.2] nonane-6-carboxylate (100 mg， 233 μmol) and LiOH. H₂O (9.79 mg， 6.49 μl， 233 μmol) in THF (10 mL) and water (10 mL) was stirred at room temperature for 16 h. Solvent was removed under reduced pressure and the crude product was purified by prep-HPLC to afford the title compound (20 mg， 20.7 ％yield) as a white solid. MS： 415.1 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) δ 8.39 (br s， 1H) ， 8.02 (d， J＝3.79 Hz， 1H) ， 7.66-7.78 (m， 1H) ， 5.17 (br d， J＝7.09 Hz， 1H) ， 2.73 (dd， J＝3.61， 7.76 Hz， 1H) ， 2.43 (br s， 1H) ， 1.96-2.04 (m， 2H) ， 1.79-1.87 (m， 2H) ， 1.68-1.77 (m， 3H) ， 1.65 (br d， J＝5.99 Hz， 2H) ， 1.52-1.61 (m， 2H) .

Example 68

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

[A] 3-Benzyloxypropanoic acid

In a 500 mL round-bottom flask， to a stirred solution of 3- (benzyloxy) propan-1-ol (3 g， 18 mmol) in acetone (120 mL) was added Jones reagent (1.26 M solution， 14.3 mL， 18.1 mmol) at 0 ℃. The Jones reagent was pre-prepared by adding CrO₃ (25 g， 0.157 mmol) to a stirring solution of water (50 mL) and concentrated H₂SO₄ (25 mL) in a 250 mL graduated cylinder at 0 ℃； the volume was adjusted to 125 mL with water (ca. 60 mL) to give Jones’ reagent (1.26 M) . After the addition， the reaction mixture was stirred for 1 h before being filtered through a plug of

The filtrate was concentrated under reduced pressure and the residue was diluted with EtOAc (200 mL) . The organic layer was washed with water (100 mL three times) and brine (50 mL) ， dried over anhydrous Na₂SO₄， filtered and concentrated in vacuo to afford the title compound (3.05 g， 93.8％yield) as light yellow liquid. MS： 181.2 [M+H] ⁺. This crude product was used directly in the next step without further purification.

[B] Ethyl 5-benzyloxy-3-oxo-pentanoate

To a stirred solution of 3-benzyloxypropanoic acid in THF (25 mL) was added CDI (2.7 g， 16.6 mmol) and the resulting reaction mixture was stirred at room temperature for 1.5 h. before magnesium chloride (1.32 g， 13.9 mmol) and potassium 3-ethoxy-3-oxopropanoate (2.36 g， 13.9 mmol) were added. After stirring at room temperature overnight， the reaction mixture was carefully neutralized with 2N aq. solution to pH ～2. The aqueous phase was extracted with EtOAc (100 mL) and the separated organic layer was then dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (petroleum ether∶EtOAc ＝ 100∶10 to 100∶50 gradient) to afford the title compound (2.3 g， 66.2％yield) as colorless liquid MS： 251.3 [M+H] ⁺.

[C] Ethyl 5-benzyloxy-2-fluoro-3-oxo-pentanoate

A stirred mixture solution of ethyl 5- (benzyloxy) -3-oxopentanoate (2 g， 7.99 mmol) and 1- (chloromethyl) -4-fluoro-1， 4-diazabicyclo [2.2.2] octane-1， 4-diium tetrafluoroborate (2.83 g， 7.99 mmol) in MeCN (15 mL) was heated at 90 ℃ for 1 h under microwave heating. 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 (petroleum ether∶EtOAc ＝ 100∶10 to 100∶50 gradient) to afford the title compound (0.98 g， 45.7％yield) as a colorless liquid. MS： 269.3 [M+H] ⁺.

[D] 6- (2- (Benzyloxy) ethyl) -2- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -5- fluoropyrimidin-4-ol

To a stirred mixture solution of 5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole-3-carboximidamide hydrochloride (Example 51/step B， 150 mg， 474 μmol) and ethyl 5- (benzyloxy) -2-fluoro-3-oxopentanoate (152 mg， 568 μmol) in MeOH (10 mL) was added sodium methoxide (51.2 mg， 947 μmoi) . The resulting reaction mixture was heated to reflux overnight while a white solid precipitated. After evaporating off most of the MeOH under vacuum， water (10 mL) was added to the remaining mixture and the solution was ultrasonated for 5 min before filtration. The filter cake was collected and dried under vacuo to give the crude product (140 mg， 61％yield) as a yellow solid. MS： 485.5 [M+H] ⁺. The crude product was used directly in the next step without further purification.

[E] 6- (2- (Benzyloxy) ethyl) -2- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -5- fluoropyrimidin-4-yl trifluoromethanesulfonate

To a stirred mixture solution of 6- (2- (benzyloxy) ethyl) -2- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -5-fluoropyrimidin-4-ol (140 mg， 289 μmol) and pyridine (114 mg， 117 μl， 1.44 mmol) in 1， 2-dichloroethane (5 mL) was dropwise added trifluoromethanesulfonic anhydride (122 mg， 433 μmol) at 0 ℃. After the addition， the reaction mixture was warmed up to room temperature and stirred for 1 h. Solvent was removed under reduced pressure and the residue was re-dissolved in EtOAc (50 ml) and washed with 0.5 N aq. HCl solution (10 mL) . The separated organic layer was dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo to give a crude product， which was purified by silica gel flash chromatography (petroleum ether∶EtOAc ＝ 100∶10 to 100∶50 gradient) to afford the title compound (150 mg， 84.2％yield) as a white solid. MS： 617.5 [M+H] ⁺.

[F] (rac) - (2S， 3S) -Methyl 3- ( (6- (2- (benzyloxy) ethyl) -2- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2- yl) -1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate

A stirred mixture solution of 6- (2- (benzyloxy) ethyl) -2- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -5-fluoropyrimidin-4-yl trifluoromethanesulfonate (150 mg， 243 μmol) ， (2S， 3S) -methyl 3-aminobicyclo [2.2.2] octane-2-carboxylate (53.5 mg， 292 μmol) ， Pd₂ (dba) ₃ (223 mg， 243 μmol) ， xantphos (141 mg， 243 μmol) and Cs₂CO₃ (159 mg， 487 μmol) in toluene (5 mL) was heated at 100 ℃ for 3 h under microwave heating. 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 (petroleum ether∶EtOAc＝100∶20 to 100∶50 gradient) to afford the title compound (85 mg， 53.8％yield) as a light yellow solid. MS： 650.7 [M+H] ⁺.

[G] (rac) - (2S， 3S) -3- ( (6- (2- (Benzyloxy) ethyl) -2- (5， 7-difluoro-1H-indazol-3-yl) -5- fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

To a stirred solution of (rac) - (2S， 3S) -methyl 3- ( (6- (2- (benzyloxy) ethyl) -2- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (100 mg， 154 μmol) in THF (2 mL) and water (2 mL) was added lithium hydroxide monohydrate (32.3 mg， 770 μmol) and the resulting reaction mixture was heated to reflux overnight. After cooling to room temperature， THF was evaporated off under reduced pressure， the remaining aqueous solution was acidified by 4 N aq. HCl solution to pH ～3 and extracted with EtOAc (30 mL) . The separated organic layer was dried over anhydrous Na₂SO₄， filtered， and concentrated in vacuo. The residue was then re-dissolved in DCM (2 mL) and TFA (0.5 ml， 154 μmol) and the mixture solution was stirred at reflux temperature for 5 h. After cooling to room temperature， solvent was removed in vacuo to give a crude product， which was purified by prep-HPLC to afford the title compound (23 mg， 26.3％ yield) as a white solid. MS： 552.6 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) δ ppm 8.02 (br d， J＝8.56 Hz， 1 H) 7.11 - 7.31 (m， 6 H) 5.14 (br d， J＝6.85 Hz， 1 H) 4.54 (s， 2 H) 3.90 (t， J＝5.81 Hz， 2 H) 3.20 (br s， 2 H) 2.95 (br d， J＝6.85 Hz， 1 H) 2.21 (br s， 1 H) 2.05 (brd， J＝3.55 Hz， 1 H) 1.98 (br d， J＝9.17 Hz， 1 H) 1.58- 1.92 (m， 7 H) .

Example 69

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

A stirred mixture solution of (rac) - (2S， 3S) -3- ( (6- (2- (benzyloxy) ethyl) -2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (Example 68， 17 mg， 30.8 μmol) and Pd/C (3.28 mg， 30.8 μmol) in MeOH (5 mL) was hydrogenated using a hydrogen balloon overnight. After filtering off the catalyst， the filtrate was concentrated in vacuo to give a crude product (11 mg， 73.5％yield) as a white solid. MS： 462.4 [M+H] ⁺. ¹H NMR (400 MHz， METHANOL-d4) δ ppm 7.92 (dd， J＝8.68， 1.83 Hz， 1 H) 7.02-7.22 (m， 1 H) 4.92-5.02 (m， 1 H) 3.87 (t， J＝5.93 Hz， 2 H) 2.95-3.05 (m， 2 H) 2.07 (br s， 1 H) 1.82 -1.96 (m， 2 H) 1.70 -1.80 (m， 2 H) 1.55 -1.67 (m， 3 H) 1.40 -1.54 (m， 3 H) .

Example 70 and Example 71

(+ or -) - (1R， 5S， 6R， 7R) -6- [ [2- (5， 7-Difluoro-1H-indazol-3-yl) -5-fluoro-6- (2-methoxyethoxy) pyrimidin-4-yl] amino] bicyclo [3.2.2] nonane-7-carboxylic acid and (-or +) - (1S， 5R， 6S， 7S ) -6- [ [2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoro-6- (2-methoxyethoxy) pyrimidin-4-yl] amino] bicyclo [3.2.2] nonane-7-carboxylic acid

A mixture solution of (rac) - (6S， 7S) -7- ( (6-chloro-2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [3.2.2] nonane-6-carboxylic acid (Example 56， 200 mg， 429 μmol) and potassium tert-butoxide (145 mg， 1.29 mmol) in 2-methoxyethanol (5 mL) was stirred at 95 ℃ for 4 h. After cooling to room temperature， the reaction mixture was concentrated in vacuo to give a crude title compound， which was purified by prep-HPLC to give a racemic mixture of title compound (170 mg， 65.7％yield) as a white solid. MS： 506.1 [M+H] ⁺. Subsequent SFC chiral separation (Chiral Pak， IC-H， 250 x 30 mm， 5 μm column， 40％MeOH in CO₂) then afforded both enantiomers as white solids.

(+ or -) (1R， 5S， 6R， 7R) -6- [ [2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoro-6- (2-methoxyethoxy) -pyrimidin-4-yl] amino] bicyclo [3.2.2] nonane-7-carboxylic acid， MS： 506.1 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) δ 8.15 (d， J＝8.56 Hz， 1H) ， 7.01-7.10 (m， 1H) ， 5.16 (d， J＝7.46 Hz， 1H) ， 4.63-4.72 (m， 2H) ， 3.81 (t， J＝4.59 Hz， 2H) ， 3.45 (s， 3H) ， 2.65 (d， J＝3.91 Hz， 1H) ， 2.51 (s， 1H) ， 2.05-2.22 (m， 2H) ， 1.87-2.00 (m， 3H) ， 1.67-1.85 (m， 4H) ， 1.54-1.64 (m， 2H) .

and (-or +) - (1S， 5R， 6S， 7S) -6- [ [2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoro-6- (2-methoxyethoxy) -pyrimidin-4-yl] amino] bicyclo [3.2.2] nonane-7-carboxylic acid. MS： 506.1 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) δ 8.09 (d， J＝8.68 Hz， 1H) ， 7.01 (t， J＝9.90 Hz， 1H) ， 5.14 (d， J＝7.46 Hz， 1H) ， 4.61-4.72 (m， 2H) ， 3.80 (t， J＝4.46 Hz， 2H) ， 3.45 (s， 3H) ， 2.63-2.72 (m， 1H) ， 2.50 (s， 1H) ， 2.03-2.17 (m， 2H) ， 1.94 (d， J＝7.70 Hz， 3H) ， 1.75 (s， 4H) ， 1.58 (s， 2H) .

Example 72

2- (5， 7-Difluoro-1H-indazol-3-yl) -5-fluoro-6- (2-methoxyethoxy) pyrimidin-4-amine

A mixture solution of (rac) - (6S， 7S) -methyl 7- ( (6-chloro-2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [3.2.2] nonane-6-carboxylate (200 mg， 417 μmol) and potassium tert-butoxide (140 mg， 1.25 mmol) in 2-methoxyethanol (5 mL) was stirred at 95 ℃ for 4 h. After cooling to room temperatue， the reaction mixture was concentrated in vacuo to give a crude product， which was purified by prep-HPLC to give the title compound (30 mg， 20.2％yield) as a white solid. MS： 340.0 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) δ 7.93 (s， 1H) ， 6.99 (s， 1H) ， 4.56-4.63 (m， 2H) ， 3.71-3.79 (m， 2H) ， 3.35 (s， 3H) .

Example 73

(rac) - (6S， 7R) -6- [ [2- (5， 7-Difluoro-1H-indazol-3-yl) -5-fluoro-6- (2-methoxyethoxy) pyrimidin-4-yl] amino] bicyclo [3.2.2] nonane-7-carboxylic acid

A mixture of (rac) - (6S， 7S) -methyl 7- ( (6-chloro-2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [3.2.2] nonane-6-carboxylate (200 mg， 417 μmol) and potassium tert-butoxide (140 mg， 1.25 mmol) in 2-methoxyethanol (5 mL) was stirred at 95 ℃ for 4 h. After cooling to room temperature， the reaction mixture was concentrated in vacuo to give a crude product， which was purified by prep-HPLC to afford the title compound (11 mg， 4.96％ yield) as a white solid. MS： 506.1 [M+H] ⁺. ¹H NMR (400 MHz， MeOH-d4) δ 7.89-7.97 (m， 1H)， 6.96-7.03 (m， 1H)， 4.87 (d， J＝8.80 Hz， 1H)， 4.57-4.64 (m， 2H) ， 3.69-3.76 (m， 2H) ， 3.34 (s， 3H) ， 3.12-3.17 (m， 1H) ， 2.25 (s， 1H) ， 2.13 (s， 1H) ， 1.56-1.99 (m， 10H) .

Example 74

(trans) -N- [ (1R，3S) -3- [ [2- (5， 7-Difluoro-1H-indazol-3-yl) -5-fluoro-6-methyl-pyrimidin-4-yl] amino] cyclohexyl] -1-methyl-imidazole-4-carboxamide

[A] 2- (5， 7-Difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -5-fluoro-6-methylpyrimidin- 4-ol

Similar to the synthesis of Example 68/step E， methyl 3-cyclopropyl-2-fluoro-3-oxopropanoate (187 mg， 1.26 mmol) was used instead to afford the title compound (350 mg， 74.5％ yield) after precipitating from MeOH/water as white solid. MS： 365.3 [M+H] ⁺.

[B] 2- (5， 7-Difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -5-fluoro-6-methylpyrimidin- 4-yl trifluoromethanesulfonate

Similar to the synthesis of Example 68/step E， 2- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -5-fluoro-6-methylpyrimidin-4-ol (350 mg， 0.96 mmol) was used instead to afford the title compound (360 mg， 74％ yield) after silica gel flash chromatography purification (petroleum ether∶EtOAc ＝ 100∶10 to 100∶50 gradient) as a light yellow solid. MS： 497.4 [M+H] ⁺.

[C] (trans) -tert-Butyl ( (1R，3S) -3- ( (2- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3- yl) -5-fluoro-6-methylpyrimidin-4-yl)amino)cyclohexyl)carbamate

Similar to the synthesis of Example 68/step F， 2- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -5-fluoro-6-methylpyrimidin-4-yl trifluoromethanesulfonate (140 mg， 0.28 mmol) and (trans) -tert-butyl ( (1R， 3S) -3-aminocyclohexyl) carbamate (72.5 mg， 0.34 mmol) were used instead to afford the title compound (93 mg， 58.8％yield) after silica gel flash chromatography purification (petroleum ether∶EtOAc ＝ 100∶10 to 100∶50 gradient) as a light yellow solid. MS： 561.6 [M+H] ⁺.

[D] (trans) - (1S， 3R) -N1- (2- (5， 7-Difluoro-1H-indazol-3-yl) -5-fluoro-6-methylpyrimidin-4- yl) cyclohexane-1， 3-diamine hydrochloride

A stirred solution of (trans) -tert-butyl ( (1R， 3S) -3- ( (2- (5， 7-difluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -5-fluoro-6-methylpyrimidin-4-yl) amino) cyclohexyl) carbamate (560 mg， 999 μmol) in 1 M HCl in EtOAc (36.4 mg， 3 ml， 999μmol) was heatedto 60℃ for 3 h. After cooling to room temperature， solvent was evaporated off under vacuum to give a crude product (480 mg， 98.9％yield) as a light yellow solid. MS： 377.2 [M+H] ⁺. This crude product was used directly in the next step without further purification.

[E] (trans) -N- [ (1R， 3S) -3- [ [2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoro-6-methyl-pyrimidin-4- yl] amino] cyclohexyl] -1-methyl-imidazole-4-carboxamide

To a stirred mixture solution of (trans) - (1S， 3R) -N1- (2- (5， 7-difluoro-1H-indazol-3-yl) -5-fluoro-6-methylpyrimidin-4-yl) cyclohexane-1， 3-diamine trihydrochloride (65 mg， 134 μmol) ， 1-methyl-1H-imidazole-4-carboxylic acid (16.9 mg， 134μmol) and 2- (3H- [1， 2， 3] triazolo [4， 5- b] pyridin-3-yl) -1， 1， 3， 3-tetramethylisouronium hexafluorophosphate (V) (50.9 mg， 134 μmol) in DCM (5 mL) was added DIPEA (86.5 mg， 117 μl， 669 μmol) and the resulting reaction mixture was stirred at room temperature for 2 h. Solvent was removed under reduced pressure and the residue was re-suspended in MeOH (5 mL) and water (1 mL) and sonicated for 3 min while a white solid precipitated. After filtration， the filter cake was washed with MeOH (2 mL) and dried under vacuum to afford the title compound (29 mg， 43.8％yield) as a white solid. MS： 485.5 [M+H] ⁺. ¹H NMR (400 MHz， DMSO-d6) δ ppm 7.96 (br d， J＝7.70 Hz， 1 H) 7.70 (d， J＝8.56 Hz， 1 H) 7.55 -7.65 (m， 3 H) 7.29 -7.38 (m， 1 H) 4.24 (br s， 1 H) 3.92 (brd， J＝8.07 Hz， 1 H) 3.67 (s， 3 H) 2.37 (d， J＝2.81 Hz， 3 H) 1.93 -2.12 (m， 2 H) 1.84 (br d， J＝10.15 Hz， 2 H) 1.24-1.63 (m， 4 H) .

Example 75

(trans) -N- [ (1R， 3S) -3- [ [2- (5， 7-Difluoro-1H-indazol-3-yl) -5-fluoro-6-methyl-pyrimidin-4-yl] amino] cyclohexyl] pyrazine-2-carboxamide

Similar to the synthesis of Example 74/step E， pyrazine-2-carboxylic acid (16 mg， 0.13 mmol) was used instead to afford the title compound (33 mg， 50.1％yield) after precipitating from MeOH/water as white solid. MS： 483.5 [M+H] ⁺. ¹H NMR (400 MHz， DMSO-d6) δ ppm 14.08 (br s， 1 H) 9.17 (s， 1 H) 8.80-8.91 (m， 2 H) 8.72 (br s， 1 H) 8.01 (brs， 1 H) 7.59 (br s， 1 H) 7.37 (br s， 1 H) 3.89 -4.30 (m， 2 H) 2.37 (br s， 3 H) 1.78 -2.20 (m， 4 H) 1.67 (br d， J＝11.25 Hz， 1 H) 1.30-1.58 (m， 3 H) .

Example 76

(trans) -N- [ (1R， 3S) -3- [ [2- (5， 7-Difluoro-1H-indazol-3-yl) -5-fluoro-6-methyl-pyrimidin-4-yl] amino] cyclohexyl] pyridine-2-carboxamide

Similar to the synthesis of Example 74/step E， (trans) -N- [ (1R， 3S) -3- [ [2- (5， 7-Difluoro-1H-indazol-3-yl) -5-fluoro-6-methyl-pyrimidin-4-yl] amino] cyclohexyl] pyridine-2-carboxamide (16 mg， 0.13 mmol) was used instead to afford the title compound (43 mg， 65.4％yield) after precipitating from MeOH/water as white solid. MS： 482.5 [M+H] ⁺. ¹H NMR (400 MHz， DMSO-d6) δ ppm 13.93 -15.22 (m， 1 H) 8.56 -8.71 (m， 2 H) 7.84 -8.07 (m， 3 H) 7.53 -7.71 (m， 2 H) 7.19 -7.45 (m， 1 H) 3.90 -4.55 (m， 2 H) 2.37 (br s， 3 H) 1.80-2.20 (m， 4 H) 1.28 -1.73 (m， 4 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

is a single or double bond；

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

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

R² 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 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^＊＊， or -P (O) (OR^＊＊) ₂， -O-P (O) (OR^＊＊) ₂； wherein R^＊＊is C_1-6 alkyl or C_3-6 cycloalkyl which can optionally be substituted with halogen； and wherein - (optionally substituted) can also be C_1-6 alkyl in the case of - (optionally substituted heterocyclyl) or - (optionally substituted carbocyclyl) ；

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

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

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

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

R⁹ is independently selected from the group consisting of -H， -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；

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

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

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

X⁴ is selected from the group consisting of C-Hal， wherein Hal may be any halogen isotope；

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

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

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

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

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

T is selected from the group consisting of

the ring A is a saturated monocyclic carbocyclic ring having 5 to 8 ring carbon atoms or a saturated bridged carbocyclic ring having 5 to 8 ring carbon atoms and 1 to 3 carbon atoms in the bridge or a saturated bridged heterocyclic ring having 5 to 8 ring carbon atoms and 0 to 2 heteroatoms in the ring， and 0 to 2 carbon atoms and 0 to 2 heteroatoms in the bridge， wherein 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， 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 (R^７) -S (O) ₂-， - (CR^７R^７) _p-S (O) -， - (CR^７R^７) _p-S (O) ₂-， - (CR^７R^７) _p-S (O) - (CR^７R^７) _p-， - (CR^７R^７) _p-S (O) ₂- (CR^７R^７) _p-， - (CR^７R^７) _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.
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 (R^７) -， -N (R^７) -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 X⁸ is N.
A pharmaceutical composition comprising：

a compound having the formula (I) as defined in any of claims 1 to 9， 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 havlng the formula (I) as defined in any of claims 1 to 9， 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.
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 9， optionally in the form of a pharmaceutically acceptable salt， solvate， polymorph， prodrug， codrug， cocrystal， tautomer， racemate， enantiomer， or diastereomer or mixture thereof.