2,3-dihydropyrollopyridine carboxamide compounds and methods of use thereof

Abstract

The present disclosure relates to compounds of Formula (I) or subformulas thereof: (I) and pharmaceutically acceptable salts thereof, and their uses in treating PMS1 -associated diseases and disorders.

Description

2,3-DIHYDROPYROLLOPYRIDINE CARBOXAMIDE COMPOUNDS AND METHODS OF USE THEREOF CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of and priority to U.S. Provisional Patent Application No.63 / 601,947, filed on November 22, 2023, which is incorporated by reference in its entirety herein. BACKGROUND

[0002] More than 90% of human genes produce multiple mature transcripts via alternative splicing. This process is essential for generating different transcripts in different cell and tissue types, during the developmental process, and in response to internal and external signals. Alternative splicing are prevalent not only for protein-coding genes but also for most other kinds of genes including microRNA genes and long noncoding genes. Splicing is carried out by the spliceosome. Small nuclear RNAs (snRNAs) are key components of the spliceosome. The major spliceosome comprises the U1, U2, U4, U5, and U6 snRNAs, and it catalyzes the removal of ~95% of human introns, while the remaining introns (called the U12-type of introns) are removed by the minor spliceosome, comprising the U11, U12, U4atac, U5, and U6atac snRNAs. These snRNAs are in complex with their respective protein partners to form the functional unit of small nuclear ribonucleoproteins (snRNPs).

[0003] Splicing is a highly regulated process, with the regulation exerted by both cis- elements and trans-factors. The cis-elements that are recognized by the snRNAs include the 5’-splice site, 3’-splice site, and the branchpoint, each of these associating with a sequence motif that is recognized by a component of the spliceosome. In addition, there are intronic splicing enhancers (ISE), intronic splicing silencer (ISS), exonic splicing enhancer (ESE), and exonic splicing enhancer (ESS), which are recognized by a myriad of trans-factors commonly known as RNA-binding proteins (RBPs). Some of these RBPs directly bind to the cis-elements in a sequencing-specific way, while other RBPs recognize RNA structures (e.g., RNA duplex or unpaired loop region), yet others function via protein-protein interaction. There are ~1600 RBPs annotated in the human genome, and they are expressed in a cell-type- specific manner and form an extensive regulatory network for splicing regulation.

[0004] Dysregulation of splicing is implicated in roughly half of human diseases. Some diseases are caused by mutations in the spliceosome components or RBPs, while others by mutations in the cis-elements such as splice sites, branchpoint, or the various splicingenhancers and silencers. Although current approaches to treating these diseases, such as CRISPR-based genome editing, virus-aided gene therapy, or a variety of oligonucleotide- based technologies, continue to improve, they still suffer major technical and clinical challenges. In particular, oligonucleotide-based therapeutics show unfavorable pharmacokinetics, can not be orally administered, and can not be delivered effectively to many tissues, especially the brain. Small-molecule drugs have excellent pharmacokinetics, effective delivery, and bioavailability, and have only recently become available for modulating RNA splicing. Yet, the currently molecules come from a few limited chemical series. Thus, there is a great need to develop additional small molecule splicing modulators (SMSMs).

[0005] Almost 50 inherited disorders in humans result from an increase in the number of copies of single repeats in genomic DNA. These DNA repeats appear to be predisposed to such expansion because they have unusual structural characteristics, which disrupt cellular replication, repair, and recombination machinery. The presence of expanding DNA repeats alters gene expression in human cells, leading to disease.

[0006] One of these inherited disorders is Huntington's disease (HD). HD is a deadly neurodegenerative disorder with no cure associated with cognitive impairment, dementia, and loss of motor coordination. It is characterized by the progressive and hereditary increase in the length of the CAG trinucleotide repeats that encode a stretch of polyglutamine, in the Huntington gene (HTT) coding region. These repeats can increase in number from one generation to the next. The normal allele of the HTT gene contains fewer than 36 CAG repeats, while the mutant allele contains more than 36 repeats. Most HD patients carry one normal allele and one mutant allele that causes the disease. Functionally, the aberrant accumulation of CAG repeats is believed to confer a toxic gain of function on the mutant HD protein, causing it to aggregate, form protein deposits (ie, inclusion bodies), and induce cell death. The severity of the disease generally reflects the extent of repeat expansion in the mutant HTT protein.

[0007] Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are associated with long repeats of polyCUG and polyCCUG in the 3'-UTR and intron 1 regions of the transcription of myotonic dystrophy protein kinase (DMPK) and protein 9 of zinc finger (ZNF9), respectively. While normal individuals have up to 30 CTG repeats, DMI patients have a higher number of repeats ranging from 50 to thousands. The severity of the disease and the age of onset correlate with the number of repetitions. Adult-onset patients show milder symptoms and have fewer than 100 repeats, juvenile-onset DM1 patients have up to 500repeats, and congenital cases typically have around 1,000 CTG repeats. Expanded transcripts containing CUG repeats form a secondary structure, accumulate in the nucleus as nuclear foci, and sequester RNA-binding proteins (RNA-BP).

[0008] Besides the extra copies of repeats inherited at birth, for many repeat expansion diseases, repeats are highly unstable and their repeat numbers continue to expand throughout the life time of patients. This repeat instability has been shown experimentally to be mediated by proteins in DNA mismatch repair (MMR) processes including PMS1, MLH1, MSH3. Human genetics data from genome-wide association studies has indicated that variants in MMR proteins are associated with clinically relevant HD symptomatology including age at motor onset, rate of progression and somatic instability. Knocking down and knocking out MMR genes have been shown to stall or slow the somatic repeat expansion in various preclinical models of repeat expansion diseases. SUMMARY

[0009] Provided herein are small molecule splicing modulators (SMSMs), which can be used to treat a wide variety of diseases, including neurodegenerative and repeat expansion diseases. These SMSMs target regions of a primary RNA transcript that are cis-elements, such as splice sites, branch points, splicing enhancers, or splicing silencers. These regions may contain unpaired nucleotides in an RNA duplex, called bulges, which may occur naturally or result from disease.

[0010] When the SMSMs come into contact with an RNA transcript, the RNA transcript may be bound by the spliceosome or the other trans-factors, most notably RNA-binding proteins (RBPs). The SMSMs reported herein may cause an alteration in the sequence or abundance of the mature transcript, which may, in turn, alter the sequence or abundance of the functional protein should the transcript be protein-coding, or the sequence or abundance of the functional RNA should the transcript be non-coding.

[0011] In one aspect, provided herein is a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein Ring A is an optionally substituted 3-12 membered heterocyclyl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is an optionally substituted 8-12 membered bicyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R1is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, and 5-8 memebered heteroaryl; each R2is independently selected from halogen and C1-6alkyl; R3is selected from H and C1-6alkyl; each Rais independently selected from the group consisting of halogen, -OH, C1-6alkyl, C1-6haloalkyl, oxo, C3-6cycloalkyl, -C(O)O-C1-6alkyl, -C(O)C1-6haloalkyl, -C(O)O-C1-6alkylene-OC(O)-C1-6alkyl, and -N(RcRd), wherein the C1-6alkyl is optionally substituted with -OH, C1-6alkoxy, C3-6cycloalkyl, -N(RcRd), or -S(O)2C1-6alkyl, or two Raattached to the same carbon atom, together with carbon atom to which they are attached, combine to form a C3-6cycloalkyl; each Rbis independently selected from the group consisting of halogen, -OH, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, and C3-6cycloalkyl, wherein the C1-6alkoxy is optionally substituted with C3-6cycloalkyl; each Rcis independently selected from H, C1-6alkyl, and C3-6cycloalkyl, wherein the C1-6alkyl is optionally substituted with -OH; each Rdis independently selected from H and C1-6alkyl; m is 0, 1, or 2; n is 0, 1, or 2; p is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4.

[0012] In some embodiments, the compound is a compound of formula (Ia),or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3; and the rest of the variables are as defined herein.

[0013] In some embodiments, the compound is a compound of formula (Ib),or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2; and the rest of the variables are as defined herein.

[0014] In some embodiments, the compound is a compound of formula (Ic),or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2; and the rest of the variables are as defined herein.

[0015] In some embodiments, the compound is a compound formula (Id),or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2; and the rest of the variables are as defined in herein.

[0016] In another aspect, the present disclosure provides a compound obtainable by, or obtained by, a method for preparing a compound as described here (e.g., a method comprising one or more steps described in herein).

[0017] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure (e.g., a compound formula (I), (Ia), (Ib), (Ic), or (Id)), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

[0018] In another aspect, the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein (e.g., the intermediate is selected from the intermediates described herein).

[0019] In another aspect, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure (e.g., a compound formula (I), (Ia), (Ib), (Ic), or (Id)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0020] In another aspet, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure (e.g., a compound formula (I), (Ia), (Ib), (Ic), or (Id)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0021] In another aspect, the present disclosure provides a compound of the present disclosure (e.g., a compound formula (I), (Ia), (Ib), (Ic), or (Id)) or a pharmaceutically acceptable salt thereof for use in treating or preventing a disease or disorder disclosed herein.

[0022] In another aspect, the present disclosure provides a compound of the present disclosure (e.g., a compound formula (I), (Ia), (Ib), (Ic), or (Id)) or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder disclosed herein.

[0023] In another aspect, the present disclosure provides use of a compound of the present disclosure (e.g., a compound formula (I), (Ia), (Ib), (Ic), or (Id)) or a pharmaceutically acceptable salt thereof for treating or preventing a disease or disorder disclosed herein.

[0024] In another aspect, the present disclosure provides use of a compound of the present disclosure (e.g., a compound formula (I), (Ia), (Ib), (Ic), or (Id)) or a pharmaceutically acceptable salt thereof for treating a disease or disorder disclosed herein.

[0025] In another aspect, the present disclosure provides use of a compound of the present disclosure (e.g., a compound formula (I), (Ia), (Ib), (Ic), or (Id)) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0026] In another aspect, the present disclosure provides use of a compound of the present disclosure (e.g., a compound formula (I), (Ia), (Ib), (Ic), or (Id)) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or disorder disclosed herein.

[0027] In another aspect, the present disclosure provides a method of preparing a compound of the present disclosure (e.g., a compound formula (I), (Ia), (Ib), (Ic), or (Id)).

[0028] In another aspect, the present disclosure provides a method of preparing a compound, comprising one or more steps described herein.

[0029] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting.

[0030] Other features and advantages of the disclosure will be apparent from the following detailed description and claims.DETAILED DESCRIPTION

[0031] Compounds described herein are generally designed to treat diseases and disorders disclosed herein. Definitions

[0032] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0033] As used herein, “alkyl”, “C1, C2, C3, C4, C5, C6alkyl” or “C1-6alkyl” is intended to include C1, C2, C3, C4, C5, or C6straight chain (linear) saturated aliphatic hydrocarbon groups and C3, C4, C5, or C6 branched saturated aliphatic hydrocarbon groups. For example, C1-6alkyl is intended to include C1, C2, C3, C4, C5,and C6alkyl groups. Examples of alkyl include, moieties having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, or n-hexyl. In some embodiments, a straight chain or branched alkyl has four or fewer carbon atoms.

[0034] As used herein, the term “alkoxy” refers to the group -OR where R is linear or branched alkyl. When the term “alkoxy” is modified with a designated number of carbon atoms (e.g., C1-6alkoxy) the number of carbon atoms refers to the number of carbon atoms in the linear or branched alkyl R. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2- dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e., with between 1 and 6 carbon atoms (“C1-6alkoxy”).

[0035] As used herein, the term “cycloalkyl” refers to a saturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spiro rings) system having 3 to 30 carbon atoms (e.g., C3-12, C3-10, or C3-8). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and adamantyl. Particular cycloalkyl groups are lower cycloalkyl, e.g., with between 3 and 6 carbon atoms (“C3-6cycloalkyl”).

[0036] As used herein, the term “heterocyclyl” refers to a saturated or partially unsaturated 3- 8 membered monocyclic (e.g., 4-7 membered monocyclic) or 7-12 membered bicyclic (fused, bridged, or spiro rings) having one or more heteroatoms e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or1-6 heteroatoms, or e.g. ̧1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from thegroup consisting of nitrogen, oxygen and sulphur, unless specified otherwise. Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl,oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6- tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl, 1,4-dioxaspiro[4.5]decanyl, 1-oxaspiro[4.5]decanyl, 1- azaspiro[4.5]decanyl, 3'H-spiro[cyclohexane-1,1'-isobenzofuran]-yl, 7'H-spiro[cyclohexane- 1,5'-furo[3,4-b]pyridin]-yl, 3'H-spiro[cyclohexane-1,1'-furo[3,4-c]pyridin]-yl, 3- azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexan-3-yl, 1,4,5,6-tetrahydropyrrolo[3,4- c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H- pyrazolo[3,4-c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2- azaspiro[3.3]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl- 2-azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxa- azaspiro[3.4]octanyl, 2-oxa-azaspiro[3.4]octan-6-yl, and the like. In the case of multicyclic heterocycloalkyl, only one of the rings in the heterocycloalkyl needs to be non-aromatic (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0037] As used herein, the term “heteroaryl” is intended to include a stable 5-, 6-, or 7- membered monocyclic or 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic aromatic heterocyclic ring (e.g., an 8-12 membered bicyclic aromatic heterocyclic ring) which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, ore.g. ̧1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting ofnitrogen, oxygen and sulphur. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or other substituents, as defined). The nitrogen and sulphur heteroatoms may optionally be oxidised (i.e., N→O and S(O)r, where r = 1 or 2). Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like. Heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., 4,5,6,7- tetrahydrobenzo[c]isoxazolyl).

[0038] Furthermore, the term “heteroaryl” includes multicyclic heteroaryl groups, e.g., tricyclic, bicyclic, e.g., benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, quinoline, isoquinoline, naphthrydine, indole, benzofuran, purine, benzofuran, deazapurine, indolizine.

[0039] Bicyclic and tricyclic systems can be edge-fused, spiro-fused, or bridged systems.

[0040] As used herein, the term “substituted,” means that any one or more hydrogen atoms on the designated atom is replaced with a selection from the indicated groups, provided that the designated atom’s normal valency is not exceeded, and that the substitution results in a stable compound. For substituted groups containing one or more heteroatoms (e.g., substituted heterocyclyl or substituted heteroaryl), the heteroatoms may be substituted provided that the heteroatoms’ normal valencies are not exceeded. When a substituent is oxo or keto (i.e., =O), then 2 hydrogen atoms on the atom are replaced. Keto substituents are not present on aromatic moieties. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N or N=N). “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0041] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any carbon atom or heteroatom in the ring, provided that the carbon atom or heteroatom’s normal valency is not exceeded. Unless specified otherwise, it is assumed that the substituent replaces a hydrogen atom of the substituted atom. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such formula. Combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0042] When any variable (e.g., R) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R moieties, then the group may optionally be substituted with up to two R moieties and R at each occurrence is selected independently from the definition of R. Also, combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0043] As used herein, the term “hydroxy” or “hydroxyl” includes groups with an -OH or -O-.

[0044] As used herein, the term “cyano” refers to the group -CN.

[0045] As used herein, the term “halo” or “halogen” refers to fluoro, chloro, bromo and iodo.

[0046] As used herein, the term “haloalkyl” refers to a branched or unbranched alkyl substituted with one or more halogens. For example, a C1-6haloalkyl is an alkyl group of from one to six carbons wherein at least one H is substituted by a halogen. Examples ofhaloalkyl include but are not limited to CFH2, CF2H, CF3, CH2CF3, CF2CF3, C(F)(CH3)2, CH2CH2Br, CH(I)CH2F, and CH2Cl.

[47] As used herein, the term “haloalkoxy” refers to alkoxy structures that are substitutedwith one or more halo groups or with combinations thereof. For example, the terms "fluoroalkyl" and "fluoroalkoxy" are haloalkyl and haloalkoxy groups, respectively, in which the halo is fluorine.

[48] As used herein, the term “amino” refers to the radical -NH2. In certain embodimentsas specified herein, one or both hydrogen atoms of -NH2may be replaced with a different group, e.g., amino-C1-7alkyl.

[49] As used herein, the expressions “one or more of A, B, or C,” “one or more A, B, orC,” “one or more of A, B, and C,” “one or more A, B, and C,” “selected from the group consisting of A, B, and C”, “selected from A, B, and C”, and the like are used interchangeably and all refer to a selection from a group consisting of A, B, and / or C, i.e., one or more As, one or more Bs, one or more Cs, or any combination thereof, unless indicated otherwise.

[50] It is to be understood that the present disclosure provides methods for the synthesis ofthe compounds of any of the Formulae described herein (e.g., compounds formula (I), (Ia), (Ib), (Ic), or (Id)). The present disclosure also provides detailed methods for the synthesis of various disclosed compounds e.g., those shown in the Examples.

[51] It is to be understood that, throughout the description, where compositions aredescribed as having, including, or comprising specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously.

[52] It is to be understood that the synthetic processes of the disclosure can tolerate a widevariety of functional groups, therefore various substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt thereof.

[53] It is to be understood that compounds of the present disclosure (e.g., compoundsformula (I), (Ia), (Ib), (Ic), and (Id)) can be prepared in a variety of ways using commerciallyavailable starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or which will be apparent to the skilled artisan in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as Smith, M. B., March, J., March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5thedition, John Wiley & Sons: New York, 2001; Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rdedition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), incorporated by reference herein, are useful and recognised reference textbooks of organic synthesis known to those in the art

[0054] One of ordinary skill in the art will note that, during the reaction sequences andsynthetic schemes described herein, the order of certain steps may be changed, such as the introduction and removal of protecting groups. One of ordinary skill in the art will recognise that certain groups may require protection from the reaction conditions via the use of protecting groups. Protecting groups may also be used to differentiate similar functional groups in molecules. A list of protecting groups and how to introduce and remove these groups can be found in Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rdedition, John Wiley & Sons: New York, 1999.

[0055] It is to be understood that, unless otherwise stated, any description of a method oftreatment includes use of the compounds to provide such treatment or prophylaxis as is described herein, as well as use of the compounds to prepare a medicament to treat or prevent such condition. It is to be understood that, unless otherwise stated, any description of a method of treatment includes use of the compounds to provide such treatment or prophylaxis as is described herein, as well as use of the compounds to prepare a medicament to treat such condition. The treatment includes treatment of human or non-human animals including rodents and other disease models.

[0056] As used herein, the terms “individual,” “patient,” or “subject” are usedinterchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferablyhumans. The compounds of the disclosure can be administered to a mammal, such as a human, but can also be other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).

[0057] As used herein, the term “treating” or “treat” includes any effect, e.g., lessening,reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder and the like.

[0058] It is to be understood that a compound of the present disclosure, or a pharmaceuticallyacceptable salt or solvate thereof, can or may also be used to prevent a relevant disease, condition or disorder, or used to identify suitable candidates for such purposes.

[0059] As used herein, the term “preventing,” “prevent,” or “protecting against” describesreducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder.

[0060] It is to be understood that one skilled in the art may refer to general reference texts fordetailed descriptions of known techniques discussed herein or equivalent techniques. These texts include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3rdedition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al., Current Protocols in Immunology, John Wiley & Sons, N.Y.; Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, N.Y.; Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18thedition (1990). These texts can, of course, also be referred to in making or using an aspect of the disclosure.

[0061] It is to be understood that the present disclosure also provides pharmaceuticalcompositions comprising any compound described herein (e.g., a compound formula (I), (Ia), (Ib), or (Ic)) in combination with at least one pharmaceutically acceptable excipient or carrier.

[0062] As used herein, the term “pharmaceutical composition” is a formulation containingthe compounds of the present disclosure (e.g., compounds formula (I), (Ia), (Ib), or (Ic)) in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or in unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial. The quantity of active ingredient (e.g., a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof) in a unit dose of composition is aneffective amount and is varied according to the particular treatment involved. One skilled in the art will appreciate that it is sometimes necessary to make routine variations to the dosage depending on the age and condition of the subject. The dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. Dosage forms for the topical or transdermal administration of a compound of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.

[0063] As used herein, the term “pharmaceutically acceptable” refers to those compounds,anions, cations, materials, compositions, carriers, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0064] As used herein, the term “pharmaceutically acceptable excipient” means an excipientthat is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use. A “pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient.

[0065] It is to be understood that a pharmaceutical composition of the disclosure isformulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., ingestion), inhalation, transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulphite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acidor sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

[0066] It is to be understood that a compound or pharmaceutical composition of thedisclosure can be administered to a subject in many of the well-known methods currently used for chemotherapeutic treatment. For example, a compound of the disclosure may be injected into the blood stream or body cavities or taken orally or applied through the skin with patches. The dose chosen should be sufficient to constitute effective treatment but not so high as to cause unacceptable side effects. The state of the disease condition (e.g., a disease or disorder disclosed herein) and the health of the subject should preferably be closely monitored during and for a reasonable period after treatment.

[0067] As used herein, the term “therapeutically effective amount” means the amount of thesubject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. Altneratively, a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and / or prophylactic effect.

[0068] It is to be understood that, for any compound, the therapeutically effective amount canbe estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic / prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50(the dose therapeutically effective in 50% of the population) and LD50(the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50 / ED50. Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the subject, and the route of administration.

[0069] Dosage and administration are adjusted to provide sufficient levels of the activeagent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance / response to therapy.

[0070] The pharmaceutical compositions containing active compounds of the presentdisclosure may be manufactured in a manner that is generally known, e.g., by means ofconventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilising processes. Pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and / or auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Of course, the appropriate formulation is dependent upon the route of administration chosen.

[0071] Pharmaceutical compositions suitable for injectable use include sterile aqueoussolutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL^ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

[0072] Sterile injectable solutions can be prepared by incorporating the active compound inthe required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilisation. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0073] Oral compositions generally include an inert diluent or an edible pharmaceuticallyacceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0074] For administration by inhalation, the compounds are delivered in the form of anaerosol spray from pressured container or dispenser, which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebuliser.

[0075] Systemic administration can also be by transmucosal or transdermal means. Fortransmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.

[0076] The active compounds can be prepared with pharmaceutically acceptable carriers thatwill protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

[0077] It is especially advantageous to formulate oral or parenteral compositions in dosageunit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the disclosure are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved.

[0078] In therapeutic applications, the dosages of the pharmaceutical compositions used inaccordance with the disclosure vary depending on the agent, the age, weight, and clinical condition of the recipient subject, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors affecting the selected dosage. Generally, the dose should be sufficient to result in slowing, and preferably regressing, the symptoms of the disease or disorder disclosed herein and also preferably causing complete regression of the disease or disorder. An effective amount of a pharmaceutical agent is that which provides an objectively identifiable improvement as noted by the clinician or other qualified observer. Improvement in survival and growth indicates regression. As used herein, the term “dosage effective manner” refers to amount of an active compound to produce the desired biological effect in a subject or cell.

[0079] It is to be understood that the pharmaceutical compositions can be included in acontainer, pack, or dispenser together with instructions for administration.

[0080] It is to be understood that, for the compounds of the present disclosure being capableof further forming salts, all of these forms are also contemplated within the scope of the claimed disclosure.

[0081] As used herein, the term “pharmaceutically acceptable salts” refer to derivatives ofthe compounds of the present disclosure wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulphonic, acetic, ascorbic, benzene sulphonic, benzoic, bicarbonic, carbonic, citric, edetic, ethanedisulphonic, 1,2-ethane sulphonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulphonic, maleic, malic, mandelic, methane sulphonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulphamic, sulphanilic, sulphuric, tannic, tartaric, toluene sulphonic, and the commonly occurring amine acids, e.g., glycine, alanine, phenylalanine, arginine, etc.

[0082] In some embodiments, the pharmaceutically acceptable salt is a sodium salt, apotassium salt, a calcium salt, a magnesium salt, a diethylamine salt, a choline salt, a meglumine salt, a benzathine salt, a tromethamine salt, an ammonia salt, an arginine salt, or a lysine salt.

[0083] Other examples of pharmaceutically acceptable salts include hexanoic acid,cyclopentane propionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulphonic acid, 2-naphthalenesulphonic acid, 4- toluenesulphonic acid, camphorsulphonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1- carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like. The present disclosure also encompasses salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. In the salt form, it is understood that the ratio of the compound to the cation or anion of the salt can be 1:1, or any ratio other than 1:1, e.g., 3:1, 2:1, 1:2, or 1:3.

[0084] It is to be understood that all references to pharmaceutically acceptable salts includesolvent addition forms (solvates) as defined herein, of the same salt.

[0085] The compounds, or pharmaceutically acceptable salts thereof, are administered orally,nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally. In one embodiment, the compound is administered orally. One skilled in the art will recognise the advantages of certain routes of administration.

[0086] A salt, for example, can be formed between an anion and a positively charged group(e.g., amino) on a substituted compound disclosed herein. Suitable anions include chloride, bromide, iodide, sulphate, bisulphate, sulphamate, nitrate, phosphate, citrate, methanesulphonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate,succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulphonate, and acetate (e.g., trifluoroacetate).

[87] It is to be understood that the compounds of the present disclosure, for example, thesalts of the compounds, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules. Nonlimiting examples of hydrates include monohydrates, dihydrates, etc. Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc.

[88] As used herein, the term “solvate” means solvent addition forms that contain eitherstoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H2O.

[89] As used herein, the term “derivative” refers to compounds that have a common corestructure and are substituted with various groups as described herein.

[90] It is also to be understood that certain compounds of any one of the Formulaedisclosed herein may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. A suitable pharmaceutically acceptable solvate is, for example, a hydrate such as hemi-hydrate, a mono-hydrate, a di-hydrate or a tri-hydrate.

[91] Compounds of any one of the Formulae disclosed herein may exist in a number ofdifferent tautomeric forms and references to compounds of formula (I), (Ia), (Ib),(Ic), and (Id) include all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all others are nevertheless embraced by formula (I), (Ia), (Ib), and (Ic). Examples of tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / aci-nitro.keto enol enolate

[0092] Compounds of any one of the Formulae disclosed herein containing an amine function may also form N-oxides. A reference herein to a compound of formula (I), (Ia), (Ib), (Ic), and (Id)that contains an amine function also includes the N-oxide. Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an N- oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle. N-oxides can be formed by treatment of the corresponding amine with an oxidising agent such as hydrogen peroxide or a peracid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with meta-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane.

[0093] The compounds of any one of the Formulae disclosed herein may be administered inthe form of a prodrug which is broken down in the human or animal body to release a compound of the disclosure. A prodrug may be used to alter the physical properties and / or the pharmacokinetic properties of a compound of the disclosure. A prodrug can be formed when the compound of the disclosure contains a suitable group or substituent to which a property-modifying group can be attached. Examples of prodrugs include derivatives containing in vivo cleavable alkyl or acyl substitutents at the ester or amide group in any one of the Formulae disclosed herein.

[0094] As used herein, the term “isomerism” means compounds that have identical molecularformulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereoisomers,” and stereoisomers that are non-superimposable mirror images of each other are termed “enantiomers” or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemic mixture.”

[0095] As used herein, the term “chiral centre” refers to a carbon atom bonded to fournonidentical substituents.

[0096] As used herein, the term “chiral isomer” means a compound with at least one chiralcentre. Compounds with more than one chiral centre may exist either as an individual diastereomer or as a mixture of diastereomers, termed “diastereomeric mixture.” When one chiral centre is present, a stereoisomer may be characterised by the absolute configuration (R or S) of that chiral centre. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral centre. The substituents attached to the chiral centre underconsideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0097] As used herein, the term “geometric isomer” means the diastereomers that owe their existence to hindered rotation about double bonds or a cycloalkyl linker (e.g., 1,3- cyclobutyl). These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.

[0098] It is to be understood that the compounds of the present disclosure may be depicted as different chiral isomers or geometric isomers. It is also to be understood that when compounds have chiral isomeric or geometric isomeric forms, all isomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any isomeric forms, it being understood that not all isomers may have the same level of activity.

[0099] It is to be understood that the structures and other compounds discussed in this disclosure include all atropic isomers thereof. It is also to be understood that not all atropic isomers may have the same level of activity.

[0100] As used herein, the term “atropic isomers” are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atropic isomers typically exist as a mixture, however as a result of recent advances in chromatography techniques, it has been possible to separate mixtures of two atropic isomers in select cases.

[0101] As used herein, the term “tautomer” is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solutions where tautomerisation is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that are interconvertible by tautomerisations is called tautomerism. Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs. Ring-chain tautomerism arises as a result of the aldehyde group (-CHO) in a sugarchain molecule reacting with one of the hydroxy groups (-OH) in the same molecule to give it a cyclic (ring-shaped) form as exhibited by glucose.

[0102] It is to be understood that the compounds of the present disclosure may be depicted as different tautomers. It should also be understood that when compounds have tautomeric forms, all tautomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any tautomer form. It will be understood that certain tautomers may have a higher level of activity than others.

[0103] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric centre, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterised by the absolute configuration of its asymmetric centre and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarised light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

[0104] The compounds of this disclosure may possess one or more asymmetric centres; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form. Some of the compounds of the disclosure may have geometric isomeric centres (E- and Z- isomers).

[0105] Accordingly, the present disclosure includes those compounds of any one of the Formulae disclosed herein as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a prodrug thereof. Accordingly, the present disclosure includes those compounds of any one of the Formulae disclosed herein that are produced by organic synthetic means and also suchcompounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of any one of the Formulae disclosed herein may be a synthetically-produced compound or a metabolically-produced compound.

[0106] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein is one that is based on reasonable medical judgment as being suitable for administration to the subject without undesirable pharmacological activities and without undue toxicity. Various forms of prodrug have been described, for example in the following documents: a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard- Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro- Drugs as Novel Delivery Systems”, A.C.S. Symposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0107] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof. An in vivo cleavable ester or ether of a compound of any one of the Formulae disclosed herein containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the subject to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester forming groups for a hydroxy group include C1-C10alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, C1-C10alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(C1-C6alkyl)2carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin- 1-ylmethyl and 4-(C1-C4alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0108] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a C1-4alkylamine such as methylamine, a (C1-C4alkyl)2amine such as dimethylamine, N-ethyl-N- methylamine or diethylamine, a C1-C4alkoxy-C2-C4alkylamine such as 2-methoxyethylamine, a phenyl-C1-C4alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.

[0109] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof. Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with C1-C10alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N- alkylaminomethyl, N,N-dialkylaminomethyl,morpholinomethyl,piperazin-1-ylmethyl and 4- (C1-C4alkyl)piperazin-1-ylmethyl.

[0110] The dosage regimen utilising the compounds is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the subject; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the subject; and the particular compound or salt thereof employed. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to counter or arrest the progress of the condition.

[0111] Techniques for formulation and administration of the disclosed compounds of the disclosure can be found in Remington: the Science and Practice of Pharmacy, 19thedition, Mack Publishing Co., Easton, PA (1995). In an embodiment, the compounds described herein, and the pharmaceutically acceptable salts thereof, are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compounds will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein.

[0112] All percentages and ratios used herein, unless otherwise indicated, are by weight. Other features and advantages of the present disclosure are apparent from the different examples. The provided examples illustrate different components and methodology useful inpracticing the present disclosure. The examples do not limit the claimed disclosure. Based on the present disclosure the skilled artisan can identify and employ other components and methodology useful for practicing the present disclosure.

[0113] In the synthetic schemes described herein, compounds may be drawn with one particular configuration for simplicity. Such particular configurations are not to be construed as limiting the disclosure to one or another isomer, tautomer, regioisomer or stereoisomer, nor does it exclude mixtures of isomers, tautomers, regioisomers or stereoisomers; however, it will be understood that a given isomer, tautomer, regioisomer or stereoisomer may have a higher level of activity than another isomer, tautomer, regioisomer or stereoisomer.

[0114] All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not intended as an admission that any is pertinent prior art, nor does it constitute any admission as to the contents or date of the same. The present disclosure having now been described by way of written description, those of skill in the art will recognize that the present disclosure can be practiced in a variety of embodiments and that the foregoing description and examples below are for purposes of illustration and not limitation of the claims that follow.

[0115] As use herein, the phrase “compound of the disclosure” refers to those compounds which are disclosed herein (e.g., compounds of formula (I), (Ia), (Ib), and (Ic)), both generically and specifically.Compounds of the Present Disclosure

[0116] In one aspect, provided herein is a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein Ring A is an optionally substituted 3-12 membered heterocyclyl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is an optionally substituted 8-12 membered bicyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R1is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, and 5-8 memebered heteroaryl; each R2is independently selected from halogen and C1-6alkyl; R3is selected from H and C1-6alkyl; each Rais independently selected from the group consisting of halogen, -OH, C1-6alkyl, C1-6haloalkyl, oxo, C3-6cycloalkyl, -C(O)O-C1-6alkyl, -C(O)C1-6haloalkyl, -C(O)O-C1-6alkylene-OC(O)-C1-6alkyl, and -N(RcRd), wherein the C1-6alkyl is optionally substituted with -OH, C1-6alkoxy, C3-6cycloalkyl, -N(RcRd), or -S(O)2C1-6alkyl, or two Raattached to the same carbon atom, together with carbon atom to which they are attached, combine to form a C3-6cycloalkyl; each Rbis independently selected from the group consisting of halogen, -OH, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, and C3-6cycloalkyl, wherein the C1-6alkoxy is optionally substituted with C3-6cycloalkyl; each Rcis independently selected from H, C1-6alkyl, and C3-6cycloalkyl, wherein the C1-6alkyl is optionally substituted with -OH; each Rdis independently selected from H and C1-6alkyl; m is 0, 1, or 2; n is 0, 1, or 2; p is 0, 1, 2, 3, or 4; andq is 0, 1, 2, 3, or 4.

[0117] In some embodiments, m is 0. In some embodiments, n is 0. In some embodiments, m and n are each 0.

[0118] In some embodiments, Ring A is an optionally substituted 5-6 membered heterocyclyl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted 5-6 membered heterocyclyl comprising 1-2 nitrogen atoms.

[0119] In some embodiments, Ring A is selected from optionally substituted piperidinyl and optionally substituted pyrrolidinyl. In some embodiments, Ring A is optionally substituted piperazinyl. In some embodiments, Ring A is optionally substituted piperidinyl. In some embodiments, Ring A is optionally substituted pyrrolidinyl.

[0120] In some embodiments, each Rais independently selected from C1-6alkyl and -N(RcRd). In some embodiments, each Rais independently C1-6alkyl. In certain embodiments, each Rais methyl. In some embodiments, each Rais independently -N(RcRd). In some embodiments, each Rcis methyl. In some embodiments, each Rdis H. In certain embodiments, each Rcis methyl and each Rdis H. In certain embodiments, each Rais -N(H)CH3. In certain embodiments, each Rais independently selected from methyl and -N(H)CH3.

[0121] In some embodiments, p is 1 or 2. In certain embodiments, p is 1. In certain embodiments, p is 2.

[0122] In some embodiments, the portion of the compound representedis selected from the group consisting

[0123] In some embodiments, the portion of the compound represented

[0125] In some embodiments, the portion of the compound representedis selected from the group consisting of, , , ,

[0126] In some embodiments, the portion of the compound representedis selected from the group consisting

[0127] In some embodiments, the compound is a compound of formula (Ia),or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3; and the rest of the variables are as defined herein.

[0128] In some embodiments, p is 0. In some embodiments, p is 1 or 2.

[0129] In some embodiments, Rais methyl.

[0130] In some embodiments, the compound is a compound of formula (Ib),or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2; and the rest of the variables are as defined herein.

[0131] In some embodiments, each Rais -N(H)CH3.

[0132] In some embodiments, p is 1.

[0133] In some embodiments, the compound is a compound formula (Ic),or a pharmaceutically acceptable salt thereof, whereinp is 0, 1, or 2; and the rest of the variables are as defined herein.

[0134] In some embodiments, the compound is a compound formula (Id),or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2; and the rest of the variables are as defined herein.

[0135] In some embodiments, p is 0.

[0136] In some embodiments, Ring B is an optionally substituted 9 membered bicyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is an optionally substituted 9 membered bicyclic heteroaryl comprising 1-2 heteratoms independently selected from nitrogen and oxygen.

[0137] In some embodiments, Ring B is selected from the group consisting of optionally substituted indazolyl, optionally substituted imidazo[1,2-a]pyridyl, and optionally substituted 2,7a-dihyrdobenzo[d]oxazolyl.

[0138] In some embodiments, each Rbis independently selected from the group consisting of halogen, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy. In some embodiments, each Rbis independently selected from the group consisting of fluoro, methyl, methoxy, ethoxy, -CHF2, and -CF3. In some embodiments, Rbis halogen. In some embodiments, Rbis C1-3alkyl. In some embodiments, Rbis C1-3haloalkyl. In some embodiments, Rbis C1-3alkoxy.

[0139] In some embodiments, q is 2 or 3. In certain embodiments, q is 2. In certain embodiments, q is 3.

[0140] In some embodiments, the portion of the compound represented byselected from the group consisting of,Rb, H, NNH ,N, Rb b b bq R q R qbN R NbNN R qN q H R H N N N N N N , N , N,NNH ,NRb, N RbRb bq R NRbq q q NH N N N N N N NNRbN N N ,q, N , NRb, N , Rb bq R q Rb bq R N q N N NNNH N N NN NN NRNRbNb,N,Rb,Rb,q,

[0141] In some embodiments, the portion of the compound represented by

[0142] In some embodiments, the portion of the compound represented by

[0143] In some embodiments, the portion of the compound represented by

[0144] In some embodiments, the portion of the compound represented by

[0145] In some embodiments, the portion of the compound represented by

[0146] In some embodiments, the portion of the compound represented byF N N , O N N N N , F N NN,N N , F N N N ,F F O F N N N N N O,O, O , S ,S, F O O NN N N N N N N N N, , , , ,

[0147] To clarify, in all embodiments where two variable groups together form an alkylene, those groups along with the atoms they are attached to and possible intervening atoms, form a ring. This ring can be cycloalkyl or heterocyclyl depending on the attachment point of the variables, but the variable groups themselves are alkylene and thus contain no heteroatoms of their own.

[0148] In some embodiments, the compound is selected from the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0149] In some embodiments, the compound is selected from the compounds described in Table 1, or from the disclosure.

[0150] In some embodiments, the compound is selected from the compounds described in Table 1.

[0151] Table 1. Exemplary compounds of the disclosure

[0152] In some embodiments, the compound is a therapeutically active substance. In some embodiments, the compound is a small molecule splicing modulator.

[0153] For the avoidance of doubt it is to be understood that, where in this specification a group is qualified by “described herein”, the said group encompasses the first occurring and broadest definition as well as each and all of the particular definitions for that group.

[0154] The various functional groups and substituents making up the compounds of formulae (I), (Ia), (Ib), (Ic), and (Id) are typically chosen such that the molecular weight of the compound does not exceed 1000 daltons. More usually, the molecular weight of the compound will be less than 900, for example less than 800, or less than 750, or less than 700, or less than 650 daltons. More conveniently, the molecular weight is less than 600 and, for example, is 550 daltons or less.

[0155] It will be understood that the compounds of any one of formulae (I), (Ia), (Ib), (Ic), and (Id) disclosed herein and any pharmaceutically acceptable salts thereof, comprise stereoisomers and mixtures of stereoisomers of all isomeric forms of said compounds.

[0156] It is to be understood that the compounds of formulae (I), (Ia), (Ib), (Ic), and (Id) described herein include the compounds themselves, as well as their salts, and their solvates, if applicable.

[0157] The in vivo effects of a compound of any one of formulae (I), (Ia), (Ib), (Ic), and (Id) disclosed herein may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of any one of formulae (I), (Ia), (Ib), (Ic), and (Id) disclosed herein. As stated hereinbefore, the in vivo effects of a compound of any one of the Formulae disclosed herein may also be exerted by way of metabolism of a precursor compound (a prodrug).

[0158] Suitably, the present disclosure excludes any individual compounds not possessing the biological activity defined herein. Alternative Embodiments

[0159] In an alternative embodiment, compounds described herein may also comprise one or more isotopic substitutions. For example, hydrogen may be2H (D or deuterium) or3H (T or tritium); carbon may be, for example,13C or14C; oxygen may be, for example,18O; nitrogen may be, for example,15N, and the like. In other embodiments, a particular isotope (e.g.,3H,13C,14C,18O, or15N) can represent at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of an element that occupies a specific site of the compound. Methods of Synthesis

[0160] In some aspects, the present disclosure provides a method of preparing a compound of the present disclosure (e.g., a compound of formula (I), (Ia), (Ib), or (Ic)).

[0161] In some aspects, the present disclosure provides a method of preparing a compound, comprising one or more steps as described herein.

[0162] In some aspects, the present disclosure provides a compound obtainable by, or obtained by, or directly obtained by a method for preparing a compound as described herein (e.g., a compound of formula (I), (Ia), (Ib), or (Ic)).

[0163] In some aspects, the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein (e.g., a compound of formula (I), (Ia), (Ib), or (Ic)).

[0164] The compounds of the present disclosure (e.g., compounds of formula (I), (Ia), (Ib), or (Ic)) can be prepared by any suitable technique known in the art. Particular processes for the preparation of these compounds are described further in the accompanying examples.

[0165] In the description of the synthetic methods described herein and in any referenced synthetic methods that are used to prepare the starting materials, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be selected by a person skilled in the art.

[0166] It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions utilized.

[0167] It will be appreciated that during the synthesis of the compounds of the disclosure (e.g., compounds of formula (I), (Ia), (Ib), or (Ic)) in the processes defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituent groups to prevent their undesired reaction. The skilled chemist will appreciate when such protection is required, and how such protecting groups may be put in place, and later removed. For examples of protecting groups see one of the many general texts on the subject, for example, ‘Protective Groups in Organic Synthesis’ by Theodora Green (publisher: John Wiley & Sons). Protecting groups may be removed by any convenient method described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with the minimum disturbance of groups elsewhere in the molecule. Thus, if reactants include, for example, groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.

[0168] By way of example, a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed by, for example, hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid ortrifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

[0169] A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium, sodium hydroxide or ammonia. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.

[0170] A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a tert-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.

[0171] Once a compound of formula (I), (Ia), (Ib), (Ic), or (Id) has been synthesised by any one of the processes defined herein, the processes may then further comprise the additional steps of: (i) removing any protecting groups present; (ii) converting the compound of a formula (I),(Ia), (Ib), (Ic), or (Id) into another compound of formula (I), (Ia), (Ib), (Ic), or (Id) ; and / or (iii) forming a pharmaceutically acceptable salt thereof.

[0172] The resultant compounds of formula (I), (Ia), (Ib), (Ic), or (Id) can be isolated and purified using techniques well known in the art.

[0173] Conveniently, the reaction of the compounds is carried out in the presence of a suitable solvent, which is preferably inert under the respective reaction conditions. Examples of suitable solvents comprise but are not limited to hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichlorethylene, 1,2- dichloroethane, tetrachloromethane, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, cyclopentylmethylether (CPME), methyl tert-butyl ether (MTBE) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone, methylisobutylketone (MIBK) or butanone; amides, such as acetamide, dimethylacetamide, dimethylformamide (DMF) or N-methylpyrrolidinone (NMP); nitriles, such as acetonitrile; sulphoxides, such as dimethyl sulphoxide (DMSO); nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate or methyl acetate, or mixtures of the said solvents or mixtures with water.

[0174] The reaction temperature is suitably between about -100 °C and 300 °C, depending on the reaction step and the conditions used.

[0175] Reaction times are generally in the range between a fraction of a minute and several days, depending on the reactivity of the respective compounds and the respective reaction conditions. Suitable reaction times are readily determinable by methods known in the art, for example reaction monitoring. Based on the reaction temperatures given above, suitable reaction times generally lie in the range between 10 minutes and 48 hours.

[0176] Moreover, by utilising the procedures described herein, in conjunction with ordinary skills in the art, additional compounds of the present disclosure (e.g., compounds of formula (I), (Ia), (Ib), or (Ic)) can be readily prepared. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.

[0177] As will be understood by the person skilled in the art of organic synthesis, compounds of the present disclosure (e.g., compounds of formula (I), (Ia), (Ib), or (Ic)) are readily accessible by various synthetic routes, some of which are exemplified in the accompanying examples. The skilled person will easily recognise which kind of reagents and reactions conditions are to be used and how they are to be applied and adapted in any particular instance – wherever necessary or useful – in order to obtain the compounds of the present disclosure. Furthermore, some of the compounds of the present disclosure can readily be synthesised by reacting other compounds of the present disclosure under suitable conditions, for instance, by converting one particular functional group being present in a compound of the present disclosure, or a suitable precursor molecule thereof, into another one by applying standard synthetic methods, like reduction, oxidation, addition or substitution reactions; those methods are well known to the skilled person. Likewise, the skilled person will apply – whenever necessary or useful – synthetic protecting (or protective) groups; suitable protecting groups as well as methods for introducing and removing them are well-known to the person skilled in the art of chemical synthesis and are described, in more detail, in, e.g.,P.G.M. Wuts, T.W. Greene, “Greene’s Protective Groups in Organic Synthesis”, 4th edition (2006) (John Wiley & Sons).

[0178] General routes for the preparation of a compound of the application are described herein. Biological Assays

[0179] Compounds designed, selected and / or optimised by methods described above, once produced, can be characterised using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity. For example, the molecules can be characterised by conventional assays, including but not limited to those assays described below, to determine whether they have a predicted activity, binding activity and / or binding specificity. Pharmaceutical Compositions

[0180] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure as an active ingredient. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound of each of the formulae described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Table 1, or from the disclosure. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Table 1.

[0181] As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0182] The compounds of present disclosure can be formulated for oral administration in forms such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. The compounds of present disclosure on can also be formulated for intravenous (bolus or in- fusion), intraperitoneal, topical, subcutaneous, intramuscular or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts.

[0183] The formulation of the present disclosure may be in the form of an aqueous solution comprising an aqueous vehicle. The aqueous vehicle component may comprise water and atleast one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of a solubility enhancing agent, chelating agent, preservative, tonicity agent, viscosity / suspending agent, buffer, and pH modifying agent, and a mixture thereof.

[0184] Any suitable solubility enhancing agent can be used. Examples of a solubility enhancing agent include cyclodextrin, such as those selected from the group consisting of hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, randomly methylated-β-cyclodextrin, ethylated-β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3- (trimethylammonio)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, sulphated β-cyclodextrin (S-β-CD), maltosyl-β-cyclodextrin, β-cyclodextrin sulphobutyl ether, branched-β- cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomly methylated-γ-cyclodextrin, and trimethyl-γ-cyclodextrin, and mixtures thereof.

[0185] Any suitable chelating agent can be used. Examples of a suitable chelating agent include those selected from the group consisting of ethylenediaminetetraacetic acid and metal salts thereof, disodium edetate, trisodium edetate, and tetrasodium edetate, and mixtures thereof.

[0186] Any suitable preservative can be used. Examples of a preservative include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, phenylmercury nitrate, phenylmercury acetate, phenylmercury neodecanoate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl-p-hydroxybenzoate, and sorbic acid, and mixtures thereof.

[0187] The aqueous vehicle may also include a tonicity agent to adjust the tonicity (osmotic pressure). The tonicity agent can be selected from the group consisting of a glycol (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and a mixture thereof.

[0188] The aqueous vehicle may also contain a viscosity / suspending agent. Suitable viscosity / suspending agents include those selected from the group consisting of cellulose derivatives, such as methyl cellulose, ethyl cellulose, hydroxyethylcellulose, polyethylene glycols (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethyl cellulose, hydroxypropylmethyl cellulose, and cross-linked acrylic acid polymers (carbomers), such aspolymers of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol (Carbopols - such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974 and Carbopol 974P), and a mixture thereof.

[0189] In order to adjust the formulation to an acceptable pH (typically a pH range of about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), the formulation may contain a pH modifying agent. The pH modifying agent is typically a mineral acid or metal hydroxide base, selected from potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, and preferably sodium hydroxide and / or hydrochloric acid. These acidic and / or basic pH modifying agents are added to adjust the formulation to the target acceptable pH range. Hence it may not be necessary to use both acid and base - depending on the formulation, the addition of one of the acid or base may be sufficient to bring the mixture to the desired pH range.

[0190] The aqueous vehicle may also contain a buffering agent to stabilise the pH. When used, the buffer is selected from the group consisting of a phosphate buffer (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), a borate buffer (such as boric acid, or salts thereof including disodium tetraborate), a citrate buffer (such as citric acid, or salts thereof including sodium citrate), and ε-aminocaproic acid, and mixtures thereof.

[0191] The formulation may further comprise a wetting agent. Suitable classes of wetting agents include those selected from the group consisting of polyoxypropylene- polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oils, polyoxyethylenated sorbitan esters (polysorbates), polymers of oxyethylated octyl phenol (Tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty esters, and polyoxyethylene fatty esters, and mixtures thereof.

[0192] According to a further aspect of the disclosure there is provided a pharmaceutical composition which comprises a compound of the disclosure as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.

[0193] The compositions of the disclosure may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (forexample as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).

[0194] The compositions of the disclosure may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and / or preservative agents.

[0195] An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat or prevent a disease or disorder referred to herein, slow its progression and / or reduce the symptoms associated with the condition.

[0196] An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat a disease or disorder referred to herein, slow its progression and / or reduce the symptoms associated with the condition.

[0197] The size of the dose for therapeutic or prophylactic purposes of a compound of Formula (I) or (II) will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or subject and the route of administration, according to well- known principles of medicine. Methods of Use

[0198] Provided herein is a method of treating a a disorder related to a nucleotide repeat expansion in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition described herein.

[0199] In some embidmments, the nucleotide repeat expansion comprises a nucleotide sequence repeated two or more times, wherein the nucleotide sequence is selected from the group consisting of CNN, ANN, TNN, and GNN, wherein N is a nucleotide selected from the group consisting of adenine (A), thymine (T), guanine (G), and cytosine (C).

[0200] In some embodiments, the nucleotide repeat expansion comprises a nucleotide sequence repeated two or more times, wherein the nucleotide sequence is selected from the group consisting of CAG, CAG / CTG, GCG, GCN, CGG, CCG, CCCCGCCCCGCG, GCA, GGGGCC, CTG, GAA, ATTCT, TGGAA, GGCCTG, AAGGG, CCCTCT, ATTTT / ATTTC, and CCCTCT, wherein N is a nucleotide selected from the group consisting of adenine (A), thymine (T), guanine (G), and cytosine (C).

[0201] In certain embodiments, the nucleotide repeat expansion comprises a trinucleotide sequence repeated two or more times, wherein the trinucleotide sequence is selected from the group consisting of CAG, CTG, CGG, and GCN.

[0202] Also provided herein is a method of treating a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition described herein, wherein the disease is selected from the group consisting of Dentatorubropallidoluysian atrophy, Huntington's disease, Spinal and bulbar muscular atrophy, SCA1 (Spinocerebellar ataxia Type 1), SCA2 (Spinocerebellar ataxia Type 2), SCA3 (Spinocerebellar ataxia Type 3 or Machado-Joseph disease), SCA6 (Spinocerebellar ataxia Type 6), SCA7 (Spinocerebellar ataxia Type 7), SCA12 (Spinocerebellar ataxia Type 12), SCA17 (Spinocerebellar ataxia Type 17), FRAXA (Fragile X syndrome), FXTAS (Fragile X-associated tremor / ataxia syndrome), FRAXE (Fragile XE mental retardation), Baratela-Scott syndrome, FRDA (Friedreich's ataxia), DM1 (Myotonic dystrophy Type 1), DM2 (Myotonic dystrophy Type 2) SCA8 (Spinocerebellar ataxia Type 8), Fuchs endothelial corneal dystrophy, Desbuquois dysplasia, amyotrophic lateral sclerosis, frontotemporal dementia, GLS (glutaminase) disease, and SBMA / Kennedy disease.

[0203] In some embodiments, the disease is Huntington’s disease.

[0204] Also provided herein is a method of treating a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition disclosed herein, wherein the disease is Huntington’s disease.

[0205] In some embodiments, the disease is myotonic dystrophy 1.

[0206] Also provided herein is a method of treating a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition disclosed herein, wherein the disease is myotonic dystrophy 1.

[0207] In some embodiments, the disease is selected from the group consisting of FRAXA (Fragile X syndrome), FXTAS (Fragile X-associated tremor / ataxia syndrome), FRAXE (Fragile XE mental retardation).

[0208] Also provided herein is a method of treating a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition disclosed herein, wherein the disease is selected from the group consisting of FRAXA (Fragile X syndrome), FXTAS (Fragile X-associated tremor / ataxia syndrome), FRAXE (Fragile XE mental retardation). Routes of Administration

[0209] The compounds of the disclosure (e.g., compounds of formula (I), (Ia), (Ib), or (Ic)) or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically / peripherally or topically (i.e., at the site of desired action).

[0210] Routes of administration include, but are not limited to, oral (e.g. by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly. Enumerated Embodiments 1. A compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein Ring A is an optionally substituted 3-12 membered heterocyclyl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is an optionally substituted 8-12 membered bicyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R1is independently selected from halogen and C1-6alkyl; each R2is independently selected from halogen and C1-6alkyl; each Rais independently selected from the group consisting of halogen, C1-6alkyl, C1-6haloalkyl, and -N(RcRd),or two Raattached to the same carbon atom, together with carbon atom to which they are attached, combine to form a C3-6cycloalkyl; each Rbis independently selected from the group consisting of halogen, -OH, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, wherein the C1-6alkoxy is optionally substituted with C3-6cycloalkyl; each Rcis independently selected from H and C1-6alkyl; each Rdis independently selected from H and C1-6alkyl; m is 0, 1, or 2; n is 0, 1, or 2; p is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4. 2. The compound of embodiment 1, wherein m and n are each 0. 3. The compound of embodiment 1 or 2, wherein Ring A is an optionally substituted 5-6 membered heterocyclyl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 4. The compound of any one of embodiments 1-3, wherein Ring A is selected from optionally substituted piperidinyl and optionally substituted pyrrolidinyl. 5. The compound of any one of embodiments 1-4, wherein each Rais independently selected from C1-6alkyl and -N(RcRd). 6. The compound of any one of embodiments 1-5, wherein each Rcis methyl and each Rdis H. 7. The compound of any one of embodiments 1-6, wherein each Rais independently selected from methyl and -N(H)CH3. 8. The compound of any one of embodiments 1-7, wherein p is 1 or 2. 9. The compound of any one of embodiments 1-8, wherein the portion of the compound representedselected from the group consisting of,10. The compound of embodiment 1, wherein the compound is a compound of formula (Ia),or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3; and the rest of the variables are as defined in embodiment 1. 11. The compound of embodiment 10, wherein p is 0. 12. The compound of embodiment 10, wherein p is 1 or 2. 13. The compound of embodiment 10 or 12, wherein each Rais methyl. 14. The compound of embodiment 1, wherein the compound is a compound of formula (Ib),or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2; and the rest of the variables are as defined in embodiment 1.15. The compound of embodiment 14, wherein each Ra is -N(H)CH3.16. The compound of embodiment 14 or 15, wherein p is 1.17. The compound of embodiment 1, wherein the compound is a compound of formula(Ic),or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2; and the rest of the variables are as defined in embodiment 1.18. The compound of embodiment 17, wherein p is 0.19. The compound of any one of embodiments 1-18, wherein Ring B is an optionallysubstituted 9 membered bicyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.20. The compound of any one of embodiments 1-19, wherein Ring B is selected from thegroup consisting of optionally substituted indazolyl, optionally substituted imidazo[1,2- a]pyridyl, and optionally substituted 2,7a-dihyrdobenzo[d]oxazolyl.21. The compound of any one of embodiments 1-20, wherein each Rb is independentlyselected from the group consisting of halogen, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy.22. The compound of any one of embodiments 1-21, wherein each Rb is independentlyselected from the group consisting of fluoro, methyl, methoxy, ethoxy, -CHF2, and -CF3.23. The compound of any one of embodiments 1-22, wherein q is 2 or 3.24. The compound of any one of embodiments 1-23, wherein the portion of the25. The compound of any one of embodiments 1-24, wherein the portion of the26. A pharmaceutical composition comprising a compound of any one of embodiments 1-25, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.27. A compound of any one of embodiments 1-25, or a pharmaceutically acceptable saltthereof, for use as a small molecule splicing modulator.28. A pharmaceutical composition comprising a compound of any one of embodiments 1-25 and 27, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.29. A method of treating a disorder related to a nucleotide repeat expansion n a subject inneed thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-25 or a pharmaceutical composition of embodiment 26.30. The method of embodiment 29, wherein the nucleotide repeat expansion comprises anucleotide sequence repeated two or more times, wherein the nucleotide sequence is selected from the group consisting of CNN, ANN, TNN, and GNN, wherein N is a nucleotide selected from the group consisting of adenine (A), thymine (T), guanine (G), and cytosine (C).31. The method of embodiment 29, wherein the nucleotide repeat expansion comprises anucleotide sequence repeated two or more times, wherein the nucleotide sequence is selected from the group consisting of CAG, CAG / CTG, GCG, GCN, CGG, CCG, CCCCGCCCCGCG, GCA, GGGGCC, CTG, GAA, ATTCT, TGGAA, GGCCTG, AAGGG, CCCTCT, ATTTT / ATTTC, and CCCTCT, wherein N is a nucleotide selected from the group consisting of adenine (A), thymine (T), guanine (G), and cytosine (C).32. The method of embodiment 30 or 31, wherein the nucleotide repeat expansioncomprises a trinucleotide sequence repeated two or more times, wherein the trinucleotide sequence is selected from the group consisting of CAG, CTG, CGG, and GCN.33. A method of treating a disease in a subject in need thereof, the method comprisingadministering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-25 or a pharmaceutical composition of embodiment 26, wherein the disease is selected from the group consisting of Dentatorubropallidoluysian atrophy, Huntington's disease, spinal and bulbar muscular atrophy, SCA1 (Spinocerebellar ataxia Type 1), SCA2 (Spinocerebellar ataxia Type 2), SCA3 (Spinocerebellar ataxia Type 3 or Machado-Joseph disease), SCA6 (Spinocerebellar ataxia Type 6), SCA7 (Spinocerebellar ataxia Type 7), SCA12 (Spinocerebellar ataxia Type 12), SCA17 (Spinocerebellar ataxia Type 17), FRAXA (Fragile X syndrome), FXTAS (Fragile X-associated tremor / ataxia syndrome), FRAXE (Fragile XE mental retardation), Baratela-Scott syndrome, FRDA (Friedreich's ataxia), DM1 (Myotonic dystrophy Type 1), DM2 (Myotonic dystrophy Type 2), SCA8 (Spinocerebellar ataxia Type 8), Fuchs endothelial corneal dystrophy, Desbuquois dysplasia, amyotrophic lateral sclerosis, frontotemporal dementia, GLS (glutaminase) disease, and SBMA / Kennedy disease.34. A method of treating a disease in a subject in need thereof, the method comprisingadministering to the subject a therapeutically effective amount of a compound of any one ofembodiments 1-25 or a pharmaceutical composition of embodiment 26, wherein the disease is Huntington’s disease.35. A method of treating a disease in a subject in need thereof, the method comprisingadministering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-25 or a pharmaceutical composition of embodiment 26, wherein the disease is Myotonic dystrophy 1.36. A method of treating a disease in a subject in need thereof, the method comprisingadministering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-25 or a pharmaceutical composition of embodiment 26, wherein the disease is selected from the group consisting of FRAXA (Fragile X syndrome), FXTAS (Fragile X- associated tremor / ataxia syndrome), and FRAXE (Fragile XE mental retardation). EXAMPLES

[0211] For exemplary purpose, neutral compounds of formula (I), (Ia), (Ib), (Ic), and / or (Id) are may be synthesized and tested in the examples. It is understood that neutral compounds of formula (I), (Ia), (Ib), (Ic), and / or (Id) may be converted to the corresponding pharmaceutically acceptable salts of the compounds using routine techniques in the art (e.g., by saponification of an ester to the carboxylic acid salt, or by hydrolyzing an amide to form a corresponding carboxylic acid and then converting the carboxylic acid to a carboxylic acid salt).

[0212] Nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz or 300 MHz as stated; the chemical shifts (δ) are reported in parts per million (ppm). Spectra were recorded using a Bruker or Varian instrument with 8, 16 or 32 scans.

[0213] LC-MS chromatograms and spectra were recorded using an Agilent 1200 or Shimadzu LC-20 AD&MS 2020 instrument using a C-18 column such as C182.1 x 30 mm, unless otherwise stated. Injection volumes were 0.7 – 8.0 µl and the flow rates were typically 0.8 or 1.2 ml / min. Detection methods were diode array (DAD) or evaporative light scattering (ELSD) as well as positive ion electrospray ionisation. MS range was 100 - 1000 Da. Solvents were gradients of water and acetonitrile both containing a modifier (typically 0.01 – 0.04 %) such as trifluoroacetic acid or ammonium carbonate. Abbreviations: ACN acetonitrile (Ac)2O acetic anhydride BINAP2,2′-bis(diphenylphosphino)-1,1′-binaphthylCDCl3chloroform-d Cs2CO3caesium carbonate DCM dichloromethane DIEA N,N-diisopropylethylamine DMAP 4-dimethylaminopyridine DMSO dimethylsulphoxide DMSO-d6hexadeuterodimethylsulphoxide ESI electrospray ionisation EA ethyl acetate FA formic acid h hour(s)1H NMR proton nuclear magnetic resonance spectroscopy H2hydrogen H2O water HCl hydrochloric acid HDMS bis(trimethylsilyl)amine HOAc acetic acid HPLC high performance liquid chromatography IPA isopropyl alcohol K2CO3potassium carbonate M molar MeOD-d4methanol-d4MeOH methanol MS mass spectrometry N2nitrogen NBS N-bromosuccinimide NH3ammonia Na2CO3sodium carbonate Na2SO4sodium sulfate NaOAc sodium acetate NMR nuclear magnetic resonance Pd / C palladium on carbon Pd(dppf)Cl2[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)Pd(OAc)2palladium (II) acetate PE petroleum ether PPTS pyridinium p-toluenesulfonate prep-HPLC preparative high performance liquid chromatography RT room temperature sat. saturated TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TMSOTf trimethylsilyl trifluoromethanesulfonate wt weight Y YieldExample 1 – Preparation of (S)-N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride (Compound 1)Step 1: Preparation of 5-bromo-2, 3-difluorobenzaldehyde

[0214] To a mixture of 2, 3-difluorobenzaldehyde (25 g, 176 mmol) in H2SO4(250 mL) was added NBS (37.6 g, 211 mmol). The mixture was stirred at 60℃ for 16 h. The reaction was poured into ice-water (200 mL) and extracted with EA (300 mL x 3). The combined organic layer was washed with brine (200 mL), dried over Na2SO4and evaporated in vacuo. The residue was purified by silica gel column chromatography (PE) to give title product (20.00 g, Y: 51.6 %) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.23 – 8.01 (m, 1H), 7.88 – 7.69 (m, 1H).Step 2: Preparation of (E)-5-bromo-2,3-difluorobenzaldehyde oxime

[0215] To a mixture of 5-bromo-2, 3-difluorobenzaldehyde (40 g, 181 mmol) in THF (400 mL) were added NH2OH·HCl (15 g, 217 mmol) and K2CO3(30 g, 217 mmol). The mixture was stirred at 40oC for 16 h. The reaction was diluted with water (300 mL) and extracted with EA (400 mL x 3). The combined organic layer was washed with brine (400 mL), dried over Na2SO4and evaporated in vacuo to give tittle product (30 g, Y: 70.5 %) as a white solid, which was used to next step without further purification. ESI-MS (M+H)+: 236.0.1H NMR (400 MHz, DMSO-d6) δ 11.98 (s, 1H), 8.23 – 8.15 (m, 1H), 7.88 – 7.76 (m, 1H), 7.71 – 7.63 (m, 1H). Step 3: Preparation of 5-bromo-7-fluoro-1H-indazole

[0216] To a mixture of (E)-5-bromo-2, 3-difluorobenzaldehyde oxime (30 g, 128 mmol) in 1,4-dioxane (300 mL) was added N2H4.H2O (44.7 g, 894 mmol). The mixture was stirred at 145oC for 16 h. The mixture was diluted with water (350 mL) and extracted with EA (450 mL x 3). The combined organic layer was washed with brine (300 mL), dried over Na2SO4and evaporated in vacuo. The crude was purified by silica gel column chromatography (PE: EA= 5:1) to give title product (16.5 g, Y: 60.2 %) as a white solid. ESI-MS (M+H)+: 215.1.1H NMR (400 MHz, DMSO-d6) δ 8.22 – 8.15 (m, 1H), 7.88 (s, 1H), 7.45 (d, J = 10.4 Hz, 1H). Step 4: Preparation of 5-bromo-7-fluoro-2-methyl-2H-indazole

[0217] To a mixture of 5-bromo-7-fluoro-1H-indazole (33 g, 154 mmol) in EA (330 mL) was added trimethyloxonium tetrafluoroborate (27.2 g, 185 mmol) and stirred at r.t for 5 h. The mixture was quenched with NaHCO3(200 mL) and extracted with EA (350 mL x 3). The combined organic layer was washed with brine (400 mL), dried over Na2SO4, filtered and concentrate in vacuo. The residue was purified by column chromatography (PE: EA= 5:1) to give title product (18 g, Y: 51.4 %) as a white solid. ESI-MS (M+H)+: 229.1.1H NMR (400 MHz, DMSO-d6) δ 8.55 – 8.36 (m, 1H), 7.81 (d, J = 1.4 Hz, 1H), 7.30 – 7.17 (m, 1H), 4.20 (s, 3H). Step 5: Preparation of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-1,1-diphenylmethanimine

[0218] To a mixture of 5-bromo-7-fluoro-2-methyl-2H-indazole (10 g, 44 mmol) and diphenylmethanimine (7.93 g, 44 mmol) in 1.4-dioxane (200 mL) were added BINAP (5.46 g, 8 mmol), Pd(OAc)2(1 g, 4.4 mmol) and Cs2CO3(28.6 g, 88 mmol). The mixture was stirred at 100 ℃ for 16 h. The reaction was diluted with water (300 mL), extracted with EA (500 mL x 3). The organic layer was washed with brine, dried over Na2SO4and evaporated in vacuo. The crude was purified by silica gel column chromatography (PE: EA =3:1) to givetitle product (7 g, yield 65%) as a yellow solid. ESI-MS (M+H)+: 330.11H NMR (400 MHz, DMSO-d6) δ 8.21 (d, J = 2.8 Hz, 1H), 7.69 – 7.64 (m, 2H), 7.56 – 7.52 (m, 1H), 7.50 – 7.44 (m, 2H), 7.34 – 7.29 (m, 3H), 7.21 – 7.16 (m, 2H), 6.68 (d, J = 1.3 Hz, 1H), 6.58 (dd, J = 12.7, 1.3 Hz, 1H), 4.10 (s, 3H). Step 6: Preparation of 7-fluoro-2-methyl-2H-indazol-5-amine hydrochloride

[0219] A mixture of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-1,1-diphenylmethanimine (5 g, 15.2 mmol) in 3M HCl / EA (70 mL) was stirred at RT for 2 h. The precipitate was filtered and dried in vacuo to give title product (2.5 g, yield 82%) as a yellow solid. ESI-MS (M+H)+: 166.1.1H NMR (400 MHz, DMSO-d6) δ 10.63 (s, 2H), 8.61 (d, J = 2.7 Hz, 1H), 7.69 (d, J = 1.4 Hz, 1H), 7.11 (dd, J = 11.7, 1.4 Hz, 1H), 4.22 (s, 3H). Step 7: Preparation of 4-chloro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine

[0220] A solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine (96 g, 627.45 mmol) in dimethylsulfide borane (600 mL, 2M in THF) was stirred at 60oC for 16 h. The mixture was diluted with MeOH (300 mL) and concentrated in vacuo, the residue was purified by column gel chromatography (PE / EA=3 / 1) to give title product (16 g, 16.45 %) as a yellow solid. ESI-MS (M+H)+: 155.2.1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 5.7 Hz, 1H), 6.42 (d, J = 5.8 Hz, 1H), 3.60 (t, J = 8.5 Hz, 2H), 3.05 (t, J = 8.5 Hz, 2H). Step 8: Preparation of tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate

[0221] To a solution of 4-chloro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (350 mg, 2.26 mmol) and tert-butyl (S)-2-methylpiperazine-1-carboxylate (904 mg, 4.52 mmol) in a sealed tube was added DIEA (1.5 g, 11.3 mmol). The reaction mixture was stirred at 140 °C for 16 h. The mixture was concentrated in vacuo and the residue was purified by column gel chromatography (DCM / MeOH=10 / 1) and C18 (0.1% FA in H2O / ACN) to give title product (200 mg, 27.86 %) as a yellow solid. ESI-MS (M+H)+: 319.2.1H NMR (400 MHz, DMSO-d6) δ 7.54 (d, J = 5.9 Hz, 1H), 6.05 (d, J = 6.0 Hz, 1H), 5.86 (s, 1H), 4.21 – 4.09 (m, 1H), 3.80 – 3.71 (m, 1H), 3.49 – 3.41 (m, 1H), 3.40 – 3.35 (m, 3H), 3.16 – 3.05 (m, 1H), 3.01 – 2.90 (m, 2H), 2.87 – 2.80 (m, 1H), 2.76 – 2.67 (m, 1H), 1.41 (s, 9H), 1.19 (d, J = 6.6 Hz, 3H). Step 9: Preparation of tert-butyl (S)-4-(1-((7-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate

[0222] To a solution of tert-butyl (S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (180 mg, 0.57 mmol) and 7-fluoro-2-methyl-2H-indazol-5- amine (188 mg, 1.14 mmol) in DCM (10 mL) were added TEA (230 mg, 2.28 mmol) andtriphosgene (271 mg, 0.91 mmol) at 0 °C. The reaction mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and the residue was purified by C18 (0.1% FA in H2O / ACN) to give title product (40 mg, 13.94 %) as a yellow solid. ESI-MS (M+H)+: 510.4.1H NMR (400 MHz, CDCl3) δ 11.65 (s, 1H), 7.84 (d, J = 5.9 Hz, 1H), 7.78 (dd, J = 6.8, 1.9 Hz, 2H), 7.01 (d, J = 12.7 Hz, 1H), 6.27 (d, J = 6.0 Hz, 1H), 4.32 – 4.24 (m, 1H), 4.14 (s, 3H), 4.12 – 4.03 (m, 2H), 3.93 – 3.84 (m, 1H), 3.48 – 3.33 (m, 2H), 3.20 – 3.12 (m, 1H), 3.06 – 2.96 (m, 3H), 2.93 – 2.82 (m, 1H), 1.42 (s, 9H), 1.23 (d, J = 6.7 Hz, 3H). Step 10: Preparation of (S)-N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(3-methylpiperazin-1- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride

[0223] To a solution of tert-butyl (S)-4-(1-((7-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (40 mg, 0.08 mmol) in EA (2 mL) was added 3 M HCl / EA (1 mL). The mixture was stirred at RT for 2 h. The precipitate was filtered, washed with EA (5 mL) and lyophilized to give title product (25 mg, 71.43 %) as a yellow solid. ESI-MS (M+H)+: 410.2.1H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 2H), 8.44 (s, 1H), 7.91 – 7.77 (m, 1H), 7.76 – 7.71 (m, 1H), 7.33 (d, J = 13.5 Hz, 1H), 7.01 – 6.68 (m, 1H), 4.38 – 4.20 (m, 2H), 4.18 (s, 3H), 4.17 – 4.11 (m, 1H), 3.61 – 3.21 (m, 7H), 3.16 – 3.08 (m, 1H), 1.32 (d, J = 6.1 Hz, 3H).Example 2 – Preparation of (R) -N- (7-fluoro-2-methyl-2H-indazol-5-yl) -4- (3- (methylamino) pyrrolidin-1-yl) -2,3-dihydro-1H-pyrrolo [2,3-b] pyridine-1-carboxamide 2,2,2-trifluoroacetate (Compound 2)Step 1: Preparation of phenyl (7-fluoro-2-methyl-2H-indazol-5-yl)carbamate

[0224] To a solution of 7-fluoro-2-methyl-2H-indazol-5-amine (400 mg, 2.42 mmol) in DCM (10 mL) were added pyridine (573 mg, 7.26 mmol) and phenyl carbonochloridate (455 mg, 2.90 mmol) at 0oC. The mixture was stirred at RT for 3 h. The reaction mixture was diluted with H2O (15 mL), the precipitate was filtered, washed with water and dried in vacuo to give title product (500 mg, 72.46 %) as yellow solid. ESI-MS (M+H)+: 286.1.1H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.39 (d, J = 2.8 Hz, 1H), 7.68 (s, 1H), 7.44 (t, J = 7.8 Hz, 2H), 7.29 – 7.14 (m, 4H), 4.16 (s, 3H). Step 2: Preparation of tert-butyl (R)-(1-(2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) pyrrolidin-3-yl) (methyl) carbamate

[0225] To a mixture of 4-chloro-2,3-dihydro-1H-pyrrolo [2,3-b] pyridine (600 mg, 3.88 mmol) in DIEA (3.2 mL) was added tert-butyl (R)-methyl(pyrrolidin-3-yl) carbamate (930 mg, 4.65 mmol). The resulting mixture was stirred at 140oC for 24 h in a sealed tube. The mixture was allowed to cooling down to room temperature and concentrated in vacuo. Thecrude was purified by silica gel column (PE / EA=1:1 to DCM / MeOH=10:1) to give title product (562 mg, 45%) as a black oil. ESI-MS (M+H)+: 319.2.1H NMR (400 MHz, DMSO- d6) δ 7.43 (d, J = 6.7 Hz, 1H), 6.01 (d, J = 6.8 Hz, 1H), 3.69 – 3.63 (m, 2H), 3.50 – 3.42 (m, 3H), 3.35 – 3.27 (m, 4H), 2.74 (s, 3H), 2.17 – 2.01 (m, 2H), 1.41 (s, 9H). Step 3: Preparation of tert-butyl (R)-(1-(1-((7-fluoro-2-methyl-2H-indazol-5-yl) carbamoyl) - 2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-4-yl) pyrrolidin-3-yl) (methyl) carbamate

[0226] To a mixture of tert-butyl (R)-(1-(2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) pyrrolidin-3-yl) (methyl) carbamate (500 mg, 1.57 mmol) in THF (5 mL) were added DMAP (20 mg, 0.16 mmol) and phenyl (7-fluoro-2-methyl-2H-indazol-5-yl) carbamate (493 mg, 1.73 mmol) at 0oC. The resulting mixture was stirred at 80oC for 16 h in a sealed tube. The mixture was allowed to cooling down to room temperature and concentrated in vacuo. The mixture was diluted with water (5 mL), extracted with EA (5 mL × 3). The organic layer was washed with brine, dried with Na2SO4and concentrated in vacuo. The crude was purified by silica gel column (PE / EA=1:1) to give title product (388 mg, 48%) as a yellow solid. ESI- MS (M+H)+: 510.3. Step 4: Preparation of (R) -N- (7-fluoro-2-methyl-2H-indazol-5-yl) -4- (3-(methylamino) pyrrolidin-1-yl) -2,3-dihydro-1H-pyrrolo [2,3-b] pyridine-1-carboxamide 2,2,2- trifluoroacetate

[0227] To a mixture of tert-butyl (R)-(1-(1-((7-fluoro-2-methyl-2H-indazol-5-yl) carbamoyl) -2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-4-yl) pyrrolidin-3-yl) (methyl) carbamate (360 mg, 0.71 mmol) in EA (5 mL) was added 3M HCl / EA (5 mL). The mixture was stirred at RT for 2 h. The mixture was diluted with water (5 mL), extracted with EA (5 mL × 3). The aqueous layer was concentrated in vacuo and purified by prep-HPLC (0.1 % TFA in water / ACN) to give title product (34.98 mg, yield: 12 %) as a white solid. ESI-MS (M+H)+: 410.2.1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 2H), 8.40 (s, 1H), 7.81 (s, 1H), 7.71 (d, J = 1.3 Hz, 1H), 7.27 (dd, J = 13.2 Hz, 1H), 6.37 (s, 1H), 4.17 (s, 3H), 4.13 – 3.97 (m, 2H), 3.94 – 3.86 (m, 2H), 3.83 – 3.66 (m, 5H), 2.67 (s, 3H), 2.34 – 2.26 (m, 1H), 2.17 – 2.16 (m, 1H).Example 3 – Preparation of (S)-N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(3- (methylamino)pyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide (CompoundStep 1: Preparation of tert-butyl (S)-(1-(2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) pyrrolidin-3-yl) (methyl) carbamate

[0228] To a mixture of 4-chloro-2,3-dihydro-1H-pyrrolo [2,3-b] pyridine (300 mg, 1.94 mmol) in DIEA (1.6 mL) was added tert-butyl (S)-methyl(pyrrolidin-3-yl) carbamate (465 mg, 2.32 mmol). The resulting mixture was stirred at 140oC for 16 h in a sealed tube. The mixture was allowed to cooling down to room temperature and concentrated in vacuo. The crude was purified by silica gel column (DCM / MeOH=10:1) to give title product (270 mg, 44%) as a yellow oil. ESI-MS (M+H)+: 319.2. Step 2: Preparation of tert-butyl (S)-(1-(1-((7-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-yl)(methyl)carbamate

[0229] To a mixture of tert-butyl (S)-(1-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)pyrrolidin-3-yl)(methyl)carbamate (200 mg, 0.63 mmol) in THF (5 mL) were added phenyl (7-fluoro-2-methyl-2H-indazol-5-yl)carbamate (197 mg, 0.69 mmol) and DMAP (8 mg, 0.06 mmol). The mixture was stirred at 80oC for 16 h. The mixture was diluted with water (10 mL) and extracted with EA (10 mL x 3). The combined organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EA=1:1) to give the title compound (40 mg, Y: 12.4%) as a yellow solid. ESI-MS: (M+H)+:510.2.1H NMR (400MHz, DMSO-d6) δ 12.02 (s, 1H), 8.34 (d, J = 2.7 Hz, 1H), 8.10 (d, J = 6.4 Hz, 1H), 7.81 (d, J = 6.1 Hz, 1H), 7.71 – 7.70 (m, 1H), 6.61 (d, J = 6.4 Hz, 1H), 4.16 (s, 3H), 4.07 – 3.96 (m, 1H), 3.96 – 3.87 (m, 2H), 3.84 – 3.72 (m, 2H), 3.70 – 3.62 (m, 4H), 2.96 (s, 3H), 2.06 – 2.04 (m, 2H), 1.42 (s, 9H). Step 3: Preparation of (S)-N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(3- (methylamino)pyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide

[0230] To a solution of tert-butyl (S)-(1-(1-((7-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-yl)(methyl) carbamate (20 mg, 0.04 mmol) in EA (1 mL) was added 4M HCl / EA (1 mL). The reaction mixture was stirred at RT for 2 h. The precipitate was filtered and the residue was purified by prep-HPLC (0.03% NH3.H2O in water / ACN) to give title product (1.31 mg, Y: 8.2%) as a white solid. ESI-MS (M+H)+: 410.2.1H NMR (400 MHz, MeOD-d4) δ 8.17 (d, J = 2.7 Hz, 1H), 7.79 (d, J = 6.1 Hz, 1H), 7.67 (d, J = 1.5 Hz, 1H), 7.17 (dd, J = 12.9, 1.5 Hz, 1H), 6.18 (d, J = 6.2 Hz, 1H), 4.20 (s, 3H), 3.99 (t, J = 8.6 Hz, 2H), 3.77 – 3.67 (m, 2H), 3.59 – 3.53 (m, 1H), 3.41 – 3.34 (m, 4H), 2.44 (s, 3H), 2.23 – 2.14 (m, 1H), 1.92 – 1.82 (m, 1H). Example 4 – Preparation of (R)-N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate (Compound 4)Step 1: Preparation of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate

[0231] To a mixture of 4-chloro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (400 mg, 2.58 mmol) in DIEA (1.7 g, 12.90 mmol) was added tert-butyl (R)-2-methylpiperazine-1-carboxylate (1.0 g, 5.16 mmol). The mixture was stirred at 140oC for 16 h in a sealed tube. The mixture was diluted with water (20 mL) and extracted with EA (20 mL x 3). The combined organic layerwas washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by silica gel column chromatography (PE / EA=3:1) to give the title compound (120 mg, 14.6 %) as a yellow oil. ESI-MS (M+H)+:319.2.1H NMR (400 MHz, DMSO-d6) δ 7.54 (d, J = 5.9 Hz, 1H), 6.05 (d, J = 6.0 Hz, 1H), 5.89 (s, 1H), 4.18 – 4.12 (m, 1H), 4.00 – 3.91 (m, 1H), 3.76 (d, J = 13.3 Hz, 1H), 3.56 (d, J = 12.3 Hz, 1H), 3.15 – 3.05 (m, 2H), 2.99 – 2.93 (m, 2H), 2.84 – 2.79 (m, 2H), 2.72 – 2.67 (m, 1H), 1.41 (s, 9H), 1.19 (d, J = 6.7 Hz, 3H). Step 2: Preparation of tert-butyl (R)-4-(1-((7-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate

[0232] To a mixture of tert-butyl (R)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (100 mg, 0.31 mmol) in THF (5 mL) were added TEA (159 mg, 1.57 mmol), triphosgene (112 mg, 0.38 mmol), 7-fluoro-2-methyl-2H-indazol-5-amine (52 mg, 0.31 mmol). The mixture was stirred at RT for 16 h. The mixture was diluted with water (10 mL) and extracted with EA (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by silica gel column chromatography (PE / EA=2:1) to give the title compound (60 mg, Y: 37.4 %) as a yellow solid. ESI-MS (M+H)+:510.3.1H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H), 8.31 (d, J = 2.8 Hz, 1H), 7.72 – 7.67 (m, 1H), 7.57 (d, J = 1.5 Hz, 1H), 7.18 (dd, J = 13.9, 1.5 Hz, 1H), 4.14 (s, 3H), 4.04 – 4.02 (m, 2H), 3.91 – 3.87 (m, 1H), 3.76 – 3.69 (m, 2H), 3.12 – 3.08 (m, 2H), 3.07 – 3.04 (m, 2H), 2.93 – 2.86 (m, 2H), 1.42 (s, 9H), 1.09 (d, J = 6.7 Hz, 3H). Step 3: Preparation of (R)-N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(3-methylpiperazin-1- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate

[0233] To a solution of tert-butyl (R)-4-(1-((7-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (40 mg, 0.08 mmol) in EA (2 mL) was added 4M HCl / EA (2 mL). The reaction mixture was stirred at RT for 2 h. The precipitate was filtered and purified by prep-HPLC (0.03% FA in water / ACN) to give title compound (5.21 mg, 14.6 %) as a white solid. ESI-MS (M+H)+:410.2.1H NMR (400 MHz, MeOD-d4) δ 8.62 – 8.43 (m, 1H), 8.19 (d, J = 2.7 Hz, 1H), 7.99 (d, J = 6.0 Hz, 1H), 7.69 (d, J = 1.4 Hz, 1H), 7.19 (dd, J = 12.8, 1.4 Hz, 1H), 6.55 (d, J = 6.1 Hz, 1H), 4.20 (s, 3H), 4.10 – 4.05 (m, 2H), 3.71 (d, J = 13.1 Hz, 2H), 3.28 – 3.22 (m, 2H), 3.17 – 3.12 (m, 3H), 3.10 – 3.07 (m, 1H), 2.82 – 2.76 (m, 1H), 1.28 (d, J = 6.5 Hz, 3H).Example 5 – Preparation of 4-(3,3-dimethylpiperazin-1-yl) -N-(7-fluoro-2-methyl-2H- indazol-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide diformate (CompounStep 1: Preparation of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate

[0234] A mixture of 4-chloro-2,3-dihydro-1H-pyrrolo[2,3-b] pyridine (250 mg, 1.62 mmol) and tert-butyl 2,2-dimethylpiperazine-1-carboxylate (1.3 g, 6.49 mmol) in a sealed tube was stirred at 140 ℃ for 16 h. The mixture was concentrated in vacuo and purified by column C18 (0.1 % FA in water / ACN) to give title product (400 mg, 61 %) as a brown solid. ESI- MS (M+H)+: 333.2.1H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 7.47 (d, J = 6.1 Hz, 1H), 6.06 (d, J = 6.3 Hz, 1H), 3.65 (t, J = 5.5 Hz, 2H), 3.51 – 3.45 (m, 2H), 3.45 – 3.38 (m, 4H), 3.16 (t, J = 8.5 Hz, 2H), 1.42 (s, 9H), 1.35 (s, 6H). Step 2: Preparation of tert-butyl 4-(1-((7-fluoro-2-methyl-2H-indazol-5-yl) carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl)-2,2-dimethylpiperazine-1-carboxylate

[0235] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate (200 mg, 0.60 mmol) and 7-fluoro-2-methyl-2H-indazol-5- amine (199 mg, 1.20 mmol) in THF (4 mL) were added TEA (182 mg, 1.81 mmol) and triphosgene (356 mg, 1.20 mmol) at 0oC. The reaction mixture was stirred at RT for 16 h. The mixture was diluted with water (4 mL), extracted with EA (4 mL × 3). The organic layer was washed with brine, dried with Na2SO4and concentrated in vacuo. The crude was purified by silica gel column (PE / EA=1:1) to give title product (140 mg, 44%) as a yellow oil. ESI-MS (M+H)+: 524.4.Step 3: Preparation of 4-(3,3-dimethylpiperazin-1-yl) -N-(7-fluoro-2-methyl-2H-indazol-5-yl) -2,3-dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide diformate

[0236] To a mixture of tert-butyl 4-(1-((7-fluoro-2-methyl-2H-indazol-5-yl) carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl)-2,2-dimethylpiperazine-1-carboxylate (120 mg, 0.23 mmol) in EA (2 mL) was added 4 M HCl / EA (2 mL). The reaction mixture was stirred at RT for 2 h. The mixture was diluted with water (2 mL), extracted with EA (2 mL × 3). The aqueous layer was concentrated in vacuo and purified by prep-HPLC (0.1 % FA in water / ACN) to give title product (42.53 mg, yield: 43 %) as a purple-pink solid. ESI-MS (M+H)+: 424.2.1H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 8.35 (d, J = 2.8 Hz, 1H), 8.22 (s, 2H), 7.94 (d, J = 6.1 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.26 (dd, J = 13.3, 1.6 Hz, 1H), 6.54 (d, J = 6.2 Hz, 1H), 4.16 (s, 3H), 3.98 (t, J = 8.6 Hz, 2H), 3.31 – 3.26 (m, 2H), 3.15 – 3.09 (m, 4H), 3.05 – 2.99 (m, 2H), 1.21 (s, 6H). Example 6 – Preparation of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(piperazin-1-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate (Compound 6)Step 1: Preparation of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate

[0237] To a solution of 4-chloro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (5 g, 32.23 mmol) and tert-butyl piperazine-1-carboxylate (12 g, 64.46 mmol) was added DIEA (10 mL). The reaction mixture was stirred at 140 °C for 16 h in a sealed tube. The mixture was concentrated in vacuo and the residue was purified by column gel chromatography (DCM / MeOH=10 / 1) and C18 (0.1% FA in H2O / ACN) to give title product (3 g, 30.61 %) as a yellow solid. ESI-MS (M+H)+: 305.2.1H NMR (400 MHz, DMSO-d6) δ 7.53 (d, J = 6.0 Hz,1H), 6.10 (d, J = 6.1 Hz, 1H), 3.46 – 3.38 (m, 6H), 3.15 – 3.09 (m, 4H), 3.01 – 2.95 (m, 2H), 1.41 (s, 9H). Step 2: Preparation of tert-butyl 4-(1-((7-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate

[0238] To a solution of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (300 mg, 0.99 mmol) and 7-fluoro-2-methyl-2H-indazol-5-amine (163 mg, 0.99 mmol) in THF (10 mL) were added TEA (300 mg, 2.97 mmol) and triphosgene (294 mg, 0.99 mmol) at 0 °C. The reaction mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by column gel chromatography (PE / EA = 1 / 2) to give title product (120 mg, 24.54 %) as a yellow solid. ESI-MS (M+H)+: 496.3.1H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 8.36 (d, J = 2.6 Hz, 1H), 7.95 (d, J = 6.1 Hz, 1H), 7.77 – 7.66 (m, 1H), 7.26 (d, J = 13.4 Hz, 1H), 6.54 (d, J = 6.2 Hz, 1H), 4.16 (s, 3H), 3.98 (t, J = 8.6 Hz, 2H), 3.48 – 3.41 (m, 4H), 3.29 – 3.27 (m, 4H), 3.12 (t, J = 8.5 Hz, 2H), 1.43 (s, 9H). Step 3: Preparation of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(piperazin-1-yl)-2,3-dihydro- 1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate

[0239] To a solution of tert-butyl 4-(1-((7-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (120 mg, 0.24 mmol) in EA (2 mL) was added 4 M HCl / EA (2 mL). The mixture was stirred at RT for 2 h. The mixture was concentrated in vacuo. The crude was purified by prep-HPLC (0.1 % FA in water / ACN) to give title product (53 mg, 49.72 %) as a yellow solid. ESI-MS (M+H)+: 396.2.1H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 8.35 (d, J = 2.7 Hz, 1H), 8.24 – 8.15 (m, 1H), 7.93 (d, J = 6.0 Hz, 1H), 7.74 – 7.65 (m, 1H), 7.26 (d, J = 13.0 Hz, 1H), 6.52 (d, J = 5.8 Hz, 1H), 4.16 (s, 3H), 3.97 (t, J = 8.5 Hz, 2H), 3.25 – 3.23 (m, 4H), 3.10 – 3.09 (m, 2H), 2.93 – 2.76 (m, 4H).Example 7 – Preparation of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4- (piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate (Compound 7)Compound 7 Step 1: Preparation of 5-bromo-4-fluoropyridin-2-amine

[0240] To a solution of 4-fluoropyridin-2-amine (24 g, 0.21 mol) in ACN (300 mL) was added NBS (38.1 g, 0.21 mol), the mixture was stirred for 4 h at RT. The mixture was diluted with water (300 mL), extracted with EA (300 mL × 3). The organic layer was washed with brine, dried with Na2SO4and concentration in vacuum. The crude was purified by silica gel column chromatography (PE: EA= 5: 1) to give title product (38 g, 92.93 %) as a white solid. ESI-MS (M+H)+: 192.9.1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 9.6 Hz, 1H), 6.28 (d, J = 10.0 Hz, 1H), 4.79 (s, 2H). Step 2: Preparation of 6-bromo-7-fluoro-2-methylimidazo[1,2-a]pyridine

[0241] To a solution of 5-bromo-4-fluoropyridin-2-amine (10 g, 52.36 mmol ) in IPA (120 mL) was added 1-bromopropan-2-one (8.8 mL, 104.71 mmol), the mixture was stirred at 85oC for 16 h. The mixture was concentrated in vacuo, the residue was diluted with 2 M NaOH (100 mL) and stirred at RT overnight. The mixture was extracted with EA (150 mL×3). The organic layer was washed with brine, dried with Na2SO4and concentration in vacuum. The crude was purified by silica gel column chromatography (PE : EA= 4 : 1) to give title product (4.4 g, 36.69%) as an off-white solid. ESI-MS (M+H)+: 231.0.1H NMR(400 MHz, CDCl3) δ 8.14 (d, J = 6.5 Hz, 1H), 7.20 (s, 1H), 7.16 (d, J = 8.9 Hz, 1H), 2.35 (d, J = 0.6 Hz, 3H). Step 3: Preparation of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-1,1- diphenylmethanimine

[0242] To a solution of 6-bromo-7-fluoro-2-methylimidazo[1,2-a]pyridine (4 g, 17.46 mmol), diphenylmethanimine (3.8 g, 20.96 mmol), Cs2CO3(17 g, 52.39 mmol) and Pd(OAc)2(39.2 mg, 0.17 mmol) in 1,4-dioxane (50 mL) was added BINAP (217 mg, 0.35 mmol), the mixture was stirred at 100oC for 16 h under N2. The mixture was diluted with water (100 mL), extracted with EA (80 mL × 3). The organic layer was washed with brine, dried with Na2SO4and concentration in vacuum. The crude was purified by silica gel column chromatography (PE : EA= 4 : 1) to give title product (2.7 g, 46.94 %) as a yellow solid. ESI-MS (M+H)+: 330.2.1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 7.2 Hz, 2H), 7.44 (s, 1H), 7.35 (t, J = 6.6 Hz, 3H), 7.22 (d, J = 20.2 Hz, 3H), 7.11 (s, 2H), 7.04 (s, 1H), 6.95 (d, J = 10.3 Hz, 1H), 2.29 (s, 3H). Step 4: Preparation of 7-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine hydrochloride

[0243] A solution of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-1,1- diphenylmethanimine (2.35 g, 7.13 mmol ) in 3M HCl / EA (24 mL) was stirred at RT for 2 h. The precipitate was filtered, washed with EA (30 mL) and dried to give the title compound (1.4 g, 97.32 %) as a white solid. ESI-MS (M+H)+: 166.1.1H NMR (400 MHz, DMSO-d6) δ 8.19 (d, J = 7.3 Hz, 1H), 7.94 (s, 1H), 7.75 (d, J = 10.0 Hz, 1H), 5.81 (s, 2H), 2.40 (s, 3H). Step 5: Preparation of tert-butyl 4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate

[0244] To a solution of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (100 mg, 0.32 mmol) and 7-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine hydrochloride (132 mg, 0.65 mmol) in THF (5 mL) was added TEA (332 mg, 3.29 mmol), then triphosgene (194 mg, 0.65 mmol) was added slowly at 0oC. The mixture was stirred at RT for 2 h. The mixture was concentrated in vacuo, the residue was purified by silica gel column chromatography (PE : EA= 1: 2) to give the compound (100 mg, 61.42%) as a yellow solid. ESI-MS (M+H)+: 496.2.1H NMR (400 MHz, CDCl3) δ 9.09 (d, J = 7.0 Hz, 1H), 7.86 (d, J = 5.9 Hz, 1H), 7.48 (dd, J = 12.1, 6.8 Hz, 1H), 7.12 (d, J = 11.1 Hz, 1H), 7.07 (t, J = 5.3 Hz, 1H), 6.30 (d, J = 6.0 Hz, 1H), 4.08 (t, J = 8.5 Hz, 2H), 3.51 – 3.47 (m, 4H), 3.20 – 3.14 (m, 4H), 3.05 (t, J = 8.4 Hz, 2H), 2.34 (s, 3H), 1.42 (s, 9H).Step 6: Preparation of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate

[0245] To a mixture of tert-butyl 4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (90 mg, 0.18 mmol) in EA (3 mL) was added 3 M HCl / EA (1.5 mL), the mixture was stirred at RT for 2 h. The precipitate was filtered and purified by prep-HPLC (0.05 % FA in water / ACN) to give title product (33 mg, Y: 45.95 %) as a white solid. ESI-MS (M+H)+: 396.1.1H NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H), 9.19 (d, J = 7.4 Hz, 1H), 8.21 (s, 1H), 7.91 (d, J = 6.0 Hz, 1H), 7.71 (s, 1H), 7.42 (d, J = 11.7 Hz, 1H), 6.57 (d, J = 6.1 Hz, 1H), 4.01 (t, J = 8.5 Hz, 2H), 3.41 – 3.38 (m, 4H), 3.16 – 3.11 (m, 2H), 3.07 – 3.01 (m, 4H), 2.29 (s, 3H). Example 8 – Preparation of N-(7-fluoro-2,6-dimethyl-2H-indazol-5-yl)-4-(piperazin-1- yl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide formate (Compound 8)Step 1: Preparation of 5-bromo-2,3-difluoro-4-methylbenzaldehyde

[0246] To a solution of 2,3-difluoro-4-methylbenzaldehyde (25 g, 0.16 mol) in concentrated H2SO4(300 mL) was added NBS (31.38 g, 0.18 mmol) . The mixture was stirred at 60oC for 16 h. The mixture was poured into ice-water (500 mL) and extracted with EA (150 mLx3). The combined organic washed with brine (300 mL x3), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (PE) to give title product (24 g, 64.10%) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 7.83 (dd, J = 5.8, 1.8 Hz, 1H), 2.37 (d, J = 2.8 Hz, 3H).Step 2: Preparation of (E)-5-bromo-2,3-difluoro-4-methylbenzaldehyde oxime

[0247] To a mixture of 5-bromo-2,3-difluoro-4-methylbenzaldehyde (24 g, 0.10 mol), NH2OH.HCl (8.58 g, 0.12 mol) in THF (300 mL) was added K2CO3(16.56 g, 0.12 mol). The mixture was stirred at 40oC for 16 h. The mixture was filtered and the filtrate was diluted with EA (300 mL), the combined organic layer was washed with brine (500 mL), dried over Na2SO4, filtered and concentrated in vacuo to give title product (20 g, 80.32%) as a yellow oil. ESI-MS (M+H)+: 293.0.1H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 8.17 (s, 1H), 7.72 (dd, J = 6.0, 1.8 Hz, 1H), 2.32 (d, J = 2.6 Hz, 3H). Step 3: Preparation of 5-bromo-7-fluoro-6-methyl-1H-indazole

[0248] To a mixture of (E)-5-bromo-2,3-difluoro-4-methylbenzaldehyde oxime (20 g, 0.08 mol) in 1.4-dioxane (200 mL) was added N2H4.H2O (20.48 g, 0.64 mol). The mixture was stirred at 150oC for 10 h. The mixture was diluted with H2O (300 mL) and extracted with EA (300 mL x 3). The organic phase was washed with brine (300 mL x 3), dried over anhydrous Na2SO4and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / 1 to 1 / 1) to afford title product (15.1 g, 82.79%) as a white solid. ESI-MS (M+H)+: 230.9.1H NMR (400 MHz, DMSO-d6) δ 8.11 (d, J = 3.4 Hz, 1H), 7.91 (s, 1H), 2.38 (d, J = 2.7 Hz, 3H). Step 4: Preparation of 5-bromo-7-fluoro-2,6-dimethyl-2H-indazole

[0249] To a mixture of 5-bromo-7-fluoro-6-methyl-1H-indazole (15.1 g, 0.07 mol) in THF (200 mL) was added NaH (5.6 g, 0.14 mol) at 0oC, the mixture was stirred at this temperature for 30 min. CH3I (29.82 g, 0.21 mol) was added to the mixture and stirred at r.t for 4 h. The mixture was diluted with H2O (100 mL) and extracted with EA (200 mL x 2). The organic phase was washed with brine (200 mLx3), dried over anhydrous Na2SO4and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / 1 to 1 / 1) to afford title product (7.4 g, 47.04%) as a white solid. ESI- MS (M+H)+:245.0.1H NMR (400 MHz, DMSO-d6) δ 8.40 (d, J = 2.8 Hz, 1H), 7.88 (s, 1H), 4.18 (s, 3H), 2.34 (d, J = 3.0 Hz, 3H). Step 5: Preparation of N-(7-fluoro-2,6-dimethyl-2H-indazol-5-yl)-1,1-diphenylmethanimine

[0250] To a mixture of 5-bromo-7-fluoro-2,6-dimethyl-2H-indazole (3 g, 12.3 mmol), diphenylmethanimine (2.69 g, 14.88 mmol) in 1,4-dioxane (50 mL) were added Pd2(dba)3(1.12 g, 1.23 mmol), BINAP (1.53 g, 2.46 mmol) and Cs2CO3(8.02 g, 24.6 mmol), the mixture was charged with Ar for three times and stirred at 115oC for 16 h. The mixture was diluted with H2O (50 mL) and extracted with EA (50 mL x 3). The organic phase was washed with brine (50 mLx3), dried over anhydrous Na2SO4and concentrated. The residuewas purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / 1 to 4 / 1) to afford title product (3.5 g, 82.96%) as a yellow solid. ESI-MS (M+H)+:344.1.1H NMR (400 MHz, DMSO-d6) δ 8.07 (s, 1H), 7.70 (d, J = 7.2 Hz, 2H), 7.50 (dt, J = 13.3, 6.7 Hz, 4H), 7.34 – 7.25 (m, 3H), 7.15 (d, J = 6.9 Hz, 2H), 6.40 (s, 1H), 4.05 (s, 3H), 2.17 (s, 3H). Step 6: Preparation of 7-fluoro-2,6-dimethyl-2H-indazol-5-amine hydrochloride

[0251] A mixture of N-(7-fluoro-2,6-dimethyl-2H-indazol-5-yl)-1,1-diphenylmethanimine (3.5 g, 10.20 mmol) in 3M EA / HCl (50 mL) was stirred at r.t for 2 h. The precipitate was filtered to give title product (1.6 g, 87.63%) as a yellow solid. ESI-MS (M+H)+: 180.0.1H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 2H), 8.55 (d, J = 2.4 Hz, 1H), 7.78 (s, 1H), 4.20 (s, 3H), 2.36 (s, 3H). Step 7: Preparation of tert-butyl 4-(1-((7-fluoro-2,6-dimethyl-2H-indazol-5-yl) carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) piperazine-1-carboxylate

[0252] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) piperazine- 1-carboxylate (100 mg, 0.33 mmol) and 7-fluoro-2,6-dimethyl-2H-indazol-5-amine (160 mg, 0.97 mmol) in THF (2 mL) were added TEA (98 mg, 0.97 mmol) and triphosgene (292 mg, 0.97 mmol) at 0oC. The reaction mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and diluted with water (3 mL), extracted with EA (3 mL×3). The organic layer was washed with brine, dried with Na2SO4and concentrated in vacuo. The crude was purified by silica gel column (EA) to give title product (40 mg, 24%) as a yellow solid. ESI-MS (M+H)+: 510.2.1H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1H), 8.32 (d, J = 2.9 Hz, 1H), 8.12 (s, 1H), 7.92 (d, J = 6.0 Hz, 1H), 6.54 (d, J = 6.2 Hz, 1H), 4.14 (s, 3H), 4.00 (t, J = 8.5 Hz, 2H), 3.47 – 3.42 (m, 4H), 3.29 – 3.26 (m, 4H), 3.14 (t, J = 8.7 Hz, 2H), 2.35 (s, 3H), 1.43 (s, 9H). Step 8: Preparation of N-(7-fluoro-2,6-dimethyl-2H-indazol-5-yl)-4-(piperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide formate

[0253] To a mixture of tert-butyl 4-(1-((7-fluoro-2,6-dimethyl-2H-indazol-5-yl) carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) piperazine-1-carboxylate (40 mg, 0.08 mmol) in EA (1 mL) was added 4M HCl / EA (1 mL). The reaction mixture was stirred at RT for 2 h. The mixture was diluted with water (2 mL), extracted with EA (2 mL×3). The aqueous layer was concentrated in vacuo and purified by prep-HPLC (0.1 % FA in water / ACN) to give title product (8.16 mg, yield: 25 %) as a white solid. ESI-MS (M+H)+: 410.5.1H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1H), 8.32 (s, 1H), 8.23 (s, 1H), 8.12 (s, 1H), 7.90 (d, J = 6.0 Hz, 1H), 6.52 (d, J = 6.2 Hz, 1H), 4.14 (s, 3H), 3.99 (t, J = 8.4 Hz, 2H), 3.29 – 3.23 (m, 4H), 3.12 (t, J = 8.4 Hz, 2H), 2.91 – 2.81 (m, 4H), 2.35 (s, 3H).Example 9 – Preparation of N-(7-methoxy-2-methyl-2H-indazol-5-yl)-4-(piperazin-1-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate (Compound 9)Step 1: Preparation of N-(7-methoxy-2-methyl-2H-indazol-5-yl)-1,1-diphenylmethanimine

[0254] To a mixture of 5-bromo-7-methoxy-2-methyl-2H-indazole (5.5 g, 22.92 mmol) in 1,4-dioxane (60 mL) were added diphenylmethanimine (4.98 g, 27.50 mmol), BINAP (2.86 g, 4.58 mmol), Cs2CO3 (14.94 g, 45.84 mmol), Pd(OAc)2 (517.54 mg, 2.29 mmol), the mixture was stirred at 100oC for 16 h under N2. The mixture was diluted with water (100 mL) and extracted with EA (100 mL x 3). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by silica gel column chromatography (PE : EA = 4:1) to give the title compound (3.0 g, Y: 38.38 %) as a yellow oil. ESI-MS (M+H)+:342.2. Step 2: Preparation of 7-methoxy-2-methyl-2H-indazol-5-amine HCl salt

[0255] A mixture of N-(7-methoxy-2-methyl-2H-indazol-5-yl)-1,1-diphenylmethanimine (3.0 g, 8.80 mmol) in 4 M HCl / EA (40 mL) was stirred at RT for 16 h. The mixture was filtered and the residue was diluted with PE / EA (v:v=1:1, 20 mL) and stirred at RT for 2 h. The precipitate was filtered and dried to give the title compound (1.30 g, Y: 83.45 %) as a white oil. ESI-MS (M+H)+:178.3.1H NMR (400 MHz, DMSO-d6) δ 10.16 (s, 2H), 8.38 (s, 1H), 7.90 (s, 1H), 7.17 (s, 1H), 4.12 (s, 3H), 3.92 (s, 3H).Step 3: Preparation of tert-butyl 4-(1-((7-methoxy-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate

[0256] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (100 mg, 0.33 mmol) in THF (5 mL) were added TEA (199 mg, 1.97 mmol), triphosgene (117 mg, 0.39 mmol), 7-methoxy-2-methyl-2H-indazol-5-amine HCl salt (70 mg, 0.39 mmol). The mixture was stirred at RT for 16 h. The mixture was diluted with water (10 mL) and extracted with EA (10 mL x 3). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by silica gel column chromatography (PE / EA=2:1) to give the title compound (50 mg, Y: 29.9 %) as a yellow solid. ESI-MS (M+H)+:508.2.1H NMR (400 MHz, DMSO-d6) δ 12.07 (s, 1H), 8.09 (s, 1H), 8.00 (s, 1H), 7.96 (d, J = 6.0 Hz, 1H), 7.00 – 6.99 (m, 1H), 6.52 (d, J = 6.1 Hz, 1H), 4.06 (s, 6H), 3.47 – 3.43 (m, 4H), 3.41 – 3.39 (m, 2H), 3.27 – 3.26 (m, 2H), 3.15 – 3.09 (m, 4H), 1.43 (s, 9H). Step 4: Preparation of N-(7-methoxy-2-methyl-2H-indazol-5-yl)-4-(piperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate

[0257] To a solution of tert-butyl 4-(1-((7-methoxy-2-methyl-2H-indazol-5-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (40 mg, 0.08 mmol) in EA (2 mL) was added 4M HCl / EA (2 mL). The reaction mixture was stirred at RT for 2 h. The precipitate was filtered and purified by prep-HPLC (0.03% FA in water / ACN) to give title compound (3.49 mg, 9.8 %) as a white solid. ESI-MS (M+H)+:408.2.1H NMR (400 MHz, MeOD-d4) δ 8.50 (s, 1H), 8.40 – 8.37 (m, 1H), 8.02 (d, J = 5.8 Hz, 1H), 7.99 (s, 1H), 6.97 (s, 1H), 6.56 (d, J = 6.0 Hz, 1H), 4.12 (s, 3H), 4.11 – 4.08 (m, 2H), 4.02 (s, 3H), 3.47 – 3.42 (m, 4H), 3.28 – 3.25 (m, 4H), 3.17 – 3.13 (m, 2H).Example 10 – Preparation of N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4- (piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate (Compound 10) NHCompound 10 Step 1: Preparation of N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-1,1- diphenylmethanimine

[0258] To a solution of 6-bromo-8-fluoro-2-methylimidazo[1,2-a]pyridine (3 g, 13.10 mmol), diphenylmethanimine (2.85 g, 15.72 mmol), Cs2CO3 (12.80 g, 39.29 mmol) and Pd(OAc)2 (29.40 mg, 0.13 mmol) in 1,4-dioxane (25 mL) was added BINAP (163 mg, 0.26 mmol), the mixture was stirred at 100oC for 16 h under N2. The mixture was concentrated in vacuo, the residue was purified by silica gel column chromatography (PE: EA= 4 : 1) to give title product (3.9 g, 90.40 %) as a yellow solid. ESI-MS (M+H)+: 330.2. Step 2: Preparation of 8-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine

[0259] A solution of N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-1,1- diphenylmethanimine (3.4 g, 10.32 mmol ) in 3M HCl / EA (35 mL) was stirred at RT for 2 h. The mixture was diluted with sat. Na2CO3(100 mL), extracted with EA (60 mL × 3). The organic layer was washed with brine, dried with Na2SO4and concentration in vacuo. The residue was purified by silica gel column chromatography (PE : EA= 1 : 9) to give title product (1.2 g, 70.38%) as a grey solid. ESI-MS (M+H)+: 166.1.1H NMR (400 MHz, CDCl3) δ 7.28 (d, J = 1.5 Hz, 1H), 7.16 (d, J = 1.3 Hz, 1H), 6.42 (dd, J = 11.4, 1.7 Hz, 1H), 2.35 (s, 3H).Step 3: Preparation of tert-butyl 4-(1-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate

[0260] To a solution of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (60 mg, 0.19 mmol) and 8-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine (130 mg, 0.78 mmol) in DCM (5 mL) were added TEA (119 mg, 1.18 mmol) and triphosgene (223 mg, 0.78 mmol) at 0oC. The mixture was stirred at RT for 2 h. The mixture was concentrated in vacuo, the residue was purified by silica gel column chromatography (PE: EA= 1: 1) to give title product (65 mg, crude) as a white solid. ESI-MS (M+H)+: 496.2. Step 4: Preparation of N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate

[0261] To a mixture of tert-butyl 4-(1-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (42 mg, 0.08 mmol) in EA (3 mL) was added 3M HCl / EA (0.5 mL). The mixture was stirred at RT for 2 h. The precipitate was filtered and purified by prep-HPLC (0.05 % FA in water / ACN) to give title product (2.65 mg, Y: 7.91 %) as a white solid. ESI-MS (M+H)+: 396.1.1H NMR (400 MHz, MeOD-d4) δ 8.61 (s, 1H), 8.19 (s, 1H), 7.88 (d, J = 5.9 Hz, 1H), 7.54 (t, J = 6.8 Hz, 1H), 7.01 (d, J = 12.0 Hz, 1H), 6.45 (d, J = 6.0 Hz, 1H), 3.94 (t, J = 8.5 Hz, 2H), 3.48 – 3.38 (m, 4H), 3.30 – 3.24 (m, 4H), 3.00 (t, J = 8.4 Hz, 2H), 2.30 (s, 3H). Example 11 – Preparation of N-(8-methoxy-2-methylimidazo[1,2-a] pyridin-6-yl) -4- (piperazin-1-yl) -2,3-dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide diformate (Compound 11)Step 1: Preparation of 6-bromo-8-methoxy-2-methylimidazo[1,2-a] pyridine

[0262] To a mixture of 5-bromo-3-methoxypyridin-2-amine (15 g, 13.89 mmol) in IPA (150 mL) were added 1-bromo-2,2-dimethoxypropane (21.64 g, 118.23 mmol) and PPTS (1847 mg, 7.39 mmol). The reaction solution was stirred at 95 ℃ for 5 h. The reaction was diluted with DCM (300 mL), washed with brine (300 mL x 3), the organic layer was concentrated in vacuo to give title product (12 g, yield: 67%) as a brown solid. ESI-MS (M+H)+: 243.0.1H NMR (400 MHz, DMSO-d6) δ 8.85 (d, J = 7.0 Hz, 1H), 8.04 (d, J = 8.7 Hz, 1H), 7.55 (s, 1H), 4.09 (s, 3H), 2.43 (d, J = 20.5 Hz, 3H). Step 2: Preparation of N-(8-methoxy-2-methylimidazo[1,2-a] pyridin-6-yl)-1,1- diphenylmethanimine

[0263] To a mixture of 6-bromo-8-methoxy-2-methylimidazo[1,2-a] pyridine (5 g, 20.75 mmol) and diphenylmethanimine (5.6 g, 31.12 mmol) in 1,4-dioxane (50 mL) were added BINAP (2.5 g, 4.15 mmol), Pd(OAc)2(467 mg, 2.08 mmol) and Cs2CO3(20.3 g, 62.25 mmol). The reaction solution was stirred at 100 ℃ for 16 h under N2. The reaction was diluted with H2O (50 mL), extracted with EA (50 mL x 3), the organic layer was washed with brine, dried over Na2SO4and concentrated in vacuo. The crude was purified by silica gel column chromatography (PE: EA=1:1) to give title product (4.7 g, yield: 66%) as a brown oil. ESI-MS (M+H)+: 342.2.1H NMR (400 MHz, DMSO-d6) δ 7.71 – 7.66 (m, 2H), 7.57 – 7.53 (m, 2H), 7.50 – 7.44 (m, 3H), 7.39 – 7.35 (m, 3H), 7.26 – 7.21 (m, 2H), 6.11 (d, J = 1.5 Hz, 1H), 3.66 (s, 3H), 2.22 (s, 3H). Step 3: Preparation of 8-methoxy-2-methylimidazo[1,2-a] pyridin-6-amine hydrochloride

[0264] To a mixture of N-(8-methoxy-2-methylimidazo[1,2-a] pyridin-6-yl)-1,1- diphenylmethanimine (4.2 g, 12.32 mmol) in EA (20 mL) was added 4M HCl / EA (40 mL). The reaction solution was stirred at RT for 2 h. The mixture was filtered, washed with EA(20 mL) and dried in vacuo. The residue was beated with PE: EA (1:1, 20 mL) to give title product (2 g, 83%) as a white solid. ESI-MS (M+H)+: 178.0.1H NMR (400 MHz, DMSO- d6) δ 8.08 – 7.95 (m, 1H), 7.91 – 7.77 (m, 1H), 7.16 – 7.02 (m, 1H), 6.03 (s, 3H), 4.02 (s, 3H), 2.40 (s, 3H). Step 4: Preparation of tert-butyl 4-(1-((8-methoxy-2-methylimidazo[1,2-a] pyridin-6-yl) carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) piperazine-1-carboxylate

[0265] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) piperazine- 1-carboxylate (100 mg, 0.33 mmol) and 8-methoxy-2-methylimidazo[1,2-a] pyridin-6-amine hydrochloride (175 mg, 0.97 mmol) in THF (3 mL) were added TEA (98 mg, 0.97 mmol) and triphosgene (288 mg, 0.97 mmol) at 0oC. The reaction mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and diluted with water (3 mL), extracted with EA (3 mL × 3). The organic layer was washed with brine, dried with Na2SO4and concentrated in vacuo. The crude was purified by silica gel column (EA) to give title product (67 mg, 40%) as a yellow solid. ESI-MS (M+H)+: 508.3. Step 5: Preparation of N-(8-methoxy-2-methylimidazo[1,2-a] pyridin-6-yl) -4-(piperazin-1- yl) -2,3-dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide diformate

[0266] To a mixture of tert-butyl 4-(1-((8-methoxy-2-methylimidazo[1,2-a] pyridin-6-yl) carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) piperazine-1-carboxylate tert-butyl 4-(1-((8-methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)-2,3-dihydro-1H- pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (40 mg, 0.08 mmol) in EA (1 mL) was added 4M HCl / EA (1 mL). The reaction mixture was stirred at RT for 2 h. The mixture was diluted with water (2 mL), extracted with EA (2 mL × 3). The aqueous layer was concentrated in vacuo and purified by prep-HPLC (0.1 % FA in water / ACN) to give title product (24.18 mg, yield: 75 %) as a white solid. ESI-MS (M+H)+: 408.2.1H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1H), 8.58 (d, J = 1.1 Hz, 1H), 8.27 (s, 2H), 7.94 (d, J = 6.1 Hz, 1H), 7.65 (s, 1H), 6.62 – 6.47 (m, 2H), 4.00 – 3.96 (m, 2H), 3.94 (s, 3H), 3.33 – 3.26 (m, 4H), 3.11 (t, J = 8.5 Hz, 2H), 2.98 – 2.83 (m, 4H), 2.28 (s, 3H).Example 12 – Preparation of N-(2,7-dimethyl-2H-indazol-5-yl)-4-(piperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide (Compound 12)Step 1: Preparation of 5-bromo-2,7-dimethyl-2H-indazole

[0267] To a mixture of 5-bromo-7-methyl-2H-indazole (9.00 g, 42.65 mmol) in EA (150 mL) was added trimethyloxonium tetrafluoroborate (9.47 g, 68.98 mmol). The mixture was stirred at r.t for 2 h. The mixture was diluted with water (300 mL), extracted with EA (200 mL×2), the organic layer washed with brine, dried with Na2SO4and concentration in vacuo to give title product (9.5 g, 96 %) as a white solid. ESI-MS (M+H)+: 225.1.1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.76 – 7.74 (m, 1H), 7.12 – 7.10 (m, 1H), 4.17 (s, 3H), 2.49 – 2.48 (m, 3H). Step 2: Preparation of N-(2,7-dimethyl-2H-indazol-5-yl)-1,1-diphenylmethanimine

[0268] A mixture of 5-bromo-2,7-dimethyl-2H-indazole (5 g, 22.22 mmol) in 1,4-dioxane (50 mL) were added diphenylmethanimine (4.22 g, 23.33 mmol), BINAP (2.77 g, 4.44 mmol), Cs2CO3(14.48 g, 44.44 mmol), Pd(OAc)2(499 mg, 2.22 mmol). The mixture was stirred at 115 °C for 16 h. The mixture was diluted with H2O (50 mL) and extracted with EA (50 mL x 3). The organic phase washed with brine (100 mL x 3), dried over anhydrous Na2SO4and concentrated in vacuo. The crude product was purified by silica gel column (PE / EA=5:1) to afford title product (1.24 g, 17 %) as a white solid. ESI-MS (M+H)+: 326.3.1H NMR (400 MHz, DMSO-d6) δ 8.02 (s, 1H), 7.67 – 7.63 (m, 2H), 7.54 – 7.44 (m, 3H), 7.33 – 7.27 (m, 3H), 7.17 – 7.13 (m, 2H), 6.60 – 6.54 (m, 2H), 4.06 (s, 3H), 2.35 (s, 3H). Step 3: Preparation of 2,7-dimethyl-2H-indazol-5-amine hydrochloride

[0269] To a solution of N-(2,7-dimethyl-2H-indazol-5-yl)-1,1-diphenylmethanimine (924 mg, 2.84 mmol) in 3M HCl / EA (10 mL) was stirred at r.t for 4 h. The precipitate was filtered to give title product (500 mg, 89 %) as a white solid. ESI-MS (M+H)+: 162.1.1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 2H), 8.42 (s, 1H), 7.58 (d, J = 1.3 Hz, 1H), 6.95 (dd, J = 1.9, 1.1 Hz, 1H), 4.19 (s, 3H), 2.53 (s, 3H). Step 4: Preparation of tert-butyl 4-(1-((2,7-dimethyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate

[0270] To a solution of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (100 mg, 0.33 mmol) and 2,7-dimethyl-2H-indazol-5-amine (110 mg, 0.66 mmol) in THF (10 mL) were added triethylamine (0.25 mL, 1.65 mmol) and triphosgene (200 mg, 0.66 mmol) at 0oC. The mixture was stirred at RT for 16 h. The precipitate was filtered and dried in vacuum to give title product (60 mg, yield: 37.03%) as a white solid. ESI-MS (M+H)+: 492.2.1H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1H), 8.18 (s, 1H), 7.95 (d, J = 6.0 Hz, 1H), 7.84 (d, J = 1.4 Hz, 1H), 6.97 (s, 1H), 6.53 (d, J = 6.2 Hz, 1H), 4.13 (s, 3H), 3.97 (t, J = 8.9 Hz, 2H), 3.44 (d, J = 4.9 Hz, 4H), 3.29 – 3.24 (m, 4H), 3.11 (t, J = 8.5 Hz, 2H), 2.48 (s, 3H), 1.43 (s, 9H). Step 5: Preparation of N-(2,7-dimethyl-2H-indazol-5-yl)-4-(piperazin-1-yl)-2,3-dihydro-1H- pyrrolo[2,3-b]pyridine-1-carboxamide

[0271] A mixture of tert-butyl 4-(1-((2,7-dimethyl-2H-indazol-5-yl)carbamoyl)-2,3-dihydro- 1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (60 mg, 0.12 mmol) in 3M HCl / EA (5 mL) was stirred at RT for 2 h. The precipitate was filtered and purified by prep-HPLC (0.1% NH3·H2O in H2O / ACN) to give title product (33.28 mg, yield: 70.92%) as a white solid. ESI-MS (M+H)+: 392.2.1H NMR (400 MHz, DMSO-d6) δ 11.65 (s, 1H), 8.18 (s, 1H), 7.96 (d, J = 6.0 Hz, 1H), 7.84 (s, 1H), 6.97 (s, 1H), 6.55 (d, J = 6.1 Hz, 1H), 4.13 (s, 3H), 3.99 (t, J = 8.5 Hz, 2H), 3.38 – 3.35 (m, 4H), 3.11 (t, J = 8.5 Hz, 2H), 3.05 – 2.99 (m, 4H), 2.49 (s, 3H).Example 13 – Preparation of N-(7-(difluoromethyl)-2-methyl-2H-indazol-5-yl)-4- (piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide 2,2,2- trifluoroacetate (Compound 13)Step 1: Preparation of methyl 2-amino-5-bromo-3-methylbenzoate

[0272] To a mixture of methyl 2-amino-3-methylbenzoate (5 g, 30.30 mmol) in DCM (40 mL) was added NBS (5.9 g, 33.34 mmol). The resulting mixture was stirred at RT for 16 h. The mixture was diluted with water (40 mL), extracted with DCM (40 mL×3). The organic layer was washed with brine, dried with Na2SO4and concentrated in vacuo to give title product (7 g, crude) as a brown solid. ESI-MS (M+H)+: 244.0.1H NMR (400 MHz, DMSO-d6) δ 7.70 (d, J = 2.4 Hz, 1H), 7.35 (dd, J = 2.4, 0.7 Hz, 1H), 6.53 (s, 2H), 3.79 (s, 3H), 2.13 (s, 3H). Step 2: Preparation of methyl 5-bromo-1H-indazole-7-carboxylate

[0273] To a mixture of methyl 2-amino-5-bromo-3-methylbenzoate (5 g, 20.57 mmol) and KOAc (2116 mg, 21.59 mmol) in CHCl3(50 mL) was added Ac2O (4 mL). The resulting mixture was stirred at 0oC for 1 h. Isopentylnitrite (6 mL, 45.25 mmol) and 18-crown-6 (977 mg, 3.70 mmol) were added to the mixture. The resulting mixture was stirred at RT for 16 h. The mixture was filtered and the filtrate was concentrated in vacuo to give title product (5 g, crude) as a white solid. ESI-MS (M+H+CH3CN)+: 297.9.1H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 1.8 Hz, 1H), 8.28 – 8.23 (m, 1H), 8.02 (d, J = 1.8 Hz, 1H), 3.98 (s, 3H). Step 3: Preparation of methyl 5-bromo-2-methyl-2H-indazole-7-carboxylate

[0274] To a mixture of methyl 5-bromo-1H-indazole-7-carboxylate (10.5 g, 41.18 mmol) in EA (100 mL) was added trimethyloxonium tetrafluoroborate (9.14 g, 61.76 mmol). The resulting mixture was stirred at RT for 2 h. The mixture was diluted with water (100 mL), extracted with EA (100 mL×3). The organic layer was washed with brine, dried with Na2SO4and concentrated in vacuo to give title product (9.43 g, 85%) as a yellow solid. ESI-MS (M+H)+: 269.0.1H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1H), 8.30 (d, J = 1.9 Hz, 1H), 7.92 (d, J = 1.9 Hz, 1H), 4.24 (s, 3H), 3.90 (s, 3H). Step 4: Preparation of (5-bromo-2-methyl-2H-indazol-7-yl) methanol

[0275] To a mixture of methyl 5-bromo-2-methyl-2H-indazole-7-carboxylate (7 g, 26.02 mmol) in dry-THF (70 mL) was added LiAlH4(52 mL, 52.04 mmol, 1.0 M in THF). The resulting mixture was stirred at 0oC for 2 h. The mixture was quenched by water (2 mL) dropwise at 0oC. Then added 15% NaOH (2 mL) and water (6 mL). The mixture was diluted with THF (20 mL) and Na2SO4. The resulting mixture was stirred at RT for 0.15 h. The mixture was filtered and the filtrate cake was washed with EA (10 mL) and DCM / MeOH (20 mL, 10:1). The filtrate was concentrated in vacuo to give title product (6 g, 96%) as a white solid. ESI-MS (M+H)+: 241.0. Step 5: Preparation of 5-bromo-2-methyl-2H-indazole-7-carbaldehyde

[0276] To a mixture of (5-bromo-2-methyl-2H-indazol-7-yl) methanol (5 g, 20.75 mmol) in DCM (50 mL) was added Dess-Martin periodinane (10.5 g, 24.89 mmol). The resulting mixture was stirred at RT for 16 h. The mixture was filtered and the filtrate was concentrated in vacuo. The crude was purified by silica gel column (PE / EA=1:1) to give title product (2 g, Y: 40.8 %) as a yellow solid. ESI-MS (M+H)+:239.0.1H NMR (400 MHz, DMSO- d6) δ10.43 (d, J = 26.9 Hz, 1H), 8.59 (s, 1H), 8.38 (d, J = 1.7 Hz, 1H), 7.98 – 7.87 (m, 1H), 4.26 (s, 3H). Step 6: Preparation of 5-bromo-7-(difluoromethyl)-2-methyl-2H-indazole

[0277] To a mixture of 5-bromo-2-methyl-2H-indazole-7-carbaldehyde (1.8 g, 7.56 mmol) in DCM (15 mL) was added DAST (2069 mg, 12.86 mmol) at 0oC. The resulting mixture was stirred at RT under N2(balloon) for 16 h. The mixture was quenched by sat. NaHCO3(15 mL) at 0oC, extracted with DCM (15 mL×3). The organic layer was washed with brine, dried with Na2SO4and concentrated in vacuo. The crude was purified by silica gel column (PE / EA=2:1) to give title product (1.43 g, Y: 72 %) as a white solid. ESI-MS (M+H)+:241.0.1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 4.4 Hz, 1H), 8.18 (s, 1H), 7.52 (dd, J = 30.9, 3.0 Hz, 1H), 7.32 (t, J = 54.7 Hz, 1H), 4.23 (s, 3H). Step 7: Preparation of N-(7-(difluoromethyl)-2-methyl-2H-indazol-5-yl)-1,1- diphenylmethanimine

[0278] To a mixture of 5-bromo-7-(difluoromethyl)-2-methyl-2H-indazole (5 g, 19.16 mmol) and diphenylmethanimine (5.2 g, 28.75 mmol) in 1,4-dioxane (50 mL) were added BINAP (2387 mg, 3.83 mmol), Pd(OAc)2(431 mg, 1.92 mmol) and Cs2CO3(18.68 g, 57.48 mmol). The reaction solution was stirred at 100 ℃ for 16 h. The reaction was diluted with H2O (50 mL), extracted with EA (50 mL x 3). The organic layer was washed with brine, dried over Na2SO4and concentrated in vacuo. The crude was purified by silica gel column chromatography (PE : EA = 5 :1) to give title product (4.3 g, yield: 62.3%) as a yellow solid. ESI-MS (M+H)+: 362.1.1H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 7.71 – 7.66 (m, 2H), 7.55 – 7.45 (m, 4H), 7.34 – 7.29 (m, 3H), 7.19 – 7.16 (m, 2H), 7.05 – 6.97 (m, 2H), 4.12 (s, 3H). Step 8: Preparation of 7-(difluoromethyl)-2-methyl-2H-indazol-5-amine hydrochloride

[0279] To a mixture of N-(7-(difluoromethyl)-2-methyl-2H-indazol-5-yl)-1,1- diphenylmethanimine (4 g, 11.08 mmol) in EA (20 mL) was added 4M HCl / EA (40 mL). The reaction solution was stirred at RT for 2 h. The precipitate was filtered, washed with EA (20 mL) and dried in vacuo. The crude was diluted with PE : EA (1 : 1, 20 mL) and stirred at RT for 1 h. The precipitate was filtered and dried in vacuo to give title product (2 g, 77.5%) as a yellow solid. ESI-MS (M+H)+: 198.2.1H NMR (400 MHz, DMSO-d6) δ 10.65 (s, 2H), 8.63 (s, 1H), 8.02 (s, 1H), 7.50 (s, 1H), 7.43 – 7.28 (m, 1H), 4.25 (s, 3H).Step 9: Preparation of tert-butyl 4-(1-((7-(difluoromethyl)-2-methyl-2H-indazol-5-yl) carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) piperazine-1-carboxylate

[0280] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) piperazine- 1-carboxylate (80 mg, 0.26 mmol) and 7-(difluoromethyl)-2-methyl-2H-indazol-5-amine hydrochloride (156 mg, 0.79 mmol) in THF (2 mL) were added TEA (80 mg, 0.79 mmol) and triphosgene (193 mg, 0.65 mmol) at 0oC. The reaction mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and diluted with water (3 mL), extracted with EA (3 mL×3). The organic layer was washed with brine, dried with Na2SO4and concentrated in vacuo to give title product (120 mg, 28%) as a brown solid. ESI-MS (M+H)+: 528.3. Step 10: Preparation of N-(7-(difluoromethyl)-2-methyl-2H-indazol-5-yl)-4-(piperazin-1-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide 2,2,2-trifluoroacetate

[0281] To a mixture of tert-butyl 4-(1-((7-(difluoromethyl)-2-methyl-2H-indazol-5-yl) carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) piperazine-1-carboxylate (100 mg, 0.19 mmol) in EA (2 mL) was added 4M HCl / EA (2 mL). The reaction mixture was stirred at RT for 2 h. The mixture was diluted with water (2 mL), extracted with EA (2 mL×3). The aqueous layer was concentrated in vacuo and purified by prep-HPLC (0.1 % TFA in water / ACN) to give title product (11.50 mg, yield: 13 %) as a white solid. ESI-MS (M+H)+: 428.2.1H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 2H), 8.41 (s, 1H), 8.09 (s, 1H), 7.96 (s, 1H), 7.61 (s, 1H), 7.34 (t, J = 55.0 Hz, 1H), 6.67 (s, 1H), 4.19 (s, 3H), 4.12 – 4.03 (m, 2H), 3.63 – 3.49 (m, 4H), 3.27 – 3.22 (m, 4H), 3.22 – 3.15 (m, 2H). Example 14 – Preparation of N-(7-methoxy-2-methyl-2H-indazol-5-yl)-4-(piperazin-1- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate (Compound 14)Step 1: Preparation of 5-bromo-2-methyl-7-(trifluoromethyl)-2H-indazole

[0282] To a mixture of 5-bromo-7-(trifluoromethyl)-1H-indazole (10 g, 37.74 mmol) in EA (100 mL) was added trimethyloxonium tetrafluoroborate (27.9 g, 188.68 mmoL). The mixture was stirred at RT for 16 h. The mixture was diluted with water (200 mL) and extracted with EA (200 mL x 3). The combined organic layer was washed with brine (300 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (9 g, Y: 85.5 %). ESI-MS (M+H)+:279.1.1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.33 (s, 1H), 7.72 (s, 1H), 4.28 (s, 3H). Step 2: Preparation of N-(2-methyl-7-(trifluoromethyl)-2H-indazol-5-yl)-1,1- diphenylmethanimine

[0283] To a mixture of 5-bromo-2-methyl-7-(trifluoromethyl)-2H-indazole (4.5 g, 16.13 mmol) in 1,4-dioxane (50 mL) were added diphenylmethanimine (4.4 g, 24.19 mmol), BINAP (2.0 g, 3.23 mmol), Cs2CO3(10.5 g, 32.26 mmol), Pd(OAc)2(363 mg, 1.61 mmol), the mixture was charged with N2for three times and stirred at 120oC for 16 h under N2. The mixture was diluted with water (100 mL) and extracted with EA (100 mL x 3). The combined organic layer was washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by silica gel column chromatography (PE: EA = 4:1) to give the title compound (5 g, Y: 81.8 %) as a yellow oil. ESI-MS (M+H)+:380.2.1H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 7.71 (s, 1H), 7.70 – 7.69 (m, 1H), 7.56 – 7.53 (m, 1H), 7.50 – 7.46 (m, 2H), 7.33 – 7.30 (m, 3H), 7.21 (s, 1H), 7.20 – 7.17 (m, 2H), 7.10 (s, 1H), 4.14 (s, 3H).Step 3: Preparation of 2-methyl-7-(trifluoromethyl)-2H-indazol-5-amine HCl salt

[0284] To a mixture of N-(2-methyl-7-(trifluoromethyl)-2H-indazol-5-yl)-1,1- diphenylmethanimine (4 g, 10.55 mmol) in EA (40 mL) was added 4M HCl / EA (40 mL). The mixture was stirred at RT for 16 h. The mixture was filtered and the residue was diluted with PE / EA (v:v=1:1, 20 mL) and stirred at RT for 2 h. The precipitate was filtered and dried to give the title compound (2.1 g, Y: 92.5 %) as a white solid. ESI-MS (M+H)+:216.2.1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 2H), 8.68 (s, 1H), 8.09 (s, 1H), 7.67 (s, 1H), 4.27 (s, 3H). Step 4: Preparation of tert-butyl 4-(1-((2-methyl-7-(trifluoromethyl)-2H-indazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate

[0285] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (120 mg, 0.39 mmol) in THF (5 mL) were added TEA (239 mg, 2.37 mmol), triphosgene (141 mg, 0.47 mmol), 2-methyl-7-(trifluoromethyl)-2H-indazol-5-amine HCl salt (85 mg, 0.39 mmol). The mixture was stirred at RT for 16 h. The mixture was diluted with water (20 mL) and extracted with EA (20 mL x 3). The combined organic layer was washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by silica gel column chromatography (PE / EA = 3:1) to give the title compound (100 mg, Y: 46.4 %) as a yellow solid. ESI-MS (M+H)+:546.2.1H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 8.47 (s, 1H), 8.16 (s, 1H), 7.97 (d, J = 6.1 Hz, 1H), 7.83 (s, 1H), 6.54 (d, J = 6.3 Hz, 1H), 4.21 (s, 3H), 4.02 – 3.97 (m, 2H), 3.46 – 3.43 (m, 4H), 3.30 – 3.28 (m, 4H), 3.14 – 3.11 (m, 2H), 1.43 (s, 9H). Step 5: Preparation of N-(2-methyl-7-(trifluoromethyl)-2H-indazol-5-yl)-4-(piperazin-1-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate

[0286] To a solution of tert-butyl 4-(1-((2-methyl-7-(trifluoromethyl)-2H-indazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (80 mg, 0.15 mmol) in EA (3 mL) was added 4M HCl / EA (3 mL). The reaction mixture was stirred at RT for 2 h. The precipitate was filtered and purified by prep-HPLC (0.03% FA in water / ACN) to give title compound (3.52 mg, 4.9 %) as a white solid. ESI-MS (M+H)+: 446.2.1H NMR (400 MHz, MeOD-d4) δ 8.50 (s, 1H), 8.28 (s, 1H), 8.14 (s, 1H), 8.03 (d, J = 6.0 Hz, 1H), 7.76 (s, 1H), 6.58 (d, J = 6.1 Hz, 1H), 4.24 (s, 3H), 4.12 – 4.08 (m, 2H), 3.47 – 3.44 (m, 4H), 3.28 – 3.25 (m, 4H), 3.16 (t, J = 8.5 Hz, 2H).Example 15 – Preparation of N-(6-ethoxy-2-methyl-2H-indazol-5-yl)-4-(piperazin-1-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate (Compound 15)Step 1: Preparation of 5-bromo-2-fluoro-4-methoxybenzaldehyde

[0287] To a solution of 2-fluoro-4-methoxybenzaldehyde (50 g, 324.7 mol) in MeOH (500 mL), Br2 (103.9 g, 649.4 mol) was added dropwise at 0oC, the mixture was stirred for 16 h at RT. The mixture was diluted with sat. Na2SO3(1000 mL) at 0oC, and stirred for 1 hour. The precipitate was filtered, washed with water and dried under vacuum to give crude product (66 g, 87.2 %) as a white solid, which was used to next step without further purification.1H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 7.99 (d, J = 7.5 Hz, 1H), 7.26 (d, J = 12.7 Hz, 1H), 3.98 (s, 3H).Step 2: Preparation of (E)-5-bromo-2-fluoro-4-methoxybenzaldehyde oxime

[0288] To a solution of 5-bromo-2-fluoro-4-methoxybenzaldehyde (100 g, 429.2 mmol) in THF (1000 mL) was added NH2OH·HCl (35.5 g, 515 mmol) and K2CO3(71.1 g, 515 mmol). The mixture was stirred at 40 ℃ for 16 h. The mixture was concentrated in vacuo to give crude. The crude was diluted with water (1000 mL) and stirred at r.t for 30 min, the precipitate was filtered and dried under vacuum to give crude title product (98 g, Y: 92.4%) as a white solid which was used to next step without further purification. ESI-MS (M+H)+: 248.0.1H NMR (400 MHz, DMSO-d6) δ 11.54 (s, 1H), 8.14 – 8.08 (m, 1H), 7.89 – 7.82 (m, 1H), 7.18 – 7.08 (m, 1H), 3.91 (s, 3H). Step 3: Preparation of 5-bromo-6-methoxy-1H-indazole

[0289] To a solution of (E)-5-bromo-2-fluoro-4-methoxybenzaldehyde oxime (50 g, 202.4 mmol) in 1,4-dioxane (500 mL) was added N2H4.H2O (75.8 g, 1516 mmol). The mixture was stirred at 145℃ for 24 h. The mixture was concentrated in vacuo. The crude was purified by silica gel column chromatography (PE: EA= 4:1) to give title product (20 g, Y: 43.7 %) as a yellow solid. ESI-MS (M+H)+: 228.9.1H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.94 (s, 1H), 7.08 (s, 1H), 3.91 (s, 3H). Step 4: Preparation of 5-bromo-6-methoxy-2-methyl-2H-indazole

[0290] To a solution of 5-bromo-6-methoxy-1H-indazole (30 g, 132 mmol) in EA (900 mL) was added BF4.OMe3(29.3 g, 198 mmol). The mixture was stirred for 2 h at RT. The mixture was concentrated in vacuo and diluted with water (400 mL), extracted with EA (400 mL x 3). The organic phase was washed with brine (300 mL), dried over Na2SO4and concentrated to give title product (25 g, Y: 78.6%) as a yellow solid which was used to next step without further purification. ESI-MS (M+H)+: 241.0.1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.98 (s, 1H), 7.09 (s, 1H), 4.11 (s, 3H), 3.87 (s, 3H). Step 5: Preparation of methyl 5-bromo-2-methyl-2H-indazol-6-ol

[0291] A mixture of 5-bromo-6-methoxy-2-methyl-2H-indazole (20 g, 83.3 mmol) in BBr3(1M, 400 mL, 400 mmol) was stirred at r.t for 16 h. The mixture was quenched with MeOH (300 mL) at 0oC and concentrated in vacuo. The residue was diluted with sat.Na2CO3(300 mL) and stirred for 16 h. The precipitate was filtered and dried under vacuum to afford title compound (16 g, 85.4% yield) as a yellow solid. ESI-MS (M+H)+: 229.0.1H NMR (400 MHz, DMSO-d6) δ 8.07 (s, 1H), 7.83 (s, 1H), 6.85 (s, 1H), 4.02 (s, 3H). Step 6: Preparation of 5-bromo-6-ethoxy-2-methyl-2H-indazole

[0292] To a solution of 5-bromo-2-methyl-2H-indazol-6-ol (50 g, 221 mmol) in DMF (1000 mL) was added K2CO3(91.5 g, 663 mmol), CH3CH2I (87.3 g, 552.5 mmol) was added at 0oC, the mixture was stirred at r.t for 16 h. The mixture was diluted with water (3000 mL), the precipitate was filtered, washed with water and dried to afford title compound (47 g, 83.3% yield) as an off-white solid. ESI-MS (M+H)+:257.0.1H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 1H), 7.97 (s, 1H), 7.06 (s, 1H), 4.15 – 4.05 (m, 5H), 1.39 (t, J = 6.9 Hz, 3H). Step 7: Preparation of N-(6-ethoxy-2-methyl-2H-indazol-5-yl)-1,1-diphenylmethanimine

[0293] To a solution of 5-bromo-6-ethoxy-2-methyl-2H-indazole (3 g, 11.76 mmol), diphenylmethanimine (2.56 g, 14.11 mmol), Cs2CO3(11.49 g, 35.28 mmol) and Pd(OAc)2(26.40 mg, 0.12 mmol) in 1,4-dioxane (50 mL) was added BINAP (146 mg, 0.23 mmol), the mixture was stirred at 100oC for 16 h under N2. The mixture was concentrate in vacuo, the residue was purified by silica gel column chromatography (PE : EA= 1 : 4) to give title product (2.2 g, 52.63 %) as a yellow solid. ESI-MS (M+H)+: 356.3.1H NMR (400 MHz, CDCl3) δ 7.74 – 7.68 (m, 2H), 7.50 (s, 1H), 7.40 (s, 1H), 7.34 (d, J = 7.6 Hz, 2H), 7.15 – 7.06 (m, 5H), 6.74 (s, 1H), 6.68 (s, 1H), 3.99 (s, 3 H), 3.87 (q, J = 7.0 Hz, 2H), 1.28 (t, J = 7.0 Hz, 3H). Step 8: Preparation of 6-ethoxy-2-methyl-2H-indazol-5-amine

[0294] A solution of N-(6-ethoxy-2-methyl-2H-indazol-5-yl)-1,1-diphenylmethanimine (2.0 g, 5.63 mmol ) in 3M HCl / EA (15 mL) was stirred at RT for 2 h. The mixture was diluted with sat. Na2CO3(40 mL), extracted with EA (60 mL × 3). The organic layer was washed with brine, dried with Na2SO4and concentration in vacuo. The crude was purified by silica gel column chromatography (PE: EA= 1: 8) to give title product (800 mg, 74.35%) as a yellow solid. ESI-MS (M+H)+: 192.2.1H NMR (400 MHz, CDCl3) δ 7.45 (s, 1H), 6.83 (s, 1H), 6.67 (s, 1H), 4.04 (q, J = 14.0, 7.0 Hz, 2H), 4.00 (s, 3H), 1.41 (t, J = 7.0 Hz, 3H). Step 9: Preparation of tert-butyl 4-(1-((6-ethoxy-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate

[0295] To a solution of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (100 mg, 0.33 mmol) and 6-ethoxy-2-methyl-2H-indazol-5-amine (125 mg, 0.66 mmol) in THF (10 mL) were added TEA (199 mg, 1.97 mmol) and triphosgene (194 mg, 0.66 mmol) at 0oC. The mixture was stirred at RT for 2 h. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (PE: EA= 1: 3) to give the compound (100 mg, 58.36%) as an off-white solid. ESI-MS (M+H)+: 522.3.1H NMR (400 MHz, CDCl3) δ 11.95 (s, 1H), 8.53 (s, 1H), 7.87 (d, J = 6.0 Hz, 1H), 7.66 (s, 1H), 6.91 (s, 1H), 6.29 (d, J = 6.0 Hz, 1H), 4.14 – 4.07 (m, 7H), 3.52 – 3.47 (m, 4H), 3.17 – 3.12 (m, 4H), 3.05 – 2.99 (m, 2H), 1.56 – 1.54 (m, 3H), 1.42 (s, 9H).Step 10: Preparation of N-(6-ethoxy-2-methyl-2H-indazol-5-yl)-4-(piperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate

[0296] To a mixture of tert-butyl 4-(1-((6-ethoxy-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (90 mg, 0.17 mmol) in EA (5 mL) was added 3M HCl / EA (1.5 mL), the mixture was stirred at RT for 2 h. The precipitate was filtered and purified by prep-HPLC (0.05 % FA in water / CN) to give title product (23 mg, Y: 31.63 %) as a white solid. ESI-MS (M+H)+: 422.2.1H NMR (400 MHz, DMSO-d6) δ 12.01 (s, 1H), 8.44 (s, 1H), 8.29 (s, 1H), 8.11 (s, 1H), 7.87 (d, J = 5.8 Hz, 1H), 6.97 (s, 1H), 6.53 (d, J = 6.0 Hz, 1H), 4.16 – 4.11 (m, 2H), 4.05 (s, 3H), 4.02 – 3.97 (m, 2H), 3.34 – 3.23 (m, 4H), 3.10 (t, J = 8.2 Hz, 2H), 3.03 – 2.85 (m, 4H), 1.52 (t, J = 6.8 Hz, 3H). Example 16 – Preparation of N-(4-methoxy-2-methylbenzo[d]oxazol-6-yl)-4-(piperazin- 1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide (Compound 16)Step 1: Preparation of N-(4-bromo-2-methoxyphenyl)acetamide

[0297] To a mixture of 4-bromo-2-methoxyaniline (20 g, 99.00 mmol) in EA (200 mL) was added Ac2O (15.14 g, 148.51 mmol) at 0oC. The mixture was stirred at r.t for 3 h. Themixture was diluted with H2O (200 mL) and extracted with EA (200 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4and concentrated in vacuo. The residue was purified by column chromatography (PE: EA=5:1) to give title product (23 g, 95.8%) as a white solid. ESI-MS (M+H)+: 244.0.1H NMR (400 MHz, DMSO-d6) δ 9.22 (s, 1H), 7.91 (d, J = 8.6 Hz, 1H), 7.20 (d, J = 2.1 Hz, 1H), 7.08 (dd, J = 8.6, 2.1 Hz, 1H), 3.85 (s, 3H), 2.09 (s, 3H). Step 2: Preparation of 6-bromo-4-methoxy-2-methylbenzo[d]oxazole

[0298] To a solution of N-(4-bromo-2-methoxyphenyl)acetamide (25 g, 102.88 mmol) in AcOH : DMF (180 mL : 22 mL) were added Pd(OAc)2(2.5 g, 0.1wt), K2S2O8(37.65 g, 154.32 mmol), TfOH (15.43 g, 102.88 mmol) at 0oC. The mixture was stirred at 100oC for 16 h. The mixture was diluted with H2O (250 mL) and extracted with DCM (250 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4and concentrated in vacuo. The residue was purified by column chromatography (PE: EA=9:1) to give title product (2.5 g, 10%) as a white solid. ESI-MS (M+H)+: 243.9. Step 3: Preparation of N-(4-methoxy-2-methylbenzo[d]oxazol-6-yl)-1,1- diphenylmethanimine

[0299] A mixture of 6-bromo-4-methoxy-2-methylbenzo[d]oxazole (250 mg, 1.00 mmol), Benzenemethanimine (280 mg, 1.55 mmol), Pd(OAc)2(23 mg, 0.10 mmol) and BINAP (128.7 mg, 0.21 mmol) in 1,4-dioxane (5 mL) was purged with N2for three times at RT. Then the mixture was stirred at 100oC for 16 hours. The mixture was cooled to RT, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column (PE: EA=10:1) to provide title product (300 mg, yield: 88%) as a yellow solid. ESI-MS (M+H)+: 345.1.1H NMR (400 MHz, CDCl3) δ 7.72 – 7.64 (m, 2H), 7.40 (t, J = 7.3 Hz, 1H), 7.33 (t, J = 7.4 Hz, 2H), 7.19 (t, J = 6.8 Hz, 3H), 7.06 (dd, J = 7.8, 1.6 Hz, 2H), 6.36 (d, J = 1.5 Hz, 1H), 6.15 (d, J = 1.5 Hz, 1H), 3.72 (s, 3H), 2.45 (s, 3H). Step 4: Preparation of 4-methoxy-2-methylbenzo[d]oxazol-6-amine

[0300] To a solution of N-(4-methoxy-2-methylbenzo[d]oxazol-6-yl)-1,1- diphenylmethanimine (280 mg, 0.82 mmol) in EA (1 mL) was added 4 M HCl / EA (3 mL) at 0oC. Then the mixture was stirred at RT for 2 hours. The precipitate was filtered, washed with EA. Then adjusted pH to 8 with Na2CO3aqueous, the precipitate was filtered and dried under vacuum to afford title product (124 mg, yield: 82%) as a white solid. ESI-MS (M+H)+: 179.1.Step 5: Preparation of tert-butyl 4-(1-((4-methoxy-2-methylbenzo[d]oxazol-6-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate

[0301] To a solution of 4-methoxy-2-methylbenzo[d]oxazol-6-amine (53.4 mg, 0.30 mmol), tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (60 mg, 0.20 mmol) in THF (1.5 mL) were added TEA (0.12 mL, 0.60 mmol) and triphosgene (89 mg, 0.30 mmol) at 0oC. Then the mixture was stirred at 60oC for 16 hours. The mixture was allowed to cool down to room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EA=1:1) to provide title product (80 mg, yield: 78%) as a white solid. ESI-MS (M+H)+: 509.2.1H NMR (400 MHz, DMSO-d6) δ 11.98 (s, 1H), 7.95 (s, 1H), 7.62 (s, 1H), 6.95 (s, 1H), 6.55 (s, 1H), 3.97 (s, 3H), 3.47 – 3.41 (m, 4H), 3.31 – 3.26 (m, 6H), 3.12 (t, J = 8.2 Hz, 2H), 2.54 (s, 3H), 1.43 (s, 9H). Step 6: Preparation of N-(4-methoxy-2-methylbenzo[d]oxazol-6-yl)-4-(piperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide

[0302] To a solution of ert-butyl 4-(1-((4-methoxy-2-methylbenzo[d]oxazol-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (50 mg, 0.10 mmol) in DCM (2 mL) were added HMDS (32.2 mg. 0.20 mmol), TMSOTf (44.4 mg, 0.20 mmol) at 0oC. Then the mixture was stirred at RT for 2 hours. The mixture was adjusted pH to 8 with Na2CO3aqueous, extracted with DCM. The organic phase was concentrated in vacuo. The crude was purified by pre-HPLC (0.03% NH3·H2O in water / ACN) to give title product (12.28 mg, Y: 30%) as a white solid. ESI-MS (M+H)+: 409.2.1H NMR (400 MHz, DMSO-d6) δ 12.02 (s, 1H), 7.93 (d, J = 6.1 Hz, 1H), 7.61 (d, J = 1.2 Hz, 1H), 6.94 (s, 1H), 6.51 (d, J = 6.2 Hz, 1H), 4.03 – 3.92 (m, 5H), 3.24 – 3.17 (m, 4H), 3.10 (t, J = 8.5 Hz, 2H), 2.85 – 2.76 (m, 4H), 2.54 (s, 3H). Example 17 – Preparation of N-(2,4-dimethylbenzo[d]oxazol-6-yl)-4-(piperazin-1-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide (Compound 17)Step 3Step 1: Preparation of 6-bromo-2,4-dimethylbenzo[d]oxazole

[0303] To a mixture of N-(4-bromo-2-methylphenyl)acetamide (10 g, 44.05 mmol) in AcOH (160 mL) and DMF (20 mL) were added TfOH (6.6 g, 44.05 mmol), K2S2O8(17.8 g, 66.08 mmol) and Pd(OAc)2(987 mg, 4.41 mmol), the mixture was charged with N2for three times and stirred at 100 ℃ for 16 h under N2. The mixture was concentrated in vacuo, the residue was purified by silica gel column chromatography eluted with (EA / PE=1:1) to give the title compound (3 g, 30 %) as a yellow solid. ESI-MS (M+H)+:226.1. Step 2: Preparation of N-(2,4-dimethylbenzo[d]oxazol-6-yl)-1,1-diphenylmethanimine

[0304] To a mixture of 6-bromo-2,4-dimethylbenzo[d]oxazole (2 g, 8.85 mmol) and diphenylmethanimine (2.4 g, 13.27 mmol) in 1,4-dioxane (50 mL) were added BINAP (1.10 g, 1.77 mmol), Pd(OAc)2(199 mg, 0.88 mmol) and Cs2CO3(8.6 g, 26.55 mmol). The reaction solution was stirred at 100℃ for 16 h. The reaction was diluted with H2O (100 mL), extracted with EA (100 mLx3), the organic layer was washed with brine (100 mL), dried over Na2SO4and concentrated in vacuo. The crude was purified by silica gel column chromatography (PE: EA=7 %) to give title product (2 g, yield: 69.32%) as a yellow solid. ESI-MS (M+H)+: 327.2.1H NMR (400 MHz, DMSO-d6) δ 7.68 – 7.64 (m, 2H), 7.55 – 7.51 (m, 1H), 7.50 – 7.44 (m, 2H), 7.34 – 7.29 (m, 3H), 7.19 – 7.15 (m, 2H), 6.72 (d, J = 1.3 Hz, 1H), 6.57 – 6.55 (m, 1H), 2.50 (s, 3H), 2.33 (s, 3H). Step 3: Preparation of 2,4-dimethylbenzo[d]oxazol-6-amine

[0305] A mixture of N-(2,4-dimethylbenzo[d]oxazol-6-yl)-1,1-diphenylmethanimine (1.9 g, 5.83 mmol) in 3M HCl / EA (10 mL) was stirred at RT for 2 h. The mixture was concentrated in vacuo, the residue was diluted with water (5 mL), adjusted pH to 7~8 by sat. Na2CO3, extracted with EA (20 mL×3). The organic layer was washed with brine (30 mL), dried with Na2SO4and concentrated in vacuo. The crude was purified by silica gel columnchromatography (EA: PE= 40 %) to give title product (1 g, yield: 98.8 %) as a white solid. ESI-MS (M+H)+: 163.1.1H NMR (400 MHz, DMSO-d6) δ 6.52 (d, J = 1.6 Hz, 1H), 6.37 (dd, J = 1.8, 0.8 Hz, 1H), 5.11 (s, 2H), 2.47 (s, 3H), 2.32 (s, 3H). Step 4: Preparation of tert-butyl 4-(1-((2,4-dimethylbenzo[d]oxazol-6-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate

[0306] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (150 mg, 0.49 mmol) and 2,4-dimethylbenzo[d]oxazol-6-amine (240 mg, 1.48 mmol) in THF (2 mL) were added TEA (247.4 mg, 2.45 mmol) and triphosgene (439.5 mg, 1.48 mmol) at 0oC. The reaction mixture was stirred at RT for 16 h. The precipitate was filtered and dried in vacuo to give title product (100 mg, 41%) as a yellow solid. ESI-MS (M+H)+: 493.3. Step 5: Preparation of N-(2,4-dimethylbenzo[d]oxazol-6-yl)-4-(piperazin-1-yl)-2,3-dihydro- 1H-pyrrolo[2,3-b]pyridine-1-carboxamide

[0307] A mixture of tert-butyl 4-(1-((2,4-dimethylbenzo[d]oxazol-6-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (100 mg, 0.20 mmol) in 4 M HCl / EA (5 mL) was stirred at RT for 15 min. The precipitate was filtered and purified by prep-HPLC (0.1% NH3.H2O in H2O / ACN) to give title product (1.89 mg, yield: 2.4 %) as a white solid. ESI-MS (M+H)+: 393.2.1H NMR (400 MHz, MeOD-d4) δ 7.94 (d, J = 6.0 Hz, 1H), 7.86 (s, 1H), 7.05 (s, 1H), 6.51 (d, J = 6.1 Hz, 1H), 4.05 (t, J = 8.6 Hz, 2H), 3.28 – 3.25 (m, 4H), 3.12 (t, J = 8.5 Hz, 2H), 2.97 – 2.92 (m, 4H), 2.60 (s, 3H), 2.51 (s, 3H). Example 18 – Preparation of N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-4-(piperazin-1- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide (Compound 18) (Ac)2OHOAc, RT, 3 hStep 1Step 2c)2 F3M HCl / EA dioxane, 100 oC, 16 hRT, 2 h Step 3Step 4Step 1: Preparation of N-(4-bromo-2,6-difluorophenyl)acetamide

[0308] To a solution of 4-bromo-2,6-difluoroaniline (25 g, 0.12 mol) in HOAc (250 mL) was added (Ac)2O (74 mL, 0.78 mol). The mixture was stirred at RT for 3 h. The reaction mixture was poured into ice water, the precipitate was filtered, washed with ice water and dried in vacuo to give title product (29 g, yield: 96.67%) as a white solid. ESI-MS (M+H)+: 251.9.1H NMR (400 MHz, DMSO-d6) δ 9.73 (s, 1H), 7.56 – 7.51 (m, 2H), 2.06 (s, 3H). Step 2: Preparation of 6-bromo-4-fluoro-2-methylbenzo[d]oxazole

[0309] To a solution of N-(4-bromo-2,6-difluorophenyl)acetamide (29 g, 0.12 mol) in 1- methylpyrrolidin-2-one (300 mL) was added Cs2CO3(97.8 g, 0.36 mol). The mixture was stirred at 150oC for 2 h. The mixture was diluted with water (300 mL) and extracted with EA (300 mL × 3). The organic layer was washed with brine, dried with Na2SO4and concentrated in vacuo to give title product (5.4 g, yield: 19.49%) as a yellow solid. ESI-MS (M+H)+: 231.9.1H NMR (400 MHz, DMSO-d6) δ 7.92 (d, J = 1.2 Hz, 1H), 7.55 (dd, J = 9.7, 1.6 Hz, 1H), 2.63 (s, 3H). Step 3: Preparation of N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-1,1-diphenylmethanimine

[0310] A mixture of 6-bromo-4-fluoro-2-methylbenzo[d]oxazole (5.3 g, 23.1 mmol), diphenylmethanimine (5.82 mL, 34.7 mmol), Cs2CO3(22.5 g, 69.3 mmol), Pd(OAc)2(520 mg, 2.31 mmol) and BINAP (2.88 g, 4.62 mmol) in 1,4-dioxane (80 mL) was stirred at 100oC for 16 h. The mixture was diluted with water (300 mL) and extracted with EA (300 mL × 3). The organic layer was washed with brine, dried with Na2SO4and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (eluted with EA: PE = 1:1) to give title product (5 g, yield: 65.79%) as a white solid. ESI-MS (M+H)+: 331.1.1H NMR (400 MHz, DMSO-d6) δ 7.70 – 7.65 (m, 2H), 7.55 – 7.54 (m, 1H), 7.48 (t, J = 7.4 Hz,2H), 7.35 – 7.30 (m, 3H), 7.23 – 7.18 (m, 2H), 6.87 (d, J = 1.6 Hz, 1H), 6.64 (dd, J = 11.3, 1.6 Hz, 1H), 2.54 (s, 3H). Step 4: Preparation of 4-fluoro-2-methylbenzo[d]oxazol-6-amine HCl salt

[0311] To a mixture of N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-1,1-diphenylmethanimine (2 g, 6.06 mmol) in MeOH (20 mL) was added 3.0 M HCl / EA (4 mL). The mixture was stirred at RT for 2 h. The precipitate was filtered and dried in vacuo to give title product (1 g, yield: 99.41%) as a white solid. ESI-MS (M+H)+: 167.1.1H NMR (400 MHz, DMSO-d6) δ 6.54 (d, J = 1.7 Hz, 1H), 6.37 (dd, J = 12.6, 1.7 Hz, 1H), 5.51 (s, 2H), 2.49 (s, 3H). Step 5: Preparation of tert-butyl 4-(1-((4-fluoro-2-methylbenzo[d]oxazol-6-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate

[0312] To a solution of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (100 mg, 0.33 mmol) and 4-fluoro-2-methylbenzo[d]oxazol-6-amine (110 mg, 0.66 mmol) in THF (10 mL) were added triethylamine (0.25 mL, 1.65 mmol) and triphosgene (200 mg, 0.66 mmol) at 0oC. The mixture was stirred at RT for 16 h. The precipitate was filtered, washed with THF (5 mL) and dried in vacuo to give title product (70 mg, yield: 42.94%) as a white solid. ESI-MS (M+H)+: 497.2. Step 6: Preparation of N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-4-(piperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide

[0313] A mixture of tert-butyl 4-(1-((4-fluoro-2-methylbenzo[d]oxazol-6-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (50 mg, 0.10 mmol) in 3.0 M HCl / EA (3 mL) was stirred at RT for 2 h. The precipitate was filtered and purified by prep-HPLC (0.1% NH3·H2O in H2O / ACN) to give title product (15.70 mg, yield: 39.65%) as a white solid. ESI-MS (M+H)+: 397.2.1H NMR (400 MHz, DMSO-d6) δ 12.22 (s, 1H), 7.93 (d, J = 6.1 Hz, 1H), 7.84 (d, J = 1.6 Hz, 1H), 7.40 (dd, J = 12.2, 1.6 Hz, 1H), 6.53 (d, J = 6.2 Hz, 1H), 3.97 (t, J = 8.5 Hz, 2H), 3.26 – 3.17 (m, 4H), 3.11 (t, J = 8.5 Hz, 2H), 2.84 – 2.78 (m, 4H), 2.60 (s, 3H).Example 19 – Preparation of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(pyrrolidin-3-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride (Compound 19)Step 1: Preparation of tert-butyl 3-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,5-dihydro- 1H-pyrrole-1-carboxylate

[0314] A mixture of 4-chloro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (2 g, 12.94 mmol), tert- butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (5.76 g, 19.41 mmol), K2CO3(5.35 g, 38.82 mmol) and Pd(dppf)Cl2(944.3 mg, 1.29 mmol) in 1,4-dioxane / H2O (30 mL / 6 mL) was stirred at 110oC for 16 h. The mixture was cooled to RT, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column (DCM : MeOH = 20 : 1) to provide title product (3.0 g, yield: 81%) as a yellow solid. ESI-MS (M+H)+: 288.3.1H NMR (400 MHz, DMSO-d6) δ 7.68 (s, 1H), 7.58 – 7.46 (m, 1H), 6.40 (s, 1H), 6.27 (d, J = 10.1 Hz, 1H), 4.38 (s, 2H), 4.22 (s, 2H), 3.48 (t, J = 8.4 Hz, 2H), 3.10 (t, J = 8.4 Hz, 2H), 1.44 (s, 9H). Step 2: Preparation of tert-butyl 3-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidine-1- carboxylate tert-butyl 3-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidine-1- carboxylate

[0315] To a solution tert-butyl 3-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,5-dihydro- 1H-pyrrole-1-carboxylate (500 mg, 1.74 mmol) in THF (10 mL) was added Pd / C (250 mg, 50 % wt). The obtained solution was charged with H2for three times and stirred at RT for 16 h. The mixture was filtered and the filtrate was concentrated in vacuo to afford the title compound (450 mg, yield: 89%) as a brown solid. ESI-MS (M+H)+:290.2. Step 3: Preparation of tert-butyl 3-(1-((7-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidine-1-carboxylate

[0316] To a solution of tert-butyl 3-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidine- 1-carboxylate (400 mg, 1.38 mmol) and 7-fluoro-2-methyl-2H-indazol-5-amine (683 mg,4.14 mmol) in THF (8 mL) were added TEA (697 mg, 6.90 mmol) and triphosgene (614 mg, 2.07 mmol) at 0oC. Then the mixture was stirred at RT for 16 hours. The mixture was allowed to cool down to room temperature and concentrated. The residue was purified by silica gel column chromatography (DCM : MeOH = 40 : 1) to provide title product (200 mg, yield: 30%) as white solid. ESI-MS (M+H)+:481.2. Step 4: Preparation of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(pyrrolidin-3-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride

[0317] To a solution of tert-butyl 3-(1-((7-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidine-1-carboxylate (40 mg, 0.08 mmol) in EA (1 mL) was added 4 M HCl / EA (3 mL) at 0oC. Then the mixture was stirred at RT for 2 hours. The precipitate was filtered, washed with EA and lyophilized to give title product (18 mg, 30%) as a yellow solid. ESI-MS (M+H)+:381.2.1H NMR (400 MHz, MeOD-d4) δ 8.32 (d, J = 2.6 Hz, 1H), 8.04 (d, J = 6.6 Hz, 1H), 7.77 (d, J = 1.5 Hz, 1H), 7.38 (d, J = 6.6 Hz, 1H), 7.33 (dd, J = 12.8, 1.5 Hz, 1H), 4.47 (t, J = 8.2 Hz, 2H), 4.24 (s, 3H), 3.87 – 3.70 (m, 2H), 3.68 – 3.62 (m, 1H), 3.54 – 3.37 (m, 4H), 2.62 – 2.51 (m, 1H), 2.25 – 2.13 (m, 1H). Example 20 – Preparation of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate (Compound 20)Step 1: Preparation of tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate

[0318] A mixture of 4-chloro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (500 mg, 3.22 mmol) and tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (1.36 g, 6.45 mmol) in a sealed tubewas stirred at 140oC for 16 h. The mixture was concentrated in vacuo. The crude was purified by silica gel column chromatography (MeOH : DCM = 15 %) to give title product (1 g, yield: 94%) as a yellow solid. ESI-MS (M+H)+: 331.2.1H NMR (400 MHz, DMSO-d6) δ 7.50 (d, J = 6.4 Hz, 1H), 6.48 – 6.40 (m, 1H), 6.17 (d, J = 6.5 Hz, 1H), 3.54 – 3.52 (m, 3H), 3.26 – 3.22 (m, 3H), 3.07 (s, 2H), 3.03 – 3.00 (m, 2H), 1.41 (s, 9H), 0.94 – 0.91 (m, 2H), 0.85 – 0.80 (m, 2H). Step 2: Preparation of tert-butyl 7-(1-((7-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5] octane-4-carboxylate

[0319] To a mixture of tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (200 mg, 0.61 mmol) and 7-fluoro-2-methyl-2H-indazol- 5-amine (199.95 mg, 1.21 mmol) in THF (20 mL) were added TEA (245 mg, 2.42 mmol) and triphosgene (359.2 mg, 1.21mmol) at 0oC. The reaction mixture was stirred at RT for 16 h. The precipitate was filtered and dried in vacuo to give title product (200 mg, 63.35 %) as a yellow solid. ESI-MS (M+H)+: 522.2.1H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.37 – 8.29 (m, 2H), 7.61 – 7.60 (m, 1H), 7.16 – 7.13 (m, 1H), 4.16 (s, 3H), 4.14 (m, 1H), 3.96 (t, J = 8.5 Hz, 1H), 3.59 – 3.52 (m, 2H), 3.45 (m, 1H), 3.32 – 3.26 (m, 3H), 3.12 – 3.06 (m, 2H), 1.42 (s, 9H), 0.96 – 0.91 (m, 2H), 0.87 – 0.82 (m, 2H). Step 3: Preparation of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(4,7-diazaspiro[2.5]octan-7- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate

[0320] A mixture of tert-butyl 7-(1-((7-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (200 mg, 0.38 mmol) in 3 M HCl / EA (10 mL) was stirred at RT for 2 h. The precipitate was filtered and purified by prep-HPLC (0.1% FA in H2O / ACN) to give title product (7.12 mg, yield: 4.45 %) as a yellow solid. ESI-MS (M+H)+: 422.1.1H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 8.35 (d, J = 2.8 Hz, 1H), 8.28 (s, 1H), 7.91 (d, J = 6.1 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.25 (dd, J = 13.3, 1.6 Hz, 1H), 6.49 (d, J = 6.2 Hz, 1H), 4.16 (s, 3H), 3.95 (t, J = 9.0 Hz, 2H), 3.26 – 3.22 (m, 2H), 3.10 (s, 2H), 3.09 – 3.04 (m, 2H), 2.88 – 2.84 (m, 2H), 0.54 – 0.46 (m, 4H).Example 21 – Preparation of N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(4- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide (CompoundStep 1: Preparation of 6-bromo-8-fluoro-2-methylimidazo[1,2-a] pyridine

[0321] A mixture of 5-bromo-3-fluoropyridin-2-amine (50 g, 263 mmol) and 1- bromopropan-2-one (89.5 g, 658 mmol) in EtOH (500 mL) was stirred at 90oC for 16 h. The reaction was cooled to r.t, the precipitated solids were collected by filtration and washed with EtOH. The cake was dissolved in H2O and basified to pH 10 with Na2CO3, the precipitated solids were collected by filtration, washed with H2O and dried by vacuum to afford title product (40 g, Y: 67%) as a white solid. ESI-MS (M+H)+: 229.1.1H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J = 1.4 Hz, 1H), 7.82 – 7.73 (m, 1H), 7.38 (dd, J = 10.7, 1.5 Hz, 1H), 2.35 (d, J = 0.6 Hz, 3H). Step 2: Preparation of N-(8-fluoro-2-methylimidazo[1,2-a] pyridin-6-yl)-1,1- diphenylmethanimine

[0322] A mixture of 6-bromo-8-fluoro-2-methylimidazo[1,2-a] pyridine (15 g, 65.8 mmol), diphenylmethanimine (12.5 g, 69.1 mmol), Pd(OAc)2(1.48 g, 6.58 mmol), BINAP (8.2 g,13.2 mmol) and Cs2CO3(42.8 g, 131.6 mmol) in 1,4-dioxane (150 mL) was purged with N2for three times at rt. Then the mixture was stirred at 115oC for 16 h. The mixture was cooled to r.t and filtered and filter was concentrated under reduce pressure. The residue was purified by silica gel column (0~50% EA in PE) to provide title product (16 g, yield: 74%) as light brown solid. ESI-MS (M+H)+: 330.4.1H NMR (400 MHz, DMSO-d6) δ 7.83 (d, J = 1.2 Hz, 1H), 7.68 (d, J = 7.3 Hz, 2H), 7.62 (d, J = 2.8 Hz, 1H), 7.56 (d, J = 7.2 Hz, 1H), 7.48 (t, J = 7.5 Hz, 2H), 7.43 – 7.35 (m, 3H), 7.24 – 7.21 (m, 2H), 6.65 – 6.63 (m, 1H), 2.27 (s, 3H). Step 3: Preparation of 8-fluoro-2-methylimidazo[1,2-a] pyridin-6-amine

[0323] To a solution of N-(8-fluoro-2-methylimidazo[1,2-a] pyridin-6-yl)-1,1- diphenylmethanimine (15 g, 45.6 mmol) in EA (100 mL) at 0oC was added 3M HCl-EA (90 mL). The mixture was stirred at r.t for 2 h. The precipitate was filtered and dissolved in H2O and basified to pH 10 with Na2CO3, the precipitated solids were collected by filtration, washed with H2O and dried by vacuum to afford title product (7.2 g, yield: 96%) as yellow solid. ESI-MS (M+H)+: 166.1.1H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.85 (s, 1H), 7.38 (d, J = 12.3 Hz, 1H), 2.43 (s, 3H). Step 4: Preparation of 4-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine

[0324] A mixture of 4-chloro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (300 mg, 1.94 mmol) and 1-methylpiperazine (580 mg, 5.81 mmol) in DIEA (1.3 g, 9.70 mmol) was stirred at 140 ℃ for 16 h in sealed tube. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM: MeOH= 10: 1) to give title product (200 mg, Y: 47 %) as a yellow solid. ESI-MS (M+H)+:219.1.1H NMR (400 MHz, DMSO-d6) δ 7.52 (d, J = 5.9 Hz, 1H), 6.06 (d, J = 6.0 Hz, 1H), 5.86 (s, 1H), 3.47 – 3.36 (m, 2H), 3.14 – 3.08 (m, 4H), 2.93 (t, J = 8.4 Hz, 2H), 2.42 – 2.35 (m, 4H), 2.20 (s, 3H). Step 5: Preparation of N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(4- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide

[0325] To a mixture of 4-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (80 mg, 0.37 mmol) in THF (5 mL) were added 8-fluoro-2-methylimidazo[1,2-a]pyridin-6- amine (182 mg, 1.10 mmol), TEA (187 mg, 1.85 mmol) and triphosgene (220 mg, 0.74 mmol) at 0 ℃. The reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residuewas purified by prep-HPLC (0.1% NH3.H2O in H2O / ACN) to give title product (42.42 mg, yield: 27 %) as a white solid. ESI-MS (M+H)+:410.2.1H NMR (400 MHz, DMSO-d6) δ 11.82 (s, 1H), 8.82 (d, J = 1.5 Hz, 1H), 7.90 (d, J = 6.1 Hz, 1H), 7.83 (d, J = 2.8 Hz, 1H), 7.23 (dd, J = 12.5, 1.5 Hz, 1H), 6.54 (d, J = 6.2 Hz, 1H), 3.97 (t, J = 8.6 Hz, 2H), 3.30 – 3.27 (m, 4H), 3.12 (t, J = 8.5 Hz, 2H), 2.46 – 2.39 (m, 4H), 2.32 (d, J = 5.1 Hz, 3H), 2.22 (s, 3H). Example 22 – Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(7-fluoro-2- methyl-2H-indazol-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide (Compound 22)Step 1: Preparation of tert-butyl (2R,6S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate

[0326] A mixture of 4-chloro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (300 mg, 1.94 mmol) and tert-butyl (2R,6S)-2,6-dimethylpiperazine-1-carboxylate (832 mg,3.88 mmol) was stirred at 140oC for 16 h in a sealed tube. The mixture was purified by column chromatography on silica gel (eluted with DCM : MeOH = 10 : 1) to give title product (200 mg, yield: 31.06%) as a white solid. ESI-MS (M+H)+: 333.2.1H NMR (400 MHz, DMSO-d6) δ 7.56 (d, J = 5.9 Hz, 1H), 6.08 (d, J = 6.0 Hz, 1H), 5.94(s, 1H), 3.86 – 3.76 (m, 4H), 3.41 – 3.36 (m, 4H), 3.02 – 2.96 (m, 1H), 2.82 – 2.76 (m, 1H), 1.39 (s, 9H), 1.16 (s, 3H), 1.15 (s, 3H). Step 2: Preparation of tert-butyl (2R,6S)-4-(1-((7-fluoro-2-methyl-2H-indazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1- carboxylate

[0327] To a solution of tert-butyl (2R,6S)-4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate (160 mg, 0.48 mmol) and 7-fluoro-2-methyl-2H-indazol-5- amine (158 mg, 0.96 mmol) in THF (15 mL) were added triethylamine (0.33 mL, 2.40 mmol)and triphosgene (285 mg, 0.96 mmol) at 0oC. The mixture was stirred at RT for 16 h. The precipitate was filtered, washed with THF (5 mL) and dried in vacuo to give title product (60 mg, yield: 23.90%) as a white solid. ESI-MS (M+H)+: 524.4. Step 3: Preparation of 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)-N-(7-fluoro-2-methyl-2H- indazol-5-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide

[0328] A mixture of tert-butyl (2R,6S)-4-(1-((7-fluoro-2-methyl-2H-indazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylpiperazine-1- carboxylate (40 mg, 0.08 mmol) in 3.0 M HCl / EA (3 mL) was stirred at RT for 2 h. The precipitate was filtered and purified by prep-HPLC (0.1% NH3·H2O in H2O / ACN) to give title product (1.05 mg, yield: 3.10%) as a white solid. ESI-MS (M+H)+: 424.2.1H NMR (400 MHz, MeOD-d4) δ 8.19 (d, J = 2.6 Hz, 1H), 8.01 (d, J = 6.0 Hz, 1H), 7.70 (d, J = 1.5 Hz, 1H), 7.20 (dd, J = 12.9, 1.5 Hz, 1H), 6.59 (d, J = 6.1 Hz, 1H), 4.21 (s, 3H), 4.14 – 4.05 (m, 2H), 3.83 (d, J = 11.9 Hz, 2H), 3.42 – 3.36 (m, 2H), 3.20 – 3.12 (m, 2H), 2.80 (dd, J = 13.1, 11.4 Hz, 2H), 1.34 (d, J = 6.5 Hz, 6H). Example 23 – Preparation of N-(6,8-dimethylimidazo[1,2-a] pyrazin-2-yl) -4-(piperazin- 1-yl) -2,3-dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide formate.Compound 23Step 1: Preparation of tert-butyl 4-(1-((6,8-dimethylimidazo[1,2-a] pyrazin-2-yl) carbamoyl) - 2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) piperazine-1-carboxylate.

[0329] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) piperazine- 1-carboxylate (100 mg, 0.33 mmol) and 6,8-dimethylimidazo[1,2-a] pyrazin-2-amine (159 mg, 0.97 mmol) in THF (3 mL) were added TEA (98 mg, 0.97 mmol) and triphosgene (288 mg, 0.97 mmol) at 0oC. The reaction mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and the residue was purified by silica gel column (PE / EA=1:3) to give title product (120 mg, 74%) as a yellow oil. ESI-MS (M+H)+: 493.3.1H NMR (400MHz, DMSO-d6) δ 11.59 (s, 1H), 7.94 (d, J = 6.1 Hz, 1H), 7.77 (s, 1H), 6.94 (s, 1H), 6.57 (d, J = 6.2 Hz, 1H), 3.48 – 3.43 (m, 4H), 3.18 – 3.16 (m, 6H), 2.71 – 2.70 (m, 2H), 2.40 (s, 3H), 2.33 (s, 3H), 1.43 (s, 9H). Step 2: Preparation of N-(6,8-dimethylimidazo[1,2-a] pyrazin-2-yl) -4-(piperazin-1-yl) -2,3- dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide formate.

[0330] To a mixture of tert-butyl 4-(1-((6,8-dimethylimidazo[1,2-a] pyrazin-2-yl) carbamoyl) -2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) piperazine-1-carboxylate (100 mg, 0.21 mmol) in EA (2 mL) was added 4M HCl / EA (2 mL). The reaction mixture was stirred at RT for 2 h. The mixture was diluted with water (2 mL), extracted with EA (2 mL×3). The aqueous layer was concentrated in vacuo and purified by prep-HPLC (0.1 % FA in water / CH3CN) to give title product (14.42 mg, yield: 17 %) as a white solid. ESI-MS (M+H)+: 393.3.1H NMR (400 MHz, DMSO-d6) δ 11.60 (s, 1H), 8.26 (s, 1H), 7.94 (d, J = 6.1 Hz, 1H), 7.83 (s, 1H), 7.62 (s, 1H), 6.57 (d, J = 6.1 Hz, 1H), 4.01 (t, J = 8.3 Hz, 2H), 3.36 – 3.28 (m, 4H), 3.15 (t, J = 8.4 Hz, 2H), 3.01 – 2.88 (m, 4H), 2.70 (s, 3H), 2.39 (s, 3H). Example 24 – Preparation of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(4- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.Step 1: Preparation of 4-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine.

[0331] A mixture of 4-chloro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (300 mg, 1.94 mmol) and 1-methylpiperazine (580 mg, 5.81 mmol) in DIEA (1.3 g, 9.70 mmol) was stirred at 140 ℃ for 16 h in sealed tube. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM: MeOH= 10: 1) to give title product (200 mg, Y: 47 %) as a yellow solid. ESI-MS (M+H)+:219.1.1H NMR (400 MHz, DMSO-d6) δ 7.52 (d, J = 5.9 Hz, 1H),6.06 (d, J = 6.0 Hz, 1H), 5.86 (s, 1H), 3.47 – 3.36 (m, 2H), 3.14 – 3.08 (m, 4H), 2.93 (t, J = 8.4 Hz, 2H), 2.42 – 2.35 (m, 4H), 2.20 (s, 3H). Step 2: Preparation of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(4-methylpiperazin-1-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

[0332] To a mixture of 7-fluoro-2-methyl-2H-indazol-5-amine (182 mg, 1.10 mmol) in THF (5 mL) were added 4-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (80 mg, 0.37 mmol), TEA (187 mg, 1.85 mmol) and triphosgene (220 mg, 0.74 mmol) at 0 ℃. The reaction mixture was stirred at r.t for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mLx3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (0.1% FA in H2O / ACN) to give title product (20.11 mg, yield: 13 %) as a white solid. ESI-MS (M+H)+:410.1.1H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 8.35 (d, J = 2.8 Hz, 1H), 8.18 (s, 1H), 7.92 (d, J = 6.1 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.26 (dd, J = 13.3, 1.6 Hz, 1H), 6.53 (d, J = 6.2 Hz, 1H), 4.16 (s, 3H), 3.99 – 3.94 (m, 2H), 3.31 – 3.27 (m, 4H), 3.11 (t, J = 8.5 Hz, 2H), 2.45 – 2.39 (m, 4H), 2.22 (s, 3H).Example 25 – Preparation of N-(5,7-dimethylimidazo[1,2-c]pyrimidin-2-yl)-4- (piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.Step 1: Preparation of ethyl 5,7-dimethylimidazo[1,2-c]pyrimidine-2-carboxylate.

[0333] To a solution of 2,6-dimethylpyrimidin-4-amine (10 g, 81.30 mmol) in EtOH (100 mL) was added ethyl 3-bromo-2-oxopropanoate (24 g, 121.95 mmol). The reaction mixture was stirred at 80oC for 16 h. The mixture was concentrated in vacuo and diluted with aq. NaHCO3(50 mL), extracted with DCM (100 mL×2), the organic was washed with brine, dried over Na2SO4and concentrated in vacuo. The crude was purified by column gel chromatography (PE / EA=1 / 1) to give title product (2 g, 11.24 %) as a yellow solid. ESI-MS (M+H)+: 220.2. Step 2: Preparation of 5,7-dimethylimidazo[1,2-c]pyrimidine-2-carboxylic acid.

[0334] To a solution of ethyl 5,7-dimethylimidazo[1,2-c]pyrimidine-2-carboxylate (2 g, 9.13 mmol) in EtOH (20 mL) was added 2 M NaOH (20 mL) at 0 °C. The reaction mixture was stirred at RT for 2 h. The mixture was concentrated in vacuo and diluted with H2O (30 mL), extracted with EA (20 mL×2). The aqueous phase was adjust to PH =2~3, theprecipitate was filtered to give title product (1.6 g, 91.95 %) as a yellow solid. ESI-MS (M+H)+: 192.2. Step 3: Preparation of tert-butyl (5,7-dimethylimidazo[1,2-c]pyrimidin-2-yl)carbamate.

[0335] To a solution of 5,7-dimethylimidazo[1,2-c]pyrimidine-2-carboxylic acid (1 g, 5.24 mmol) in DCM (20 mL) were added TEA (1.6 g, 15.72 mmol) and DPPA (1.6 g, 5.76 mmol). The mixture was stirred at RT for 1 h. The mixture was concentrated in vacuo, the residue was diluted with t-BuOH (20 mL) and stirred at 85oC for 16 h. The mixture was concentrated in vacuo and the residue was purified by column gel chromatography (PE / EA=1 / 1) to give title product (200 mg, 14.60 %) as a yellow solid. ESI-MS (M+H)+: 263.1.1H NMR (400 MHz, CDCl3) δ 8.34 – 8.16 (m, 1H), 7.55 (s, 1H), 7.04 (s, 1H), 2.68 (s, 3H), 2.42 (s, 3H), 1.49 (s, 9H). Step 4: Preparation of 5,7-dimethylimidazo[1,2-c]pyrimidin-2-amine.

[0336] To a solution of tert-butyl (5,7-dimethylimidazo[1,2-c]pyrimidin-2-yl)carbamate (200 mg, 0.76 mmol) in EA (2 mL) was added 4 M HCl / EA (2 mL). The mixture was stirred at RT for 2 h. The precipitate was filtered, washed with EA (5 mL) and concentrated in vacuo. The crude was diluted with aq. Na2CO3,the precipitate was filtered to give title product (100 mg, 81.30 %) as a yellow solid. ESI-MS (M+H)+: 163.3.1H NMR (400 MHz, DMSO-d6) δ 6.91 (s, 1H), 6.66 (s, 1H), 5.25 (s, 2H), 2.58 (s, 3H), 2.34 (s, 3H). Step 5: Preparation of tert-butyl 4-(1-((5,7-dimethylimidazo[1,2-c]pyrimidin-2- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate.

[0337] To a solution of 5,7-dimethylimidazo[1,2-c]pyrimidin-2-amine (80 mg, 0.31 mmol) and tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (94 mg, 0.31 mmol) in THF (5 mL) were added TEA (94 mg, 0.93 mmol) and triphosgene (92 mg, 0.31 mmol) at 0 °C. The reaction mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and the residue was purified by column gel chromatography (PE / EA=0 / 1) to give title product (100 mg, 66.45 %) as a yellow solid. ESI-MS (M+H)+: 493.2. Step 6: Preparation of N-(5,7-dimethylimidazo[1,2-c]pyrimidin-2-yl)-4-(piperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.

[0338] To a solution of tert-butyl 4-(1-((5,7-dimethylimidazo[1,2-c]pyrimidin-2- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (100 mg, 0.20 mmol) in EA (2 mL) was added 4 M HCl / EA (3 mL). The mixture was stirred at RT for 2 h. The precipitate was filtered, washed with EA (5 mL) and lyophilized to give title product (74 mg, 85.06 %) as a yellow solid. ESI-MS (M+H)+: 393.2.1H NMR (400 MHz,DMSO-d6) δ 9.44 (s, 2H), 8.01 – 7.92 (m, 1H), 7.80 (s, 1H), 7.30 (s, 1H), 6.85 – 6.58 (m, 1H), 4.20 – 4.01 (m, 2H), 3.72 – 3.43 (m, 4H), 3.28 – 3.16 (m, 6H), 2.80 (s, 3H), 2.46 (s, 3H). Example 26 – Preparation of N-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4-(piperazin- 1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.Compound 26Step 1: Preparation of tert-butyl 4-(1-((4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate.

[0339] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (100 mg, 0.33 mmol) in THF (5 mL) were added 4,6-dimethylpyrazolo[1,5- a]pyrazin-2-amine (107 mg, 0.66 mmol), TEA (196 mg, 1.65 mmol) and triphosgene (196 mg, 0.66 mmol) at 0 ℃. The reaction mixture was stirred at r.t for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM: EA=1:1) to give title product (80 mg, yield: 49 %) as a yellow solid. ESI-MS (M+H)+:493.3.1H NMR (400 MHz, DMSO-d6) δ 12.32 (s, 1H), 8.31 (s, 1H), 7.96 (d, J = 6.1 Hz, 1H), 6.98 (s, 1H), 6.56 (d, J = 6.2 Hz, 1H), 4.02 (t, J = 8.6 Hz, 2H), 3.47 – 3.42 (m, 4H), 3.30 – 3.27 (m, 4H), 3.15 (t, J = 8.5 Hz, 2H), 2.62 (s, 3H), 2.38 (s, 3H), 1.43 (s, 9H). Step 2: Preparation of N-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4-(piperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.

[0340] To a mixture of tert-butyl 4-(1-((4,6-dimethylpyrazolo[1,5-a]pyrazin-2- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (70 mg, 0.14 mmol) in EA (5 mL) was added 4M HCl / EA (5 mL). The mixture was stirred at r.t for 2 h. The mixture was concentrated in vacuo and lyophilized to give title compound (31.71mg, 52 %) as a white solid. ESI-MS (M+H)+:393.1.1H NMR (400 MHz, DMSO-d6) δ 12.32 (s, 1H), 9.06 (s, 2H), 8.41 (s, 1H), 8.00 (s, 1H), 7.08 (s, 1H), 6.65 (s, 1H), 4.11 – 4.08 (m, 2H), 3.56 – 3.48 (m, 4H), 3.24 – 3.16 (m, 6H), 2.68 (s, 3H), 2.41 (s, 3H). Example 27 – Preparation of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(1- methylpyrrolidin-3-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide.Compound 27Step 1: Preparation of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(1-methylpyrrolidin-3-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide.

[0341] To a solution of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(pyrrolidin-3-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide (60 mg, 0.16 mmol) in MeOH / THF (2 mL / 2 mL) were added (HCHO)n(14 mg, 0.48 mmol) and AcOH (48 mg, 0.80 mmol). The mixture was stirred at r.t for 1h. Then NaBH3CN (30 mg, 0.80 mmol) was added to the mixture and stirred at 50oC for 16 h. The mixture was concentrated in vacuo, the residue was purified by silica gel column (DCM: MeOH = 20:1) to provide title product (20 mg, yield: 32%) as a white solid. ESI-MS (M+H)+:395.1.1H NMR (400 MHz, DMSO-d6) δ 11.57 (s, 1H), 8.37 (d, J = 2.8 Hz, 1H), 8.09 (d, J = 5.5 Hz, 1H), 7.74 (d, J = 1.5 Hz, 1H), 7.28 (dd, J = 13.3, 1.5 Hz, 1H), 6.98 (d, J = 5.6 Hz, 1H), 4.17 (s, 3H), 4.04 (t, J = 8.6 Hz, 2H), 3.10 (t, J = 8.6 Hz, 2H), 2.80 – 2.67 (m, 2H), 2.59 – 2.52 (m, 3H), 2.32 (s, 3H), 2.30 – 2.25 (m, 1H), 1.75 (dd, J = 13.2, 7.4 Hz, 1H). Example 28 – Preparation of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(1- methylpiperidin-4-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.Step 1: Preparation of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(1-methylpiperidin-4-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

[0342] A mixture of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(piperidin-4-yl)-2,3-dihydro- 1H-pyrrolo[2,3-b]pyridine-1-carboxamide (100 mg, 0.25 mmol), (CH2O)n(68 mg, 0.76 mmol), TEA (76 mg, 0.76 mmol) and NaBHCN (45.6 mg, 0.76 mmol) in MeOH (5 mL) was stirred at RT for 2 h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.1% FA in H2O / ACN) to give title product (35.59 mg, yield: 34.89%) as a pink solid. ESI-MS (M+H)+: 409.1.1H NMR (400 MHz, DMSO-d6) δ 11.56 (s, 1H), 8.37 (d, J = 2.7 Hz, 1H), 8.21 (s, 1H), 8.10 (d, J = 5.5 Hz, 1H), 7.73 (d, J = 1.3 Hz, 1H), 7.28 (dd, J = 13.3, 1.3 Hz, 1H), 6.90 (d, J = 5.6 Hz, 1H), 4.17 (s, 3H), 4.05 (t, J = 8.6 Hz, 2H), 3.11 (t, J = 8.5 Hz, 2H), 2.97 (d, J = 11.2 Hz, 2H), 2.61 – 2.52 (m, 1H), 2.29 (s, 3H), 2.17 – 2.11 (m, 2H), 1.75 – 1.68 (m, 4H). Example 29 – Preparation of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(piperidin-4-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.Step 1: Preparation of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,6- dihydropyridine-1(2H)-carboxylate.

[0343] A mixture of 4-chloro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (2 g, 12.94 mmol), tert- butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (7.9 g, 25.87 mmol), Pd(dppf)Cl2(948 mg, 1.29 mmol) and K2CO3(5.35 mg,38.32 mmol) in 1,4-dioxane / H2O (20 mL / 5 mL) was stirred at 100oC for 16 h under N2. The mixture was diluted with water (30 mL), extracted with EA (30 mL×3). The organic layer was washedwith brine (30 mL), dried with Na2SO4and concentrated in vacuo. The crude was purified by silica gel column chromatography (EA: PE= 71 %) to give title product (1.7 g, yield: 43.64 %) as a yellow solid. ESI-MS (M+H)+: 302.2.1H NMR (400 MHz, DMSO-d6) δ 7.65 (d, J = 5.5 Hz, 1H), 6.36 (d, J = 5.6 Hz, 1H), 5.76 (br.s, 1H), 4.00 – 3.95 (m, 2H), 3.50 (t, J = 5.5 Hz, 2H), 3.41 (t, J = 8.4 Hz, 2H), 3.03 (t, J = 8.3 Hz, 2H), 2.37 (d, J = 1.5 Hz, 2H), 2.37 (d, J = 1.5 Hz, 2H), 1.43 (s, 9H). Step 2: Preparation of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidine-1- carboxylate.

[0344] A mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,6- dihydropyridine-1(2H)-carboxylate (1.1 g, 3.32 mmol), Pd(OH)2(250 mg) and Pd / C (250 mg) in THF (50 mL) was stirred at RT for 2 h under H2. The precipitate was filtered and the filtrate was dried in vacuo to give title product (1 g, yield: 99.41 %) as a white solid. ESI-MS (M+H)+: 304.1.1H NMR (400 MHz, DMSO- d6) δ 7.62 (d, J = 5.5 Hz, 1H), 6.30 (d, J = 5.5 Hz, 1H), 6.21 (s, 1H), 4.05 (d, J = 11.3 Hz, 2H), 3.43 (t, J = 8.1 Hz, 2H), 2.96 (t, J = 8.4 Hz, 2H), 2.84 – 2.70 (m, 2H), 2.63 – 2.57 (m, 1H), 1.68 – 1.61 (m, 2H), 1.46 – 1.38 (m, 11H). Step 3: Preparation of tert-butyl 4-(1-((7-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidine-1-carboxylate.

[0345] A mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidine-1- carboxylate (437,6 mg, 1.44 mmol), phenyl (7-fluoro-2-methyl-2H-indazol-5-yl)carbamate (343 mg 1.20 mmol) and DMAP (14.6 mg, 0.12 mmol) in THF (10 mL) was stirred at 80oC for 16 h. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (EA: PE= 100%) to give title product (400 mg, yield: 60.52 %) as a white solid. ESI-MS (M+H)+: 495.2.1H NMR (400 MHz, DMSO- d6) δ 11.55 (s, 1H), 8.37 (s, 1H), 8.10 (d, J = 4.5 Hz, 1H), 7.74 (s, 1H), 7.28 (d, J = 13.1 Hz, 1H), 6.92 (d, J = 5.1 Hz, 1H), 4.17 (s, 3H), 4.08 – 4.03 (m, 3H), 3.15 – 3.11 (m, 2H), 2.84 – 2.76 (m, 4H), 1.74 – 1.69 (m, 2H), 1.56 – 1.50 (m, 2H), 1.43 (s, 9H). Step 4: Preparation of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(piperidin-4-yl)-2,3-dihydro- 1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.

[0346] A mixture of tert-butyl 4-(1-((7-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidine-1-carboxylate (350 mg, 0.71 mmol) in 3M HCl / EA (5 mL) was stirred at RT for 2 h. The precipitate was filtered to give title product (200 mg, yield: 71.31 %) as a pink solid. ESI-MS (M+H)+: 395.2.1H NMR (400 MHz, DMSO-d6) δ 11.45 (s, 1H), 9.02 (s, 2H), 8.38 (d, J = 2.8 Hz, 1H), 8.15 (d, J = 5.6 Hz, 1H), 7.74 (d, J = 1.5 Hz, 1H), 7.29 (dd, J = 13.3, 1.5 Hz, 1H), 6.85 (d, J = 5.6 Hz, 1H), 4.17 (s,3H), 4.11 – 4.10 (m, 2H), 3.41 – 3.35 (m, 2H), 3.19 – 3.13 (m, 2H), 3.06 – 2.93 (m, 3H), 1.96– 1.85 (m, 4H).Example 30 – Preparation of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(3- (methylamino)azetidin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

[0347] To a solution of 4-chloro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (300 mg, 1.94 mmol) and tert-butyl azetidin-3-yl(methyl)carbamate (541 mg, 2.91 mmol) was added DIEA (2 mL). The reaction mixture was stirred at 120 °C for 16 h in a sealed tube. The mixture was concentrated in vacuo and purified by column gel chromatography (PE / EA=1 / 2) to give title product (200 mg, 34.01 %) as a yellow solid. ESI-MS (M+H)+: 305.1. Step 2: Preparation of tert-butyl (1-(1-((7-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)azetidin-3-yl)(methyl)carbamate.

[0348] To a solution of tert-butyl (1-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)azetidin-3- yl)(methyl)carbamate (200 mg, 0.66 mmol) and 7-fluoro-2-methyl-2H-indazol-5-amine (109 mg, 0.66 mmol) in THF (5 mL) were added TEA (200 mg, 1.98 mmol) and triphosgene (196 mg, 0.66 mmol) at 0 °C. The reaction mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by column chromatography (PE / EA=0 / 1) to give title product (50 mg, 15.34 %) as a yellow solid. ESI-MS (M+H)+: 496.4. Step 3: Preparation of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-(3-(methylamino)azetidin-1- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

[0349] To a solution of tert-butyl (1-(1-((7-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)azetidin-3-yl)(methyl)carbamate (50 mg, 0.10 mmol) in EA (2 mL) was added 4 M HCl / EA (0.5 mL). The mixture was stirred at RT for 2 h. Themixture was concentrated in vacuo. The crude was purified by prep-HPLC (0.1 % FA in water / CH3CN) to give title product (2 mg, 4.49 %) as a yellow solid. ESI-MS (M+H)+: 396.2.1H NMR (400 MHz, MeOD-d4) δ 8.42 (s, 1H), 8.18 (d, J = 2.4 Hz, 1H), 7.85 (d, J = 5.9 Hz, 1H), 7.68 (s, 1H), 7.18 (d, J = 13.6 Hz, 1H), 6.07 (d, J = 5.9 Hz, 1H), 4.39 (t, J = 7.9 Hz, 2H), 4.20 (s, 3H), 4.08 – 3.99 (m, 4H), 3.95 – 3.87 (m, 1H), 3.14 (t, J = 8.6 Hz, 2H), 2.57 (s, 3H). Example 31 – Preparation of 4-(piperazin-1-yl)-N-(quinolin-4-yl)-2,3-dihydro-1H- pyrrolo[2,3-b]pyridine-1-carboxamide formate.Compound 31Step 1: Preparation of tert-butyl 4-(1-(quinolin-4-ylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3- b]pyridin-4-yl)piperazine-1-carboxylate.

[0350] To a solution of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (100 mg, 0.33 mmol) and quinolin-4-amine (48 mg, 0.33 mmol) in THF (5 mL) were added TEA (100 mg, 0.99 mmol) and triphosgene (98 mg, 0.33 mmol) at 0 °C. The reaction mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by column chromatography (PE / EA=1 / 2) to give title product (50 mg, 32.05 %) as a yellow solid. ESI-MS (M+H)+: 475.4.1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J = 5.1 Hz, 1H), 8.34 (d, J = 5.2 Hz, 1H), 8.30 (d, J = 8.0 Hz, 1H), 8.16 (d, J = 6.1 Hz, 1H), 8.05 – 7.99 (m, 1H), 7.83 – 7.72 (m, 2H), 6.64 (d, J = 6.2 Hz, 1H), 4.09 – 4.04 (m, 2H), 3.49 – 3.44 (m, 4H), 3.37 – 3.35 (m, 4H), 3.20 – 3.19 (m, 2H), 1.43 (s, 9H). Step 2: Preparation of 4-(piperazin-1-yl)-N-(quinolin-4-yl)-2,3-dihydro-1H-pyrrolo[2,3- b]pyridine-1-carboxamide formate.

[0351] To a solution of tert-butyl 4-(1-(quinolin-4-ylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3- b]pyridin-4-yl)piperazine-1-carboxylate (50 mg, 0.11 mmol) in EA (2 mL) was added 4 M HCl / EA (0.5 mL). The mixture was stirred at RT for 2 h. The mixture was concentrated invacuo. The crude was purified by prep-HPLC (0.1 % FA in water / CH3CN) to give title product (27 mg, 60.95 %) as a yellow solid. ESI-MS (M+H)+: 375.2.1H NMR (400 MHz, DMSO-d6) δ 13.06 (s, 1H), 8.76 (d, J = 5.1 Hz, 1H), 8.33 (d, J = 5.1 Hz, 1H), 8.30 (d, J = 8.1 Hz, 1H), 8.21 (s, 1H), 8.14 (d, J = 6.1 Hz, 1H), 8.04 – 7.97 (m, 1H), 7.84 – 7.71 (m, 2H), 6.62 (d, J = 6.2 Hz, 1H), 4.06 (t, J = 8.5 Hz, 2H), 3.33 – 3.29 (m, 4H), 3.20 – 3.15 (m, 2H), 2.92 – 2.84 (m, 4H). Example 32 – Preparation of N-(1-methyl-1H-pyrrolo[2,3-b] pyridin-4-yl)-4-(piperazin- 1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide formate.Compound 32Step 1: Preparation of tert-butyl 4-(1-((1-methyl-1H-pyrrolo[2,3-b] pyridin-4-yl) carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) piperazine-1-carboxylate.

[0352] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) piperazine- 1-carboxylate (100 mg, 0.33 mmol) and 1-methyl-1H-pyrrolo[2,3-b] pyridin-4-amine (60 mg, 0.39 mmol) in THF (2 mL) were added TEA (99 mg, 0.99 mmol) and triphosgene (116 mg, 0.39 mmol) at 0oC. The reaction mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and diluted with water (3 mL), extracted with EA (3 mL×3). The organic layer was washed with brine, dried with Na2SO4and concentrated in vacuo. The crude was purified by silica gel column (PE: EA = 2: 1) to give title product (120 mg, 70%) as a yellow solid. ESI-MS (M+H)+: 478.3. Step 2: Preparation of N-(1-methyl-1H-pyrrolo[2,3-b] pyridin-4-yl)-4-(piperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b] pyridine-1-carboxamide formate.

[0353] To a mixture of tert-butyl 4-(1-((1-methyl-1H-pyrrolo[2,3-b] pyridin-4-yl) carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b] pyridin-4-yl) piperazine-1-carboxylate (100 mg, 0.21 mmol) in EA (1 mL) was added 4M HCl / EA (1 mL). The reaction mixture was stirredat RT for 2 h. The mixture was diluted with water (2 mL), extracted with EA (2 mL×3). The aqueous layer was concentrated in vacuo and purified by Prep-HPLC (0.1 % FA in water / CH3CN) to give title product (12.75 mg, yield: 16 %) as a yellow solid. ESI-MS (M+H)+: 378.2.1H NMR (400 MHz, DMSO-d6) δ 12.56 (s, 1H), 8.31 (s, 1H), 8.18 – 8.06 (m, 2H), 7.86 (d, J = 4.5 Hz, 1H), 7.45 (s, 1H), 6.58 (s, 2H), 4.03 – 4.00 (m, 2H), 3.81 (s, 3H), 3.39 – 3.27 (m, 4H), 3.18 – 3.08 (m, 2H), 3.06 – 2.84 (m, 4H). Example 33 – Preparation of N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.Step 1: Preparation of tert-butyl 7-(1-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5] octane-4- carboxylate.

[0354] To a solution of tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (100 mg, 0.30 mmol) and 8-fluoro-2-methylimidazo[1,2- a]pyridin-6-amine (99 mg, 0.60 mmol) in THF (10 mL) were added TEA (153 mg, 1.51 mmol) and triphosgene (179 mg, 0.60 mmol) at 0oC. The mixture was stirred at r.t for 3 h. The mixture was concentrated and purified by silica gel column chromatography (PE: EA= 1: 3) to give the compound (110 mg, 36.90%) as a yellow solid. ESI-MS (M+H)+: 522.3.1H NMR (400 MHz, DMSO-d6) δ 11.80 (s, 1H), 8.82 (d, J = 1.6 Hz, 1H), 7.91 (d, J = 6.1 Hz, 1H), 7.83 (d, J = 2.6 Hz, 1H), 7.24 (d, J = 12.6 Hz, 1H), 6.54 (d, J = 6.2 Hz, 1H), 3.99 – 3.94 (m, 2H), 3.59 – 3.54 (m, 4H), 3.18 – 3.16 (m, 2H), 3.11 – 3.07 (m, 2H), 2.32 (s, 3H), 1.42 (s, 9H), 0.96 – 0.92 (m, 2H), 0.86 – 0.83 (m, 2H).Step 2: Preparation of N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

[0355] To a mixture of tert-butyl 3-((1-((7-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)pyrrolidine-1-carboxylate (100 mg, 0.19 mmol) in EA (3 mL) was added 3M HCl / EA (1 mL), the mixture was stirred at r.t for 2 h. The precipitate was filtered and purified by prep-HPLC (0.05 % FA in water / ACN) to give title product (43 mg, Y: 53.21%) as a white solid. ESI-MS (M+H)+: 422.2.1H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.82 (s, 1H), 8.19 (s, 1H), 7.89 (d, J = 5.6 Hz, 1H), 7.83 (s, 1H), 7.23 (d, J = 12.3 Hz, 1H), 6.51 (d, J = 5.8 Hz, 1H), 4.00 – 3.93 (m, 2H), 3.28 – 3.22 (m, 2H), 3.15 – 3.04 (m, 4H), 2.92 – 2.84 (m, 2H), 2.33 (s, 3H), 0.51 (d, J = 8.4 Hz, 4H). Example 34 – Preparation of N-(6-(cyclopropylmethoxy)-2-methyl-2H-indazol-5-yl)-4- (piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.Step 1: Preparation of 5-bromo-6-(cyclopropylmethoxy)-2-methyl-2H-indazole.

[0356] To a mixture of 5-bromo-2-methyl-2H-indazol-6-ol (3.0 g, 13.22 mmol) and (bromomethyl)cyclopropane (2.14 g, 15.86 mmol) in DMF (30 mL) was added K2CO3(5.47 g, 39.66 mmol). The mixture was stirred at r.t for 16 h. The mixture was diluted with water (30 mL). The precipitate was filtered, washed with water and dried in vacuo to give title product (3.5 g, 80.76 %) as a yellow solid. ESI-MS (M+H)+: 283.1.Step 2: Preparation of N-(6-(cyclopropylmethoxy)-2-methyl-2H-indazol-5-yl)-1,1- diphenylmethanimine.

[0357] A mixture of 5-bromo-6-(cyclopropylmethoxy)-2-methyl-2H-indazole (3.5 g, 12.46 mmol), diphenylmethanimine (5.64 g, 31.15 mmol) and Cs2CO3(8.12 g, 24.92 mmol) in 1,4- dioxane (40 mL) were added Pd(OAc)2(285.04 mg, 1.25 mmol) and BINAP (1.55 g, 2.49 mmol). The mixture was stirred at 100oC for 16 h under N2. The mixture was diluted with H2O (40 mL) and extracted with EA (40 mL x 3). The organic phase was washed with brine (40 mL x 3), dried over anhydrous Na2SO4and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / 1 to 1 / 1) to afford title product (1.4 g, 29.45%) as a brown solid. ESI-MS (M+H)+:382.2. Step 3: Preparation of 6-(cyclopropylmethoxy)-2-methyl-2H-indazol-5-amine hydrochloride.

[0358] A mixture of N-(6-(cyclopropylmethoxy)-2-methyl-2H-indazol-5-yl)-1,1- diphenylmethanimine (1.4 g, 3.67 mmol) in 3M HCl / EA (15 mL) was stirred at rt for 2 h. The precipitate was filtered, washed with EA and dried in vacuo to give title product (800 mg, 86.16 %) as a brown solid. ESI-MS (M+H)+: 218.3.1H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 2H), 8.38 (s, 1H), 7.91 (s, 1H), 7.13 (s, 1H), 4.12 (s, 3H), 3.99 (d, J = 6.7 Hz, 2H), 1.38 – 1.26 (m, 1H), 0.66 – 0.56 (m, 2H), 0.51 – 0.39 (m, 2H). Step 4: Preparation of tert-butyl 4-(1-((6-(cyclopropylmethoxy)-2-methyl-2H-indazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate.

[0359] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (150 mg, 0.44 mmol), 6-(cyclopropylmethoxy)-2-methyl-2H-indazol-5-amine hydrochloride (111.32 mg, 0.44 mmol) in THF (10 mL) were added TEA (133.32 mg, 1.32 mmol) and triphosgene (156.82 mg, 0.53 mmol) at 0oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with H2O (20 mL) and extracted with EA (20 mL x 3). The organic phase was washed with brine (20 mL x 3), dried over anhydrous Na2SO4and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / 1 to 1 / 1) to afford title product (80 mg, 33.23%) as a white solid. ESI-MS (M+H)+: 548.3.1H NMR (400 MHz, DMSO-d6) δ 12.06 (s, 1H), 8.44 (s, 1H), 8.10 (s, 1H), 7.90 (d, J = 6.0 Hz, 1H), 6.93 (s, 1H), 6.51 (d, J = 6.1 Hz, 1H), 4.05 (s, 3H), 4.03 – 3.98 (m, 2H), 3.96 – 3.91 (m, 2H), 3.47 – 3.43 (m, 4H), 3.28 – 3.08 (m, 6H), 1.43 (s, 9H), 1.24 – 1.11 (m, 1H), 0.71 – 0.60 (m, 2H), 0.43 – 0.39 (m, 2H).Step 5: Preparation of N-(6-(cyclopropylmethoxy)-2-methyl-2H-indazol-5-yl)-4-(piperazin-1- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.

[0360] To a mixture of tert-butyl 4-(1-((6-(cyclopropylmethoxy)-2-methyl-2H-indazol-5- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (80 mg, 0.15 mmol) in 3M HCl / EA (5 mL) was stirred at r.t for 2 h. The precipitate was filtered, washed with EA and dried in vacuo to give title product (54 mg, 74.38 %) as a white solid. ESI-MS (M+H)+: 448.3.1H NMR (400 MHz, DMSO-d6) δ 9.38 (s, 2H), 8.42 (s, 1H), 8.21 (s, 1H), 7.92 (d, J = 5.9 Hz, 1H), 6.97 (s, 1H), 6.61 (d, J = 5.2 Hz, 1H), 4.08 (s, 3H), 4.07 – 4.01 (m, 2H), 3.97 (d, J = 6.8 Hz, 2H), 3.58 – 3.48 (m, 4H), 3.22 – 3.14 (m, 6H), 1.43 – 1.34 (m, 1H), 0.66 – 0.61 (m, 2H), 0.45 – 0.40 (m, 2H). Example 35 – Preparation of N-(6-fluoro-2-methyl-2H-indazol-5-yl)-4-(piperazin-1-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.Step 1: Preparation of 6-fluoro-2-methyl-5-nitro-2H-indazole.

[0361] To a solution of 6-fluoro-5-nitro-1H-indazole (1.69 g, 9.34 mmol) in EA (50 mL) were added trimethyloxonium tetrafluoroborate (2.07 g, 14.01 mmol) at 0℃, The mixture was stirred at r.t for 5 h. The mixture was diluted with sat. NaHCO3(20 mL), extracted with EA (30 mL). The organic layer was washed with brine, dried and concentrated to afford the title product (1.2 g, 65%) as a yellow solid. ESI-MS (M+CAN+H)+237.0.1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J = 7.6 Hz, 1H), 8.77 (s, 1H), 7.68 (d, J = 12.7 Hz, 1H), 4.23 (s, 3H).Step 2: Preparation of 6-fluoro-2-methyl-2H-indazol-5-amine.

[0362] To a solution of 6-fluoro-2-methyl-5-nitro-2H-indazole (1.2 g, 6.15 mmol) in MeOH (30 mL) and DCM (30 mL) was added Pd / C (880 mg, 10% w.t). The mixture was charged with H2for three times and stirred at r.t for 16 h. The mixture was filtered and the filtrate concentration to afford title product (500 mg, Y=49%) as a gray solid. ESI-MS (M+H)+166.0.1H NMR (400 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.19 (d, J = 12.3 Hz, 1H), 6.79 (d, J = 9.0 Hz, 1H), 4.87 (s, 2H), 4.03 (s, 3H). Step 3: Preparation of tert-butyl 4-(1-((6-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate.

[0363] To a solution of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (100 mg, 0.33 mmol) in THF (5 mL) were added 6-fluoro-2-methyl-2H-indazol- 5-amine (163 mg, 0.99 mmol) and TEA (167 mg, 1.65 mmol), triphosgene (196 mg, 0.66 mmol) at 0℃, The mixture was stirred at r.t for 16 h. After concentration, the residue was diluted with water (10 mL), extracted with DCM (10 mLx3). The organic layer washed with brine (10 mL), dried with Na2SO4and concentrated in vacuo. The crude was purified by silica gel column chromatography (EA: PE=3:1) to give title product (70 mg, 42 %) as a yellow solid. ESI-MS (M+H)+496.3.1H NMR (400 MHz, DMSO-d6) δ 12.00 (d, J = 2.8 Hz, 1H), 8.43 (d, J = 7.9 Hz, 1H), 8.30 (s, 1H), 7.90 (d, J = 6.0 Hz, 1H), 7.46 (d, J = 3.2 Hz, 1H), 6.58 – 6.48 (m, 1H), 4.12 (s, 3H), 4.03 – 3.98 (m, 2H), 3.47 – 3.42 (m, 4H), 3.30 – 3.27 (m, 4H), 3.17 – 3.12 (m, 2H), 1.43 (s, 9H). Step 4: Preparation of N-(6-fluoro-2-methyl-2H-indazol-5-yl)-4-(piperazin-1-yl)-2,3-dihydro- 1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

[0364] To a solution of tert-butyl 4-(1-((6-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (50 mg, 0.10 mmol) in EA (5 mL) was added 4M HCl / EA (5 mL). The mixture was stirred at r.t for 2 h. The mixture was concentrated under reduced pressure, the residue was purified by prep-HPLC (0.1% FA in H2O / ACN) to give title product (4.17 mg, 10%) as a white solid. ESI-MS (M+H)+:396.1.1H NMR (400 MHz, MeOD-d4) δ 8.42 (d, J = 7.7 Hz, 2H), 8.15 (s, 1H), 8.00 (d, J = 6.0 Hz, 1H), 7.31 (d, J = 11.8 Hz, 1H), 6.59 (d, J = 6.0 Hz, 1H), 4.17 (s, 3H), 4.12 (d, J = 8.8 Hz, 2H), 3.54 – 3.45 (m, 4H), 3.30 – 3.28 (m, 4H), 3.21 – 3.16 (m, 2H).Example 36 – Preparation of N-(5-fluoro-2-methylbenzo[d]oxazol-6-yl)-4-(piperazin-1- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.Step 1: Preparation of 5-fluoro-2-methylbenzo[d]oxazol-6-amine.

[0365] To a mixture of 5-fluoro-2-methyl-6-nitrobenzo[d]oxazole (1 g, 5.10 mmol) in THF (30 mL) and MeOH (10 mL) was added Raney-Nickel (5 mL), the mixture was stirred at room temperature for 3h under H2.The mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (820 mg, 94.44%) as an amaranth solid. ESI-MS (M+H)+: 167.1.1H NMR (400 MHz, DMSO-d6) δ 7.31 (d, J = 11.0 Hz, 1H), 6.94 (d, J = 7.6 Hz, 1H), 5.25 (s, 2H), 3.33 (s, 3H). Step 2: Preparation of tert-butyl 4-(1-((5-fluoro-2-methylbenzo[d]oxazol-6-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate.

[0366] To a solution of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (150 mg, 0.09 mmol) and 5-fluoro-2-methylbenzo[d]oxazol-6-amine (163 mg, 0.98 mmol) in THF (4mL) were added TEA (249 mg, 2.48 mmol) and triphosgene (292 mg, 0.98 mmol) at 0oC. The mixture was stirred at r.t. for 16 h. The mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE: EA= 1: 3) to give title compound (160 mg, 65.39 %) as a white solid. ESI-MS (M+H)+: 497.2. Step 3: Preparation of N-(5-fluoro-2-methylbenzo[d]oxazol-6-yl)-4-(piperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.

[0367] To a mixture of tert-butyl 4-(1-((5-fluoro-2-methylbenzo[d]oxazol-6-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (140 mg, 0.28 mmol) in DCM (5 mL) were added HMDS (136 mg, 0.84 mmol) and TMSOTf (187 mg, 0.184 mmol) at 0oC, the mixture was stirred at r.t for 2 h. The precipitate was filtered and triturated with MeOH (5 mL), then filtered and lyophilized to give title product (55 mg, 49.21 %) as a white solid. ESI-MS (M+H)+: 397.1.1H NMR (400 MHz, DMSO-d6) δ 12.19 (s, 1H), 9.78 (s, 2H),8.50 (d, J = 6.5 Hz, 1H), 7.94 (d, J = 6.0 Hz, 1H), 7.65 (d, J = 10.8 Hz, 1H), 6.61 (d, J = 6.1 Hz, 1H), 4.03 (t, J = 8.5 Hz, 2H), 3.58 – 3.54 (m, 4H), 3.18 – 3.14 (m, 6H), 2.59 (s, 3H). Example 37 – Preparation of N-(2,7-dimethylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide.Step 1: Preparation of 6-bromo-2,7-dimethylimidazo[1,2-a]pyridine.

[0368] To a solution of 5-bromo-4-methylpyridin-2-amine (10 g, 0.05 mol) in IPA(100 mL) was added 1-chloropropan-2-one (15 g, 0.16 mol), the mixture was stirred at 85 ℃ for 16 hours. The mixture was concentrated, the residue was diluted with 2M NaOH (30 mL) and stirred at room temperature for 1 h. The resulting mixture was extracted with EA (100 mL *2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE: EA= 2:1 to afford title product (9 g, yield: 74.8%) as a yellow solid. ESI-MS (M+H)+: 224.9.1H-NMR (400 MHz, MeOD-d4) δ 8.97 (s, 1H), 7.41 (s, 1H), 7.22 (s, 1H), 2.44 (s, 3H), 2.34 (s, 3H). Step 2: Preparation of N-(2,7-dimethylimidazo[1,2-a]pyridin-6-yl)-1,1-diphenylmethanimine.

[0369] A mixture of 6-bromo-2,7-dimethylimidazo[1,2-a]pyridine (5 g, 0.02 mol), diphenylmethanimine (6.03 g, 0.03 mol), BINAP(2.77 g, 0.004 mol), Cs2CO3(14.49 g, 0.04 mol) and Pd(OAc)2(0.50 g, 0.002 mmol) in 1,4-dioxane (50 mL) was stirred for 16 hours at 100℃ under N2atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE: EA (1:1) to afford product (4 g, yield: 55.4%) as a dark yellow solid. ESI-MS (M+H)+: 326.2.1H NMR (400 MHz, DMSO-d6) δ 7.74 – 7.70 (m, 2H), 7.54 (d, J = 7.2 Hz, 2H), 7.48 (dd, J = 8.0, 6.7 Hz, 2H), 7.33 (dd, J = 11.8, 9.0 Hz, 4H), 7.21 (dd, J = 7.8, 1.6 Hz, 3H), 2.24 – 2.19 (m, 6H).Step 3: Preparation of 2,7-dimethylimidazo[1,2-a]pyridin-6-amine.

[0370] A solution of N-(2,7-dimethylimidazo[1,2-a]pyridin-6-yl)-1,1-diphenylmethanimine (2 g, 0.01 mol) in 3M HCl / EA(20 mL) was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo, the residue was purified by C18 column chromatography eluted with CH3CN:H2O (0.1% NH3.H2O=21%) to afford title product (0.9 g, yield: 90.8 %) as a dark yellow solid. ESI-MS (M+H)+: 162.1.1H NMR (400 MHz, DMSO-d6) δ 7.65 (s, 1H), 7.36 (s, 1H), 7.06 (s, 1H), 4.55 (s, 2H), 2.22 (s, 3H), 2.16 (s, 3H). Step 4: Preparation of tert-butyl 4-(1-((2,7-dimethylimidazo[1,2-a]pyridin-6-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate.

[0371] To a solution of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (189 mg, 0.62 mmol) in THF (1.5 mL) were added TEA (188.2 mg, 1.86 mmol) and Triphosgene (221 mg, 0.75 mmol) at 0℃, the mixture was stirred at room temperature for 1 hour.2,7-dimethylimidazo[1,2-a]pyridin-6-amine (100 mg, 0.62 mmol) was added to the mixture and stirred at room temperature for 15 h. The mixture was concentrated in vacuo, the residue was purified by C18 column chromatography eluted with CH3CN:H2O (0.1% NH3.H2O) = 60-95% to afford title product (60 mg, 20%) as a yellow solid. ESI-MS (M+H)+: 492.3. Step 5: Preparation of N-(2,7-dimethylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide.

[0372] A solution of tert-butyl 4-(1-((2,7-dimethylimidazo[1,2-a]pyridin-6-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (50 mg, 0.10 mmol) in 3M HCl / EA(1 mL) was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.1% NH3.H2O in H2O / ACN) to give title product (21.29 mg, yield: 53.47 %) as a white solid. ESI-MS (M+H)+: 392.2.1H NMR (400 MHz, MeOD-d4) δ 8.97 (s, 1H), 7.87 (d, J = 6.0 Hz, 1H), 7.41 (s, 1H), 7.22 (s, 1H), 6.48 (d, J = 6.1 Hz, 1H), 4.03 (t, J = 8.6 Hz, 2H), 3.28 – 3.24 (m, 4H), 3.11 (t, J = 8.5 Hz, 2H), 2.97 – 2.91 (m, 4H), 2.44 (s, 3H), 2.34 (s, 3H).Example 38 – Preparation of N-(6-methoxy-2-methyl-2H-indazol-5-yl)-4-(piperazin-1- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate.Step 1: Preparation of tert-butyl (2R,6S)-2,6-dimethyl-4-(1-((7-methyl-[1,2,4]triazolo[1,5- a]pyridin-6-yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate.

[0373] To a solution of 6-methoxy-2-methyl-2H-indazol-5-amine (209 mg, 1.18 mmol) and TEA (1.64 mL, 11.83 mmol) in THF (21 mL) was added triphosgene (350 mg, 1.18 mmol) at 0oC, after 10 min, tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (300 mg, 0.98 mmol) was added at 0oC. The mixture was stirred at r.t for 16 h. The mixture was diluted with water (80 mL). The precipitate was filtered and triturated with MeOH (10 mL) to give the compound (280 mg, crude) as a white solid. ESI-MS (M+H)+: 508.2. Step 2: Preparation of N-(6-methoxy-2-methyl-2H-indazol-5-yl)-4-(piperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate.

[0374] To a mixture of tert-butyl 4-(1-((6-methoxy-2-methyl-2H-indazol-5-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (260 mg, 0.51 mmol) in EA (2 mL) was added HCl / EA(5 mL, 4M). The mixture was stirred at r.t for 2 h. The precipitate was filtered and purified by prep-HPLC (0.05 % TFA in water / ACN) to give title product (195 mg, Y: 67.91 %) as a white solid. ESI-MS (M+H)+: 407.1.1H NMR (400 MHz, DMSO-d6) δ 11.97 (s, 1H), 8.81 (s, 2H), 8.39 (s, 1H), 8.13 (s, 1H), 8.00 (d, J = 6.0 Hz, 1H), 7.01 (s, 1H), 6.59 (d, J = 6.1 Hz, 1H), 4.06 (s, 3H), 4.02 (t, J = 8.6 Hz, 2H), 3.96 (s, 3H), 3.51 – 3.46 (m, 4H), 3.26 – 3.20 (m, 4H), 3.17 – 3.11 (m, 2H).Example 39 – Preparation of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.Step 1: Preparation of tert-butyl 7-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate.

[0375] To a solution of 7-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine (120 mg, 0.72 mmol) and TEA (734 mg, 7.26 mmol) in THF (15 mL) was added triphosgene (215 mg, 0.72 mmol) at 0oC, after 10 min, tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (200 mg, 0.60 mmol) was added at 0oC to the mixture and stirred at r.t for 16 h. The mixture was diluted with water (50 mL). The precipitate was filtered and triturated with MeOH (10 mL) to give the compound (170 mg, 53.85 %) as a white solid. ESI-MS (M+H)+:522.4. Step 2: Preparation of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.

[0376] To a mixture of tert-butyl 4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (170 mg, 0.34 mmol) in EA (3 mL) was added HCl / EA (8 mL, 4 M). The mixture was stirred at r.t for 2 h. The precipitate was filtered and triturated with DCM: MeOH (8 mL, 10:1), then filtered and lyophilized to give title product (110 mg, 76.08 %) as an off-white solid. ESI-MS (M+H)+:422.2.1H NMR (400 MHz, DMSO-d6) δ 12.38 (s, 1H), 10.01 (s, 2H), 9.64 (s, 1H), 8.18 (s, 1H), 8.08 (d, J = 9.9 Hz, 1H), 7.96 (d, J = 6.1 Hz, 1H), 6.67 (d, J = 5.4 Hz, 1H), 4.10 – 4.03 (m, 2H), 3.71 (s, 2H), 3.51 – 3.46 (m, 2H), 3.33 – 3.27 (m, 2H), 3.23 – 3.15 (m, 2H), 2.46 (s, 3H), 1.15 (t, J = 5.9 Hz, 2H), 0.94 – 0.90 (m, 2H).Example 40 – Preparation of (R)-N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.Step 1: Preparation of tert-butyl (R)-4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1- carboxylate.

[0377] To a mixture of 2-cyclopropylimidazo[1,2-a]pyridin-6-amine (259 mg, 1.57 mmol) and TEA (1.27 g, 12.58 mmol) in THF (40 mL) was added triphosgene (466.3 mg, 1.57 mmol) at 0oC, the mixture was stirred at 0oC for 30 min, tert-butyl (R)-4-(2,3-dihydro-1H- pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (400 mg, 1.26 mmol) was added to the mixture and stirred at RT for 16 h. The mixture was diluted with H2O (50 mL), stirred at rt for 1 h. The precipitate was filtered and triturated with MeOH to afford title product (400 mg, 62.37 %) as a white solid. ESI-MS (M+H)+: 510.2. Step 2: Preparation of (R)-N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.

[0378] A mixture of tert-butyl (R)-4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (400 mg, 0.78 mmol) in 4M HCl / EA (10 mL) was stirred at RT for 2 h. The precipitate was filtered and dried in vacuo to give title product (191.03 mg, yield: 59.88 %) as a white solid. ESI-MS (M+H)+: 410.1.1H NMR (400 MHz, D2O) δ 8.91 (d, J = 6.1 Hz, 1H), 7.74 (d, J = 7.3 Hz, 1H), 7.71 – 7.66 (m, 2H), 6.74 (d, J = 7.1 Hz, 1H), 4.31 – 4.22 (m, 2H), 4.12 – 4.03 (m, 2H), 3.55 – 3.46 (m, 3H), 3.41 – 3.26 (m, 4H), 2.42 (s, 3H), 1.33 (d, J = 6.6 Hz, 3H).Example 41 – Preparation of N-(7-ethoxy-2-methylimidazo[1,2-a]pyridin-6-yl)-4- (piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide.Step 1: Preparation of 5-bromo-4-ethoxypyridin-2-amine.

[0379] To a solution of 4-ethoxypyridin-2-amine (50 g, 0.07 mol) in DCM (500 mL) was added NBS (14 g, 0.08 mol) at 0℃, the mixture was stirred at room temperature for 16 hours. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (eluted with PE: EA= 1:3) to afford title product (45 g, yield: 57.7 %) as a yellow solid. ESI-MS (M+H)+: 218.9.1H NMR (400 MHz, DMSO-d6) δ 7.83 (s, 1H), 6.10 (s, 1H), 6.01 (s, 2H), 4.05 (q, J = 7.0 Hz, 2H), 1.35 (t, J = 7.0 Hz, 3H). Step 2:

[0380] Preparation of 6-bromo-7-ethoxy-2-methylimidazo[1,2-a]pyridine. To a solution of 5-bromo-4-ethoxypyridin-2-amine (20 g, 0.09 mol) in IPA(100 mL) was added 1- chloropropan-2-one (26 g, 0.28 mol), the mixture was stirred at 80 ℃ for 16 hours. The mixture was concentrated, the residue was diluted in 2M NaOH (100 mL) and stirred at room temperature for 1 h. The resulting mixture was extracted with EA (200 mL *2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluted with PE: EA= 1:4) to afford title product (6 g, yield: 25.53%) as a dark yellow solid. ESI-MS (M+H)+:257.0.1H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 1H), 7.43 (s, 1H), 6.92 (s, 1H), 4.13 (q, J = 6.9 Hz, 2H), 2.26 (s, 3H), 1.39 (t, J = 6.9 Hz, 3H). Step 3: Preparation of N-(7-ethoxy-2-methylimidazo[1,2-a]pyridin-6-yl)-1,1- diphenylmethanimine.

[0381] A mixture of 6-bromo-7-ethoxy-2-methylimidazo[1,2-a]pyridine (5 g, 0.02 mol), diphenylmethanimine (5.32 g, 0.03 mol), BINAP (2.44 g, 0.004 mol), Cs2CO3(12.78 g, 0.04 mol) and Pd(OAc)2(0.44 g, 0.002 mol) in 1.4-dioxane (50 mL) was stirred at 100℃ for 16 hours under N2atmosphere. The mixture was allowed to cool down to room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluted with PE: EA=3:1) to afford title product (4 g, yield: 57.5%) as a dark yellow solid. ESI-MS (M+H)+: 356.3.1H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J = 18.7 Hz, 3H), 7.77 – 7.74 (m, 4H), 7.72 – 7.67 (m, 2H), 7.58 (t, J = 7.6 Hz, 4H), 4.19 – 4.06 (m, 2H), 2.27 (s, 3H), 1.41 (t, J = 6.8 Hz, 3H). Step 4: Preparation of 7-ethoxy-2-methylimidazo[1,2-a]pyridin-6-amine.

[0382] A solution of N-(7-ethoxy-2-methylimidazo[1,2-a]pyridin-6-yl)-1,1- diphenylmethanimine (2 g, 5.62 mmol) in 3M HCl / EA (20 mL) was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo, the residue was purified by C18 column chromatography (eluted with 0.1% NH3.H2O in water / CH3CN) to afford title product (0.5 g, yield: 46.5 %) as a yellow solid. ESI-MS (M+H)+: 192.1.1H NMR (400 MHz, DMSO-d6) δ 7.68 (s, 1H), 7.37 (s, 1H), 6.78 (s, 1H), 4.11 (q, J = 6.9 Hz, 2H), 2.23 (s, 3H), 1.40 (t, J = 6.9 Hz, 3H). Step 5: Preparation of tert-butyl 4-(1-((7-ethoxy-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate.

[0383] To a solution oftert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (122 mg, 0.40 mmol) in THF (1.5 mL) were added TEA (122 mg, 0.21 mmol) and Triphosgene (144 mg, 0.48 mmol) at 0℃, the mixture was stirred at room temperature for 1 hour.7-ethoxy-2-methylimidazo[1,2-a]pyridin-6-amine (100 mg, 0.52 mmol) was added to the mixture and stirred at room temperature overnight. The mixture was concentrated in vacuo. The residue was purified by C18 column chromatography (eluted with 0.1% NH3.H2O in water / CH3CN) to afford title product (60 mg, yield: 21.97 %) as a yellow solid. ESI-MS (M+H)+: 522.3.Step 6: Preparation of N-(7-ethoxy-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide.

[0384] A solution of tert-butyl 4-(1-((2,7-dimethylimidazo[1,2-a]pyridin-6-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (60 mg, 0.14 mmol) in 3M HCl / EA (1 mL) was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.1% FA in water / ACN) to give title product (17 mg, yield: 35.1%) as a white solid. ESI-MS (M+H)+:422.2.1H NMR (400 MHz, DMSO-d6) δ 12.06 (s, 1H), 9.15 (s, 1H), 8.25 (s, 1H), 7.85 (d, J = 6.0 Hz, 1H), 7.51 (s, 1H), 6.87 (s, 1H), 6.53 (d, J = 6.0 Hz, 1H), 4.17 (q, J = 6.8 Hz, 2H), 3.99 (t, J = 8.4 Hz, 2H), 3.24 (s, 4H), 3.14 – 3.09 (m, 2H), 2.86 (s, 4H), 2.24 (s, 3H), 1.51 (t, J = 6.9 Hz, 3H), 1.24 (s, 1H). Example 42 – Preparation of N-(2-methyl-7-(trifluoromethyl)imidazo[1,2-a]pyridin-6- yl)-4-(piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.Step 1: Preparation of 5-bromo-4-(trifluoromethyl)pyridin-2-amine.

[0385] To a mixture of 4-(trifluoromethyl)pyridin-2-amine (30.1 g, 185.8 mmol) in DCM (300 mL) was added NBS (36.38 g, 204.4 mmol) at 0℃. The reaction solution was stirred atr.t for 2 h. The mixture was concentrated in vacuo, the residue was diluted with (PE: EA=5:1) (200mL) and stirred at r.t for 2h. The precipitate was filtered and dried in vacuo to give title product (50 g, crude) as a yellow solid. ESI-MS (M+H)+: 242.7.1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 6.88 (s, 1H). Step 2: Preparation of 6-bromo-2-methyl-7-(trifluoromethyl)imidazo[1,2-a]pyridine.

[0386] To a mixture of 5-bromo-4-(trifluoromethyl)pyridin-2-amine (5 g, 20.75 mmol) in EtOH (50 mL) was added 1-chloropropan-2-one (3.82 g, 41.49 mmol). The reaction solution was stirred at 100℃ for 48 h. The reaction concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM: MeOH=10:1) to give title product (4 g, 68%) as a yellow solid. ESI-MS (M+H)+: 280.8.1H NMR (400 MHz, DMSO-d6) δ 9.52 (s, 1H), 8.31 (s, 1H), 8.17 (s, 1H), 2.53 (s, 3H). Step 3: Preparation of N-(2-methyl-7-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)-1,1- diphenylmethanimine.

[0387] To a mixture of 6-bromo-2-methyl-7-(trifluoromethyl)imidazo[1,2-a]pyridine (5 g, 14.34 mmol) and diphenylmethanimine (2.59 g, 14.34 mmol) in 1,4-dioxane (40 mL) were added BINAP (1.78 g, 2.86 mmol), Pd(OAc)2(349 mg, 1.43 mmol) and Cs2CO3(14 g, 43.1 mmol). The reaction solution was stirred at 100℃ for 16 h under N2. The reaction was diluted with H2O (60 mL), extracted with EA (60 mLx3), the organic layer was washed with brine, dried over Na2SO4and concentrated in vacuo. The crude was purified by silica gel column chromatography (PE: EA=3:1) to give title product (4 g, 73.4%) as a yellow solid. ESI-MS (M+H)+: 380.3.1H NMR (400 MHz, DMSO-d6) δ 7.85 (s, 1H), 7.82 (s, 1H), 7.73 – 7.67 (m, 2H), 7.61 – 7.55 (m, 2H), 7.51 (t, J = 7.4 Hz, 2H), 7.39 (d, J = 1.5 Hz, 1H), 7.38 – 7.34 (m, 2H), 7.22 (dd, J = 7.9, 1.5 Hz, 2H), 2.28 (s, 3H). Step 4: Preparation of 2-methyl-7-(trifluoromethyl)imidazo[1,2-a]pyridin-6-amine.

[0388] A mixture of N-(2-methyl-7-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)-1,1- diphenylmethanimine (3.6 g, 9.47 mmol) in 4M HCl / EA (21 mL) was stirred at RT for 2 h. The precipitate was filtered, diluted with sat. Na2CO3(20 mL) and stirred at r.t for 30 min. The precipitate was filtered and dried in vacuo to give title product (1.1 g, 55%) as a yellow solid. ESI-MS (M+H)+: 216.0.1H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.70 (s, 1H), 7.66 (s, 1H), 4.83 (s, 2H), 2.31 (s, 3H). Step 5: Preparation of tert-butyl 4-(1-((2-methyl-7-(trifluoromethyl)imidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate.

[0389] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (100 mg, 0.33 mmol) and 72-methyl-7-(trifluoromethyl)imidazo[1,2-a]pyridin-6-amine (142 mg, 0.66 mmol) in THF (3 mL) were added TEA (100 mg, 0.99 mmol) and triphosgene (243 mg, 0.82 mmol) at 0oC. The reaction mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and purified by silica gel column (PE: EA=1:3) to give title product (100 mg, 56.0%) as a white solid. ESI-MS (M+H)+: 546.0. Step 6: Preparation of N-(2-methyl-7-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)-4- (piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

[0390] A mixture of tert-butyl 4-(1-((2-methyl-7-(trifluoromethyl)imidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (80 mg, 0.15 mmol) in 4M HCL / EA (6 mL) was stirred at RT for 1 h. The mixture concentrated in vacuo and purified by Prep-HPLC (0.1 % FA in water / CH3CN) to give title product (34 mg, 52.1 %) as a white solid. ESI-MS (M+H)+: 446.2.1H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 9.13 (s, 1H), 8.33 (s, 1H), 7.92 (d, J = 5.9 Hz, 2H), 7.82 (d, J = 6.1 Hz, 1H), 6.51 (d, J = 6.1 Hz, 1H), 4.01 – 3.95 (m, 2H), 3.26 – 3.20 (m, 4H), 3.16 – 3.10 (m, 2H), 2.87 – 2.79 (m, 4H), 2.38 (s, 3H). Example 43 – Preparation of N-(6-hydroxy-2-methyl-2H-indazol-5-yl)-4-(piperazin-1- yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.Step 1: Preparation of N-(6-methoxy-2-methyl-2H-indazol-5-yl)-1,1-diphenylmethanimine.

[0391] To a solution of 5-bromo-6-methoxy-2-methyl-2H-indazole (3 g, 12.44 mmol), diphenylmethanimine (3.38 g, 18.67 mmol), Cs2CO312.16 g, 37.33 mmol) and Pd(OAc)2(139.68 mg, 0.62 mmol) in 1,4-dioxane (50 mL) was added BIANP (774 mg, 1.24 mmol), the mixture was stirred at 100oC for 16 h under N2. The mixture was concentrated in vacuo, the residue was purified by silica gel column chromatography (PE: EA= 5: 1) to give titlecompound (2.45 g, 57.87 %) as a yellow solid. ESI-MS (M+H)+: 342.1.1H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.65 (d, J = 7.5 Hz, 2H), 7.52 (d, J = 6.8 Hz, 1H), 7.46 (t, J = 7.3 Hz, 2H), 7.26 (d, J = 6.7 Hz, 3H), 7.11 (d, J = 6.8 Hz, 2H), 6.82 (s, 1H), 6.62 (s, 1H), 3.99 (s, 3H), 3.70 (s, 3H). Step 2: Preparation of 6-methoxy-2-methyl-2H-indazol-5-amine HCl salt.

[0392] A mixture of N-(6-methoxy-2-methyl-2H-indazol-5-yl)-1,1-diphenylmethanimine (2,15 g, 8.30 mmol) in 3M HCl / EA (20 mL) was stirred at r.t for 2 h. The precipitate was filtered and washed with EA (30 mL) and dried to give the title compound (1.62 g, crude) as a white solid. ESI-MS (M+H)+: 178.0.1H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 2H), 8.36 (s, 1H), 7.85 (s, 1H), 7.18 (s, 1H), 4.12 (s, 3H), 3.93 (s, 3H). Step 3: Preparation of tert-butyl 4-(1-((6-methoxy-2-methyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate.

[0393] To a solution of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (300 mg, 0.98 mmol) and 6-methoxy-2-methyl-2H-indazol-5-amine HCl salt (349 mg, 1.97 mmol) in THF (30 mL) was added TEA (498 mg, 4.93 mmol), then triphosgene (584 mg,1.97 mmol) was added slowly at 0oC. The mixture was stirred at r.t for 16 h. The mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE: EA= 1: 1) to give the compound (230 mg, 45.98 %) as a yellow solid. ESI-MS (M+H)+: 508.3 Step 4: Preparation of N-(6-hydroxy-2-methyl-2H-indazol-5-yl)-4-(piperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

[0394] To a mixture of tert-butyl 4-(1-((6-methoxy-2-methyl-2H-indazol-5-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (140 mg, 0.27 mmol) in DCM (0.5 mL) was added 1 M BBr3(3 mL), the mixture was stirred at r.t for 2 h. The precipitate was filtered and purified by prep-HPLC (0.05 % FA in water / ACN) to give title product (35 mg, Y: 32.24%) as a white solid. ESI-MS (M+H)+: 394.2.1H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 10.19 (s, 1H), 8.34 (s, 1H), 8.23 (s, 1H), 8.05 (s, 1H), 7.84 (d, J = 6.1 Hz, 1H), 6.84 (s, 1H), 6.49 (d, J = 6.1 Hz, 1H), 4.02 (s, 3H), 4.01 – 3.96 (m, 2H), 3.24 – 3.21 (m, 4H), 3.12 – 3.08 (m, 2H), 2.89 – 2.84 (m, 4H).Example 44 – Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(7-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1- carboxamide benzoate salt.Step 1: Preparation of 5-bromo-4-fluoropyridin-2-amine.

[0395] To a solution of 4-fluoropyridin-2-amine (50 g, 0.45 mol) in ACN (600 mL) was added NBS (79 g, 0.45 mol), the mixture was stirred at 15oC for 16 h. The mixture was concentrated in vacuo and the residue was diluted with water (500 mL), extracted with EA (1000 mL×3). The organic layer was washed with brine, dried with Na2SO4and concentrated in vacuo. The residue was triturated with PE / EA (1200 mL, 10 / 1), stirred at r.t overnight. The precipitate was filtered and dried to give title product (76 g, Y: 89.21 %) as a white solid. ESI-MS (M+H)+: 191.0.1H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 9.5 Hz, 1H), 6.26 (d, J = 10.0 Hz, 1H), 4.69 (s, 2H). Step 2: Preparation of 6-bromo-7-fluoro-2-methylimidazo[1,2-a]pyridine.

[0396] To a solution of 5-bromo-4-fluoropyridin-2-amine (110 g, 0.58 mol) and 1-bromo- 2,2-dimethoxypropane (127 g, 0.69 mol) in IPA (1000 mL) was added PPTS (15.9 g, 63.35mmol), the mixture was stirred at 85oC for 16 h. The reaction was concentrated in vacuo, the residue was diluted with water (1000 mL), adjusted pH to 11 by sat. NaOH, stirred at r.t for 1h. The precipitate was filtered and purified by column chromatography (EA) to give title product (93.3 g, 70.75 %) as a yellow solid. ESI-MS (M+H)+: 231.0.1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 6.5 Hz, 1H), 7.20 (s, 1H), 7.16 (d, J = 8.9 Hz, 1H), 2.35 (d, J = 0.6 Hz, 3H). Step 3: Preparation of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-1,1- diphenylmethanimine.

[0397] To a solution of 6-bromo-7-fluoro-2-methylimidazo[1,2-a]pyridine (50 g, 0.22 mol), diphenylmethanimine (43.96 mL, 0.26 mol), Cs2CO3(142 g, 0.43 mol) and Pd(OAc)2(4.90 g, 21.83 mmol) in 1,4-dioxane (500 mL) was added BIANP (27.19 g, 43.66 mmol), the mixture was stirred for at 100oC for 16 h under N2. The mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE: EA= 3: 1) to give title product (51.4 g, 71.49 %) as a yellow solid. ESI-MS (M+H)+: 330.2.1H NMR (400 MHz, DMSO-d6) δ 8.00 (d, J = 7.7 Hz, 1H), 7.69 (dd, J = 5.2, 3.3 Hz, 2H), 7.63 – 7.57 (m, 1H), 7.50 (t, J = 7.5 Hz, 2H), 7.45 (s, 1H), 7.40 – 7.35 (m, 3H), 7.23 – 7.19 (m, 3H), 2.23 (s, 3H). Step 4: Preparation of 7-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine hydrochloride.

[0398] To a solution of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-1,1- diphenylmethanimine (50 g, 151.80 mmol) in EA (20 mL) was added HCl in EA (400 mL, 4 M), the mixture was stirred at r.t for 16 h. The precipitate was filtered, triturated with DCM / MeOH (2 L, 10 / 1) and filtered to give the title compound (28.8 g, 94.09 %) as an off- white solid. ESI-MS (M+H)+: 166.2.1H NMR (400 MHz, DMSO-d6) δ 8.63 (s, 2H), 8.22 (d, J = 7.4 Hz, 1H), 7.96 (s, 1H), 7.74 (d, J = 10.0 Hz, 1H), 2.40 (s, 3H). Step 5: Preparation of 7-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine.

[0399] A solution of 7-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine hydrochloride (50 g, 119.19 mmol) in H2O (800 mL) was adjusted to pH = 9 with solid Na2CO3, then the mixture was stirred for at r.t for 2 h. The mixture was extracted with EA (1000 mL×6). The organic layer was washed with brine, dried with Na2SO4and concentrated in vacuum to give title product (33 g, 80.57%) as a brown solid. ESI-MS (M+H)+: 166.2.1H NMR (400 MHz, DMSO-d6) δ 7.84 (d, J = 8.4 Hz, 1H), 7.51 (s, 1H), 7.22 (d, J = 11.7 Hz, 1H), 4.93 (s, 2H), 2.28 (s, 3H).Step 6: Preparation of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2- dimethylpiperazine-1-carboxylate.

[0400] A mixture of 4-chloro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (50 g, 32.34 mmol), tert-butyl 2,2-dimethylpiperazine-1-carboxylate (83.17 g, 38.81 mmol) in DIEA (50 mL) was stirred at 140oC for 48 h. The mixture was diluted with water (200 mL), extracted with EA (200 mL×3). The organic layer was washed with brine (200 mL), dried with Na2SO4and concentrated in vacuo. The residue was triturated with EA (1 L) and filtered to afford title product (85 g, 79.05 %) a white solid. ESI-MS (M+H)+: 333.2.1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 6.0 Hz, 1H), 5.98 (d, J = 6.1 Hz, 1H), 4.22 (s, 1 H), 3.75 – 3.70 (m, 2H), 3.54 (t, J = 8.1 Hz, 2H), 3.49 – 3.45 (m, 2H), 3.33 (s, 2H), 3.17 (t, J = 8.2 Hz, 2H), 1.49 (s, 9H), 1.43 (s, 6H). Step 7: Preparation of tert-butyl 4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate.

[0401] To a solution of 7-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine (4.97 g, 30.08mmol) and TEA (41.8 mL,300.80 mmol) in THF (500 mL) was added triphosgene (8.93 g, 30.08 mmol) at 0oC and stirred at for 30 min, tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3- b]pyridin-4-yl)-2,2-dimethylpiperazine-1-carboxylate (8 g, 24.06 mmol) was added to the mixture and stirred at r.t for 16 h. The mixture was diluted with water (1 L) and stirred at r.t for 2 h. The precipitate was filtered and triturated with MeOH (300 mL) to give the compound (8 g, 63.49 %) as a white solid. ESI-MS (M+H)+: 524.2.1H NMR (400 MHz, DMSO-d6) δ 12.11 (d, J = 1.9 Hz, 1H), 9.19 (d, J = 7.4 Hz, 1H), 7.81 (d, J = 6.1 Hz, 1H), 7.71 (s, 1H), 7.41 (d, J = 11.6 Hz, 1H), 6.41 (d, J = 6.3 Hz, 1H), 4.00 – 3.93 (m, 2H), 3.73 – 3.67 (m, 2H), 3.60 – 3.55 (m, 2H), 3.17 (d, J = 5.2 Hz, 4H), 2.28 (s, 3H), 1.43 (s, 9H), 1.38 (s, 6H). Step 8: Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(7-fluoro-2-methylimidazo[1,2- a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide.

[0402] To a mixture of tert-butyl 4-(1-((7-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,2-dimethylpiperazine-1- carboxylate (28 g, 53.47 mmol) in EA (30 mL) was added HCl / EA(350 mL, 4M). The mixture was stirred at r.t for 16 h. The precipitate was filtered and diluted with water (300 mL), then adjusted to pH 9 with saturated sodium carbonate aqueous solution. The mixture was stirred at r.t for 4 h. The precipitate was filtered, washed with water (1 L) and dried to give the title compound (17.5 g, 77.4 %) as a white solid. ESI-MS (M+H)+: 424.1.1H NMR(400 MHz, DMSO-d6) δ 11.93 (d, J = 2.0 Hz, 1H), 9.19 (d, J = 7.4 Hz, 1H), 7.92 (d, J = 6.0 Hz, 1H), 7.72 (s, 1H), 7.42 (d, J = 11.6 Hz, 1H), 6.59 (d, J = 6.2 Hz, 1H), 4.05 – 3.98 (m, 2H), 3.42 – 3.38 (m, 2H), 3.25 – 3.21 (m, 2H), 3.20 – 3.11 (m, 4H), 2.29 (s, 3H), 1.30 (s, 6H). Step 9: Preparation of 4-(3,3-dimethylpiperazin-1-yl)-N-(7-fluoro-2-methylimidazo[1,2- a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide benzoate salt.

[0403] To a solution of 4-(3,3-dimethylpiperazin-1-yl)-N-(7-fluoro-2-methylimidazo[1,2- a]pyridin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide (35 g, 82.74 mmol) in EtOH (500 mL), DCM (500 mL) and MeOH (500 mL) was added benzoate (10.60 g, 86.87 mmol) at 50oC, and the mixture was stirred at 50oC for 16 h. The mixture was concentrated in vacuo, the residue was triturated with DCM (100 mL) and stirred at r.t for 2 h. The precipitate was filtered and dried to give title product (39 g, 85.5%) as an off-white solid. ESI-MS (M+H)+: 424.2.1H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 9.19 (d, J = 7.4 Hz, 1H), 7.94 (t, J = 7.0 Hz, 3H), 7.72 (s, 1H), 7.62 (t, J = 7.3 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.42 (d, J = 11.7 Hz, 1H), 6.60 (d, J = 6.1 Hz, 1H), 4.02 (t, J = 8.4 Hz, 2H), 3.43 (s, 2H), 3.26 (s, 2H), 3.18 (d, J = 8.0 Hz, 4H), 2.29 (s, 3H), 1.33 (s, 6H). Example 45 – Preparation of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(4- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-Step 1: Preparation of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(4- methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.

[0404] To a mixture of N-(7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide (110 mg, 0.27 mmol), (HCHO)n(75 mg, 0.83 mmol) and TEA (84 mg, 0.83 mmol) in MeOH (2 mL) was added NaBHCN (50mg, 0.83mmol).The mixture was stirred at r.t for 2 h. The mixture was filtered and the filtrate was purified by prep-HPLC (0.05 % TFA in water / ACN) to give title product (10 mg, Y: 45.95 %) as an orange solid. ESI-MS (M+H)+: 410.1.1H NMR (400 MHz, MeOD-d4) δ 9.59 (d, J = 6.3 Hz, 1H), 7.98 (d, J = 5.9 Hz, 1H), 7.92 (s, 1H), 7.81 (d, J = 9.5 Hz, 1H), 6.65 (d, J = 5.9 Hz, 1H), 4.20 – 4.12 (m, 2H), 4.04 – 3.79 (m, 2H), 3.70 – 3.38 (m, 4H), 3.29 – 3.16 (m, 4H), 2.98 (s, 3H), 2.51 (s, 3H). Example 46 – Preparation of (R)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- (methylamino)pyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.Step 1: Preparation of tert-butyl (R)-(1-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)pyrrolidin-3-yl)(methyl)carbamate.

[0405] To a mixture of 4-chloro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (350 mg, 2.26 mmol) in DIEA (1.5 g, 11.30 mmol) was added tert-butyl (R)-methyl(pyrrolidin-3-yl)carbamate (678 mg, 3.39 mmol). The reaction mixture was stirred at 140 ℃ for 16 h in a sealed tube. The reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mLx3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM: MeOH=10:1) to give title product (500 mg, yield: 69 %) as a yellow oil. ESI-MS (M+H)+:319.4.1H NMR (400 MHz, DMSO-d6) δ 7.42 (d, J = 6.0 Hz, 1H), 5.81 (d, J = 6.1 Hz, 1H), 5.76 (d, J = 5.8 Hz, 1H), 4.71 – 4.49 (m, 1H), 3.57 – 3.51 (m, 2H), 3.40 (d, J = 9.3 Hz, 4H), 3.22 – 3.18 (m, 2H), 2.74 (s, 3H), 2.05 – 1.96 (m, 2H), 1.41 (s, 9H). Step 2: Preparation of tert-butyl (R)-(1-(1-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-yl)(methyl)carbamate.

[0406] To a mixture of tert-butyl (R)-(1-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)pyrrolidin-3-yl)(methyl)carbamate (100 mg, 0.31 mmol) in THF (5 mL) were added 8- fluoro-2-methylimidazo[1,2-a]pyridin-6-amine hydrochloride (155 mg, 0.94 mmol), TEA(157 mg, 1.55 mmol) and triphosgene (184 mg, 0.62 mmol) at 0 ℃. The reaction mixture was stirred at r.t for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mLx3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM: EA=2:1) to give title product (80 mg, yield: 50 %) as a gray solid. ESI-MS (M+H)+:510.6.1H NMR (400 MHz, DMSO-d6) δ 11.98 (s, 1H), 8.81 (t, J = 4.3 Hz, 1H), 7.81 (dd, J = 12.3, 4.4 Hz, 2H), 7.22 (dd, J = 12.6, 1.5 Hz, 1H), 6.23 (d, J = 6.2 Hz, 1H), 3.92 (dd, J = 16.3, 7.1 Hz, 2H), 3.71 – 3.64 (m, 2H), 3.55 – 3.34 (m, 5H), 2.76 (s, 3H), 2.32 (s, 3H), 2.11 – 2.01 (m, 2H), 1.42 (s, 9H). Step 3: Preparation of R)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- (methylamino)pyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide hydrochloride.

[0407] To a mixture of tert-butyl (R)-(1-(1-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-yl)(methyl)carbamate (60 mg, 0.12 mmol) in EA (3 mL) was added 4M HCl / EA (3 mL). The mixture was stirred at r.t for 2 h. The mixture was concentrated in vacuo give title compound (14.37 mg, 29 %) as a white solid. ESI-MS (M+H)+:410.2.1H NMR (400 MHz, MeOD-d4) δ 9.12 (s, 1H), 8.09 (s, 1H), 8.04 (d, J = 12.0 Hz, 1H), 7.83 – 7.71 (m, 1H), 6.72 – 6.57 (m, 1H), 4.46 – 4.28 (m, 2H), 4.21 – 3.89 (m, 5H), 3.79 – 3.65 (m, 2H), 2.83 (s, 3H), 2.57 (s, 3H), 2.56 – 2.49 (m, 1H), 2.39 – 2.28 (m, 1H). Example 47 – Preparation of (S)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- (methylamino)pyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.Step 1: Preparation of tert-butyl (S)-(1-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)pyrrolidin-3-yl)(methyl)carbamate.

[0408] A mixture of 4-chloro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine(1 g, 6.45 mmol) and tert-butyl (S)-methyl(pyrrolidin-3-yl)carbamate (3 mL) was stirred at 140oC for 16h in a sealed tube. The mixture was concentrated in vacuo. The residue was purified by silica gel column (DCM: MeOH = 10:1) to provide title product (1.9 g, yield: 91%) as a brown solid. ESI-MS (M+H)+:319.3.1H NMR (400 MHz, DMSO-d6) δ 7.44 (d, J = 7.1 Hz, 1H), 6.14 (d, J = 7.3 Hz, 1H), 3.80 – 3.71 (m, 2H), 3.65 – 3.50 (m, 5H), 3.44 – 3.32 (m, 2H), 2.75 (s, 3H), 2.14 – 1.97 (m, 2H), 1.42 (s, 9H). Step 2: Preparation of tert-butyl (S)-(1-(1-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-yl)(methyl)carbamate.

[0409] To a solution of tert-butyl (S)-(1-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)pyrrolidin-3-yl)(methyl)carbamate (100 mg, 0.31 mmol) in THF (5 mL) were added TEA (313 mg, 3.10 mmol) and triphosgene (276 mg, 0.93 mmol) at 0oC. Then 8-fluoro-2- methylimidazo[1,2-a]pyridin-6-amine (93 mg, 0.47 mmol) was added to the reaction after stirring for 0.5 h. Then the mixture was stirred at r.t for 16h. The mixture was concentrated in vacuo. The residue was purified by silica gel column (PE: EA=1:3) to provide title product (140 mg, yield: 89%) as a white solid. ESI-MS (M+H)+:510.4. Step 3: Preparation of (S)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3- (methylamino)pyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide formate.

[0410] To a solution of tert-butyl (S)-(1-(1-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-yl)(methyl)carbamate (130 mg, 0.26 mmol) in EtOAc (2 mL) was added 4M HCl / EtOAc (6 mL) at 0oC. Then the mixture was stirred at r.t for 2 hours. The reaction mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.05% FA in H2O / ACN) to give title compound (35 mg, yield: 33%) as a white solid. ESI-MS (M+H)+: 410.1.1H NMR (400 MHz, DMSO-d6) δ 12.02 (s, 1H), 8.81 (s, 1H), 8.28 (s, 1H), 7.83 (s, 1H), 7.77 (d, J = 6.0 Hz, 1H), 7.22 (d, J = 12.6 Hz, 1H), 6.19 (d, J = 6.0 Hz, 1H), 3.92 (t, J = 8.7 Hz, 2H), 3.70 – 3.64 (m, 2H), 3.62 – 3.60 (m, 1H), 3.55 – 3.62 (m,, 1H), 3.38 – 3.40 (m,, 2H), 3.27 – 3.24 (m,, 1H), 2.32 (s, 6H), 2.07 – 1.99 (m,, 1H), 1.82 – 1.78 (m, 1H).

[0411] Example 48 – Preparation of N-(6-(difluoromethyl)-2-methyl-2H-indazol-5-yl)-4- (piperazin-1-yl)-2, 3-dihydro-1H-pyrrolo [2, 3-b] pyridine-1-carboxamide formate.S46 hlStep 7Compound 48Step 1: Preparation of methyl 5-bromo-2-methyl-2H-indazole-6-carboxylate.

[0412] To a solution of methyl 5-bromo-2-methyl-2H-indazole-6-carboxylate (3 g, 11.81 mmol) in EA (30 mL) was added trimethyloxonium tetrafluoroborate (2.1 g, 14.17 mmol). The resulting mixture was stirred at RT for 2 h. The mixture was diluted with water (30 mL), extracted with EA (30 mL×3). The organic layer was washed with brine, dried with Na2SO4and concentrated in vacuo to give title product (3 g, 93%) as a yellow solid. ESI-MS (M+H+CH3CN)+: 310.0.1H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H), 8.14 (s, 1H), 8.05 (s, 1H), 4.23 (s, 3H), 3.88 (s, 3H). Step 2: Preparation of (5-bromo-2-methyl-2H-indazol-6-yl) methanol.

[0413] To a solution of methyl 5-bromo-2-methyl-2H-indazole-6-carboxylate (3 g, 11.19 mmol) in dry-THF (30 mL) was added LiAlH4(851 mg, 22.39 mmol) at 0oC. The resulting mixture was stirred at 0oC for 2 h. The mixture was quenched by water (0.85 mL) at 0oC, followed by 15% NaOH (0.85 mL) and water (1.7 mL). The mixture was diluted with THF (5mL) and Na2SO4. The resulting mixture was stirred at RT for 0.5 h. The mixture was filtered and the filtrate was concentrated in vacuo to give title product (3 g, crude) as a white solid. ESI-MS (M+H)+: 243.0.1H NMR (400 MHz, DMSO-d6) δ 8.28 (d, J = 14.7 Hz, 1H), 7.97 (s, 1H), 7.69 (s, 1H), 4.55 (s, 2H), 4.16 (s, 3H). Step 3: Preparation of 5-bromo-2-methyl-2H-indazole-6-carbaldehyde.

[0414] To a solution of (5-bromo-2-methyl-2H-indazol-6-yl) methanol (3 g, 12.50 mmol) in DCM (30 mL) was added Dess-martain (6.4 g, 15.00 mmol). The resulting mixture was stirred at RT for 16 h. The mixture was filtered and the filtrate was concentrated in vacuo. The crude was purified by silica gel column (PE / EA=2:1) to give title product (2.3 g, Y: 68 %) as a yellow solid. ESI-MS (M+H)+:238.9.1H NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.48 (d, J = 3.2 Hz, 1H), 8.21 (t, J = 11.8 Hz, 2H), 4.25 (s, 3H). Step 4: Preparation of 5-bromo-6-(difluoromethyl)-2-methyl-2H-indazole.

[0415] To a solution of 5-bromo-2-methyl-2H-indazole-6-carbaldehyde (2 g, 8.40 mmol) in DCM (20 mL) was added DAST (2299 mg, 14.29 mmol) at 0oC under N2. The resulting mixture was stirred at RT for 16 h. The mixture was quenched by aq NaHCO3(15 mL) at 0oC, extracted with DCM (20 mL×3). The organic layer was washed with brine, dried with Na2SO4and concentrated in vacuo. The crude was purified by silica gel column (PE / EA=2:1) to give title product (1.2 g, Y: 55 %) as a yellow solid. ESI-MS (M+H)+:261.1.1H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J = 3.6 Hz, 1H), 8.18 (s, 1H), 7.96 (s, 1H), 7.31 – 7.02 (m, 1H), 4.22 (d, J = 5.0 Hz, 3H). Step 5: Preparation of N-(6-(difluoromethyl)-2-methyl-2H-indazol-5-yl)-1, 1- diphenylmethanimine.

[0416] To a solution of 5-bromo-6-(difluoromethyl)-2-methyl-2H-indazole (1 g, 3.83 mol) and diphenylmethanimine (1040 mg, 5.75 mmol) in 1,4-dioxane (10 mL) were added BINAP (479 mg, 0.77 mmol), Pd(OAC)2(86 mg, 0.38 mmol) and Cs2CO3(3734 mg, 11.49 mmol). The reaction solution was stirred at 100℃ for 16 h under N2. The reaction was diluted with H2O (10 mL), extracted with EA (10 mLx3), the organic layer was washed with brine, dried over Na2SO4and concentrated in vacuo. The crude was purified by reserve silica gel column chromatography (PE: EA=2:1) to give title product (1.7 g, yield: 99%) as a yellow solid. ESI- MS (M+H)+: 362.1.1H NMR (400 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.81 (s, 1H), 7.75 – 7.70 (m, 2H), 7.57 – 7.52 (m, 1H), 7.51 – 7.46 (m, 2H), 7.36 – 7.26 (m, 4H), 7.21 – 7.17 (m, 2H), 6.98 (t, J = 31.5 Hz, 1H), 4.09 (s, 3H).Step 6: Preparation of 6-(difluoromethyl)-2-methyl-2H-indazol-5-amine HCl salt.

[0417] To a solution of N-(6-(difluoromethyl)-2-methyl-2H-indazol-5-yl)-1,1- diphenylmethanimine (1.5 g, 5.75 mmol) in EA (10 mL) was added 4M HCl / EA (10 mL). The reaction solution was stirred at RT for 2 h. The precipitate was filtered, washed with EA (20 mL), then diluted with EA (20 mL) and stirred at RT for 16 h. The precipitate was filtered and dried in vacuo to give title product (1.068 g, y: 90%) as a yellow solid. ESI-MS (M+H)+: 198.2.1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.06 (s, 1H), 8.00 (s, 1H), 7.47 (t, J = 54.6 Hz, 1H), 4.24 (s, 3H). Step 7: Preparation of tert-butyl 4-(1-((6-(difluoromethyl)-2-methyl-2H-indazol-5-yl) carbamoyl)-2, 3-dihydro-1H-pyrrolo [2, 3-b] pyridin-4-yl) piperazine-1-carboxylate.

[0418] To a solution of tert-butyl 4-(2, 3-dihydro-1H-pyrrolo [2, 3-b] pyridin-4-yl) piperazine-1-carboxylate (100 mg, 0.33 mmol) and 6-(difluoromethyl)-2-methyl-2H-indazol- 5-amine HCl salt (95 mg, 0.39 mmol) in THF (2 mL) were added TEA (100 mg, 0.99 mmol) and triphosgene (116 mg, 0.39 mmol) at 0oC. The reaction mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and diluted with water (3 mL), extracted with EA (3 mL×3). The organic layer was washed with brine, dried with Na2SO4and concentrated in vacuo. The crude was purified by silica gel column (EA) to give title product (60 mg, 34%) as a yellow solid. ESI-MS (M+H)+: 528.0. Step 8: Preparation of N-(6-(difluoromethyl)-2-methyl-2H-indazol-5-yl)-4-(piperazin-1-yl)-2, 3-dihydro-1H-pyrrolo [2, 3-b] pyridine-1-carboxamide formate.

[0419] To a solution of tert-butyl 4-(1-((6-(difluoromethyl)-2-methyl-2H-indazol-5-yl) carbamoyl)-2, 3-dihydro-1H-pyrrolo [2, 3-b] pyridin-4-yl) piperazine-1-carboxylate (60 mg, 0.11 mmol) in EA (1 mL) was added 4M HCl / EA (1 mL). The reaction mixture was stirred at RT for 2 h. The mixture was diluted with water (2 mL), extracted with EA (2 mL×3). The aqueous layer was concentrated in vacuo and purified by prep-HPLC (0.1 % FA in water / CH3CN) to give title product (14.89 mg, yield: 30 %) as a white solid. ESI-MS (M+H)+: 428.2.1H NMR (400 MHz, DMSO-d6) δ 11.72 (s, 1H), 8.38 (s, 1H), 8.31 (s, 1H), 8.19 (s, 1H), 7.92 – 7.78 (m, 2H), 7.13 (t, J = 54.8 Hz, 1H), 6.50 (d, J = 6.1 Hz, 1H), 4.19 (s, 3H), 4.01 – 3.96 (m, 2H), 3.28 – 3.21 (m, 4H), 3.15 – 3.08 (m, 2H), 2.85 (s, 4H).Example 49 – Preparation of N-(2,5-dimethylbenzo[d]oxazol-6-yl)-4-(piperazin-1-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide.Step 1: Preparation of 2,5-dimethyl-6-nitrobenzo[d]oxazole.

[0420] To a solution of 2,5-dimethylbenzo[d]oxazole (9.7 g, 0.066 mol) in H2SO4(100 mL) was added HNO3(8.3 mL, 0.198 mol) at 0oC. Then, the mixture was stirred at 0oC for 3 h. The solution was slowly poured into ice-water. The precipitate was filtered, washed with water and dried in vacuo to give title product (10 g, yield: 79.36%) as a white solid. ESI-MS (M+H)+: 192.9.1H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 7.79 (s, 1H), 2.68 (s, 3H), 2.60 (s, 3H). Step 2: Preparation of 2,5-dimethylbenzo[d]oxazol-6-amine.

[0421] A solution of 2,5-dimethyl-6-nitrobenzo[d]oxazole (10 g, 0.052 mol), NH4HCO3(16.38 g, 0.26 mol) and 10% Pd / C (1 g) in MeOH (100 mL) was stirred at 80oC for 0.5 h under H2. The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluted with EA:PE = 1:5 to give title product (2.4 g, yield: 28.49%) as a white solid. ESI-MS (M+H)+: 163.1.1H NMR (400 MHz, DMSO-d6) δ 7.18 (s, 1H), 6.78 (s, 1H), 5.00 (s, 2H), 2.47 (s, 3H), 2.11 (s, 3H). Step 3: Preparation of tert-butyl 4-(1-((2,5-dimethylbenzo[d]oxazol-6-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate.

[0422] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (200 mg, 0.66 mmol) and 2,5-dimethylbenzo[d]oxazol-6-amine (214 mg, 1.32 mmol) in THF (80 mL) were added TEA (458 μL, 3.30 mmol) and triphosgene (392 mg, 1.32 mmol, dissolved in THF (1 mL)) at 0oC. Then, the mixture was stirred at RT for 16 h. The mixture was diluted with water (30 mL) and extracted with EA (30 mL x 3). The mixture wasconcentrated in vacuo and purified by column chromatography on silica gel eluted with DCM:MeOH = 50:1 to give title product (70 mg, yield: 21.56%) as a white solid. ESI-MS (M+H)+: 493.3.1H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 8.39 (s, 1H), 7.92 (d, J = 6.0 Hz, 1H), 7.50 (s, 1H), 6.54 (d, J = 6.1 Hz, 1H), 4.04 – 3.98 (m, 2H), 3.44 (s, 6H), 3.26 – 3.21 (m, 2H), 3.18 – 3.04 (m, 8H), 1.43 (s, 9H). Step 4: Preparation of N-(2,5-dimethylbenzo[d]oxazol-6-yl)-4-(piperazin-1-yl)-2,3-dihydro- 1H-pyrrolo[2,3-b]pyridine-1-carboxamide.

[0423] To a solution of tert-butyl 4-(1-((2,5-dimethylbenzo[d]oxazol-6-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (60 mg, 0.12 mmol) in DCM (5 mL) were added HMDS (51 μL, 0.24 mmol) and TMSOTf (42 μL, 0.24 mmol) at 0oC. Then, the mixture was stirred at RT for 2 h. The mixture was diluted with water (10 mL) and extracted with DCM (20 mL x 3). The organic layer was washed with brine, dried with Na2SO4and concentrated in vacuo to give title product (27.83 mg, 59.16%) as a white solid. ESI-MS (M+H)+: 393.2.1H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 8.38 (s, 1H), 7.87 (d, J = 6.0 Hz, 1H), 7.48 (s, 1H), 6.49 (d, J = 6.1 Hz, 1H), 3.98 (t, J = 8.5 Hz, 2H), 3.22 – 3.15 (m, 4H), 3.10 (t, J = 8.5 Hz, 2H), 2.84 – 2.72 (m, 4H), 2.55 (s, 3H), 2.42 (s, 3H). Example 50 – Preparation of N-(5-fluoro-2,4-dimethylbenzo[d]oxazol-6-yl)-4- (piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide.Step 1: Preparation of N-(3-fluoro-2-methylphenyl)acetamide.

[0424] To a solution of 3-fluoro-2-methylaniline (8 g, 64 mmol) in DCM (100 mL) was added Ac2O (9.8 g, 96 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo to provide title compound (10 g, crude) as a pink solid. ESI-MS (M+H)+:168.1.1H NMR (400 MHz, DMSO-d6) δ 9.46 (s, 1H), 7.31 – 7.10 (m, 2H), 7.04 – 6.90 (m, 1H), 2.12 – 2.04 (m, 6H). Step 2: Preparation of N-(4-bromo-3-fluoro-2-methylphenyl)acetamide.

[0425] To a mixture of N-(3-fluoro-2-methylphenyl)acetamide (11 g, 65.87 mmol) in AcOH (110 mL) was added Br2(31.6 g, 197.6 mmol). The mixture was stirred at RT for 2 h. The mixture was diluted with water (400 mL), the precipitate was filtered and washed with H2O (50 mL), dried in vacuum to give title product (12 g, 74.5 %) as a yellow solid. ESI-MS (M+H)+:246.0.1H NMR (400 MHz, DMSO-d6) δ 9.52 (s, 1H), 7.47 (t, J = 8.3 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 2.14 (d, J = 2.3 Hz, 3H), 2.07 (s, 3H). Step 3: Preparation of 6-bromo-5-fluoro-2,4-dimethylbenzo[d]oxazole.

[0426] To a suspension of N-(4-bromo-3-fluoro-2-methylphenyl)acetamide (13.4 g, 54.69 mmol) in DMF :HOAC(10 mL: 80 mL) were added K2S2O8(22.2 g, 82.04 mmol), TfOH (8.2 g, 54.69 mmol) and Pd(OAc)2(1.2 g, 5.47 mmol). The reaction mixture was stirred at 100oC for 16 h. The mixture was concentrated in vacuo. The crude was purified by flash column chromatography (PE / EA = 0 % to 50 %) to provide title product (2.5 g, 18.8 %) as a yellow solid. ESI-MS (M+H)+:244.0.1H NMR (400 MHz, DMSO-d6) δ 7.97 (d, J = 5.5 Hz, 1H), 2.61 (s, 3H), 2.45 (d, J = 1.7 Hz, 3H). Step 4: Preparation of N-(5-fluoro-2,4-dimethylbenzo[d]oxazol-6-yl)-1,1- diphenylmethanimine.

[0427] To a mixture of 6-bromo-5-fluoro-2,4-dimethylbenzo[d]oxazole (3.2 g, 13.17 mmol), diphenylmethanimine (3.6 g, 19.75 m mol) in 1,4-dioxane (100 mL) were added Cs2CO3(13 g, 39.51 mmol), BINAP (1.6 g, 2.63 mmol) and Pd(OAc)2(300 mg,1.32 mmol), the mixture was charged with N2for three times and stirred at 100oC for 16 h. The reaction mixture was evaporated to give crude title compound. The crude was purified by silica gel column chromatography eluted with (EtOAc / PE=1:2) to give title compound (3 g, crude) as a brown solid. ESI-MS (M+H)+:345.1.1H NMR (400 MHz, DMSO-d6) δ 7.71 – 7.68 (m, 2H), 7.59 – 7.54 (m, 1H), 7.51 – 7.47 (m, 3H), 7.33 – 7.31 (m, 2H), 7.21 – 7.16 (m, 2H), 6.92 (d, J = 6.5 Hz, 1H), 2.52 (s, 3H), 2.29 (s, 3H).Step 5: Preparation of N-(5-fluoro-2,4-dimethylbenzo[d]oxazol-6-yl)-1,1- diphenylmethanimine.

[0428] To a solution of N-(5-fluoro-2,4-dimethylbenzo[d]oxazol-6-yl)-1,1- diphenylmethanimine (3 g, 8.72 mmol) was added HCl in EA (30 mL, 4 M) at RT, the mixture was stirred for 1 h at RT. The mixture was concentrated in vacuo and the residue was diluted with water (10 mL), adjusted the PH≈ 8 with aq.NaHCO3. Exacted with DCM (80 mL*3), the organic layer was washed with brine, dried over Na2SO4and evaporated in vacuo. The residue was purified by silica gel column chromatography eluted with (EtOAc / PE=1:3) to give title compound (600 mg, 38.3 %) as a brown solid. ESI-MS (M+H)+:181.1.1H NMR (400 MHz, DMSO-d6) δ 6.77 (d, J = 7.2 Hz, 1H), 5.17 (s, 2H), 2.49 (s, 3H), 2.33 (s, 3H). Step 6: Preparation of tert-butyl 4-(1-((5-fluoro-2,4-dimethylbenzo[d]oxazol-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate.

[0429] To a solution of 5-fluoro-2,4-dimethylbenzo[d]oxazol-6-amine (150 mg, 0.83 mmol) and tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (278 mg, 0.91 mmol) in THF (15 mL) was added TEA (421 mg, 4.18 mmol), triphosgene (271 mg, 0.91 mmol) was added slowly at 0oC. The mixture was stirred at r.t for 16 h. The mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE: EA= 1: 2) to give the compound (230 mg, crude) as a yellow solid. ESI-MS (M+H)+: 511.2. Step 7: Preparation of N-(5-fluoro-2,4-dimethylbenzo[d]oxazol-6-yl)-4-(piperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide.

[0430] To a mixture of tert-butyl 4-(1-((5-fluoro-2,4-dimethylbenzo[d]oxazol-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (200 mg, 0.39 mmol) in DCM (5 mL) were added HMDS (189 mg, 1.18 mmol) and TMSOTf (261 mg, 1.18 mmol) at 0oC, the mixture was stirred at r.t for 2 h. The mixture was diluted with H2O (50 mL), extracted with EA (30 mL×3). The organic layer was washed with brine, dried with Na2SO4and concentration in vacuum. The crude was purified by prep-HPLC (0.05 % NH3.H2O in water / ACN) to give title product (6 mg, Y: 3.73 %) as a white solid. ESI-MS (M+H)+: 411.2.1H NMR (400 MHz, DMSO-d6) δ 12.25 (s, 1H), 8.35 (d, J = 6.2 Hz, 1H), 7.89 (d, J = 6.0 Hz, 1H), 6.52 (d, J = 6.2 Hz, 1H), 4.04 – 3.95 (m, 2H), 3.22 (d, J = 4.8 Hz, 4H), 3.15 – 3.10 (m, 2H), 2.85 – 2.77 (m, 4H), 2.59 (s, 3H), 2.45 (s, 3H).Example 51 – Preparation of N-(5-fluoro-2,4-dimethylbenzo[d]oxazol-6-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide .Step 1: Preparation of tert-butyl 7-(1-((5-fluoro-2,4-dimethylbenzo[d]oxazol-6- yl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate.

[0431] To a mixture of 5-fluoro-2,4-dimethylbenzo[d]oxazol-6-amine (163.6 mg, 0.91 mmol) and tert-butyl 7-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate (150 mg, 0.45 mmol) in THF (10 mL) were added TEA (227.2 mg, 2.25 mmol) and triphosgene (267.3mg, 0.90 mmol) at 0oC for 15 min. The reaction mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo, the crude was purified by silica gel column chromatography (EA: PE= 100 %) to give title product (80 mg, yield: 16.4 %) as a yellow solid. ESI-MS (M+H)+: 537.2. Step 2: Preparation of N-(5-fluoro-2,4-dimethylbenzo[d]oxazol-6-yl)-4-(4,7- diazaspiro[2.5]octan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide.

[0432] A mixture of tert-butyl 7-(1-((5-fluoro-2,4-dimethylbenzo[d]oxazol-6-yl)carbamoyl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (70 mg, 0.13 mmol), HMDS (42 mg, 0.26mmol) and TMSOTf (58 mg, 0.26 mmol) in DCM (10 mL) was stirred at 0oC for 2 h. The mixture was diluted with water (20 mL), extracted with DCM (20 mL×3). The organic layer was washed with brine (20 mL), dried with Na2SO4 and concentrated in vacuo. The residue was purified by prep-HPLC (0.1% NH3·H2O in H2O / ACN) to give title product (1.2 mg, yield: 2.11 %) as a white solid. ESI-MS (M+H)+: 437.2.1H NMR (400 MHz, CDCl3) δ 12.16 (s, 1H), 8.40 (d, J = 6.3 Hz, 1H), 7.96 (d, J = 6.0 Hz, 1H), 6.34 (d, J = 6.0 Hz, 1H), 4.20 – 4.13 (m, 2H), 3.29 (d, J = 4.9 Hz, 2H), 3.20 – 3.13 (m, 2H), 3.13 – 3.10 (m, 2H), 3.09 – 3.04 (m, 2H), 2.62 (s, 3H), 2.52 (d, J = 1.6 Hz, 3H), 0.89 – 0.81 (m, 2H), 0.70 – 0.61 (m, 2H).Example 52 – Preparation of N-(2,6-dimethyl-2H-indazol-5-yl)-4-(piperazin-1-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate.Step 1: Preparation of 2,6-dimethyl-5-nitro-2H-indazole.

[0433] To a solution of 6-methyl-5-nitro-1H-indazole (1 g, 0.01 mol) in EA (10 mL) was added Trimethyloxonium Tetrafluoroborate (1 g, 0.01 mol), the mixture was stirred at room temperature for 16 hours. The mixture was diluted with water (50 mL), extracted with EA (30 mL *2). The combined organic layer was washed with brine, dried over Na2SO4,filtered and concentrated in vacuo. The residue was purified by C18 column chromatography eluted with CH3CN: H2O (0.1% NH3.H2O) = 30-80 % to afford product (1 g, yield: 92.7%) as a yellow solid. ESI-MS (M+H)+:192.1.1H NMR (400 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.60 (s, 1H), 7.61 (s, 1H), 4.21 (s, 3H), 2.56 (d, J = 0.8 Hz, 3H). Step 2: Preparation of 2,6-dimethyl-2H-indazol-5-amine.

[0434] To a solution of 2,6-dimethyl-5-nitro-2H-indazole (3 g, 15.62 mmol) in MeOH (30 mL) were added Raney Nickel (300 mg,) and NH3.H2O (3 mL). The mixture was charged with H2for three times and stirred at r.t for 2 h. The mixture was filtered and the filtrate was concentrated in vacuo to afford title product (1.4 g, yield: 55 %) as a purple solid. ESI-MS (M+H)+:162.1.1H NMR (400 MHz, DMSO-d6) δ 7.81 (s, 1H), 7.20 (s, 1H), 6.65 (s, 1H), 4.54 (s, 2H), 4.01 (s, 3H), 2.18 (s, 3H). Step 3: Preparation of phenyl (2,6-dimethyl-2H-indazol-5-yl)carbamate.

[0435] To a solution of 2,6-dimethyl-2H-indazol-5-amine (100 mg, 0.62 mmol) in DCM (5 mL) were added phenyl carbonochloridate (116 mg, 0.75 mmol) and pyridine (147 mg, 1.86mmol) at 0℃. The mixture was stirred at r.t for 2 h. The reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give title product (100 mg, yield: 57 %) as a brown solid. ESI-MS (M+H)+:282.2. Step 4: Preparation of tert-butyl 4-(1-((2,6-dimethyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate formate.

[0436] To a mixture of tert-butyl 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1- carboxylate (70 mg, 0.23 mmol) in THF (5 mL) were added phenyl (2,6-dimethyl-2H- indazol-5-yl)carbamate (65 mg, 0.23 mmol) and TEA (70 mg, 0.69 mmol). The reaction mixture was stirred at 70℃ for 16 h in a sealed tube. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (0.1% FA in H2O / ACN) to give title product (30 mg, Y: 26 %) as a white solid. ESI-MS (M+H)+:492.1.1H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 8.44 (s, 1H), 8.28 (s, 1H), 8.17 (s, 1H), 7.91 (d, J = 6.1 Hz, 1H), 7.44 (s, 1H), 6.52 (d, J = 6.1 Hz, 1H), 4.10 (s, 3H), 4.00 (t, J = 8.6 Hz, 2H), 3.45 (s, 4H), 3.28 – 3.26 (m, 4H), 3.13 (t, J = 8.7 Hz, 2H), 2.44 (s, 3H), 1.43 (s, 9H). Step 5: Preparation of N-(2,6-dimethyl-2H-indazol-5-yl)-4-(piperazin-1-yl)-2,3-dihydro-1H- pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate.

[0437] To a solution of tert-butyl 4-(1-((2,6-dimethyl-2H-indazol-5-yl)carbamoyl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate formate (20 mg, 0.041 mmol) in EA (3 mL) was added 4M HCl / EA (3 mL). The mixture was stirred at r.t for 2 h. The reaction solution was concentrated in vacuo, the residue was diluted with TFA () (5 mL, 0.5 M), concentrated in vacuo and lyophilized to give title product (9.83 mg, 47%) as a white solid. ESI-MS (M+H)+:392.2.1H NMR (400 MHz, MeOD-d4) δ 8.55 – 8.51 (m, 1H), 7.83 (s, 1H), 7.78 (d, J = 6.4 Hz, 1H), 7.58 (s, 1H), 6.92 (s, 1H), 4.48 – 4.36 (m, 2H), 4.30 (s, 3H), 4.02 – 3.91 (m, 4H), 3.62 – 3.52 (m, 2H), 3.48 – 3.40 (m, 4H), 2.48 (s, 3H).Example 53 – Preparation of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-5-methyl-4- (piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.Step 1: Preparation of 4-chloro-5-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine.

[0438] To a solution of 4-chloro-5-methyl-1H-pyrrolo[2,3-b]pyridine (1 g, 6.02 mmol) in MeOH (20 mL) was added Raney-Ni (360 mg, 20% w.t). The mixture was stirred at 70oC for 16 h under H2. The mixture was cooled down to r.t. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column (PE: EA = 1:1) to provide title product (400 mg, yield: 40%) as a white solid. ESI-MS (M+H)+:169.2.1H NMR (400 MHz, DMSO-d6) δ 7.60 (d, J = 0.5 Hz, 1H), 6.45 (s, 1H), 3.50 (t, J = 8.6 Hz, 2H), 2.99 (t, J = 8.5 Hz, 2H), 2.09 (s, 3H). Step 2: Preparation of tert-butyl 4-(5-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)piperazine-1-carboxylate.

[0439] A mixture of 4-chloro-5-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (300 mg, 1.79 mmol) and tert-butyl piperazine-1-carboxylate (997 mg, 5.36 mmol) was stirred at 140oC for 16 h. The mixture was concentrated in vacuo. The residue was purified by silica gel column (DCM: MeOH = 10:1) to provide title product (200 mg, yield: 35%) as a brown solid. ESI- MS (M+H)+:319.2.1H NMR (400 MHz, DMSO-d6) δ 7.44 (s, 1H), 5.87 (s, 1H), 3.41 – 3.37 (m, 4H), 3.24 – 3.22 (m, 2H), 3.08 (t, J = 8.4 Hz, 2H), 2.97 – 2.94 (m, 4H), 2.01 (s, 3H), 1.42 (s, 9H).Step 3: Preparation of tert-butyl 4-(1-((7-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)-5- methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate.

[0440] To a solution of tert-butyl 4-(5-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4- yl)piperazine-1-carboxylate (150 mg, 0.47 mmol) in THF (10 mL) were added TEA (143 mg, 1.42 mmol) and triphosgene (56 mg, 0.19 mmol) at 0oC. Then 6-ethoxy-2-methyl-2H- indazol-5-amine (117 mg, 0.71 mmol) was added to the reaction after stirring for 1h. Then the mixture was stirred at r.t for 16 h. The mixture was concentrated in vacuo. The residue was purified by silica gel column (PE: EA=1:1) to provide title product (70 mg, yield: 30%) as a white solid. ESI-MS (M+H)+:510.4.1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.86 (d, J = 1.4 Hz, 1H), 7.84 (s, 1H), 7.83 (s, 1H), 4.32 (s, 3H), 3.53 – 3.51 (m, 4H), 3.49 – 3.45 (m, 4H), 3.43 – 3.41 (m, 2H), 3.36 – 3.33 (m, 2H), 2.20 (s, 3H), 1.49 (s, 9H). Step 4: Preparation of N-(7-fluoro-2-methyl-2H-indazol-5-yl)-5-methyl-4-(piperazin-1-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2-trifluoroacetate.

[0441] To a solution of 4-(1-((7-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)-5-methyl-2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (50 mg, 0.10 mmol) in EtOAc (1 mL) was added 4M HCl / EtOAc (3 mL). The reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.05% FA in H2O / ACN), 0.5 M TFA (1 mL) was added and lyophilized to give title compound (22 mg, yield: 54%) as a white solid. ESI-MS (M+H)+:410.2.1H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 8.77 (s, 2H), 8.37 (d, J = 2.8 Hz, 1H), 7.93 (s, 1H), 7.72 (d, J = 1.6 Hz, 1H), 7.25 (dd, J = 13.3, 1.6 Hz, 1H), 4.17 (s, 3H), 4.03 – 4.00 (m, 2H), 3.33 – 3.28 (m, 4H), 3.26 – 3.19 (m, 6H), 2.19 (s, 3H).Example 54 – Preparation of N-(7-fluoro-2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-4- (piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide 2,2,2- trifluoroacetate.Step 1: Preparation of tert-butyl (4-fluoropyridin-2-yl)carbamate.

[0442] To a solution of 4-fluoropyridin-2-amine (18 g, 160.71 mmol) and DMAP (1.98 g, 16.07 mmol) in DCM (200 mL) was added Boc2O (42.04 g, 192.86 mmol), the mixture stirred at r.t for 2 h. The mixture was diluted with water (200 mL) and extracted with DCM (200 mLx3). The organic layer concentrated in vacuo. The crude was purified by reserve silica gel column chromatography (PE: DCM=2:1) to give title compound (30 g, y: 87.9) as a white solid. ESI-MS (M+H)+: 213.0.1H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H), 8.27 (dd, J = 9.4, 5.7 Hz, 1H), 7.61 (dd, J = 12.3, 2.3 Hz, 1H), 6.95 (ddd, J = 8.2, 5.7, 2.4 Hz, 1H), 1.48 (s, 9H). Step 2: Preparation of tert-butyl (4-fluoro-3-methylpyridin-2-yl)carbamate.

[0443] To a solution of tert-butyl (4-fluoropyridin-2-yl)carbamate (30.1 g, 141.31 mmol) in dry-THF (300 mL) was added N1,N1,N2,N2-tetramethylethane-1,2-diamine (40.98 g, 353.29 mmol) at -78℃ for 0.5 h, n-BuLi (169.6 mL, 423.94 mmol, 2.5 M) was added to the mixtureand stirred at -78℃ for 0.5 h. MeI (60.2 g, 423.94 mmol) was added, the mixture stirred at - 78℃ for 0.5 h then warm to r.t and stirred at r.t for 2 h. The mixture was quenched with NH4Cl (200 mL) and extracted with EA (200 mLx3). The organic layer concentrated in vacuo to give title compound (36 g, crude) as a yellow solid. ESI-MS (M+H)+: 227.0. Step 3: Preparation of 4-fluoro-3-methylpyridin-2-amine HCl salt.

[0444] A mixture of tert-butyl (4-fluoro-3-methylpyridin-2-yl)carbamate (34 g, 149.78 mmol) in EA (100 mL) and 4M HCl / EA (140 mL) was stirred at RT for 2 h. The mixture concentrated in vacuo to give title product (21 g, crude) as a yellow solid. ESI-MS (M+H)+: 126.9. Step 4: Preparation of 5-bromo-4-fluoro-3-methylpyridin-2-amine.

[0445] To a mixture of 4-fluoro-3-methylpyridin-2-amine (19 g, 149.61 mmol) in DCM (300 mL) was added NBS (29.3 g, 164.57 mmol) at 0℃. The reaction solution was stirred at r.t for 2 h. The reaction concentrated in vacuo to give title product (40 g, crude) as a yellow solid. ESI-MS (M+H)+: 204.9.1H NMR (400 MHz, DMSO-d6) δ 8.40 (d, J = 7.4 Hz, 1H), 2.11 (d, J = 1.9 Hz, 3H). Step 5: Preparation of 6-bromo-7-fluoro-2,8-dimethylimidazo[1,2-a]pyridine.

[0446] To a mixture of 5-bromo-4-fluoro-3-methylpyridin-2-amine (14 g, 68.31 mmol) in IPA (140 mL) were added 1-bromo-2,2-dimethoxypropane (25 g, 136.61 mmol) and PPTS (1.71 g, 6.83 mmol). The reaction solution was stirred at 95℃ for 48 h. The reaction was concentrated in vacuo the residue was diluted with water (100 mL), adjusted pH to 11 by sat. NaOH, stirred at r.t for 1h. The precipitate was filtered and purified by column chromatography (EA) to give title product (5.5 g, yield: 33.1%) as a yellow solid. ESI-MS (M+H)+: 244.9.1H NMR (400 MHz, DMSO-d6) δ 9.32 (d, J = 6.1 Hz, 1H), 8.00 (s, 1H), 2.50 (s, 3H), 2.49 (s, 3H). Step 6: Preparation of N-(7-fluoro-2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-1,1- diphenylmethanimine.

[0447] To a mixture of 6-bromo-7-fluoro-2,8-dimethylimidazo[1,2-a]pyridine (5 g, 20.58 mmol) and diphenylmethanimine (4.1 g, 22.63 mmol) in 1,4-dioxane (100 mL) were added BINAP (2.58 g, 4.12 mmol), Pd2(dba)3(1.88 g, 2.06 mmol) and Cs2CO3(20.06 g, 61.73 mmol). The reaction solution was stirred at 100℃ for 16 h under N2. The reaction was diluted with H2O (100 mL), extracted with EA (100 mLx3), the organic layer was washed with brine, dried over Na2SO4and concentrated in vacuo. The crude was purified by silica gel column chromatography (PE: EA=2:1) t...

Claims

CLAIMS WHAT IS CLAIMED:

1. A compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein Ring A is an optionally substituted 3-12 membered heterocyclyl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is an optionally substituted 8-12 membered bicyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R1is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, and 5-8 memebered heteroaryl; each R2is independently selected from halogen and C1-6alkyl; R3is selected from H and C1-6alkyl; each Rais independently selected from the group consisting of halogen, -OH, C1-6alkyl, C1-6haloalkyl, oxo, C3-6cycloalkyl, -C(O)O-C1-6alkyl, -C(O)C1-6haloalkyl, -C(O)O-C1-6alkylene-OC(O)-C1-6alkyl, and -N(RcRd), wherein the C1-6alkyl is optionally substituted with -OH, C1-6alkoxy, C3-6cycloalkyl, -N(RcRd), or -S(O)2C1-6alkyl, or two Raattached to the same carbon atom, together with carbon atom to which they are attached, combine to form a C3-6cycloalkyl; each Rbis independently selected from the group consisting of halogen, -OH, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, and C3-6cycloalkyl, wherein the C1-6alkoxy is optionally substituted with C3-6cycloalkyl; each Rcis independently selected from H, C1-6alkyl, and C3-6cycloalkyl, wherein the C1-6alkyl is optionally substituted with -OH; each Rdis independently selected from H and C1-6alkyl; m is 0, 1, or 2;n is 0, 1, or 2; p is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4.

2. The compound of claim 1, wherein m and n are each 0.

3. The compound of claim 1 or 2, wherein Ring A is an optionally substituted 5-6 membered heterocyclyl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

4. The compound of any one of claims 1-3, wherein Ring A is selected from optionally substituted piperidinyl and optionally substituted pyrrolidinyl.

5. The compound of any one of claims 1-4, wherein each Rais independently selected from C1-6alkyl and -N(RcRd).

6. The compound of any one of claims 1-5, wherein each Rcis methyl and each Rdis H.

7. The compound of any one of claims 1-6, wherein each Rais independently selected from methyl and -N(H)CH3.

8. The compound of any one of claims 1-7, wherein p is 1 or 2.

9. The compound of any one of claims 1-8, wherein the portion of the compound10. The compound of claim 9, wherein the portion of the compound represented by.

11. The compound of any of claims 1-8, wherein the portion of the compound represented12. The compound of any one of claims 1-8, wherein the portion of the compound13. The compound of claim 1, wherein the compound is a compound of formula (Ia),or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3; and the rest of the variables are as defined in claim 1.

14. The compound of claim 13, wherein p is 0.

15. The compound of claim 13, wherein p is 1 or 2.

16. The compound of claim 13 or 15, wherein each Rais methyl.

17. The compound of claim 1, wherein the compound is a compound of formula (Ib),or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2; and the rest of the variables are as defined in claim 1.

18. The compound of claim 17, wherein each Rais -N(H)CH3.

19. The compound of claim 17 or 18, wherein p is 1.

20. The compound of claim 1, wherein the compound is a compound of formula (Ic),or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2; and the rest of the variables are as defined in claim 1.

21. The compound of claim 20, wherein p is 0.

22. The compound of claim 1, wherein the compound is a compound formula (Id),or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2; and the rest of the variables are as defined as in claim 1.

23. The compound of any one of claims 1-22, wherein Ring B is an optionally substituted 9 membered bicyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

24. The compound of any one of claims 1-23, wherein Ring B is selected from the group consisting of optionally substituted indazolyl, optionally substituted imidazo[1,2-a]pyridyl, and optionally substituted 2,7a-dihyrdobenzo[d]oxazolyl.

25. The compound of any one of claims 1-20, wherein each Rbis independently selected from the group consisting of halogen, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy.

26. The compound of any one of claims 1-21, wherein each Rbis independently selected from the group consisting of fluoro, methyl, methoxy, ethoxy, -CHF2, and -CF3.

27. The compound of any one of claims 1-22, wherein q is 2 or 3.

28. The compound of any of claims 1-22, wherein the portion of the compound representedRbRbq q Rb bq R N q N N NNNH NN NN NN NbN Nb,bRbNR, ,R R,q, RbRbq q RbRbq q RbRbq N NH N N , ,Rb, H , NH, Rb bN q R N q RbN q NH NH N RbNbRb,q, Rb, NHR ,q,29. The compound of any one of claims 1-23, wherein the portion of the compound30. The compound of claim 23, wherein the portion of the compound represented byF N FF O O O N N N N N N N N N N , N , N , N, O, F F O F N N N N N O,O, O , S ,S, F O O NN N N N N N N N N, , , , ,31. The compound of any one of claims 1-24, wherein the portion of the compound32. A compound of selected from those described in Table 1 or a pharmaceutically acceptable salt thereof.

33. A pharmaceutical composition comprising a compound of any one of claims 1-32, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

34. A compound of any one of claims 1-32, or a pharmaceutically acceptable salt thereof, for use as a small molecule splicing modulator.

36. A pharmaceutical composition comprising a compound of any one of claims 1-32 and 34, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

37. A method of treating a disorder related to a nucleotide repeat expansion n a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-32 or a pharmaceutical composition of claim 33.

38. The method of claim 37, wherein the nucleotide repeat expansion comprises a nucleotide sequence repeated two or more times, wherein the nucleotide sequence is selected from the group consisting of CNN, ANN, TNN, and GNN, wherein N is a nucleotide selected from the group consisting of adenine (A), thymine (T), guanine (G), and cytosine (C).

39. The method of claim 37, wherein the nucleotide repeat expansion comprises a nucleotide sequence repeated two or more times, wherein the nucleotide sequence is selected from the group consisting of CAG, CAG / CTG, GCG, GCN, CGG, CCG, CCCCGCCCCGCG, GCA, GGGGCC, CTG, GAA, ATTCT, TGGAA, GGCCTG, AAGGG, CCCTCT, ATTTT / ATTTC, and CCCTCT, wherein N is a nucleotide selected from the group consisting of adenine (A), thymine (T), guanine (G), and cytosine (C).

40. The method of claim 38 or 39, wherein the nucleotide repeat expansion comprises a trinucleotide sequence repeated two or more times, wherein the trinucleotide sequence is selected from the group consisting of CAG, CTG, CGG, and GCN.

41. A method of treating a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-32 or a pharmaceutical composition of claim 33, wherein the disease is selected from the group consisting of Dentatorubropallidoluysian atrophy, Huntington's disease, spinal and bulbar muscular atrophy, SCA1 (Spinocerebellar ataxia Type 1), SCA2 (Spinocerebellar ataxia Type 2), SCA3 (Spinocerebellar ataxia Type 3 or Machado-Joseph disease), SCA6 (Spinocerebellar ataxia Type 6), SCA7 (Spinocerebellar ataxia Type 7), SCA12 (Spinocerebellar ataxia Type 12), SCA17 (Spinocerebellar ataxia Type 17), FRAXA (Fragile X syndrome), FXTAS (Fragile X-associated tremor / ataxia syndrome), FRAXE (Fragile XE mental retardation), Baratela-Scott syndrome, FRDA (Friedreich's ataxia), DM1 (Myotonic dystrophy Type 1), DM2 (Myotonic dystrophy Type 2), SCA8 (Spinocerebellar ataxia Type 8), Fuchs endothelial corneal dystrophy, Desbuquois dysplasia, amyotrophic lateral sclerosis, frontotemporal dementia, GLS (glutaminase) disease, and SBMA / Kennedy disease.

42. A method of treating a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one ofclaims 1-32 or a pharmaceutical composition of claim 33, wherein the disease is Huntington’s disease.

43. A method of treating a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-32 or a pharmaceutical composition of claim 33, wherein the disease is Myotonic dystrophy 1.

44. A method of treating a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-32 or a pharmaceutical composition of claim 33, wherein the disease is selected from the group consisting of FRAXA (Fragile X syndrome), FXTAS (Fragile X-associated tremor / ataxia syndrome), and FRAXE (Fragile XE mental retardation).

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