Novel FAK degradation compounds and their uses

Abstract

Compounds and compositions that reduce FAK protein concentration are provided herein. In some embodiments, the compound is of formula I: It has the structure shown in TIFF2026522189000199.tif3392. In some embodiments, the compound and composition are provided for the treatment of FAK-related diseases (e.g., cancer).

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims priority under § 119(e) of U.S. Patent Application No. 63 / 568,728, filed on 22 March 2024, and incorporates its disclosure herein by reference.

[0002] This disclosure relates to novel focal adhesion kinase (FAK) degraders and methods for administering FAK degraders that are useful for treating abnormal cell proliferation (e.g., cancer) in mammals (particularly humans). [Background technology]

[0003] Compelling evidence suggests that focal adhesion kinases (FAKs), specifically cytoplasmic non-receptor tyrosine kinases called PTK2, play a crucial role in cell-matrix signaling pathways (Clark and Brugge 1995, Science 268: 233-239), and that abnormal activation is associated with increased tumor metastatic potential (Owens et al. 1995, Cancer Research 55: 2752-2755). FAKs are encoded by the human PTK2 gene and were originally identified as a highly tyrosine-phosphorylated 125kDa protein in cells transformed with v-Src. FAK was later identified as a tyrosine kinase localized to adhesion plaques, a macromolecular assembly that forms contact points between the cytoskeleton and the extracellular matrix (ECM), acting as both a mechanical sensor and a signal transduction hub (Geiger et al. 2009, Nat Rev Mol Cell Biol. 10: 21-33). FAK is phosphorylated and then activated in response to extracellular matrix bound to integrins. Recent studies have shown that increased FAK mRNA concentration is associated with invasive transformation of tumors, and that decreased FAK expression (through the use of antisense oligonucleotides) induces apoptosis in tumor cells (Xu et al. 1996, Cell Growth and Diff 7: 413-418). In addition to being expressed in most histological types, FAK is found at high concentrations in most human cancers (e.g., highly invasive metastatic cancer). For example, US Pat. No. 8,247,411 relates to a broad category of novel pyrimidine derivatives that are kinase inhibitors (more specifically FAK inhibitors). These compounds may be useful in treating abnormal cell proliferation.

[0004] Cancer can be recognized by the immune system, which controls and even eliminates tumors. Immune checkpoints refer to a rich set of inhibitory pathways that help maintain autoimmune tolerance and regulate the duration and intensity of physiological immune responses in peripheral tissues, thereby minimizing incidental tissue damage. Tumors incorporate specific immune checkpoint pathways as mechanisms of immune resistance, particularly against T cells that are specific to tumor antigens. The development of antibodies that inhibit checkpoints, targeting or subjecting inhibitory receptors such as cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death 1 (PD-1) receptors, may facilitate the treatment of the diseases or disorders described herein (e.g., abnormal cell proliferation, e.g., cancer (e.g., cancer as described herein)). Significant efforts have been made to identify drugs that can enhance T-cell killing of tumor cells and increase the effectiveness of checkpoint inhibitors. Focal adhesion kinases (FAKs) and their closely related family member PYK2 may be effective targets given the role these enzymes play in controlling major cell populations within the tumor microenvironment. FAK inhibitors may increase cytotoxic T cells (CD8+-expressing cytotoxic T cells) within tumors and decrease immune cell populations that suppress the host's anti-tumor immune response (T-regs, M2 tumor-associated macrophages, and myeloid suppressor cells).

[0005] Compounds described herein, such as FAK inhibitors, may be used to prevent and treat diseases or disorders described herein, such as abnormal cell proliferation (e.g., cancer as described herein). [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Clark and Brugge 1995, Science 268: 233-239 [Non-Patent Document 2] Owens et al. 1995, Cancer Research 55: 2752-2755

Non-Patent Document 3

Non-Patent Document 4

Summary of the Invention

[0007] This specification relates to formula (I):

Chemical formula

Chemical formula

[0008] The compounds disclosed herein may be used for pharmaceutical use and in methods of treating cancer, which include administering therapeutically effective amounts of the compounds to mammals having cancer.

[0009] As used herein, the terms “comprising” and “including” may be used interchangeably. The terms “comprising” and “including” should be interpreted as indicating the presence of the described features or components, as noted, and not as excluding the presence or addition of one or more features or components or groups thereof. Furthermore, the terms “comprising” and “including” are intended to include examples encompassed by the term “consisting of.” In conclusion, the term “consisting of” may be used instead of the terms “comprising” and “including” to provide more specific embodiments of the present invention.

[0010] The term "consisting of" means that the object has at least 90%, 95%, 97%, 98%, or 99% of the listed features or components that constitute it. In another embodiment, the term "consisting of" excludes from any subsequent enumeration all other features or components except those that are essential for achieving the technical effect.

[0011] As used herein, the term "or" should be interpreted as an inclusive "or" meaning any one or any combination thereof. Therefore, "A, B, or C" means any of the following: "A; B; C; A and B; A and C; B and C; A, B, and C." An exception to this definition occurs only when any combination of iodine, function, step, or action is, for any reason, essentially mutually exclusive.

[0012] In this specification, any concentration range, percentage range, ratio range, or integer range should be understood to include any integer value within the range described, and, where appropriate, fractions thereof (e.g., 1 / 10 and 1 / 100 of the integer value), unless otherwise specified. Similarly, any numerical range relating to any physical characteristic described herein (e.g., polymer subunit, size, or thickness) should be understood to include any integer within the range described, unless otherwise specified. As used herein, the terms “about” and “approximately” mean ±20%, ±10%, ±5%, or ±1% of the specified range, value, or structure, unless otherwise specified.

[0013] The "alkyl" group consists of 1 to 10 carbon atoms (C1-C 10Alkyl groups are saturated, partially saturated, or unsaturated linear or branched acyclic hydrocarbons having 1 to 8 carbon atoms (C1-C8 alkyl), or in some embodiments, 1 to 6 carbon atoms (C1-C6 alkyl), 1 to 4 carbon atoms (C1-C4 alkyl), 1 to 3 carbon atoms (C1-C3 alkyl), or 2 to 6 carbon atoms (C2-C6 alkyl). In some embodiments, alkyl groups are saturated alkyl groups. Typical saturated alkyl groups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; on the other hand, saturated branched alkyl groups include -isopropyl, -sec-butyl, -isobutyl, tert-butyl, -isopentyl, -neopentyl, tert-pentyl, -2-methylpentyl, -3-methylpentyl, -4-methylpentyl, -2,3-dimethylbutyl, etc. In some embodiments, alkyl groups are unsaturated alkyl groups, also referred to as alkenyl or alkynyl groups. An "alkenyl" group is an alkyl group containing one or more carbon-carbon double bonds. An "alkynyl" group is an alkyl group containing one or more carbon-carbon triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, allyl, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, -C≡CH, -C≡C(CH3), -C≡C(CH2CH3), -CH2C≡CH, -CH2C≡C(CH3), and CH2C≡C(CH2CH3). Alkyl groups may be substituted or unsubstituted.Where an alkyl group described herein is described as “substituted,” it may be substituted with any one or more substituents, as seen in the example compounds and embodiments disclosed herein, as well as halogens; hydroxyl; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, cycloalkylalkyloxy, arylalkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy; oxo(=O); amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino, cycloalkylalkylamino , arylalkylamino, heterocyclylalkylamino, heteroarylalkylamino; imino; imide; amidino; guanidino; enamino; acylamino; sulfonylamino; urea, nitrourea; oxime; hydroxylamino; alkoxyamino; aralkoxyamino; hydrazino; hydrazide; hydrazono; azide; nitro; thio(-SH), alkylthio; =S; sulfinyl; sulfonyl; aminosulfonyl; phosphonate; phosphinyl; acyl; formyl; carboxy; ester; carbamate; amide; cyano; isocyanate; isothiocyanato; cyanate; thiocyanato; or may be substituted with -B(OH)2.Where, in a particular embodiment, an alkyl group described herein is described as “substituted,” it may be substituted with any one or more substituents, as seen in the example compounds and embodiments disclosed herein, and may also be substituted with halogens (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; B(OH)2, or -O(alkyl)aminocarbonyl.

[0014] The "cycloalkyl" group is a monocyclic or polycyclic fused ring or a crosslinked ring having 3 to 10 carbon atoms (C3-C3), which may be substituted as appropriate. 10A cycloalkyl group is a saturated or partially saturated cyclic alkyl group of the cycloalkyl type. In some embodiments, the cycloalkyl group has 3 to 8 ring carbon atoms (C3-C8 cycloalkyl), while in other embodiments, the range of ring carbon atoms is 3 to 5 (C3-C5 cycloalkyl), 3 to 6 (C3-C6 cycloalkyl), or 3 to 7 (C3-C7 cycloalkyl). In some embodiments, the cycloalkyl group is a saturated cycloalkyl group. Such saturated cycloalkyl groups include, for example, monocyclic structures (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, etc.) or polycyclic or crosslinked ring structures (e.g., 1-bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl, etc.). In other embodiments, the cycloalkyl group is an unsaturated cycloalkyl group. Examples of unsaturated cycloalkyl groups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl. Cycloalkyl groups may be substituted or unsubstituted. Examples of such substituted cycloalkyl groups include cyclohexanol.

[0015] A "heterocyclyl" is a non-aromatic cycloalkyl group in which 1 to 4 ring carbon atoms are independently substituted with heteroatoms selected from O, S, and N. In some embodiments, a heterocyclyl group contains 3 to 10 ring atoms, while other such groups have 3 to 5, 3 to 6, or 3 to 8 ring atoms. Heterocyclyls can also be bonded to other groups at any ring atom (i.e., any carbon or heteroatom of the heterocycle). Heterocycloalkyl groups may be substituted or unsubstituted. Heterocyclyl groups encompass saturated and partially saturated ring systems. Furthermore, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which may be fused with an aryl or heteroaryl ring, regardless of its bonding site to other parts of the molecule. This phrase also encompasses bridging polycyclic systems containing heteroatoms. Typical examples of heterocyclyl groups include, but are not limited to, azilidinyl, azetidinyl, azepanil, pyrrolidyl, imidazolidinyl (e.g., imidazolidine-4-onyl or imidazolidine-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranil, piperidyl, piperazinyl (e.g., piperazine-2-onyl), morpholinyl, thiomorpholinyl, tetrahydropyranil (e.g., tetrahydro-2H-pyranil), tetrahydrothiopyranil, oxathianil, dithianil, 1,4-dioxaspiro[4.5]decanyl, homopiperazinyl, quinuclidyl, or tetrahydropyrimidine-2(1H)-one. Typical substituted heterocyclyl groups may be monosubstituted or bisubstituted, and are not limited to the following, but include pyridyl or morpholinyl groups that are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted, with various substituents listed below.

[0016] The "aryl" group is a monocyclic (e.g., phenyl) or polycyclic fused ring (e.g., naphthyl or anthryl) group with 6 to 14 carbon atoms (C6-C6). 14 It is an aromatic carbocyclic group of the aryl group. In some embodiments, the aryl group has 6 to 14 carbon atoms (C6-C) in the ring portion of the group. 14Contains aryls, and in other embodiments, 6 to 12 (C6-C) 12 (aryl), or 6-10 pieces (C6-C) 10 It contains a carbon atom in an aryl group. Certain aryls include phenyl, biphenyl, and naphthyl. The aryl group may be substituted or unsubstituted. The phrase "aryl group" also includes groups containing fused rings, such as aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, etc.).

[0017] A "heteroaryl" group is an aromatic ring system having 1 to 4 heteroatoms as ring atoms in a heteroaromatic ring system, with the remaining atoms being carbon atoms. In some embodiments, the heteroaryl group contains 3 to 6 atoms in the ring portion of the group, and in other embodiments, it contains 6 to 9 or 6 to 10 atoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen. In certain embodiments, the heteroaryl ring system is monocyclic or bicyclic. Examples that are not limited to the following include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzoisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, pyrrolyl, pyridadinyl, pyrimidyl, pyrazinyl, thiophenyl, benzothiophenyl, furanil, benzofuranil, indolyl (e.g., indolyl-2-onyl or isoindoline-1-onyl), azaindolyl (pyrrolopyridyl or 1H-pyrrolo[2,3-b]pyridyl), indazolyl, benzimidazolyl (e.g., 1H-benzo[d]imidazolyl). Examples of such groups include imidazopyridyl (e.g., azabenzimidazolyl or 1H-imidazo[4,5-b]pyridyl), pyrazolopyridyl, triazolopyridyl, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzoxazolyl (e.g., benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, isoxazolopyridyl, thianaphthalenyl, prinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl (e.g., 3,4-dihydroisoquinoline-1(2H)-onyl), tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups may be substituted or unsubstituted.

[0018] "Halogen" or "halo" refers to fluorine, chlorine, bromine, or iodine.

[0019] The "alkoxy" group is -O-(alkyl), and the alkyl group is as defined above.

[0020] The "oxo" group is an "=O" group that is bonded to carbon.

[0021] The "amino" group is -NH2, and one or both of its hydrogen atoms may be substituted with alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups.

[0022] The "amide" group is an amide group represented by the formula -NHC(O)-, and the hydrogen atom may be substituted with an alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group.

[0023] The "heteroaryl-oxy" group is -O-(heteroaryl), and the heteroaryl is as defined above. The "heterocyclyl-oxy" group is -O-(heterocyclyl), and the heterocyclyl is as defined above. The "cycloalkyl-oxy" group is -O-(cycloalkyl), and the cycloalkyl is as defined above.

[0024] Where a group described herein is described as “substituted,” except for alkyl groups, amino groups, and amino groups, it may be substituted with one or more suitable substituents. Examples of substituents include substituents found in the example compounds and embodiments of this disclosure, as well as halogens (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxo(=O); B(OH)2,-O(alkyl)aminocarbonyl; cycloalkyl (e.g., cyclopropyl) which may be monocyclic, condensed, or uncondensed polycyclic. Examples include cyclobutyl, cyclopentyl, or cyclohexyl; or heterocyclyls which may be monocyclic, condensed, or non-condensed polycyclic (e.g., pyrrolidyl, piperidyl, piperazinyl, morpholinyl, or thiadinyl); monocyclic, condensed, or non-condensed polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanil, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridadinyl, pyrimidyl, benzimidazolyl, benzothiophenyl, or benzofuranil); cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, cycloalkylalkyloxy, arylalkyloxy, heterocyclylalkyloxy, and heteroarylalkyloxy.

[0025] Embodiments of this disclosure are intended to encompass pharmaceutically acceptable salts, tautomers, isotopic species, and stereoisomers of compounds provided herein (e.g., compounds represented by formula (I)).

[0026] As used herein, the term “pharmaceutically acceptable salt” refers to a salt prepared from a pharmaceutically acceptable, non-toxic acid or base (including inorganic acids and inorganic bases, as well as organic acids and organic bases). Suitable pharmaceutically acceptable base addition salts of the compound represented by formula (I) include, but are not limited to, metal salts made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc, or organic salts made from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methyl-glucamine), and procaine. Suitable non-toxic acids include, but are not limited to, inorganic and organic acids (e.g., acetic acid, arginine acid, anthranilic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethensulfonic acid, formic acid, fumaric acid, furic acid, galacturonic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucoic acid, nitric acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, propionic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid). Specific non-toxic acids include hydrochloric acid, hydrobromic acid, maleic acid, phosphoric acid, sulfuric acid, and methanesulfonic acid. Specific examples of salts, therefore, include hydrochloride salts, formate salts, and mesylate salts. Other salts are well known in this field (see, for example, Remington's Pharmaceutical Sciences, 18th eds., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19th eds., Mack Publishing, Easton PA (1995)).

[0027] As used herein, the terms “stereoisomer” or “stereoisomerically pure” mean, unless otherwise specified, one stereoisomer of a particular compound, to the extent that there are substantially no other stereoisomers of that compound. For example, a stereoisomerically pure compound having a chiral center will substantially not have an opposite enantiomer of that compound. A stereoisomerically pure compound having two chiral centers will substantially not have any other diastereomers of that compound. Typical stereoisomerically pure compounds contain approximately 80% or more by weight of one stereoisomer and less than 20% by weight of the other stereoisomer of that compound; approximately 90% or more by weight of one stereoisomer and less than 10% by weight of the other stereoisomer of that compound; approximately 95% or more by weight of one stereoisomer and less than 5% by weight of the other stereoisomer of that compound; or approximately 97% or more by weight of one stereoisomer and less than 3% by weight of the other stereoisomer of that compound. The compounds of this disclosure may have chiral centers and may exist as racemates, individual enantiomers or diastereomers, or mixtures thereof. All such isomers, including mixtures thereof, are included in embodiments of this disclosure.

[0028] The use of stereoisomerically pure forms of the compounds of this disclosure, as well as the use of mixtures of those forms, are encompassed in embodiments of this disclosure. For example, mixtures containing equates or asequates of enantiomers of a particular compound may be used in the methods and compositions of this disclosure. These isomers may be synthesized asymmetrically or resolved using conventional techniques (e.g., chiral columns or optical resolution agents). For example, Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, SH, et al., Tetrahedron 33:2725 (1977); Eliel, EL, Stereochemistry of Carbon Compounds (McGraw Hill, NY, 1962); Wilen, SH, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972); Todd, M., Separation Of Enantiomers : Synthetic Methods (Wiley-VCH Verlag GmbH & Co. KgaA, Weinheim, Germany, 2014); Toda, F., Enantiomer Separation: Fundamentals and Practical Methods (Springer Science & Business Media, 2007); Subramanian, G. See Chiral Separation Techniques: A Practical Approach (John Wiley & Sons, 2008); and Ahuja, S., Chiral Separation Methods for Pharmaceutical and Biotechnological Products (John Wiley & Sons, 2011).

[0029] A "tautomer" refers to an isomer of a compound that is in equilibrium based on proton transfer. The concentration of isomers varies depending on the environment in which the compound is present, for example, whether the compound is a solid or contained in an organic solution or aqueous solution. For example, in aqueous solution, pyrasol has the following isomers, which are called tautomers: [ka] It can exist.

[0030] As will be readily apparent to those skilled in the art, a wide variety of functional groups and other structures may exhibit tautomerism, and all tautomers of the compound represented by formula (I) are within the scope of this disclosure.

[0031] The compounds of this disclosure may contain unnatural proportions of isotopes in one or more atoms. For example, the compounds may be radiolabeled with radioactive isotopes (e.g., tritium). 3 H), Iodine-125( 125 I), Sulfur-35( 35 S), or carbon-14 ( 14 C)), or isotope enrichment may be used (for example, deuterium ( 2 H), carbon-13 ( 13 C), or nitrogen-15( 15N)). As used herein, “isotope species” refers to isotope-enriched compounds. The term “isotope enrichment” refers to an atom having an isotope composition other than that of its natural isotope composition. “Isotope enrichment” also refers to a compound containing at least one atom having an isotope composition other than that of its natural isotope composition. The term “isotope composition” refers to the amount of each isotope present in a given atom. Radiolabeled and isotope-enriched compounds are useful as therapeutic agents (e.g., cancer drugs, research reagents (e.g., binding assay reagents), diagnostic reagents (e.g., in vivo contrast agents)). All isotopic changes of the compounds described herein, whether radioactive or not, are intended to be included within the scope of the embodiments provided herein. In some embodiments, isotope species of the compounds of this disclosure are provided, for example, isotope species are deuterium, carbon-13, and / or nitrogen-15 enriched compounds. As used herein, “deuterated” refers to a compound in which at least one hydrogen (H) atom is deuterium (D or 2 A compound substituted with (represented by H) means that the compound is deuterium-rich at at least one position.

[0032] Regardless of stereoisomerism or isotopic composition, it is understood that each compound in this disclosure may be provided in any pharmaceutically acceptable salt form described herein. Similarly, it is understood that the isotopic composition may vary independently of the stereoisomer composition of each compound described herein. Furthermore, although the isotopic composition is limited to the elements contained in each compound or its salts in this disclosure, it may vary independently of the selection of a pharmaceutically acceptable salt of each compound.

[0033] It should be noted that if there is a discrepancy between the depicted structure and its name, the depicted structure should be given priority.

[0034] As used herein, “treatment” means the overall or partial relief of a disorder, disease, or condition, or one or more symptoms associated with such disorder, disease, or condition, or slowing or stopping the further progression or worsening of those symptoms, or reducing or eliminating the cause of the disorder, disease, or condition. In some embodiments, the disorder is a neurodegenerative disease or its symptoms as described herein.

[0035] As used herein, “prevention” means delaying, in whole or in part, the onset, recurrence, or progression of a disability, disease, or condition; preventing an object from acquiring a disability, disease, or condition; or reducing the risk to an object from acquiring a disability, disease, or condition. In some embodiments, the disability is a neurodegenerative disease or its symptoms as described herein.

[0036] In relation to the compounds in this disclosure, the term "effective amount" means an amount that can treat or prevent a disorder, disease, condition, or symptom thereof as described herein.

[0037] As used herein, the terms “subject” or “patient” include animals (including, but not limited to, animals such as cattle, monkeys, horses, sheep, pigs, chickens, turkeys, quail, cats, dogs, mice, rats, rabbits, or guinea pigs), mammals in some embodiments, and humans in other embodiments. In some embodiments, the subject is a human being who has, may have, or is experiencing symptoms of a FAK-mediated disease.

[0038] Various features of the present invention may be described in the context of one embodiment, but these features may be provided separately or in any suitable combination. Conversely, the present invention may be described herein in the context of separate embodiments for clarity, but the present invention may also be implemented in one embodiment.

[0039] compound

[0040] 1. In a first embodiment, the present invention relates to formula (I): [ka] [In formula: [ka] It does not exist, or it is a double bond; X is independently selected from C and N; Y is independently selected from C and N; YY is independently selected from C and N; Z is independently selected from C and N; ZZ is independently selected from C and N; R 1 These are independently selected from hydrogen, halogen, and C1-C6 alkyl; R 2 The alkyl or cycloalkyl group is independently selected from hydrogen, halogen, -(=O), -C1-C6 alkyl, and 3-6 membered cycloalkyl groups, and the alkyl or cycloalkyl group is -R 9 , -N(R 9 R 10 ), and -OR 9 It may be replaced as appropriate; R 3 They do not exist independently, or are selected from hydrogen and halogens; R 4 They do not exist independently, or are selected from hydrogen and -C1-C6 alkyl groups; R 5 These elements either do not exist independently, or are selected from hydrogen, halogens, and C1-C6 alkyl groups; R 6 The rings are independently selected from 5- to 12-membered aryl and 5- to 12-membered heteroaryl rings, where the aryl and heteroaryl rings have 1, 2, or 3 -R rings. 9 , -N(R 9 R 10 ), and -OR 9 It may be replaced as appropriate; R 7 is hydrogen or halogen; R 8is independently -N(R 9 R 10 ) and selected from 4- to 12-membered heterocycles, which heterocycles may be optionally substituted with 1, 2, or 3 -R 9 , -N(R 9 R 10 ), and -OR 9 ; R 9 is independently selected from hydrogen, halogen, -OR 10 , -N(R 10 R 10 ), -C1-C6 alkyl, -O-C1-C6 alkyl, -CN, 3- to 12-membered cycloalkyl, and 4- to 12-membered heterocycles; The alkyl, cycloalkyl, or heterocycle in R 9 is each independently unsubstituted or substituted with 1, 2, or 3 R 10 substituents; In each case, R 10 is independently selected from hydrogen, -OH, -C1-C6 alkyl, -C2-C6 alkenyl, halogen, -O-(C1-C6 alkyl)-, -N(R 11 R 11 ), 3- to 12-membered cycloalkyl, 4- to 12-membered heterocycles, 5- to 12-membered aryl, and 5- to 12-membered heteroaryl rings; The alkyl, alkenyl, cycloalkyl, heterocycle, aryl, or heteroaryl ring in R 10 is each independently unsubstituted or substituted with 1, 2, or 3 R 11 substituents; and R 11 is independently selected from hydrogen, halogen, -OH, and -C1-C6 alkyl, and the alkyl, heterocycle, and heteroaryl rings in each R 6 , R 8 , R 9 , and R 10 may independently contain 1, 2, or 3 heteroatoms selected from O, N, or S] The present invention provides compounds represented by, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, clathrates, polymorphs, or tautomers, pharmaceutically acceptable salts of polymorphs or tautomers, any of the aforementioned stereoisomers, or mixtures thereof.

[0041] 2. In some embodiments, [ka] The compound according to Embodiment 1, wherein the bond is a double bond.

[0042] 3. In some embodiments, [ka] The compound according to Embodiment 1, in which the compound is absent.

[0043] 4. The compound according to any one of Embodiments 1, 2, or 3, wherein X is C in some embodiments.

[0044] 5. A compound according to any one of Embodiments 1 to 4, wherein Y is N in some embodiments.

[0045] 6. A compound according to any one of Embodiments 1 to 4, wherein Y is C in some embodiments.

[0046] 7. A compound according to any one of embodiments 1 to 6, wherein YY is N in some embodiments.

[0047] 8. A compound according to any one of Embodiments 1 to 6, wherein YY is C in some embodiments.

[0048] 9. A compound according to any one of Embodiments 1 to 8, wherein Z is N in some embodiments.

[0049] 10. A compound according to any one of Embodiments 1 to 8, wherein Z is C in some embodiments.

[0050] 11. The compound according to any one of Embodiments 1 to 10, wherein ZZ is N in some embodiments.

[0051] 12. The compound according to any one of Embodiments 1 to 10, wherein ZZ is C in some embodiments.

[0052] 13. In some embodiments, R 1 is hydrogen, and the compound according to any one of Embodiments 1 to 12.

[0053] 14. In some embodiments, R 2 is hydrogen, and the compound according to any one of Embodiments 1 to 12.

[0054] 15. In some embodiments, R 3 is hydrogen, and the compound according to any one of Embodiments 1 to 14.

[0055] 16. In some embodiments, R 4 is absent, and the compound according to any one of Embodiments 1 to 15. [[ID=3l]]

[0056] 17. In some embodiments, R 4 [[ID=3y]] is hydrogen, and the compound according to any one of Embodiments 1 to 15.

[0057] 18. In some embodiments, R 4 is -C1-C6 alkyl, and the compound according to any one of Embodiments 1 to 15.

[0058] 19. In some embodiments, R 4 is -CH3, and the compound according to Embodiment 18.

[0059] <OO00705>20. In some embodiments, R 4 is -CH2CH3, and the compound according to Embodiment 18.

[0060] [[ID=A7]] 21. In some embodiments, R5 A compound according to any one of Embodiments 1 to 20, wherein the compound is hydrogen.

[0061] 22. In some embodiments, R 5 A compound according to any one of Embodiments 1 to 20, wherein is a C1-C6 alkyl group.

[0062] 23. In some embodiments, R 5 The compound according to Embodiment 22, wherein -CH3.

[0063] 24. In some embodiments, R 5 A compound according to any one of Embodiments 1 to 20, wherein the compound is a halogen.

[0064] 25. Formula (Ia) in some embodiments: [ka] [In formula: R 5 It does not exist independently, or is selected from hydrogen, halogen, or C1-C6 alkyl; R 6 The rings are independently selected from 5- to 12-membered aryl or 5- to 12-membered heteroaryl rings, and the aryl and heteroaryl rings have 1, 2, or 3 -R groups. 9 , -N(R 9 R 10 ), or -OR 9 It may be replaced as appropriate; R 7 is hydrogen or halogen; R 8 -N(R 9 R 10 ), selected from 4- to 12-membered heterocycles, the heterocycle having 1, 2, or 3 -R 9 , -N(R 9 R 10 ), or -OR 9 It may be replaced as appropriate; R 9 These are independently hydrogen, halogen, -C1-C6 alkyl, and -OR 10, -N(R 10 R 10 Selected from ), -CN, 3-12 membered cycloalkyl groups, or 4-12 membered heterocycles; R 9 The alkyl, cycloalkyl, or heterocycles within each are independently unsubstituted or have 1, 2, or 3 R rings. 10 Substituting with a substituent; In each case, R 10 R is independently selected from hydrogen, halogen, -OH, -C1-C6 alkyl, 3-12 membered cycloalkyl, and 4-12 membered heterocycle; 10 The alkyl, cycloalkyl, and heterocycles within each are independently unsubstituted or have 1, 2, or 3 R groups. 11 Substituting with a substituent; R 11 These are independently hydrogen, halogen, -OH, and -C1-C6 alkyl, and further Each R 6 , R 8 , R 9 , and R 10 The cycloalkyl, heterocycle, and heteroaryl rings within may contain one, two, or three heteroatoms independently selected from O, N, or S. A compound described in any one of embodiments 1-2, 4-5, 8, 10-11, 13-15, and 21-24 shown herein, or a pharmaceutically acceptable salt thereof, solvate, hydrate, cocrystal, clathrate, polymorph, or tautomer, a pharmaceutically acceptable salt of a polymorph or tautomer, any of the aforementioned stereoisomers, or a mixture thereof.

[0065] 26. In some embodiments, R 5 The compound according to embodiment 25, wherein the compound is hydrogen.

[0066] 27. In some embodiments, R 5 The compound according to embodiment 25, wherein is a halogen.

[0067] 28. In some embodiments, R 5The compound according to Embodiment 27, wherein is Cl or F.

[0068] 29. In some embodiments, R 5 The compound according to Embodiment 25, wherein is a C1-C6 alkyl group.

[0069] 30. In some embodiments, R 5 The compound according to embodiment 29, wherein is -CH3.

[0070] 31. In some embodiments, R 6 The aryl ring is selected from 5-12 membered rings, and has 1, 2, or 3 -R rings. 9 , -N(R 9 R 10 ), or -OR 9 The compound according to any one of embodiments 25 to 30, which may be appropriately substituted with the compound.

[0071] 32. In some embodiments, R 6 The -R is selected from a 5- to 12-membered heteroaryl ring, with 1, 2, or 3 -R 9 , -N(R 9 R 10 ), or -OR 9 The compound according to any one of embodiments 25 to 30, which may be appropriately substituted with the compound.

[0072] 33. In some embodiments, R 7 A compound according to any one of embodiments 25 to 32, wherein the compound is hydrogen.

[0073] 34. In some embodiments, R 7 A compound according to any one of embodiments 25 to 32, wherein is a halogen.

[0074] 35. The compound according to Embodiment 34, wherein the halogen is F or Cl in some embodiments.

[0075] 36. In some embodiments, R 8 -N(R 9 R10 ) and a compound according to any one of embodiments 25 to 34, selected from a 4- to 12-membered heterocycle.

[0076] 37. In some embodiments, R 8 ga-N(R 9 R 10 The compound according to embodiment 36, which is the compound described above.

[0077] 38. In some embodiments, R 8 The compound according to embodiment 36, wherein is a 4- to 12-membered heterocycle.

[0078] 39. In some embodiments, R 9 A compound according to any one of embodiments 25 to 40, wherein the compound is hydrogen.

[0079] 40. In some embodiments, R 9 A compound according to any one of embodiments 25 to 40, wherein is a halogen.

[0080] 41. The compound according to embodiment 42, wherein the halogen is selected from Cl and F in some embodiments.

[0081] 42. The compound according to embodiment 43, wherein the halogen is selected from Cl in some embodiments.

[0082] 43. The compound according to embodiment 43, wherein the halogen is selected from F in some embodiments.

[0083] 44. In some embodiments, represented by formula (Ia), R 9 A compound according to any one of embodiments 25 to 38, wherein is a C1-C6 alkyl group.

[0084] 45. The compound according to Embodiment 41, wherein in some embodiments, the -C1-C6 alkyl is selected from -CH3, -CH2CH3, -CH(CH3)2, and -C(CH3)3.

[0085] 46. ​​In some embodiments, R 9 ga-OR 10 , -N(R 10 R 10 ), -CN, a 3-12 membered cycloalkyl group, or a 4-12 membered heterocycle; R 9 The alkyl, cycloalkyl, or heterocycle within each ring is independently unsubstituted, or contains 1, 2, or 3 R rings. 10 A compound according to any one of embodiments 25 to 38, which is substituted with a substituent.

[0086] 47. In some embodiments, in each case, R 10 These independently form hydrogen, halogen, -OH, -C1-C6 alkyl, and -N(R) 11 R 11 ), selected from 3-12 membered cycloalkyl groups and 4-12 membered heterocycles; R 10 The alkyl, cycloalkyl, and heterocycles within each are independently unsubstituted, or have 1, 2, or 3 R groups. 11 A compound according to any one of embodiments 25 to 46, which is substituted with a substituent.

[0087] 48. In some embodiments, R 11 The compound according to any one of embodiments 25 to 47, wherein is independently hydrogen, halogen, -OH, or -C1-C6 alkyl.

[0088] 49. In some embodiments, R 6 They became independent [ka] A compound selected from Embodiment 1 and any one of Embodiments 25-48.

[0089] 50. In some embodiments, R 8 They became independent [ka] A compound selected from any one of Embodiments 1 and 25-49.

[0090] 51. Formula (Ib) in some embodiments: [ka] [In formula: R 6 teeth [ka] and R 8 teeth [ka] [is] The compound described in Embodiment 1, or a pharmaceutically acceptable salt thereof, solvate, hydrate, cocrystal, clathrate, polymorph, or tautomer, a pharmaceutically acceptable salt of a polymorph or tautomer, any of the aforementioned stereoisomers, or mixtures thereof.

[0091] 52. Formula (Ic) in some embodiments: [ka] [In formula: X is either C or N; R 4 These are independently selected from hydrogen or -C1-C6 alkyl; R 6 They became independent [ka] Selected from; and R 8 They became independent [ka] [or selected from -N(CH3CH3)] The compound according to Embodiment 1, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph, or tautomer thereof, a pharmaceutically acceptable salt of a polymorph or tautomer, any stereoisomer of any of the foregoing, or a mixture thereof.

[0092] 53. In some embodiments, R 4 is hydrogen, and the compound according to Embodiment 52.

[0093] 54. In some embodiments, R 4 is -C1-C6 alkyl, and the compound according to Embodiment 52.

[0094] 55. In some embodiments, -C1-C6 alkyl is -CH3, and the compound according to Embodiment 54.

[0095] 56. In some embodiments, R 6 is [[ID=2​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​

[0099] 60. The compound according to any one of embodiments 52-59, wherein X is C in some embodiments.

[0100] 61. The compound according to any one of embodiments 52-59, wherein X is N in some embodiments.

[0101] 62. In another embodiment, formula (Id):

Chemical formula

[0103] 64. In some embodiments,

Chemical formula

[0104] 65. In some embodiments, a method for reducing the FAK protein concentration, comprising contacting cells with an effective amount of the compound according to any one of Embodiments 1 to 64, or a pharmaceutically acceptable salt, tautomer, isotopic molecular species, or stereoisomer thereof.

[0105] 66. The method according to Embodiment 65, wherein the cells are present in a subject.

[0106] 67. In some embodiments, a method for preventing or treating cancer in a subject, comprising administering to the subject in need thereof an effective amount of the compound according to any one of Embodiments 1 to 66, or a pharmaceutically acceptable salt, tautomer, isotopic molecular species, or stereoisomer thereof.

[0107] 68. The method according to Embodiment 67, wherein the cancer is selected from gastric cancer, lung cancer, pancreatic cancer, ovarian cancer, breast cancer, skin cancer, colon cancer, neuroblastoma, osteosarcoma, uterine cancer, rectal cancer, and kidney cancer.

[0108] 69. The method according to embodiment 68, wherein in some embodiments, the cancer is selected from pancreatic ductal adenocarcinoma (PDAC), small cell lung cancer, non-small cell lung cancer (NSCLC), high-grade serous ovarian cancer, triple-negative breast cancer, serous uterine carcinoma, Ewing's sarcoma, melanoma, colon cancer, and clear cell renal cell carcinoma (ccRCC).

[0109] 70. A compound according to any one of Embodiments 1 to 64, for use as a pharmaceutical in some embodiments.

[0110] 71. A compound according to any one of embodiments 1 to 64 and 70 for use in a method of treating cancer, comprising administering a therapeutically effective amount of the compound to a mammal having cancer, in some embodiments.

[0111] 72. Use of a compound described in any one of embodiments 1-64 and 70-71, or a pharmaceutically acceptable salt thereof, tautomer, isotope, or stereoisomer, in the manufacture of a pharmaceutical for reducing FAK protein concentration, in some embodiments.

[0112] 73. Use in the manufacture of a pharmaceutical product for the prevention or treatment of cancer, in some embodiments, of a compound described in any one of embodiments 1-64 and 70-71, or a pharmaceutically acceptable salt thereof, tautomer, isotopic species, or stereoisomer thereof.

[0113] 74. The compound for use according to Embodiment 72, wherein in some embodiments, the cancer is selected from gastric cancer, lung cancer, pancreatic cancer, ovarian cancer, breast cancer, skin cancer, colon cancer, neuroblastoma, osteosarcoma, uterine cancer, rectal cancer, and kidney cancer.

[0114] 75. The compound for use according to Embodiment 72, in some embodiments, wherein the cancer is selected from pancreatic ductal adenocarcinoma (PDAC), small cell lung cancer, non-small cell lung cancer (NSCLC), high-grade serous ovarian cancer, triple-negative breast cancer, serous uterine carcinoma, Ewing's sarcoma, melanoma, colon cancer, and clear cell renal cell carcinoma (ccRCC).

[0115] 76. A compound for use according to any one of embodiments 70 to 75, wherein the use in some embodiments further comprises the administration of a therapeutically effective amount of another secondary active agent or supportive therapy, the other secondary active agent being a therapeutic antibody, hematopoietic growth factor, cytokine, anticancer agent, antibiotic, Cox-2 inhibitor, immunomodulator, immunosuppressant, corticosteroid, or a pharmacologically active variant or derivative thereof that specifically binds to a cancer antigen.

[0116] In this specification, all descriptions, variations, embodiments, or aspects of a part may be combined with all descriptions, variations, embodiments, or aspects of other parts, as if any combination of descriptions were specifically and individually enumerated. For example, R represented by formula (I) 1 All descriptions, variations, embodiments, or aspects provided herein relating to R are as if any combination of descriptions were specifically and individually listed. 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 All descriptions, variations, embodiments, or aspects of X, Y, YY, Z, and ZZ may be combined with this. Furthermore, all descriptions, variations, embodiments, or aspects of formula (I) are understood to apply, where applicable, to other formulas described herein as if every description, variation, embodiment, or aspect were listed separately and individually for each formula. For example, all descriptions, variations, embodiments, or aspects of formula (I) apply, where applicable, to any other formulas described herein (e.g., formulas (Ia), (Ib), (Ic), (Id), and (Ie)) as if every description, variation, embodiment, or aspect were listed separately and individually for each formula.

[0117] In some embodiments, compounds selected from the compounds shown in Table 1 or their pharmaceutically acceptable salts are provided. While certain compounds described in this disclosure (including Table 1) exist as specific stereoisomers and / or non-stereochemical forms, it is understood that any stereochemical form of any compound in this disclosure (any enantiomer or diastereomer, and any tautomer or other form) is described herein.

[0118] How to use

[0119] Embodiments of this disclosure provide methods for degrading FAK, reducing FAK protein concentrations, and preventing or treating target diseases (e.g., cancer) that require such degradation.

[0120] In one embodiment, this specification provides a method for degrading FAK of an object requiring such degradation, comprising contacting cells with an effective amount of a compound represented by formula (I). FAK degradation can be evaluated and demonstrated by a wide variety of methods known in the art. Kits and commercially available assays (including cell-based assays) can be used to determine whether and to what extent FAK is degraded. In some embodiments, the compound represented by formula (I) partially degrades FAK. In some embodiments, the compound represented by formula (I) completely degrades FAK.

[0121] In some embodiments, the compound represented by formula (I) degrades FAK by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the compound represented by formula (I) is approximately 1-100%, 5-100%, 10-100%, 15-100%, 20-100%, 25-100%, 30-100%, 35-100%, 40-100%, 45-100%, 50-100%, 55-100%, 60-100%, 65-100%, 70-100%, 75-100%, 80-100%, 85-10% Decompose FAK in the following percentages: 0%, 90-100%, 95-100%, 5-95%, 5-90%, 5-85%, 5-80%, 5-75%, 5-70%, 5-65%, 5-60%, 5-55%, 5-50%, 5-45%, 5-40%, 5-35%, 5-30%, 5-25%, 5-20%, 5-15%, 5-10%, 10-90%, 20-80%, 30-70%, or 40-60%.

[0122] In some embodiments, this specification provides a method for reducing FAK kinase protein concentration, comprising contacting cells with an effective amount of a compound represented by formula (I). The reduction in FAK kinase protein concentration can be evaluated and demonstrated by a wide variety of methods known in the art. Kits and commercially available assays (including cell-based assays) may be used to determine whether and to what extent the kinase protein concentration is reduced.

[0123] In some embodiments, the compound represented by formula (I) reduces the FAK kinase protein concentration by approximately 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the compound represented by formula (I) is approximately 1-100%, 5-100%, 10-100%, 15-100%, 20-100%, 25-100%, 30-100%, 35-100%, 40-100%, 45-100%, 50-100%, 55-100%, 60-100%, 65-100%, 70-100%, 75-100%, 80-100%, 85-100%, 90- Reduce FAK kinase protein concentration by 100%, 95-100%, 5-95%, 5-90%, 5-85%, 5-80%, 5-75%, 5-70%, 5-65%, 5-60%, 5-55%, 5-50%, 5-45%, 5-40%, 5-35%, 5-30%, 5-25%, 5-20%, 5-15%, 5-10%, 10-90%, 20-80%, 30-70%, or 40-60%.

[0124] In some embodiments, the compound represented by formula (I) is measured by the EC2 of the FAK degradation assay. 50 The values ​​are approximately 0.0003 μM to 1 μM, or approximately 0.0003 μM to 0.2 μM, or approximately 0.0003 μM to 0.05 μM. In some embodiments, the compound represented by formula (I) has an EC of approximately 0.05 μM to 0.2 μM. 50 It has. In some embodiments, the compound represented by formula (I) has an EC concentration of about 0.2 μM to about 1 μM. 50 It has. In some embodiments, the compound represented by formula (I) has an EC of less than about 1 μM. 50 It has. In some embodiments, the compound represented by formula (I) has an EC of less than about 0.2 μM, less than 0.05 μM, less than 0.001 μM, or less than 0.0003 μM. 50 It holds.

[0125] In another embodiment, a method for treating a target cancer requiring the treatment thereof is provided herein, comprising administering an effective amount of a compound represented by formula (I) to the target. In some embodiments, a method for preventing a target cancer requiring the treatment thereof is provided herein, comprising administering an effective amount of a compound represented by formula (I) to the target. In some embodiments, cancer is selected from brain cancer, head and neck cancer, esophageal cancer, thyroid cancer, small cell carcinoma, non-small cell carcinoma, breast cancer, lung cancer, stomach cancer, gallbladder / bile duct cancer, liver cancer, pancreatic cancer, colon cancer, rectal cancer, ovarian cancer, choriocarcinoma, endometrial cancer, cervical cancer, renal pelvis / ureteral cancer, bladder cancer, prostate cancer, penile cancer, testicular cancer, fetal cancer, Wilms' cancer, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's tumor, soft tissue sarcoma, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, polycythemia vera, malignant lymphoma, multiple myeloma, Hodgkin lymphoma, and non-Hodgkin lymphoma.

[0126] In some embodiments, cancer is selected from gastric cancer, lung cancer, pancreatic cancer, ovarian cancer, breast cancer, skin cancer, colon cancer, neuroblastoma, osteosarcoma, uterine cancer, rectal cancer, and kidney cancer. In some embodiments, cancer is selected from pancreatic ductal adenocarcinoma (PDAC), small cell lung cancer, non-small cell lung cancer (NSCLC), high-grade serous ovarian cancer, triple-negative breast cancer, serous uterine carcinoma, Ewing's sarcoma, melanoma, colon cancer, and clear cell renal cell carcinoma (ccRCC).

[0127] In some embodiments, administering the compound shown in formula (I) to a subject with a predisposition to cancer prevents the subject from developing any symptoms of cancer (e.g., tumor growth or metastasis). In some embodiments, administering the compound shown in formula (I) to a subject who has not yet shown any symptoms of cancer prevents the subject from developing any symptoms of cancer. In some embodiments, administering the compound shown in formula (I) to a subject who needs it reduces the severity of the cancer in that subject. In some embodiments, administering the compound shown in formula (I) to a subject who needs it stabilizes the cancer (prevents or delays its progression). In some embodiments, administering the compound shown in formula (I) to a subject who needs it delays the onset or recurrence of cancer. In some embodiments, administering the compound shown in formula (I) to a subject who needs it slows the progression of cancer. In some embodiments, administering the compound shown in formula (I) to a subject who needs it provides partial remission of cancer. In some embodiments, administering the compound shown in formula (I) to a subject who needs it provides complete remission of cancer. In some embodiments, administering the compound represented by formula (I) to a subject who needs it reduces the dosage of one or more other medications required for the treatment of cancer. In some embodiments, administering the compound represented by formula (I) to a subject who needs it enhances the effectiveness of another medication used to treat cancer. In some embodiments, administering the compound represented by formula (I) to a subject who needs it slows the progression of cancer. In some embodiments, administering the compound represented by formula (I) to a subject who needs it improves the quality of life of a subject with cancer. In some embodiments, administering the compound represented by formula (I) to a subject who needs it extends the survival time of a subject with cancer.

[0128] In one embodiment, the present invention provides a method for preventing a subject with a cancer predisposition from developing cancer, the method comprising administering a compound represented by formula (I) to the subject.

[0129] In some embodiments, a method for reducing the severity of a target cancer is provided herein, comprising administering a compound represented by formula (I) to the target. In some embodiments, a method for stabilizing a target cancer is provided herein, comprising administering a compound represented by formula (I) to the target. In some embodiments, the method prevents the progression of the cancer.

[0130] In another embodiment, the present invention provides a method for delaying the onset or recurrence of a target cancer, comprising administering a compound represented by formula (I) to the target.

[0131] In some embodiments, a method for slowing the progression of a target cancer is provided herein, comprising administering a compound represented by formula (I) to the target. In some embodiments, the method provides partial remission of the cancer. In some embodiments, the method provides complete remission of the cancer.

[0132] In a further embodiment, the Specified Method provides a method for reducing the amount of one or more other drugs required to treat a target cancer, comprising administering a compound represented by formula (I) to the target. In some embodiments, the Specified Method provides a method for improving the effect of another drug used to treat a target cancer, comprising administering a compound represented by formula (I) to the target.

[0133] Furthermore, this specification provides a method for slowing the progression of a target cancer, comprising administering a compound represented by formula (I) to the target. In some embodiments, the method improves the quality of life of a subject with cancer. In some embodiments, the method extends the survival time of a subject with cancer.

[0134] In some embodiments, the compound represented by formula (I) is useful in the manufacture of pharmaceuticals that reduce FAK kinase protein concentration. In some embodiments, the compound represented by formula (I) is useful in the manufacture of pharmaceuticals for the prevention or treatment of FAK-related diseases.

[0135] The methods and uses described herein may include a compound represented by formula (I), used alone or in combination with one or more additional treatments (e.g., non-pharmacological treatments or therapeutic agents).

[0136] In some embodiments, the compound for use described in any one of embodiments 70 to 75 further comprises the administration of a therapeutically effective amount of another secondary active agent or supportive therapy, wherein the other secondary active agent is a therapeutic antibody, hematopoietic growth factor, cytokine, anticancer agent, antibiotic, Cox-2 inhibitor, immunomodulator, immunosuppressant, corticosteroid, or a pharmaceutically active variant or derivative thereof that specifically binds to a cancer antigen.

[0137] The compound represented by formula (I) may be administered before, after, or concurrently with one or more additional treatments. When combined, the dose of the compound represented by formula (I) and the dose of one or more additional treatments (e.g., non-pharmacological treatments or therapeutic treatments) may provide a therapeutic effect (e.g., a synergistic effect or an additional therapeutic effect). The compound represented by formula (I) and the additional treatments (e.g., anticancer agents) may be administered together (e.g., in a single pharmaceutical composition) or separately, and if administered separately, this may be done simultaneously or sequentially. Such sequential administrations may be close together or far apart in time.

[0138] In some embodiments, additional treatment involves the administration of an adverse reaction inhibitor (e.g., a drug to reduce the occurrence or severity of adverse reactions to the treatment). For example, in some embodiments, the compound represented by formula (I) may be used in combination with a drug to treat nausea. Examples of drugs that may be used to treat nausea include, but are not limited to, dronabinol, granisetron, metoclopramide, ondansetron, prochlorperazine, and their pharmaceutically acceptable salts.

[0139] In some embodiments, one or more additional treatments include non-pharmacological treatments (e.g., surgery or radiation therapy). In some embodiments, one or more additional treatments include therapeutic agents (e.g., compounds or biological agents that are antiproliferative agents). In some embodiments, one or more additional treatments include non-pharmacological treatments and therapeutic agents. In other embodiments, one or more additional treatments include two therapeutic agents. In yet another embodiment, one or more additional treatments include three therapeutic agents. In some embodiments, one or more additional treatments include four or more therapeutic agents.

[0140] Pharmaceutical composition and route of administration

[0141] The compounds provided herein can be administered orally, topically, or parenterally to a subject in conventional preparation forms (e.g., capsules, microcapsules, tablets, granules, powders, lozenges, tablets, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, and emulsions).

[0142] The compounds disclosed herein may be administered orally, topically, or parenterally to a target in conventional preparation forms (e.g., capsules, microcapsules, tablets, granules, powders, lozenges, tablets, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, and emulsions). Suitable formulations may include excipients (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, or calcium carbonate), binders (e.g., cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose, or starch), disintegrants (e.g., starch, carboxymethylcellulose, hydroxypropyl starch, low-substituted hydroxypropylcellulose, sodium bicarbonate, calcium phosphate, or calcium citrate), and lubricants (e.g., magnesium stearate, light anhydrous silica). It may be prepared in a commonly used manner using conventional organic or inorganic additives such as acids, talc, or sodium lauryl sulfate, fragrances (e.g., citric acid, menthol, glycine, or orange powder), preservatives (e.g., sodium benzoate, sodium bisulfite, methylparaben, or propylparaben), stabilizers (e.g., citric acid, sodium citrate, or acetic acid), suspending agents (e.g., methylcellulose, polyvinylpyrrolidone, or aluminum stearate), dispersants (e.g., hydroxypropyl methylcellulose), diluents (e.g., water), and base waxes (e.g., cocoa butter, white petrolatum, or polyethylene glycol). The effective amount of the compound represented by formula (I) in the pharmaceutical composition may be at a concentration that produces the desired effect: for example, about 0.005 mg / kg of body weight to about 10 mg / kg of body weight per unit dose, both for oral and parenteral administration.

[0143] The dosage of the compound represented by formula (I) administered to a subject is fairly broad and depends on the judgment of the healthcare professional. Generally, the compounds disclosed herein may be administered 1 to 4 times a day in doses of about 0.005 mg / kg of body weight to about 10 mg / kg of body weight, but the above doses may be appropriately varied depending on the subject's age, weight, and medical condition, as well as the type of administration. In some embodiments, the dose is about 0.001 mg / kg of body weight to about 5 mg / kg of body weight, about 0.01 mg / kg to about 5 mg / kg of body weight, about 0.05 mg / kg to about 1 mg / kg of body weight, about 0.1 mg / kg to about 0.75 mg / kg of body weight, or about 0.25 mg / kg to about 0.5 mg / kg of body weight. In some embodiments, it is administered once a day. In any case, the amount of the compound represented by formula (I) administered depends on factors such as the solubility of the active ingredient, the formulation used, and the route of administration.

[0144] In some embodiments, the compound represented by formula (I) is administered to subjects at doses of approximately 0.01 mg / day to approximately 750 mg / day, approximately 0.1 mg / day to approximately 375 mg / day, approximately 0.1 mg / day to approximately 150 mg / day, approximately 0.1 mg / day to approximately 75 mg / day, approximately 0.1 mg / day to approximately 50 mg / day, approximately 0.1 mg / day to approximately 25 mg / day, or approximately 0.1 mg / day to approximately 10 mg / day.

[0145] In another embodiment, unit dose formulations containing a compound represented by formula (I) in amounts of about 0.1 mg to 500 mg, about 1 mg to 250 mg, about 1 mg to about 100 mg, about 1 mg to about 50 mg, about 1 mg to about 25 mg, or about 1 mg to about 10 mg are provided herein.

[0146] In certain embodiments, unit dose formulations containing about 0.1 mg or about 100 mg of the compound represented by formula (I) are provided herein.

[0147] In another embodiment, unit dose formulations containing a compound represented by formula (I) in amounts of 0.5 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 35 mg, 50 mg, 70 mg, 100 mg, 125 mg, 140 mg, 175 mg, 200 mg, 250 mg, 280 mg, 350 mg, 500 mg, 560 mg, 700 mg, 750 mg, 1000 mg, or 1400 mg are provided herein.

[0148] The compound represented by formula (I) may be administered once, twice, three times, four times, or more times per day. In certain embodiments, doses of 100 mg or less are administered once daily, and doses exceeding 100 mg are administered twice daily, each dose being half of the total daily dose.

[0149] The compound represented by formula (I) may be administered orally for convenience. In one embodiment, when administered orally, the compound represented by formula (I) is administered with food and water. In another embodiment, the compound represented by formula (I) is dispersed in water, or juice (e.g., apple juice or orange juice), or any other liquid and administered orally as a solution or suspension.

[0150] The compounds disclosed herein may also be administered intradermally, intramuscularly, intraperitoneally, percutaneously, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, percutaneously, rectally, mucous membrane, by inhalation, or topically to the ear, nose, eye, or skin. The method of administration may be at the discretion of the healthcare professional and may depend in part on the site of the condition.

[0151] In one embodiment, capsules comprising a compound represented by formula (I), without the addition of a carrier, excipient, or vehicle, are provided herein.

[0152] In another embodiment, the following compositions are provided herein, comprising an effective amount of a compound represented by formula (I) and a pharmaceutically acceptable carrier or vehicle, wherein the pharmaceutically acceptable carrier or vehicle may contain excipients, diluents, or mixtures thereof. In one embodiment, the composition is a pharmaceutical composition.

[0153] The compositions may be in the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, lozenges, suppositories, spray-dried dispersions, and suspensions. The compositions may be formulated to contain a daily dose, or a convenient amount of the daily dose, in a single tablet or capsule, or in a convenient amount of liquid. In some embodiments, solutions are prepared from water-soluble salts (e.g., hydrochloride). Generally, all compositions are prepared according to known methods of medicinal chemistry. Capsules may be prepared by mixing the compound represented by formula (I) with a suitable carrier or diluent and filling a capsule with a suitable amount of the mixture. Common carriers and diluents include, but are not limited to, inert powders, e.g., numerous types of starches, powdered cellulose (especially crystalline cellulose and microcrystalline cellulose), sugars (e.g., fructose, mannitol, and sucrose), whole grains, and similar edible powders.

[0154] Tablets can be prepared by direct compression, wet granulation, or dry granulation. These formulations typically incorporate diluents, binders, lubricants, and disintegrants, as well as compounds. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or calcium sulfate, inorganic salts (e.g., sodium chloride), and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders include substances such as starch, gelatin, and sugars (e.g., lactose, fructose, glucose, etc.). Natural and synthetic rubbers are also convenient, including acacia, alginate, methylcellulose, and polyvinylpyrrolidine. Polyethylene glycol, ethylcellulose, and waxes can also function as binders.

[0155] In tablet formulations, lubricants may be needed to prevent the tablets and punch from sticking to the dye. Lubricants can be selected from slippery solids, such as talc, magnesium stearate and calcium stearate, stearic acid, and hydrogenated vegetable oils. Tablet disintegrants are substances that swell when wet, breaking the tablets and releasing the compounds. These include starch, clay, cellulose, algin, and rubber. More specifically, for example, corn starch and potato starch, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation exchange resins, alginic acid, guar gum, citrus pulp, and carboxymethylcellulose can be used, similar to sodium lauryl sulfate. To alter the solubility of the tablets, they may be coated with sugars as fragrances and sealants, or with film-forming protective agents. Compositions can also be formulated as chewable tablets, for example, by using substances such as mannitol in the formulation.

[0156] When it is desired to administer the compound represented by formula (I) as a suppository, typical bases can be used. Cocoa butter is a traditional suppository base and can be modified by adding wax to slightly increase its melting point. In particular, water-miscible suppository bases containing polyethylene glycol of various molecular weights are widely used.

[0157] The effects of the compound represented by formula (I) can be delayed or prolonged by a suitable formulation. For example, slow-dissolving pellets of the compound represented by formula (I) can be prepared and incorporated into tablets or capsules, or as sustained-release implantable devices. The technique also includes producing pellets with several different dissolution rates and filling mixtures of pellets into capsules. The tablets or capsules can be coated with a film that is difficult to dissolve for a predictable period. Even parenteral formulations can be produced as long-acting formulations by dissolving or suspending the compound represented by formula (I) in an oily or emulsified vehicle and slowly dissolving it in serum. [Examples]

[0158] The following examples are for illustrative purposes only and not limiting purposes. Those skilled in the art will be able to modify the procedures described in the illustrative examples to obtain the desired product.

[0159] Salts of the compounds described herein can be prepared by standard methods (for example, by adding an acid (e.g., TFA, formic acid, or HCl) to the mobile phase during chromatographic purification, and then stirring the product with an acidic solution (e.g., HCl solution) after chromatographic purification).

[0160] Unless otherwise specified, all reactions are carried out at room temperature.

[0161] The following abbreviations may be relevant to this application.

[0162] Abbreviation [Table 1]

[0163] Synthesis example

[0164] Synthesis method

[0165] The compounds described herein may be prepared by conventional organic chemical synthesis and using commercially available starting materials or by methods provided herein. For example, but not limited to, the compound represented by formula (I) may be prepared as briefly described in Scheme 1 and the Examples provided herein. Those skilled in the art should note that they will know how to modify the procedures shown in the explanatory scheme and Examples to reach the desired product (e.g., by selecting starting materials (or racemic starting materials) having different stereochemistry to reach the desired product having different stereochemistry).

[0166] Generally, the compound represented by formula (I) can be obtained as shown in Scheme 1 below. By reacting aryl stannane (2a) or boronate (2b) with aryl iodide (1), intermediate 3, a biaryl, can be obtained. By substituting the fluoride of intermediate 3 with amine (4), intermediate 5 can be obtained. The amide and ester of intermediate 5 can be reacted under various conditions (including acid treatment) to form a glutalimide ring. In some embodiments, the iodide of intermediate 1 may be substituted with stannane or boronate, and intermediate 2 may be an aryl halide. In some embodiments, intermediate 1 may consist of a different heterocycle and different substituents than those shown in Scheme 1. In some embodiments, the order of the reaction steps may be rearranged. Unless otherwise stated, all reactions in the following schemes are carried out at room temperature.

[0167] The embodiment of the present invention can be further understood by referring to the following embodiments, which are provided for illustrative purposes only and not to limit.

[0168] Generally, the procedures of this disclosure produce a mixture of positional isomers alkylated at the 1H or 2H position of the pyrazolopyrimidine ring system (these are also referred to as the N1 and N2 positional isomers, respectively, with reference to the alkylated nitrogen). In the formulas, the N2 positional isomer is sometimes not shown for convenience, but it should be understood that the N2 positional isomer is present in the initial product mixture and is subsequently separated (e.g., by preparative HPLC). [ka]

[0169] The mixture of positional isomers may be separated early in the synthesis, and the remaining synthesis steps may be carried out using the 1H positional isomer, or, if necessary, the synthesis may proceed with the mixture of positional isomers and separate them later.

[0170] The aforementioned “modes for carrying out the invention” include portions that are primarily or exclusively relevant to a particular part or aspect of the invention. This is for clarity and convenience, and it should be understood that certain features may be relevant in places other than where they are disclosed, and that this disclosure includes any appropriate combination with disclosures described elsewhere. Similarly, while various descriptions in this disclosure relate to specific embodiments of the invention, it should be understood that even if a particular feature is described in a particular figure or embodiment, that feature may, to an appropriate extent, be used in other figures or embodiments, in combination with other features, or in the invention in general.

[0171] All starting materials were prepared using the following procedure or purchased from commercial suppliers (e.g., Sigma-Aldrich, Combi-Blocks, Enamine, and eMolecules). All reagents were purchased through a commercial supplier (e.g., Sigma-Aldrich).

[0172] Furthermore, although the present invention has been described in particular from the viewpoint of certain preferred embodiments, the present invention is not limited to such preferred embodiments. Rather, the scope of the present invention is limited by the appended claims.

[0173] Scheme I illustrates the most common route used to synthesize the embodiments described herein. Variations of this route are shown in the following embodiments.

[0174] Scheme I [ka]

[0175] As will be apparent to those skilled in the art, the compounds disclosed below and in Table 1 can exist in various stereochemical forms. In the examples and the compounds in Table 1, if the stereochemistry is shown to be between piperidine-dione and isoindolinone, that stereochemistry is absolute stereochemistry. Other stereocenters where the stereochemistry is shown as R or S may be relative stereochemistry. Racemates and single enantiomers were prepared according to the experimental procedures described below. In specific cases, to obtain individual enantiomers, the enantiomers were separated from the racemate by chiral SFC.

[0176] All the necessary nuclei and precursor intermediates related to the key steps described above are described in the following experiments in this specification.

[0177] Intermediate synthesis:

[0178] Intermediate A: 6-fluoro-4-iodo-1H-pyrazolo[3,4-b]pyridine [ka]

[0179] Step A1: 2,6-difluoro-4-iodopyridine-3-carbaldehyde [ka]

[0180] Lithium diisopropylamide (24.9 mL, 49.8 mmol) was added dropwise to a solution of 2,6-difluoro-4-iodopyridine (10,000 g, 41.5 mmol) / tetrahydrofuran (100 mL) under nitrogen at -78°C. The mixture was stirred under nitrogen at -78°C for 1 hour. Ethyl formate (15.37 g, 207.49 mmol) was then added to the mixture. The mixture was stirred under nitrogen at -78°C for 3 hours. The mixture was poured into a saturated aqueous solution of ammonium chloride (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic layers were washed together with brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (0-30% ethyl acetate / petroleum ether) to obtain 2,6-difluoro-4-iodopyridine-3-carboaldehyde (3,200 g, 11.90 mmol, 29% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ 10.12 (s, 1H), 7.55 (d, J=4.0, 1H).

[0181] Step A2: 6-Fluoro-4-iodo-1H-pyrazolo[3,4-b]pyridine [ka] To a solution of 2,6-difluoro-4-iodopyridine-3-carboaldehyde (4.700 g, 17.47 mmol) in ethanol (50 mL), hydrazine hydrate (1.340 g, 22.71 mmol) was added. The mixture was stirred at 80°C for 12 hours. The mixture was filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (30-60% ethyl acetate / petroleum ether) to obtain 6-fluoro-4-iodo-1H-pyrazolo[3,4-b]pyridine (3.000 g, 11.41 mmol, 66% yield) as a yellow solid. 11H NMR (400MHz, DMSO-d6)δ 14.0(s, 1H), 8.00(s, 1H), 7.51(s, 1H), 3.53(q, J=6.0 Hz, 2H), 3.00 - 2.99(m, 6H), 2.52(t, J=6.0 Hz, 2H), 1.46(s, 9H). MS(ESI)m / z: 263.9[M+1] + .

[0182] Intermediate B: 3-chloro-6-fluoro-4-iodo-1H-pyrazolo[3,4-b]pyridine [ka]

[0183] A mixture of 6-fluoro-4-iodo-1H-pyrazolo[3,4-b]pyridine (intermediate A) (0.400 g, 1.52 mmol) and N-chlorosuccinimide (0.305 g, 2.28 mmol) / DMF (10 mL) was stirred under nitrogen at 25°C for 12 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (30 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate solids, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (10% ethyl acetate / petroleum ether) to obtain 3-chloro-6-fluoro-4-iodo-1H-pyrazolo[3,4-b]pyridine (0.280 g, 0.94 mmol, 62% yield) as a pale yellow solid. 1 H NMR (400MHz, DMSO-d6) δ 14.34 - 14.20 (m, 1H), 7.67 (d, J=1.2 Hz, 1H). MS(ESI)m / z:297.8[M+1] + .

[0184] Intermediate C:tert-butyl (S)-5-amino-4-(5-(bromomethyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate [ka]

[0185] Step C1: 4-Bromo-2-methylbenzoate methyl benzoate [ka]

[0186] To a solution of compound 4-bromo-2-methylbenzoic acid (600 g, 2.79 mol, 1.00 eq) / methanol (3.00 L), thionyl chloride (365 g, 3.07 mol, 1.10 eq) was added dropwise at 15°C, and the mixture was stirred at 60°C for 16 hours. TLC (petroleum ether:ethyl acetate = 1:1, R) f The reaction was completed by a pH of 0.9. The reaction mixture was concentrated under vacuum. The residue was mixed with ethyl acetate (15.0 L) and water (5.00 L) and adjusted to pH 8 with saturated sodium bicarbonate aqueous solution. The organic layer was washed with brine (5.00 L), dried over sodium sulfate, and concentrated under vacuum to obtain compound 4-bromo-2-methylbenzoate methyl (3.15 kg, 99% yield) as a yellow oil. 1 H NMR (400 MHz CDCl3) δ 7.78 (d, J=8.4 Hz, 1H), 7.42 (s, 1H), 7.38 (dd, J=8.4, 2.0 Hz, 1H), 3.88 (s, 3H), 2.58 (s, 3H).

[0187] Step C2: 4-Bromo-2-(bromomethyl)benzoate [ka]

[0188] A mixture of methyl 4-bromo-2-methylbenzoate (275 g, 1.20 mol, 1.00 eq), NBS (321 g, 1.80 mol, 1.50 eq), and AIBN (29.6 g, 180 mmol, 0.15 eq) / isopropyl acetate (3.00 L) was stirred at 80°C for 2 hours and irradiated with a 1000 watt lamp. TLC (petroleum ether:ethyl acetate = 10:1, R) fA reaction of 0.45 (=0.45) indicated that the reaction was almost complete. The reaction mixture was cooled to room temperature and diluted with methyl tert-butyl ether (3.00 L). The mixture was filtered. The filtrate was washed with water (20.0 L x 2), 5% aqueous sodium bicarbonate solution (10.0 L), and brine (10.0 L), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 4-bromo-2-(bromomethyl)benzoate methyl (2.60 kg, crude) as a pale yellow solid. 1 H NMR (400 MHz CDCl3) δ 7.84 (d, J=8.4 Hz, 1H), 7.63 (d, J=2.0 Hz, 1H), 7.51 (dd, J=8.4, 2.0 Hz, 1H), 4.90 (s, 2H) 3.94 (s, 3H).

[0189] Step C3: tert-butyl(S)-5-amino-4-(5-bromo-1-oxoisoindolin-2-yl)-5-oxopentanoate [ka]

[0190] DIEA (210 g, 1.62 mol, 2.50 eq) was added at 20°C to a solution of compound 4-bromo-2-(bromomethyl)benzoate methyl (200 g, 649 mmol, 1.00 eq) and compound tert-butyl(S)-4,5-diamino-5-oxopentanoate hydrochloride (155 g, 649 mmol, 1.00 eq) / acetonitrile (2.00 L). The reaction mixture was stirred at 50°C for 16 hours. TLC (petroleum ether:ethyl acetate = 10:1, R) fThe reaction was completed at a reading of 0.02. The reaction mixture was concentrated under vacuum. The residues were combined and mixed with ethyl acetate:THF (4:1, 30.0 L) and water (20.0 L). The aqueous layer was extracted with ethyl acetate (7.50 L x 2). The organic layers were combined and washed with brine (10.0 L), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residues were triturated with methyl tert-butyl ether (8.00 L) for 0.5 hours and filtered. The filtered cake was washed with methyl tert-butyl ether (1.00 L) and dried under reduced pressure to obtain tert-butyl(S)-5-amino-4-(5-bromo-1-oxoisoindorin-2-yl)-5-oxopentanoate (1.60 kg, 99.3% purity, 48% yield in 2 steps) as a white solid. 1 H NMR(400 MHz DMSO-d6)δ 7.88(s, 1H), 7.67-7.69(m, 1H), 7.62-7.64(m, 1H), 7.59(br.s, 1H), 7.21(br.s, 1H), 4. 71-4.74(m, 1H), 4.44-4.63(m, 2H), 2.13-2.18(m, 3H), 1.89-2.00(m, 1H), 1.32(s, 9H). MS(ESI)m / z: 397.1(M+1) + .

[0191] Step C4: (Tributylstannyl)methanol [ka]

[0192] To a solution of LDA (2.00 M, 1.03 L, 1.20 eq) / dried THF (2.50 L), tributyltin hydride compound (500 g, 1.72 mol, 455 mL, 1.00 eq) was added at -70°C. After stirring at 0°C for 2 hours, (HCHO)n (108 g, 0.40 eq) was added to the reaction mixture at -70°C. After addition, the reaction mixture was stirred at 20°C for 16 hours. TLC (petroleum ether / ethyl acetate = 10:1, R) fAt 0.84, it was indicated that the starting material had been depleted. The reaction was quenched at 0°C with saturated ammonium chloride aqueous solution (10.0 L), and ethyl acetate (4.00 L) was added. The organic layer was separated, washed with brine (4.00 L x 2), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography using petroleum ether / ethyl acetate (1:0~10:1) to obtain (tributylstannyl)methanol (2.0 kg, 6.23 mol, 72.27% yield) as a yellow oil.

[0193] Step C5: tert-butyl(S)-5-amino-4-(5-(hydroxymethyl)-1-oxoisoindolin-2-yl)-5-oxopentanoate [ka]

[0194] To a degassed solution of the compound tert-butyl(S)-5-amino-4-(5-bromo-1-oxoisoindorin-2-yl)-5-oxopentanoate (500 g, 1.26 mol, 1.00 eq) / dried 1,4-dioxane (3.0 L), (tributylstannyl)methanol (525 g, 1.64 mol, 1.30 eq) and tetrakis(triphenylphosphine)-palladium(0) (72.7 g, 62.9 mmol, 0.05 eq) were added at 20°C. After addition, the reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was concentrated under vacuum. The crude product was triturated with methyl tert-butyl ether / petroleum ether (5 / 1, 6 L) at 25°C for 4 hours. The suspension was filtered, the filter cake was washed with petroleum ether (5.0 L), and dried under vacuum to obtain tert-butyl(S)-5-amino-4-(5-(hydroxymethyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (900 g, 2.30 mol, 61% yield, 88.9% purity) as an off-white solid. 1H NMR 400 MHz CDCl3δ 7.57(d, J=7.6 Hz, 1H), 7.37(s, 1H), 7.27-7.30(m, 1H), 7.00(s, 1H), 4.85-4.88(m, 1H), 4.29-4.44(m, 2H), 2.16-2.28(m, 4H), 1.37(s, 9H).

[0195] Step C6: tert-butyl(S)-5-amino-4-(5-formyl-1-oxoisoindoline-2-yl)-5-oxopentanoate [ka]

[0196] A mixture of tert-butyl(S)-5-amino-4-(5-(hydroxymethyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (100 g, 287 mmol, 1.00 eq) and manganese dioxide (200 g, 2.30 mol, 8.00 eq) / DCM (700 mL) was degassed and purged three times with nitrogen. The mixture was stirred under a nitrogen atmosphere at 40°C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The crude product was triturated with ethyl acetate / DCM (9 / 1, 4 L) at 25°C for 60 minutes. The suspension was filtered, the filter cake was washed with ethyl acetate (1 L), and dried under vacuum to obtain tert-butyl(S)-5-amino-4-(5-formyl-1-oxoisoindorin-2-yl)-5-oxopentanoate (510 g, 1.37 mol, 60% yield, 93.3% purity) as an off-white solid. 1 H NMR 400 MHz CDCl3δ 10.14(s, 1H), 8.14(s, 1H), 8.03(d, J=7.6 Hz, 1H), 7.89-7.91(m, 1H), 7.61(s, 1H), 7.22(s, 1H), 4.72 - 4.77(m, 1H), 4.68(s, 1H), 4.56-4.60(m, 1H), 1.99-2.20(m, 4H), 1.32(s, 9H).

[0197] Step C7: (S)-tert-butyl 5-amino-4-(5-(hydroxymethyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate [ka]

[0198] (S)-tert-butyl 5-amino-4-(5-formyl-1-oxoisoindolin-2-yl)-5-oxopentanoate (10,000 g, 28.87 mmol) / tetrahydrofuran (200 mL) was mixed with sodium tetrahydroborate (2,270 g, 60.05 mmol) at 0°C. The mixture was then stirred at 0°C for 1 hour under nitrogen. The reaction mixture was quenched with 1 M phosphoric acid and extracted with ethyl acetate (100 mL x 2). The organic layers were dried together over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the product (S)-tert-butyl 5-amino-4-(5-(hydroxymethyl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (10,000 g, 28.70 mmol, 99% yield) as a light brown solid. 1 H NMR (400MHz, DMSO-d6)δ 7.64(d, J=7.6 Hz, 1H), 7.54(s, 2H), 7.42(d, J=7.6 Hz, 1H), 7.16(s, 1H), 5.37(t, J=5.6 Hz, 1H), 4.73(dd, J=4.4, 10.4 Hz, 1H), 4.63 - 4.54 (m, 3H), 4.50 - 4.39 (m, 1H), 2.20 - 2.10 (m, 3H), 1.98 - 1.92 (m, 1H), 1.33 (s, 9H). MS(ESI)m / z: 349.2 [M+1] + .

[0199] Step C8: (S)-tert-butyl 5-amino-4-(5-(bromomethyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate [ka]

[0200] (S)-tert-butyl 5-amino-4-(5-(hydroxymethyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (9.000 g, 25.83 mmol) and triethylamine (7.842 g, 77.5 mmol) / THF (200 mL) were mixed with methylsulfonyl methanesulfonate (9.000 g, 51.67 mmol) at 0°C. The mixture was then heated to 25°C and stirred for 4 hours. Bromolium (22.436 g, 258.33 mmol) was then added. The mixture was stirred at 25°C for 6 hours. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (100 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica column chromatography (0-75% ethyl acetate / petroleum ether) to obtain the product (S)-tert-butyl 5-amino-4-(5-(bromomethyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (5.600 g, 13.62 mmol, 53% yield) as a pale yellow solid. 1 H NMR(400MHz, DMSO-d6)δ 7.73 - 7.65(m, 2H), 7.60 - 7.52(m, 2H), 7.20(s, 1H), 4.82(s, 2H), 4.77 - 4.69(m, 1H), 4.63 - 4.55(m, 1H), 4.51 - 4.43 (m, 1H), 2.21 - 2.11 (m, 3H), 1.98 - 1.93 (m, 1H), 1.32 (s, 9H). MS(ESI)m / z: 355.2 [M-55] +

[0201] Intermediate D: tert-butyl 5-amino-4-[5-[(6-fluoro-4-iodopyrazolo[3,4-b]pyridine-1-yl)methyl]-1-oxo-isoindorin-2-yl]-5-oxo-pentanoate [ka]

[0202] To a solution of 6-fluoro-4-iodo-1H-pyrazolo[3,4-b]pyridine (intermediate A) (0.844 g, 3.21 mmol) / DMF (8.00 mL), tert-butyl 5-amino-4-[5-(bromomethyl)-1-oxo-isoindorin-2-yl]-5-oxo-pentanoate (intermediate C) (1.200 g, 2.92 mmol) and cesium carbonate (2.850 g, 8.75 mmol) were added. The mixture was stirred at 50°C for 2 hours. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (20 mL x 3). The organic layers were washed together with saturated brine (20 mL x 2) and dried over anhydrous sodium sulfate. The organic layers were filtered, and the filtrate was concentrated under vacuum. The residue was purified by preparative HPLC (42-72% acetonitrile + 0.225% formic acid / water, 13 minutes). The desired fractions were combined and concentrated under vacuum. The aqueous solution was extracted with ethyl acetate (20 mL x 3). The organic layers were combined and dried over anhydrous sodium sulfate. The organic layers were filtered, and the filtrate was concentrated under vacuum to obtain tert-butyl 5-amino-4-[5-[(6-fluoro-4-iodopyrazolo[3,4-b]pyridine-1-yl)methyl]-1-oxo-isoindorin-2-yl]-5-oxo-pentanoate (0.360 g, 0.61 mmol, 21% yield) as a yellow solid. 1 1H NMR (400MHz, CDCl3)δ 7.90(s, 1H), 7.80(d, J=8.0 Hz, 1H), 7.47(d, J=8.4 Hz, 1H), 7.42(s, 1H), 7.27(s, 1H), 6.36(s, 1H), 5.67(s, 2H), 5.57(s, 1H), 4.89(dd, J=6.0, 8.8 Hz, 1H), 4.52 - 4.48(m, 1H), 4.42 - 4.38(m, 1H), 2.33(d, J=3.6 Hz, 1H), 2.30 - 2.27(m, 1H), 2.23(s, 1H), 2.17 - 2.11(m, 1H), 1.41(s, 9H). MS(ESI)m / z: 537.9[M+1] + .

[0203] Intermediate E: tert-butyl(S)-5-amino-4-(5-((6-fluoro-4-(tributylstannyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate [ka]

[0204] A mixture of tert-butyl(S)-5-amino-4-(5-((6-fluoro-4-iodo-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (2.000 g, 3.37 mmol), tributyl(tributylstannyl)stannan (2.542 g, 4.38 mmol), tris-o-tolylphosphan (0.205 g, 0.67 mmol), triethylamine (1.5 mL, 8.43 mmol), and palladium acetate (0.076 g, 0.34 mmol) / acetonitrile (30 mL) was stirred under nitrogen at 85°C for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by alumina column chromatography (0-100% ethyl acetate / petroleum ether) to obtain the crude product tert-butyl(S)-5-amino-4-(5-((6-fluoro-4-(tributylstannyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (2,000 g, 2.64 mmol, 78% yield) as a brown oil. MS(ESI)m / z: 758.4 [M+1] +

[0205] Intermediate F:tert-butyl(S)-5-amino-4-(5-((6-(3-fluoroazetidine-1-yl)-4-iodo-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate [ka]

[0206] tert-butyl(S)-5-amino-4-(5-((6-(3-fluoroazetidine-1-yl)-4-iodo-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate. To a solution of tert-butyl(S)-5-amino-4-(5-((6-fluoro-4-iodo-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (intermediate D) (3.000 g, 5.06 mmol) / acetonitrile (20 mL), 3-fluoroazetidine hydrochloride (0.677 g, 6.07 mmol) and N-ethyl-N-isopropylpropan-2-amine (4 mL, 20.22 mmol) were added. The mixture was stirred at 50°C for 2 hours. The mixture was diluted with water (60 mL) and extracted with ethyl acetate (30 mL x 3). The organic layers were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain tert-butyl(S)-5-amino-4-(5-((6-(3-fluoroazetidine-1-yl)-4-iodo-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (2.700 g, 4.16 mmol, 82% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3)δ 7.78(d, J=8.0 Hz, 1H), 7.65(s, 1H), 7.45(d, J=7.6 Hz, 1H), 7.35(s, 1H), 6.64(s, 1H), 6.25(s, 1H), 5.57 - 5.39(m, 3H), 5.29(s, 1H), 4.87(dd, J=6.6, 8.8 Hz, 1H), 4.48 - 4.35(m, 4H), 4.27 - 4.18(m, 2H), 2.34 - 2.13(m, 4H), 1.41(s, 9H).

[0207] Intermediate G: tert-butyl(S)-5-amino-4-(5-((6-(3-fluoroazetidine-1-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate [ka]

[0208] In a 40 mL screw-cap vial, tert-butyl(S)-5-amino-4-(5-((6-(3-fluoroazetidine-1-yl)-4-iodo-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (intermediate F) (1.0 g, 1.542 mmol) was dissolved in 1,4-dioxane (20 mL). To this solution, bis(pinacolato)diborone (0.783 g, 3.08 mmol), potassium acetate (0.454 g, 4.63 mmol), and PdCl2(dppf)·DC adduct (0.126 g, 0.154 mmol) were added. The mixture was purged with nitrogen for 5 minutes and stirred at 80°C for 2 hours. The mixture was filtered through Celite and washed with ethyl acetate (100 mL). The filtrate was concentrated under reduced pressure to obtain tert-butyl(S)-5-amino-4-(5-((6-(3-fluoroazetidine-1-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (1.2 g, 0.722 mmol, 47% yield) as a brown viscous solid. MS(ESI, +ve ion) m / z: 649.2(M+1) + .

[0209] Intermediate H:tert-butyl(S)-5-amino-4-(5-((5-fluoro-6-(3-fluoroazetidine-1-yl)-4-iodo-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate

[0210] [ka]

[0211] To a solution of tert-butyl(S)-5-amino-4-(5-((6-(3-fluoroazetidine-1-yl)-4-iodo-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (intermediate F) (2.700 g, 4.16 mmol) / acetonitrile (1 mL), 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane;ditetrafluoroborate (1.480 g, 4.16 mmol) was added. The mixture was stirred at 40°C for 12 hours. The mixture was filtered and purified by semi-preparative reverse-phase HPLC (52-82% acetonitrile / water + 0.225% formic acid, 10 minutes). The target fraction was concentrated to remove most of the acetonitrile, and the aqueous solution was then extracted with ethyl acetate (30 mL x 3). The organic layers were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the product tert-butyl(S)-5-amino-4-(5-((5-fluoro-6-(3-fluoroazetidine-1-yl)-4-iodo-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.520 g, 0.78 mmol, 19% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3)δ 7.79(d, J=7.2 Hz, 1H), 7.64(s, 1H), 7.44(d, J=8.0 Hz, 1H), 7.35(s, 1H), 6.29(d, J=2.0 Hz, 1H), 5.58 - 5.41(m, 4H), 4.90 - 4.86 (m, 1H), 4.58 - 4.33 (m, 6H), 2.36 - 2.11 (m, 4H), 1.41 (s, 9H). MS(ESI)m / z: 667.1 [M+1] + .

[0212] Intermediate I: tert-butyl 5-amino-4-(2-(bromomethyl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-yl)-5-oxopentanoate [ka] [ka]

[0213] Step I1. Methyl 6-chloro-2-methylnicotinate. Diazomethyl(trimethyl)silane (289.3 mL, 578.62 mmol) was added at 0°C to a solution of 6-chloro-2-methylnicotinic acid (25.00 g, 115.72 mmol) in methanol (50 mL) and tetrahydrofuran (100 mL). The mixture was stirred at 25°C for 12 hours. The reaction mixture was quenched at 0°C with 5 mL of acetic acid, diluted with water (100 mL), and extracted with ethyl acetate (100 mL x 2). The organic layers were washed together with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-5% ethyl acetate / petroleum ether) to obtain methyl 6-chloro-2-methylnicotinate (25.0 g, 108.67 mmol, 94% yield) as a white solid. 1 H NMR (400MHz, CDCl3) δ 8.15 (d, J=8.4 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 3.91 (s, 3H), 2.81 (s, 3H).

[0214] Step I2. Methyl 2-(bromomethyl)-6-chloronicotinate. A mixture of methyl 6-chloro-2-methylnicotinate (25.000 g, 134.69 mmol), N-bromosuccinimide (22.670 g, 202.04 mmol), and AIBN (17.694 g, 107.75 mmol) / DCM (150 mL) was stirred at 85°C for 24 hours. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic layer was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by semi-preparative reverse-phase HPLC (30-60% acetonitrile / water + 0.225% formic acid, 18 minutes). The fraction of interest was extracted with ethyl acetate (100 mL x 2). The organic layers were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain methyl 2-(bromomethyl)-6-chloronicotinate (12,300 g, 46.50 mmol, 34% yield) as a pink solid. 1H NMR (400MHz, CDCl3) δ 8.25 (d, J=8.4 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 5.05 (s, 2H), 3.97 (s, 3H).

[0215] Step 3. tert-butyl(S)-5-amino-4-(2-chloro-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-yl)-5-oxopentanoate. A mixture of methyl 2-(bromomethyl)-6-chloronicotinate (8.300 g, 31.38 mmol), tert-butyl(S)-4,5-diamino-5-oxopentanoate (7.616 g, 37.66 mmol), potassium carbonate (10.826 g, 78.45 mmol), and potassium iodide (5.209 g, 31.38 mmol) / acetonitrile (100 mL) was stirred at 80°C for 12 hours. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (80 mL x 3). The organic layer was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-60% ethyl acetate / petroleum ether) to obtain tert-butyl(S)-5-amino-4-(2-chloro-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-yl)-5-oxopentanoate (9.100 g, 25.72 mmol, 82% yield) as a yellow solid. 1 H NMR(400MHz, CDCl3)δ 8.00(d, J=8.0 Hz, 1H), 7.41(d, J=8.0 Hz, 1H), 6.64(s, 1H), 6.02(s, 1H), 4.96(dd, J=6.0, 8.8 Hz, 1H), 4.71 - 4.43(m, 2H), 2.35 - 2.24(m, 3H), 2.15 - 2.08(m, 1H), 1.39(s, 9H). MS(ESI)m / z: 386.0 [M+1] + .

[0216] Step 4. tert-butyl(S)-5-amino-5-oxo-4-(5-oxo-2-vinyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-yl)pentanoate. A mixture of tert-butyl(S)-5-amino-4-(2-chloro-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-yl)-5-oxopentanoate (7.000 g, 19.79 mmol), trifluoro(vinyl)-14-borane, potassium salt (3.975 g, 29.68 mmol), bis(triphenylphosphine)palladium chloride (2.286 g, 1.98 mmol), and cesium carbonate (16.075 g, 49.46 mmol) in water (5 mL) and DMF (50 mL) was stirred at 90°C for 12 hours. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (80 mL x 3). The organic layers were combined, washed with saturated brine (80 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-80% ethyl acetate / petroleum ether). The fractions of interest were combined and concentrated under reduced pressure. The residue was further purified by semi-preparative reverse-phase HPLC (20-50% acetonitrile / water + 0.225% formic acid, 20 minutes). The fractions of interest were combined and extracted with ethyl acetate (100 mL x 3). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the product tert-butyl(S)-5-amino-5-oxo-4-(5-oxo-2-vinyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-yl)pentanoate (2.800 g, 8.107 mmol, 41% yield) as a yellow solid. 1H NMR (400MHz, CDCl3)δ 8.03(d, J=8.0 Hz, 1H), 7.40(d, J=8.0 Hz, 1H), 6.88(dd, J=10.8, 17.6 Hz, 1H), 6.44(s, 1H), 6.38(d, J=17.2 Hz, 1H), 5.71(s, 1H), 5.64(d, J=10.8 Hz, 1H), 4.97(dd, J=6.4, 8.8 Hz, 1H), 4.68 - 4.44(m, 2H), 2.44 - 2.23(m, 3H), 2.21 - 2.10(m, 1H), 1.42(s, 9H). MS(ESI)m / z: 289.2 [M+1] + .

[0217] Step 5. tert-butyl(S)-5-amino-4-(2-(hydroxymethyl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-yl)-5-oxopentanoate. A solution of tert-butyl(S)-5-amino-5-oxo-4-(5-oxo-2-vinyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-yl)pentanoate (1,000 g, 2.90 mmol) in methanol (10 mL) and DCM (10 mL) was stirred under ozone at -78°C for 0.5 hours. Then sodium borohydride (0.340 g, 8.99 mmol) was added. The mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched with water and extracted with ethyl acetate (50 mL x 3). The organic layers were combined and concentrated under vacuum to obtain tert-butyl(S)-5-amino-4-(2-(hydroxymethyl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-yl)-5-oxopentanoate (0.800 g, 2.29 mmol, 79% yield) as a gray solid.

[0218] Step 6. tert-butyl(S)-5-amino-4-(2-(bromomethyl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-yl)-5-oxopentanoate. To a solution of tert-butyl(S)-5-amino-4-(2-(hydroxymethyl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-yl)-5-oxopentanoate (0.800 g, 2.29 mmol) and triethylamine (1.0 mL, 6.87 mmol) / THF (30 mL), methylsulfonyl methanesulfonate (0.997 g, 5.72 mmol) was added. The reaction mixture was stirred at 0°C for 10 minutes. Bromolium (1.989 g, 22.9 mmol) was then added. The resulting mixture was stirred at 0°C for 0.5 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. It was purified by silica gel chromatography (0-90% ethyl acetate / petroleum ether) to obtain the product tert-butyl(S)-5-amino-4-(2-(bromomethyl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-yl)-5-oxopentanoate (0.740 g, 1.79 mmol, 78% yield) as a yellow solid. MS(ESI)m / z: 412.1 [M+1] + .

[0219] Intermediate J:tert-butyl(S)-5-amino-4-(3-(bromomethyl)-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-yl)-5-oxopentanoate [ka]

[0220] Step J1: 5-Bromo-3-(dibromomethyl)picolinate methyl 5-bromo-3-(dibromomethyl)picolinate [ka] A mixture of methyl 5-bromo-3-methylpyridine-2-carboxylate (8.120 g, 35.30 mmol), NBS (12.564 g, 70.59 mmol), and benzoyl peroxide (0.427 g, 1.76 mmol) / carbon tetrachloride (80 mL) was stirred under nitrogen at 80°C for 24 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-25% ethyl acetate / petroleum ether) to obtain methyl 5-bromo-3-(dibromomethyl)picolinate (13.689 g, 35.30 mmol, 100.0% yield) as a yellow oil. MS(ESI)m / z: 387.8 [M+1] + .

[0221] Step J2: 5-Bromo-3-(bromomethyl)picolinate methyl 5-bromo-3-(bromomethyl)picolinate [ka]

[0222] A mixture of methyl 5-bromo-3-(dibromomethyl)picolinate (13.689 g, 35.29 mmol), N-ethyl-N-isopropylpropan-2-amine (5.018 g, 38.82 mmol), and 1-ethoxyphosphonoyloxyethane (5.362 g, 38.82 mmol) / THF (150 mL) was stirred at 25°C for 12 hours. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (50 mL x 2). The organic layers were combined and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-25% ethyl acetate / petroleum ether) to obtain methyl 5-bromo-3-(bromomethyl)picolinate (10.670 g, 34.54 mmol, 98% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ 8.69 (d, J=2.4 Hz, 1H), 8.06 (d, J=2.4 Hz, 1H), 4.89 (s, 2H), 4.02 (s, 3H). MS(ESI)m / z: 309.9 [M+1] + .

[0223] Step J3: tert-butyl(S)-5-amino-4-(3-bromo-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-yl)-5-oxopentanoate [ka]

[0224] A mixture of methyl 5-bromo-3-(bromomethyl)picolinate (10.670 g, 34.54 mmol), tert-butyl(S)-4,5-diamino-5-oxopentanoate (9.080 g, 44.90 mmol), and N-ethyl-N-isopropylpropan-2-amine (12.0 mL, 69.07 mmol) / acetonitrile (150 mL) was stirred under nitrogen at 100°C for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-80% ethyl acetate / petroleum ether) to obtain tert-butyl(S)-5-amino-4-(3-bromo-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-yl)-5-oxopentanoate (13.750 g, 34.53 mmol, 100% yield) as a pale yellow solid. 1 H NMR (400MHz, DMSO-d6)δ 8.84(d, J=2.0 Hz, 1H), 8.38(d, J=2.0 Hz, 1H), 7.62(s, 1H), 7.24(s, 1H), 4.82 - 4.71(m, 1H), 4.64 - 4.56(m, 1H), 4.53 - 4.43(m, 1H), 2.23 - 2.13(m, 3H), 1.95(s, 1H), 1.32(s, 9H). MS(ESI)m / z: 400.0 [M+1] + .

[0225] Step J4: tert-butyl(S)-5-amino-5-oxo-4-(7-oxo-3-vinyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-yl)pentanoate [ka] A mixture of tert-butyl(S)-5-amino-4-(3-bromo-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-yl)-5-oxopentanoate (2.000 g, 5.02 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.160 g, 7.53 mmol), 2M potassium carbonate (5.0 mL, 10.04 mmol), and bis-triphenylphosphine-palladium(II) chloride (0.353 g, 0.50 mmol) / DMF (20 mL) was stirred at 110°C for 1 hour under nitrogen. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (50 mL x 2). The organic layers were combined and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-81% ethyl acetate / petroleum ether) to obtain tert-butyl(S)-5-amino-5-oxo-4-(7-oxo-3-vinyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-yl)pentanoate (1,700 g, 4.92 mmol, 98% yield) as a yellow oily substance. 1 H NMR (400MHz, DMSO-d6)δ 8.80(d, J=1.6 Hz, 1H), 8.19(d, J=1.6 Hz, 1H), 7.61(s, 1H), 7.22(s, 1H), 6.91(dd, J=11.2, 17.6 Hz, 1H), 6.12(d, J=17.6 Hz, 1H), 5.53(d, J=11.2 Hz, 1H), 4.77(dd, J=4.4, 10.4 Hz, 1H), 4.64 - 4.55(m, 1H), 4.53 - 4.43(m, 1H), 2.23 - 2.13(m, 3H), 2.07 - 1.99(m, 1H), 1.35 - 1.30(m, 9H). MS(ESI)m / z: 346.1 [M+1] + .

[0226] Step J5: tert-butyl(S)-5-amino-4-(3-(hydroxymethyl)-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-yl)-5-oxopentanoate [ka]

[0227] 1.700 g, 4.92 mmol of tert-butyl(S)-5-amino-5-oxo-4-(7-oxo-3-vinyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-yl)pentanoate was dissolved in 10 mL of dichloromethane and 10 mL of methanol, and then cooled to -78°C. The solution was saturated with ozone, and ozone was continuously bubbled through it for 30 minutes while stirring. Nitrogen was then passed through the solution while stirring for 10 minutes. The solution was heated to 0°C, and sodium borohydride (0.344 g, 9.10 mmol) was added. The mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched with water (2 mL), dried over anhydrous sodium sulfate solids, filtered, and concentrated under reduced pressure to obtain the crude product tert-butyl(S)-5-amino-4-(3-(hydroxymethyl)-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-yl)-5-oxopentanoate (1.700 g, 4.87 mmol, 98.9% yield) as a brown solid. MS(ESI)m / z: 350.3 [M+1] + .

[0228] Step J6: tert-butyl(S)-5-amino-4-(3-(bromomethyl)-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-yl)-5-oxopentanoate [ka]

[0229] To a solution of tert-butyl(S)-5-amino-4-(3-(hydroxymethyl)-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-yl)-5-oxopentanoate (1.700 g, 4.87 mmol) and triethylamine (2 mL, 14.6 mmol) / tetrahydrofuran (20 mL), methanesulfonic anhydride (1.695 g, 9.73 mmol) was added at 0°C. The mixture was then heated to 25°C and stirred for 2 hours. Lithium bromide (2.113 g, 24.33 mmol) was added, and the reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (20 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate solids, filtered, and concentrated under reduced pressure to obtain tert-butyl(S)-5-amino-4-(3-(bromomethyl)-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-yl)-5-oxopentanoate (1,600 g, 3.88 mmol, 80% yield) as a yellow oil. MS(ESI)m / z: 411.8 [M+1] + .

[0230] Intermediate K: tert-butyl(S)-5-amino-4-(4-fluoro-5-(((methylsulfonyl)oxy)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate [ka]

[0231] Step K1: tert-butyl(S)-5-amino-4-(4-fluoro-5-(hydroxymethyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate [ka]

[0232] A mixture of tert-butyl(S)-5-amino-4-(5-bromo-4-fluoro-1-oxoisoindorin-2-yl)-5-oxopentanoate (prepared as described in WO2022216644) (5.000 g, 12.04 mmol), tributylstannyl methanol (4.639 g, 14.45 mmol), and tetrakis(triphenylphosphine)palladium(0) (1.391 g, 1.20 mmol) / dioxane (50 mL) was stirred at 100 °C for 48 hours under nitrogen. The reaction mixture was quenched with potassium fluoride solution and filtered. The filtrate was extracted with ethyl acetate (50 mL x 2). The organic layers were combined and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to obtain tert-butyl(S)-5-amino-4-(4-fluoro-5-(hydroxymethyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (2.600 g, 7.10 mmol, 59% yield) as a white solid. MS(ESI)m / z: 372.2 [M+1] + .

[0233] Step K2: tert-butyl(S)-5-amino-4-(4-fluoro-5-(((methylsulfonyl)oxy)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate [ka]

[0234] To a solution of tert-butyl(S)-5-amino-4-(4-fluoro-5-(hydroxymethyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (2.600 g, 7.10 mmol) and N-ethyl-N-isopropylpropan-2-amine (6.2 mL, 35.48 mmol) / tetrahydrofuran (100 mL), methylsulfonyl methanesulfonate (3.708 g, 21.29 mmol) was added at 0°C. The mixture was then stirred at 25°C for 30 minutes. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 2). The organic layers were combined and dried over anhydrous sodium sulfate solids, filtered, and concentrated under reduced pressure to obtain the crude product tert-butyl(S)-5-amino-4-(4-fluoro-5-(((methylsulfonyl)oxy)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (2.550 g, 5.74 mmol, 81% yield) as a yellow oil. MS(ESI)m / z: 445.2 [M+1] + .

[0235] Intermediate L:tert-butyl(S)-5-amino-4-(7-fluoro-5-(((methylsulfonyl)oxy)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate [ka] [ka]

[0236] Step L1: 4-Bromo-2-fluoro-6-methylbenzoate [ka]

[0237] To a solution of 4-bromo-2-fluoro-6-methylbenzoic acid (35,000 g, 150.20 mmol) / methanol (250 mL), sulfuric acid (12 mL, 225.31 mmol) was added. The mixture was stirred at 80°C for 36 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with 200 mL of water and extracted with ethyl acetate (200 mL x 2). The organic layers were washed together with 200 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-30% ethyl acetate / petroleum ether) to obtain the product 4-bromo-2-fluoro-6-methylbenzoate methyl (35,000 g, 141.70 mmol, 94% yield) as a colorless oil. NMR (400 MHz, chloroform): δ 7.13 (s, 1H), 7.08 (d, J=9.2 Hz, 1H), 3.87 (s, 3H), 2.32 (s, 3H).

[0238] Step L2: 4-Bromo-2-(bromomethyl)-6-fluorobenzoate methyl [ka]

[0239] To a solution of methyl 4-bromo-2-fluoro-6-methylbenzoate (5.000 g, 20.24 mmol) / acetonitrile (250 mL), N-bromosuccinimide (9.010 g, 50.59 mmol) and (E)-2,2'-(diazene-1,2-diyl)bis(2-methylpropanenitrile) (3.320 g, 20.24 mmol) were added. The mixture was stirred at 80°C for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (200 mL) and extracted with ethyl acetate (100 mL x 2). The organic layers were combined, washed with 200 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-5% ethyl acetate / petroleum ether) to obtain the crude product methyl 4-bromo-2-(bromomethyl)-6-fluorobenzoate (4.500 g, 13.81 mmol, 68.2% yield) as a yellow oily substance. 1¹H NMR (400 MHz, chloroform): δ 7.39 (s, 1H), 7.30 - 7.27 (m, 1H), 4.61 (s, 2H), 3.98 (s, 3H).

[0240] Step L3: tert-butyl(S)-5-amino-4-(5-bromo-7-fluoro-1-oxoisoindolin-2-yl)-5-oxopentanoate

[0241] Potassium iodide (1.78 g, 10.74 mmol) was added to a solution of methyl 4-bromo-2-(bromomethyl)-6-fluorobenzoate (3.500 g, 10.74 mmol), tert-butyl(S)-4,5-diamino-5-oxopentanoate (3.260 g, 16.11 mmol), and potassium carbonate (4.450 g, 32.21 mmol) / acetonitrile (50 mL). The reaction mixture was stirred at 80°C for 12 hours. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (150 mL x 3). The collected organic layer was washed with saturated brine (80 mL x 3). The organic layer was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-60% ethyl acetate / petroleum ether) and concentrated to obtain tert-butyl(S)-5-amino-4-(5-bromo-7-fluoro-1-oxoisoindorin-2-yl)-5-oxopentanoate (4.000 g, 9.63 mmol, 90% yield) as a yellow solid. 1 ¹H NMR (400 MHz, chloroform) δ 7.43 (d, J=0.8 Hz, 1H), 7.32 - 7.27 (m, 1H), 6.51 (s, 1H), 5.41 (s, 1H), 4.90 (dd, J=6.4, 8.8 Hz, 1H), 4.66 - 4.40 (m, 2H), 2.44 - 2.44 (m, 1H), 2.38 - 2.20 (m, 3H), 2.17 - 2.07 (m, 1H), 1.42 (s, 9H). MS (ESI) m / z: 359.0 [M-55] + .

[0242] Step L4: tert-butyl(S)-5-amino-4-(7-fluoro-5-(hydroxymethyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate [ka]

[0243] (Tributylstannyl)methanol (0.464 g, 1.44 mmol) was added to a solution of tert-butyl(S)-5-amino-4-(5-bromo-7-fluoro-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.500 g, 1.20 mmol) and tetrakis(triphenylphosphine)palladium (0.278 g, 0.24 mmol) / 1,4-dioxane (20 mL). The reaction mixture was stirred at 100 °C for 36 hours. The mixture was quenched with potassium fluoride solution and extracted with ethyl acetate (80 mL x 2). The organic layers were combined and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-95% ethyl acetate / petroleum ether) and concentrated to obtain tert-butyl(S)-5-amino-4-(7-fluoro-5-(hydroxymethyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.450 g, 1.23 mmol, 102% yield) as a yellow solid. 1 ¹H NMR (400MHz, chloroform) δ 7.19 (s, 1H), 7.05 (s, 1H), 6.98 (d, J=10.0 Hz, 1H), 5.67 (s, 1H), 4.92 (dd, J=6.0, 8.4 Hz, 1H), 4.74 (s, 2H), 4.58 - 4.33 (m, 2H), 3.45 - 2.70 (m, 1H), 2.37 - 2.18 (m, 3H), 2.15 - 2.06 (m, 1H), 1.41 (s, 9H). MS (ESI) m / z: 311.0 [M-55] + .

[0244] Step L5: tert-butyl(S)-5-amino-4-(7-fluoro-5-(((methylsulfonyl)oxy)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate [ka]

[0245] To a solution of tert-butyl(S)-5-amino-4-(7-fluoro-5-(hydroxymethyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.450 g, 1.23 mmol) and triethylamine (0.5 mL, 3.00 mmol) / THF (20 mL), methanesulfonic anhydride (0.387 g, 1.47 mmol) was added at 0°C. The reaction mixture was stirred at 25°C for 0.5 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate solids, filtered, and concentrated under reduced pressure to obtain tert-butyl(S)-5-amino-4-(7-fluoro-5-(((methylsulfonyl)oxy)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.480 g, 1.08 mmol, 88% yield) as a yellow solid. MS(ESI)m / z: 445.1 [M+1] + .

[0246] Intermediate M: 3-chloro-2-(tributylstannyl)-5-(trifluoromethyl)pyridine [ka]

[0247] To a solution of 2-bromo-3-chloro-5-(trifluoromethyl)pyridine (5.000 g, 19.20 mmol) / toluene (80 mL), 2.5 M n-butyllithium (9.2 mL, 23.04 mmol) was added at -78°C. The mixture was stirred under nitrogen at -78°C for 1 hour. Then, tributylchlorostannane (7.8 mL, 28.85 mmol) was added, and the mixture was stirred under nitrogen at -78°C for 2 hours. The reaction mixture was quenched with saturated aqueous solution of ammonium chloride (200 mL) and extracted with ethyl acetate (100 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by neutral alumina chromatography (eluted with 100% petroleum ether) to obtain 3-chloro-2-(tributylstannyl)-5-(trifluoromethyl)pyridine (7,000 g, 14.88 mmol, 78% yield) as a colorless oil. 1 H NMR (400MHz, CDCl3)δ 8.87(s, 1H), 7.73(s, 1H), 1.60 - 1.56(m, 6H), 1.37 - 1.29(m, 7H), 1.26 - 1.21(m, 5H), 0.89(t, J=7.2 Hz, 9H).

[0248] Intermediate N:2-(2-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] Step N1: 1-Bromo-2-chloro-4-(2,2,2-trifluoroethoxy)benzene. Potassium carbonate (1,330 g, 9.64 mmol) was added to a solution of 4-bromo-3-chlorophenol (1,000 g, 4.82 mmol) in dimethylformamide (10 mL). The mixture was stirred at 25°C for 0.5 hours. Then, 2,2,2-trifluoroethyl trifluoromethanesulfonic acid (1,170 g, 5.06 mmol) dissolved in dimethylformamide (10 mL) was added, and the mixture was stirred at 100°C for 12 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic layers were combined, washed with saturated sodium chloride (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1-bromo-2-chloro-4-(2,2,2-trifluoroethoxy)benzene (1,300 g, 4.49 mmol, 93% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ 7.53 (d, J=8.8 Hz, 1H), 7.07 (d, J=2.8 Hz, 1H), 6.75 (dd, J=2.8, 8.8 Hz, 1H), 4.33 (q, J=8.0 Hz, 2H).

[0249] Step N2: 2-(2-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. To a solution of 1-bromo-2-chloro-4-(2,2,2-trifluoroethoxy)benzene (0.200 g, 0.69 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.211 g, 0.83 mmol) / 1,4-dioxane (2 mL), potassium acetate (0.203 g, 2.07 mmol) and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (0.056 g, 0.07 mmol) were added. The mixture was stirred under nitrogen at 100 °C for 12 hours. The mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (9% ethyl acetate / petroleum ether) to obtain 2-(2-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.050 g, 0.15 mmol, 22% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ 7.69 (d, J=8.4 Hz, 1H), 6.96 (d, J=2.4 Hz, 1H), 6.83 (dd, J=2.4, 8.4 Hz, 1H), 4.40 - 4.33 (m, 2H).

[0250] Intermediate O:2-[3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propan-2-ol [ka] Step O1: 2-(4-bromo-3-chlorophenyl)propan-2-ol. Methylmagnesium bromide (5.34 mL, 16.03 mmol) was added to a solution of methyl 4-bromo-3-chlorobenzoate (2.000 g, 8.02 mmol) / tetrahydrofuran (20 mL) under nitrogen at -78°C. The mixture was stirred under nitrogen at 25°C for 2 hours. The mixture was poured into saturated ammonium chloride (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic layers were combined, washed with brine (50 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10-30% ethyl acetate / petroleum ether) to obtain product 2-(4-bromo-3-chlorophenyl)propan-2-ol (1.500 g, 6.01 mmol, 75% yield) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ 7.60(d, J=2.4, 1H), 7.60(d, J=8.4, 1H), 7.24 - 7.22(m, 1H), 1.57(s, 6H).

[0251] Step O2: 2-[3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propan-2-ol. To a solution of 2-(4-bromo-3-chlorophenyl)propan-2-ol (1.500 g, 6.01 mmol) / 1,4-dioxane (15 mL), bis(pinacorato)diborone (3.050 g, 12.02 mmol), potassium acetate (1.770 g, 18.03 mmol), and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (0.491 g, 0.60 mmol) were added. The mixture was stirred under nitrogen at 85°C for 12 hours. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10-30% ethyl acetate / petroleum ether) to obtain 2-[3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propan-2-ol (1,500 g, 5.06 mmol, 84% yield) as a colorless oil. 1H NMR (400MHz, CDCl3) δ 7.67(d, J=7.6 Hz, 1H), 7.34(d, J=1.6 Hz, 1H), 1.57(s, 6H), 1.37(s, 12H).

[0252] Intermediate P: 2-[4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propan-2-ol [ka] Step P1: 2-(3-bromo-4-chlorophenyl)propan-2-ol. Methylmagnesium bromide (4.01 mL, 12.02 mmol) was added at 0°C to a solution of methyl 3-bromo-4-chlorobenzoate (1.000 g, 4.01 mmol) / tetrahydrofuran (10 mL). The mixture was stirred at 25°C for 12 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The organic layers were washed together with saturated brine (10 mL x 2) and dried over anhydrous sodium sulfate. The organic layers were filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (9%~33% ethyl acetate / petroleum ether) to obtain 2-(3-bromo-4-chlorophenyl)propan-2-ol (0.870 g, 3.49 mmol, 87% yield) as a white oil. 1 H NMR (400MHz, CDCl3) δ 7.77 (s, 1H), 7.42 - 7.40 (m, 1H), 7.37 - 7.35 (m, 1H), 1.57 (s, 6H).

[0253] Step P2: 2-[4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propan-2-ol. To a solution of 2-(3-bromo-4-chlorophenyl)propan-2-ol (1,300 g, 5.21 mmol) and bis(pinacolato)diborone (1,455 g, 5.73 mmol) / 1,4-dioxane (15 mL), (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (0.425 g, 0.52 mmol) and potassium acetate (1.531 g, 15.63 mmol) were added. The mixture was stirred under nitrogen at 85°C for 12 hours. The mixture was concentrated under reduced pressure and purified by silica gel chromatography (0%~25% ethyl acetate / petroleum ether) to obtain 2-[4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propan-2-ol (1.100 g, 3.71 mmol, 71% yield) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ 7.78(d, J=2.4 Hz, 1H), 7.42(s, 1H), 7.30(d, J=2.0 Hz, 1H), 1.57(s, 6H), 1.38(s, 12H).

[0254] Synthesis example

[0255] Example 2: (3S)-3-[5-({5-chloro-4-[3-chloro-5-(trifluoromethyl)pyridine-2-yl]-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl}methyl)-1-oxo-2,3-dihydro-1H-isoindole-2-yl]piperidine-2,6-dione [ka]

[0256] A. (3S)-3-(5-((5-chloro-4-(3-chloro5-(trifluoromethyl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione. (S)-3-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (165 mg, 0.263 mmol) (synthesized according to Example 6) was dissolved in DMF (3 mL) and treated with N-chlorosuccinimide (42.1 mg, 0.315 mmol). The reaction mixture was sealed and heated in a microwave reactor at 100°C for 30 minutes. The reaction mixture was purified by preparative HPLC using the following method: column: X-bridge C18 (150x19) mm, 5 micron; diluent: THF:water:ACN (50:20:30); mobile phase A: 5 mM ammonium formate / water; mobile phase B: acetonitrile to obtain (3S)-3-(5-((5-chloro-4-(3-chloro5-(trifluoromethyl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (54 mg, 0.079 mmol, 30.2% yield) as an off-white solid. 1H NMR (400MHz, DMSO-d6)δ 10.98(br s, 1H), 9.16(d, J=1.0 Hz, 1H), 8.79(d, J=1.5 Hz, 1H), 7.72(d, J=8.0 Hz, 1H), 7.67(s, 1H), 7.55(s, 1H), 7.48(d, J=7.5 Hz, 1H), 5.73 - 5.61(m, 2H), 5.59 - 5.38(m, 1H), 5.10(dd, J=5.3, 13.3 Hz, 1H), 4.77 - 4.61 (m, 2H), 4.50 - 4.26 (m, 4H), 2.98 - 2.85 (m, 1H), 2.65 - 2.56(m, 1H), 2.43 - 2.34(m, 1H), 2.06 - 1.94(m, 1H); MS(ESI, +ve)m / z: 662.1(M+1) + .

[0257] Example 3: 3-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-5-fluoro-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione [ka]

[0258] A. tert-butyl(4S)-5-amino-4-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-5-fluoro-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate. To a solution of tert-butyl(S)-5-amino-4-(5-((5-fluoro-6-(3-fluoroazetidine-1-yl)-4-iodo-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (intermediate H) (0.120 g, 0.18 mmol) / 1,4-dioxane (3 mL), 3-chloro-2-(tributylstannyl)-5-(trifluoromethyl)pyridine (intermediate M) (0.085 g, 0.18 mmol), tetrakis(triphenylphosphine)palladium(0) (0.016 g, 0.02 mmol), and copper(I) iodide (0.003 g, 0.02 mmol) were added under nitrogen. The mixture was stirred at 85°C for 12 hours. The reaction mixture was quenched with 50 mL of aqueous potassium fluoride solution, then diluted with water (50 mL), and extracted with ethyl acetate (50 mL x 2). The organic layers were washed together with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC. The substance was further purified by semi-preparative reverse-phase HPLC (55%~85% acetonitrile / water + 0.225% formic acid, 5 min). The fraction of interest was concentrated under vacuum and then extracted with ethyl acetate (100 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain tert-butyl(4S)-5-amino-4-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-5-fluoro-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.060 g, 0.08 mmol, 46% yield) as a yellow solid. MS(ESI)m / z: 720.2 [M+1] + .

[0259] B.(4S)-5-amino-4-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-5-fluoro-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoic acid. To a solution of tert-butyl(4S)-5-amino-4-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-5-fluoro-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.060 g, 0.08 mmol) / dichloromethane (2 mL), TFA (0.5 mL) was added. The reaction mixture was quenched with N-ethyl-N-isopropylpropan-2-amine (5 mL), then diluted with water (20 mL), and extracted with ethyl acetate (20 mL x 2). The organic layers were combined and concentrated under reduced pressure to obtain crude (4S)-5-amino-4-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-5-fluoro-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoic acid (0.050 g, 0.08 mmol, 90.4% yield). The substance was used in the next step without purification. MS(ESI)m / z: 664.1 [M+1] + .

[0260] C.3-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-5-fluoro-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione. (4S)-5-amino-4-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-5-fluoro-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoic acid (0.050 g, 0.08 mmol) / acetonitrile (3 mL) was mixed with N-ethyl-N-isopropylpropan-2-amine (0.02 mL, 0.23 mmol), di(1H-imidazole-1-yl)methanone (0.012 g, 0.08 mmol), and N,N-dimethylpyridine-2-amine (0.010 g, 0.08 mmol). The mixture was stirred at 80°C for 12 hours. The reaction products were purified by semi-preparative reverse-phase HPLC (47%-77% acetonitrile / water + 0.225% formic acid, 5 minutes). The fraction of interest was concentrated under vacuum and then freeze-dried to obtain 3-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-5-fluoro-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (0.025 g, 0.04 mmol, 51% yield, 100% purity) as a yellow solid. 1H NMR (400MHz, DMSO)δ 11.17 - 10.76(m, 1H), 9.16(d, J=1.2 Hz, 1H), 8.78(d, J=1.6 Hz, 1H), 7.74 - 7.68(m, 2H), 7.53 - 7.49(m, 1H), 7.43(d, J=7.6 Hz, 1H), 5.64(s, 2H), 5.62 - 5.43(m, 1H), 5.10(dd, J=5.2, 12.8 Hz, 1H), 4.65 - 4.53(m, 2H), 4.47 - 4.41(m, 1H), 4.37 - 4.24(m, 3H), 2.96 - 2.84 (m, 1H), 2.58 - 2.56 (m, 1H), 2.43 - 2.36 (m, 1H), 2.03 - 1.94 (m, 1H). MS(ESI)m / z: 646.2 [M+1] + .

[0261] Example 6: (3S)-3-[5-({4-[3-chloro-5-(trifluoromethyl)pyridine-2-yl]-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl}methyl)-1-oxo-2,3-dihydro-1H-isoindole-2-yl]piperidine-2,6-dione [ka]

[0262] A.tert-butyl(S)-5-amino-4-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-6-fluoro-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate. To a solution of 3-chloro-2-(tributylstannyl)-5-(trifluoromethyl)pyridine (intermediate M) (119 mg, 0.253 mmol) / 1,4-dioxane (5 mL), tert-butyl(S)-5-amino-4-(5-((6-fluoro-4-iodo-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (intermediate C) (100 mg, 0.169 mmol), copper(I) iodide (48.1 mg, 0.253 mmol), and tetrakis(triphenylphosphine)palladium(O) (29.2 mg, 0.025 mmol) were added. The mixture was stirred at 100°C under nitrogen for 12 hours. The reaction mixture was filtered through Celite, washed with ethyl acetate, and concentrated under vacuum. The residue was purified by reverse-phase HPLC (using an acetonitrile / 0.1% formic acid gradient) to obtain t-butyl(S)-5-amino-4-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-6-fluoro-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (70 mg, 0.108 mmol, 64.1% yield) as an off-white solid. MS(ESI)m / z: 647.0 [M] + .

[0263] B.tert-butyl(S)-5-amino-4-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate. To a stirred solution of tert-butyl(S)-5-amino-4-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-6-fluoro-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (100 mg, 0.147 mmol) / acetonitrile (3 mL), 3-fluoroazetidine HCl (35 mg, 0.314 mmol) was added, and the mixture was stirred at 80°C for 4 hours. The mixture was evaporated under vacuum, the residue was diluted with DCM (5 mL), washed with water (5 mL), and the organic layer was concentrated to obtain tert-butyl(S)-5-amino-4-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate 3 (100 mg, 0.122 mmol, 83% yield) as a yellow solid. MS(ESI, +ve)m / z: 702.3(M+1) + .

[0264] (S)-3-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione. To a stirred solution of tert-butyl(S)-5-amino-4-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5 oxopentanoate (100 mg, 0.122 mmol) / acetonitrile (3 mL), p-toluenesulfonic acid (106 mg, 0.558 mmol) was added, and the mixture was stirred overnight at 60°C. The reaction mixture was evaporated, and the crude product was purified by preparative HPLC (under the following conditions: column: Xselect CSH C18 (250x19) mm 10.0 μm, mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, flow rate: 14 mL / min, 15-90% B for 20 minutes). The resulting fraction was evaporated, and the residue was dissolved in ACN / water (1:1 mixture, 5 mL) for 24 hours, lyophilized, and (S)-3-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (39 mg, 0.062 mmol, 50.7% yield) as an off-white solid. 1H NMR (400MHz, DMSO-d6)δ: 10.98(s, 1H), 9.13(dd, J=1.9, 0.8 Hz, 1H), 8.70-8.74(m, 1H), 7.80(s, 1H), 7.70(d, J=7.9 Hz, 1H), 7.50(s, 1H), 7.42(d, J=8.8 Hz, 1H), 6.63(s, 1H), 5.59-5.70(m, 3H), 5.48(dq, J=5.8, 3.0 Hz, 1H), 5.10(dd, J=13.3, 5.1 Hz, 1H), 4.38-4.52(m, 2H), 4.12-4.34(m, 3H), 2.85-2.96(m, 1H), 2.28-2.49(m, 2H), 1.92-2.04(m, 1H). MS(ESI,+ve)m / z: 628.2(M+1) + .

[0265] Example 9: (3S)-3-(5-((4-(3-chloro-5-fluoropyridine-2-yl)-5-fluoro-6-(isopropylamino)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione [ka]

[0266] A. tert-butyl(S)-5-amino-4-(5-((4-iodo-6-(isopropylamino)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate. To a solution of tert-butyl(S)-5-amino-4-(5-((6-fluoro-4-iodo-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (intermediate C) (0.350 g, 0.59 mmol) / acetonitrile (4 mL), propan-2-amine (0.042 g, 0.71 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.3 mL, 1.77 mmol) were added. The mixture was stirred at 50°C for 12 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain tert-butyl(S)-5-amino-4-(5-((4-iodo-6-(isopropylamino)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.350 g, 0.55 mmol, 93.8% yield) as a yellow oil. MS(ESI)m / z: 633.3 [M+1] + .

[0267] B.tert-butyl(S)-5-amino-4-(5-((5-fluoro-4-iodo-6-(isopropylamino)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate. To a solution of tert-butyl(S)-5-amino-4-(5-((4-iodo-6-(isopropylamino)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.350 g, 0.55 mmol) / acetonitrile (4 mL), 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanefluoride (tetrafluoroborate) (0.235 g, 0.66 mmol) was added. The mixture was stirred at 25°C for 3 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by semi-preparative reverse-phase HPLC (53-83% acetonitrile / water + 0.225% formic acid, 7 minutes). The collected fraction was then concentrated to remove most of the acetonitrile, and subsequently lyophilized to obtain the product tert-butyl(S)-5-amino-4-(5-((5-fluoro-4-iodo-6-(isopropylamino)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.120 g, 0.18 mmol, 33.3% yield) as a yellow oil. 1 H NMR(400MHz, CDCl3)δ 7.78(d, J=7.6 Hz, 1H), 7.60(s, 1H), 7.48(d, J=8.0 Hz, 1H), 7.40(s, 1H), 6.39(s, 1H), 5.67(s, 1H), 5.58(s, 2H), 4.91 - 4.85 (m, 2H), 4.50 - 4.36 (m, 2H), 4.33 - 4.28 (m, 1H), 2.36 - 2.10 (m, 4H), 1.41 (s, 9H), 1.31 (d, J=6.4 Hz, 6H). MS(ESI)m / z: 651.1 [M+1] + .

[0268] C.tert-butyl(4S)-5-amino-4-(5-((4-(3-chloro-5-fluoropyridine-2-yl)-5-fluoro-6-(isopropylamino)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate. To a solution of tert-butyl(S)-5-amino-4-(5-((5-fluoro-4-iodo-6-(isopropylamino)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.100 g, 0.15 mmol) / dioxane (1 mL), 3-chloro-5-fluoro-2-(tributylstannyl)pyridine (intermediate G) (0.071 g, 0.17 mmol), tetrakis(triphenylphosphine)palladium (0) (0.014 g, 0.02 mmol), and copper(I) iodide (0.029 g, 0.15 mmol) were added. The mixture was stirred under nitrogen at 85°C for 12 hours. The mixture was filtered and concentrated. The mixture was then purified by preparative TLC (80% ethyl acetate / petroleum ether) to obtain the product tert-butyl(4S)-5-amino-4-(5-((4-(3-chloro-5-fluoropyridine-2-yl)-5-fluoro-6-(isopropylamino)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.050 g, 0.08 mmol, 49.7% yield) as a yellow oil. MS(ESI)m / z: 654.2 [M+1] + .

[0269] D.(3S)-3-(5-((4-(3-chloro-5-fluoropyridine-2-yl)-5-fluoro-6-(isopropylamino)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione. To a solution of tert-butyl(4S)-5-amino-4-(5-((4-(3-chloro-5-fluoropyridine-2-yl)-5-fluoro-6-(isopropylamino)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.040 g, 0.06 mmol) / acetonitrile (1 mL), p-toluenesulfonic acid (0.021 g, 0.12 mmol) was added. The mixture was stirred at 60°C for 12 hours, then at 80°C for 3 hours. The mixture was treated with an aqueous sodium bicarbonate solution (8 mL), diluted with water (2 mL), and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by semi-preparative reverse-phase HPLC (43-73% acetonitrile / water + 0.225% formic acid, 7 minutes). The desired fraction was concentrated under vacuum and then freeze-dried to obtain the product. The product was separated by SFC separation (column: DAIEL CHIRALPAK IC (250 mm x 30 mm, 10 μm), mobile phase: phase A CO2, phase B IPA (0.1% NH3H2O); gradient elution: IPA (0.1% NH3H2O) / CO2 60%-60%, flow rate: 80 mL / min; 7 min, 50 min) to obtain two fractions. The early elution fraction was concentrated under vacuum to obtain the residue. The residue was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was redissolved in water (10 mL) and acetonitrile (10 mL), and then lyophilized to obtain the product (3S)-3-(5-((4-(3-chloro-5-fluoropyridine-2-yl)-5-fluoro-6-(isopropylamino)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (0.013 g, 0.02 mmol, 37.5% yield, 99.2% purity, 100% ee) as an off-white solid.1 H NMR (400MHz, DMSO-d6)δ 10.97(d, J=2.0 Hz, 1H), 8.81(d, J=2.4 Hz, 1H), 8.37(dd, J=2.8, 8.0 Hz, 1H), 7.74 - 7.68(m, 1H), 7.52(s, 2H), 7.44(d, J=8.0 Hz, 1H), 7.18(d, J=7.6 Hz, 1H), 5.60(s, 2H), 5.09(dd, J=4.8, 13.2 Hz, 1H), 4.45 - 4.27 (m, 3H), 2.88 (d, J=13.6 Hz, 1H), 2.59 (s, 1H), 2.40 - 2.37(m, 1H), 1.99 - 1.95(m, 1H), 1.25(dd, J=2.8, 6.8 Hz, 6H). MS(ESI)m / z: 580.2[M+1] + .

[0270] Example 13: 5-Chloro-6-(6-(dimethylamino)-1-((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)methyl)-1H-pyrrolo[2,3-b]pyridine-4-yl)nicotinonitrile [ka]

[0271] A. tert-butyl 5-amino-4-[5-[(6-amino-4-bromo-pyrrolo[2,3-b]pyridine-1-yl)methyl]-1-oxo-isoindorin-2-yl]-5-oxo-pentanoate. To a solution of 4-bromo-1H-pyrrolo[2,3-b]pyridine-6-amine (0.420 g, 1.98 mmol) / DMF (4 mL), tert-butyl 5-amino-4-[5-(bromomethyl)-1-oxo-isoindorin-2-yl]-5-oxo-pentanoate (intermediate C) (0.815 g, 1.98 mmol) and cesium carbonate (1.931 g, 5.94 mmol) were added. The mixture was stirred at 40°C for 2 hours. The mixture was purified by semi-preparative reverse-phase HPLC (Phenomenex Synergi Max-RP 250x50mmx10μm, 25-55% acetonitrile / water + 0.1% TFA, 22 minutes). The fraction of interest was concentrated to remove most of the acetonitrile, and then lyophilized to obtain the product tert-butyl 5-amino-4-[5-[(6-amino-4-bromo-pyrrolo[2,3-b]pyridine-1-yl)methyl]-1-oxo-isoindorin-2-yl]-5-oxo-pentanoate (0.450 g, 0.83 mmol, 41.9% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6)δ 7.62(d, J=7.6 Hz, 1H), 7.51(s, 1H), 7.35(s, 1H), 7.25(d, J=7.6 Hz, 1H), 7.19 - 7.12(m, 2H), 6.56(s, 1H), 6.22(d, J=3.6 Hz, 1H), 5.39(s, 2H), 4.70 - 4.65(m, 1H), 4.54 - 4.50(m, 1H), 4.42 - 4.37(s, 1H), 2.17 - 2.05(m, 3H), 1.98 - 1.87(m, 1H), 1.30(s, 9H). MS(ESI)m / z: 542.0[M+1] + .

[0272] B. tert-butyl 5-amino-4-[5-[[4-bromo-6-(dimethylamino)pyrrolo[2,3-b]pyridine-1-yl]methyl]-1-oxo-isoindorin-2-yl]-5-oxo-pentanoate. To a solution of tert-butyl 5-amino-4-[5-[(6-amino-4-bromo-pyrrolo[2,3-b]pyridine-1-yl)methyl]-1-oxo-isoindorin-2-yl]-5-oxo-pentanoate (0.400 g, 0.74 mmol) / methanol (4 mL), formaldehyde (0.12 mL, 2.21 mmol) and acetic acid (0.1 mL) were added. The mixture was stirred at 25°C for 10 minutes. Then, borane; 2-methylpyridine (0.237 g, 2.21 mmol) was added to the mixture. The mixture was stirred at 25°C for 2 hours. The mixture was purified by semi-preparative reverse-phase HPLC (Waters Xbridge C18 150x50mmx10μm, 46-76% acetonitrile / water + 10mM ammonium bicarbonate, 11 minutes). The collected fraction was then concentrated to remove most of the acetonitrile, and then lyophilized to obtain the product tert-butyl 5-amino-4-[5-[[4-bromo-6-(dimethylamino)pyrrolo[2,3-b]pyridine-1-yl]methyl]-1-oxo-isoindorin-2-yl]-5-oxo-pentanoate (0.070 g, 0.12 mmol, 16.6% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6)δ 7.63(d, J=7.6 Hz, 1H), 7.50(s, 2H), 7.39(d, J=7.6 Hz, 1H), 7.29(d, J=3.6 Hz, 1H), 7.14(s, 1H), 6.71(s, 1H), 6.23(d, J=3.6 Hz, 1H), 5.41(s, 2H), 4.72 - 4.65(m, 1H), 4.56 - 4.49(m, 1H), 4.44 - 4.37(m, 1H), 3.05(s, 6H), 2.12(s, 3H), 1.97 - 1.88(m, 1H), 1.30(s, 9H). MS(ESI)m / z: 570.1[M+1] + .

[0273] C.tert-butyl 5-amino-4-[5-[[4-(2-chloro-4-cyanophenyl)-6-(dimethylamino)pyrrolo[2,3-b]pyridine-1-yl]methyl]-1-oxo-isoindorin-2-yl]-5-oxo-pentanoate. To a solution of tert-butyl 5-amino-4-[5-[[4-bromo-6-(dimethylamino)pyrrolo[2,3-b]pyridine-1-yl]methyl]-1-oxo-isoindorin-2-yl]-5-oxo-pentanoate (0.080 g, 0.14 mmol) / 1,4-dioxane (2 mL), 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (0.055 g, 0.21 mmol), sodium carbonate (0.21 mL, 0.42 mmol), and tetrakis[triphenylphosphine]palladium (0) (0).012 g, 0.01 mmol) were added. The mixture was stirred under nitrogen at 100 °C for 12 hours. The mixture was purified by semi-preparative reverse-phase HPLC (Phenomenex Synergi C18 150x25mmx10μm, 60-90% acetonitrile / water + 0.1% TFA, 10 minutes). The collected fraction was then concentrated to remove most of the acetonitrile, and subsequently lyophilized to obtain the product tert-butyl 5-amino-4-[5-[[4-(2-chloro-4-cyanophenyl)-6-(dimethylamino)pyrrolo[2,3-b]pyridine-1-yl]methyl]-1-oxo-isoindorin-2-yl]-5-oxo-pentanoate (0.050 g, 0.08 mmol, 56.8% yield) as a yellow solid. MS(ESI)m / z: 627.3[M+1] + .

[0274] D.3-Chloro-4-[6-(dimethylamino)-1-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindorin-5-yl]methyl]pyrrolo[2,3-b]pyridin-4-yl]benzonitrile. tert-butyl 5-amino-4-[5-[[4-(2-chloro-4-cyanophenyl)-6-(dimethylamino)pyrrolo[2,3-b]pyridin-1-yl]methyl]-1-oxo-isoindorin-2-yl]-5-oxo-pentanoate (0.050 g, 0.08 mmol) / acetonitrile (2 mL) was mixed with methanesulfonic acid (0.023 g, 0.24 mmol). The mixture was stirred at 80°C for 12 hours. The mixture was purified by semi-preparative reverse-phase HPLC (Phenomenex Luna C18 75x30mmx3μm, 48-78% acetonitrile / water + 0.1% TFA, 7 minutes). The collected fraction was then concentrated to remove most of the acetonitrile, and subsequently lyophilized to obtain the product 3-chloro-4-[6-(dimethylamino)-1-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindorin-5-yl]methyl]pyrrolo[2,3-b]pyridine-4-yl]benzonitrile (24.06 mg, 0.0428 mmol, 54% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6)δ 10.98(s, 1H), 8.22(d, J=1.6 Hz, 1H), 7.96 - 7.91(m, 1H), 7.71 - 7.64(m, 2H), 7.58(s, 1H), 7.49(d, J=8.0 Hz, 1H), 7.27(d, J=3.6 Hz, 1H), 6.46(s, 1H), 5.99(d, J=3.6 Hz, 1H), 5.46(s, 2H), 5.13 - 5.05(m, 1H), 4.45 - 4.41(m, 1H), 4.32 - 4.25(m, 1H), 3.09(s, 6H), 2.95 - 2.85 (m, 1H), 2.61 - 2.55 (m, 1H), 2.42 - 2.31 (m, 1H), 2.03 - 1.90 (m, 1H). MS(ESI)m / z: 553.2[M+1] + .

[0275] Example 14: 5-Chloro-6-(6-(dimethylamino)-1-((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)methyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-4-yl)nicotinonitrile [ka]

[0276] A. tert-butyl 5-amino-4-[5-[(6-amino-4-bromo-pyrrolo[2,3-b]pyridine-1-yl)methyl]-1-oxo-isoindorin-2-yl]-5-oxo-pentanoate. To a solution of 4-bromo-1H-pyrrolo[2,3-b]pyridine-6-amine (0.240 g, 1.13 mmol) / DMF (4 mL), tert-butyl 5-amino-4-[5-(chloromethyl)-1-oxo-isoindorin-2-yl]-5-oxo-pentanoate (prepared similarly to intermediate C) (0.415 g, 1.13 mmol) and cesium carbonate (1.103 g, 3.40 mmol) were added. The mixture was stirred at 40°C for 2 hours. The mixture was purified by semi-preparative reverse-phase HPLC (Phenomenex luna C18 150x40mmx15μm, 31-61% acetonitrile / water + 0.1% TFA, 11 minutes). The fractions of interest were combined, concentrated under vacuum, and then lyophilized to obtain the product tert-butyl 5-amino-4-[5-[(6-amino-4-bromo-pyrrolo[2,3-b]pyridine-1-yl)methyl]-1-oxo-isoindorin-2-yl]-5-oxo-pentanoate (0.240 g, 0.44 mmol, 39.1% yield) as a brown solid. MS(ESI)m / z: 542.0[M+1] +

[0277] B.tert-butyl 5-amino-4-[5-[[4-bromo-6-(dimethylamino)pyrrolo[2,3-b]pyridine-1-yl]methyl]-1-oxo-isoindorin-2-yl]-5-oxo-pentanoate. To a solution of tert-butyl 5-amino-4-[5-[(6-amino-4-bromo-pyrrolo[2,3-b]pyridine-1-yl)methyl]-1-oxo-isoindorin-2-yl]-5-oxo-pentanoate (0.230 g, 0.42 mmol) / methanol (3 mL), aldehyde (0.07 mL, 1.27 mmol) and acetic acid (0.1 mL) were added. The mixture was stirred at 25°C for 10 minutes. Then sodium borocyanohydride (0.081 g, 1.27 mmol) was added to the mixture. The mixture was stirred at 25°C for 2 hours. The mixture was purified by semi-preparative reverse-phase HPLC (Waters Xbridge 150x25mmx5μm, 50-80% acetonitrile / water + 10mM ammonium bicarbonate, 9 minutes). The fraction of interest was concentrated under vacuum and lyophilized to obtain the product tert-butyl 5-amino-4-[5-[[4-bromo-6-(dimethylamino)pyrrolo[2,3-b]pyridine-1-yl]methyl]-1-oxo-isoindorin-2-yl]-5-oxo-pentanoate (0.040 g, 0.07 mmol, 16.5% yield) as a white solid. MS(ESI)m / z: 570.1[M+1] + .

[0278] C. tert-butyl 5-amino-4-[5-[[4-bromo-6-(dimethylamino)-2,3-dihydropyrrolo[2,3-b]pyridine-1-yl]methyl]-1-oxo-isoindorin-2-yl]-5-oxo-pentanoate. To a solution of tert-butyl 5-amino-4-[5-[[4-bromo-6-(dimethylamino)pyrrolo[2,3-b]pyridine-1-yl]methyl]-1-oxo-isoindorin-2-yl]-5-oxo-pentanoate (0.040 g, 0.07 mmol) / acetic acid (1 mL), sodium borocyanohydride (0.022 g, 0.35 mmol) was added. The mixture was stirred at 25°C for 36 hours. The mixture was purified by semi-preparative reverse-phase HPLC (Phenomenex Luna C18 75x30mmx3μm, 38-68% acetonitrile / water + 0.1% TFA, 7 minutes). The fraction of interest was concentrated under vacuum and lyophilized to obtain tert-butyl 5-amino-4-[5-[[4-bromo-6-(dimethylamino)-2,3-dihydropyrrolo[2,3-b]pyridine-1-yl]methyl]-1-oxo-isoindorin-2-yl]-5-oxo-pentanoate (0.020 g, 0.03 mmol, 49.8% yield) as a yellow solid. MS(ESI)m / z: 572.0[M+1] + .

[0279] D.tert-butyl 5-amino-4-[5-[[4-(2-chloro-4-cyanophenyl)-6-(dimethylamino)-2,3-dihydropyrrolo[2,3-b]pyridine-1-yl]methyl]-1-oxo-isoindorin-2-yl]-5-oxo-pentanoate. To a solution of tert-butyl 5-amino-4-[5-[[4-bromo-6-(dimethylamino)-2,3-dihydropyrrolo[2,3-b]pyridine-1-yl]methyl]-1-oxo-isoindorin-2-yl]-5-oxo-pentanoate (0.020 g, 0.03 mmol) / 1,4-dioxane (1 mL), 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (0.014 g, 0.05 mmol), sodium carbonate (0.05 mL, 0.10 mmol), and tetrakis[triphenylphosphine]palladium (0) (0).010 g, 0.01 mmol) were added. The mixture was stirred under nitrogen at 100 °C for 12 hours. The mixture was purified by preparative TLC (9.1% methanol / dichloromethane) to obtain tert-butyl 5-amino-4-[5-[[4-(2-chloro-4-cyanophenyl)-6-(dimethylamino)-2,3-dihydropyrrolo[2,3-b]pyridine-1-yl]methyl]-1-oxo-isoindorin-2-yl]-5-oxo-pentanoate (0.020 g, 0.03 mmol, 91.0% yield) as a yellow solid. MS(ESI)m / z: 629.2[M+1] + .

[0280] E.3-Chloro-4-[6-(dimethylamino)-1-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]methyl]-2,3-dihydropyrrolo[2,3-b]pyridine-4-yl]benzonitrile. tert-butyl 5-amino-4-[5-[[4-(2-chloro-4-cyanophenyl)-6-(dimethylamino)-2,3-dihydropyrrolo[2,3-b]pyridine-1-yl]methyl]-1-oxo-isoindolin-2-yl]-5-oxo-pentanoate (0.020 g, 0.03 mmol) / acetonitrile (1 mL) was mixed with methanesulfonic acid (0.009 g, 0.10 mmol). The mixture was stirred at 80°C for 12 hours. The mixture was purified by semi-preparative reverse-phase HPLC (Phenomenex Synergi C18 150x25mmx10μm, 31-61% acetonitrile / water + 0.1% TFA, 10 minutes). The fraction of interest was concentrated under vacuum and then lyophilized to obtain 3-chloro-4-[6-(dimethylamino)-1-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindorin-5-yl]methyl]2,3-dihydropyrrolo[2,3-b]pyridine-4-yl]benzonitrile (7.7 mg, 0.013 mmol, 41% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6)δ 10.98(s, 1H), 8.16(d, J=1.6 Hz, 1H), 7.90 - 7.85(m, 1H), 7.70(d, J=8.0 Hz, 1H), 7.61 - 7.54(m, 2H), 7.49(d, J=8.0 Hz, 1H), 5.57(s, 1H), 5.14 - 5.07(m, 1H), 4.62(s, 2H), 4.43(s, 1H), 4.33 - 4.29(m, 1H), 3.37(t, J=8.0 Hz, 2H), 2.97(s, 6H), 2.92 - 2.87(m, 1H), 2.65 - 2.61(m, 3H), 2.44 - 2.34(m, 1H), 2.04 - 1.95(m, 1H). MS(ESI)m / z: 555.1[M+1] + .

[0281] Example 15: 3-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrrolo[2,3-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione [ka]

[0282] A. 4-chloro-1H-pyrrolo[2,3-b]pyridine 7-oxide 3-chlorobenzoate. 4-chloro-1H-pyrrolo[2,3-b]pyridine (2.00 g, 13.11 mmol) was suspended in a mixture of ethyl acetate (32.8 mL) and hexane (32.8 mL), and then cooled to 0°C. mCPBA (3.92 g, 17.04 mmol) was added to this suspension in several portions over approximately 4 minutes. After complete addition, the reaction mixture was warmed to room temperature and stirred for 2 hours. The resulting slurry was filtered through a Buchner funnel, and the filter cake was rinsed with a 1:1 mixture of ethyl acetate / hexane, and then rinsed with pure hexane. The resulting pink solid was collected and dried under vacuum to obtain 4-chloro-1H-pyrrolo[2,3-b]pyridine 7-oxide 3-chlorobenzoate (3.32 g, 10.22 mmol, 78% yield) as a pink solid, but no further purification was performed. 1 H NMR (400MHz, DMSO-d6)δ 13.29(br s, 1H), 12.85(br s, 1H), 8.14(d, J=6.6 Hz, 1H), 7.95 - 7.84(m, 2H), 7.70(ddd, J=8.1, 2.1, 1.2 Hz, 1H), 7.61 - 7.50(m, 2H), 7.21(d, J=6.6 Hz, 1H), 6.59(d, J=3.2 Hz, 1H); MS(ESI)m / z: 169.0 [M+1] + .

[0283] B. 4-Chloro-6-(3-fluoroazetidine-1-yl)-1H-pyrrolo[2,3-b]pyridine. 4-Chloro-1H-pyrrolo[2,3-b]pyridine 7-oxide. 3-chlorobenzoate (1.25 g, 3.84 mmol) was placed in a round-bottom flask and placed under nitrogen. Acetonitrile (15.38 mL) was added, followed by dimethyl sulfate (0.441 mL, 4.61 mmol). The reaction mixture was sealed and stirred overnight at 60°C. After completion, the reaction mixture was cooled to room temperature, and 3-fluoroazetidine hydrochloride (0.858 g, 7.69 mmol) and DIPEA (2.69 mL, 15.38 mmol) were added to the reaction vessel. The reaction mixture was sealed again and heated at 60°C for 4 hours. The reaction mixture was then cooled to room temperature, and the solvent was removed under reduced pressure. The crude substance was purified by silica gel chromatography using ethyl acetate and hexane to obtain 4-chloro-6-(3-fluoroazetidine-1-yl)-1H-pyrrolo[2,3-b]pyridine (400 mg, 1.77 mmol, 46% yield). MS(ESI)m / z: 226.0 [M+1] + .

[0284] C.4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrrolo[2,3-b]pyridine. 4-chloro-6-(3-fluoroazetidine-1-yl)-1H-pyrrolo[2,3-b]pyridine (80 mg, 0.355 mmol), potassium acetate (104 mg, 1.064 mmol), bis(pinacorato)diborone (108 mg, 0.425 mmol), XPhos-Pd-G2 (20.89 mg, 0.027 mmol), and XPhos (12.68 mg, 0.027 mmol) were all placed in vials and placed under nitrogen. 1,4-dioxane (1.18 mL) was added, and the resulting suspension was heated to 80°C and stirred overnight. After allowing the reaction to proceed overnight, the reaction mixture was cooled to room temperature. PdCl2 (dppf) (25.9 mg, 0.035 mmol) and 2-bromo-3-chloro-5-(trifluoromethyl)pyridine (102 mg, 0.390 mmol) were added to the reaction mixture, and the vial was quickly recapped. Potassium carbonate (2.0 M aqueous solution, 0.36 mL, 0.709 mmol) and 1,4-dioxane (0.5 mL) were added by syringe. The reaction mixture was degassed with nitrogen for 5 minutes. The reaction mixture was then heated to 80°C and stirred for 7 hours. After completion, the reaction mixture was cooled to room temperature and diluted with DCM. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained crude residue was purified by silica gel chromatography (SiO2; ethyl acetate / hexane gradient) to obtain 4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrrolo[2,3-b]pyridine (120 mg, 0.320 mmol, 90% yield) as an orange solid. MS(ESI)m / z: 371.0 [M+1] + .

[0285] D.3-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrrolo[2,3-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione. 4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrrolo[2,3-b]pyridine (55 mg, 0.148 mmol), tert-butyl(S)-5-amino-4-(5-(bromomethyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (intermediate C) (85 mg, 0.208 mmol), and cesium carbonate (193 mg, 0.593 mmol) were placed in oven-dried vials and placed under nitrogen. DMF (742 μl) was added by syringe, and the reaction mixture was heated overnight at 75°C with stirring. After completion, the resulting reaction mixture was cooled to room temperature and diluted with MeCN. The resulting suspension was filtered through Celite and diluted with MeCN. The filtrate was concentrated under reduced pressure, then resuspended in DMF and DMSO, and filtered through a micron syringe filter. The obtained filtrate was purified by reverse-phase preparative HPLC (column: Xselect CSH C18, 30 mm x 100 mm, 5 μm particle size; mobile phase B: acetonitrile, mobile phase A: 10 mM ammonium acetate aqueous solution; flow rate: 40.00 mL / min; column temperature: 25 °C). The pure fractions were combined and lyophilized to obtain 3-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrrolo[2,3-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (12.8 mg, 0.020 mmol, 14% yield) as a yellow solid. 1H NMR (400MHz, DMSO-d6)δ 10.98(s, 1H), 9.11 - 9.07(m, 1H), 8.66(d, J=1.3 Hz, 1H), 7.71(d, J=7.8 Hz, 1H), 7.56(s, 1H), 7.49(s, 1H), 7.35(d, J=3.5 Hz, 1H), 6.44(s, 1H), 6.16(d, J=3.4 Hz, 1H), 5.64 - 5.42(m, 3H), 5.10(dd, J=13.2, 5.0 Hz, 1H), 4.49 - 4.40 (m, 1H), 4.40 - 4.25 (m, 3H), 4.15 - 3.98 (m, 2H), 2.97 - 2.85 (m, 1H), 2.62 - 2.57 (m, 1H), 2.40 - 2.33 (m, 1H), 2.03 - 1.93 (m, 1H). MS(ESI)m / z: 627.0 [M+1] + .

[0286] Example 16: 3-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-2-ethyl-6-(3-fluoroazetidine-1-yl)-1H-pyrrolo[2,3-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione [ka]

[0287] A. 4-Bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine. Sodium hydride (1.218 g, 30.45 mmol, 60% purity) was added at 0°C to a solution of 4-bromo-1H-pyrrolo[2,3-b]pyridine (5.000 g, 25.38 mmol) in tetrahydrofuran (50 mL). The mixture was then stirred for 0.5 hours. Benzenesulfonyl chloride (5.378 g, 30.45 mmol) was added, and the reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (20 mL x 3). The organic layers were combined and concentrated under vacuum. The residue was further purified by silica gel chromatography (0-17% ethyl acetate / petroleum ether) to obtain the product 4-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (8.000 g, 23.73 mmol, 93.5% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6)δ 8.24(d, J=5.2 Hz, 1H), 8.15 - 8.09(m, 2H), 8.05(d, J=4.0 Hz, 1H), 7.76 - 7.70(m, 1H), 7.67 - 7.57 (m, 3H), 6.79 (d, J=4.0 Hz, 1H).

[0288] B. 4-Bromo-2-ethyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine. 4-Bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (5.000 g, 14.83 mmol) / tetrahydrofuran (100 mL) was mixed with 2 M (diisopropylamino) lithium (8.9 mL, 17.79 mmol) under nitrogen at -40°C. The mixture was then stirred at -40°C for 1 hour. Iodoethane (11.564 g, 74.14 mmol) was added, and the mixture was stirred under nitrogen at 25°C for 3 hours. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (50 mL x 2). The organic layers were combined and concentrated under reduced pressure. The residue was purified by semi-preparative reverse-phase HPLC (50-80% acetonitrile / water + 0.2251% formic acid, 10 minutes). The fraction of interest was extracted with ethyl acetate (50 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate solids, filtered, and concentrated under reduced pressure to obtain the product 4-bromo-2-ethyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (1.880 g, 5.15 mmol, 35% yield) as a pale yellow solid. 1 H NMR (400MHz, DMSO-d6)δ 8.15(d, J=5.2 Hz, 1H), 8.11 - 8.07(m, 2H), 7.73 - 7.68(m, 1H), 7.63 - 7.57(m, 2H), 7.53(d, J=5.2 Hz, 1H), 6.53(s, 1H), 3.22 - 3.14(m, 2H), 1.36(t, J=7.2 Hz, 3H). MS(ESI)m / z: 367.0 [M+1] + .

[0289] C. 4-Bromo-2-ethyl-1H-pyrrolo[2,3-b]pyridine. A mixture of 4-bromo-2-ethyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.500 g, 1.37 mmol) and 1 M tetrabutylammonium fluoride (2.7 mL, 2.74 mmol) / tetrahydrofuran (20 mL) was stirred under nitrogen at 80°C for 4 hours. The reaction mixture was diluted with water (30 mL) and filtered. The filtered cake was concentrated under reduced pressure to obtain the crude product 4-bromo-2-ethyl-1H-pyrrolo[2,3-b]pyridine (0.320 g, 1.42 mmol) as a yellow solid, which was used directly in the next step. MS(ESI)m / z: 224.9 [M+1] + .

[0290] D. Bromo-2-ethyl-1H-pyrrolo[2,3-b]pyridine 7-oxide; 3-chlorobenzoic acid. A mixture of 4-bromo-2-ethyl-1H-pyrrolo[2,3-b]pyridine (0.320 g, 1.42 mmol) and 3-chloroperbenzoic acid (0.577 g, 2.84 mmol, 85% purity) / ethyl acetate (10 mL) was stirred at 0°C for 4 hours. The reaction mixture was filtered, and the filtered cake was concentrated under reduced pressure to obtain the crude product 4-bromo-2-ethyl-1H-pyrrolo[2,3-b]pyridine 7-oxide; 3-chlorobenzoic acid (0.500 g, 1.26 mmol, 88% yield) as a yellow solid, which was used directly in the next step. MS(ESI)m / z: 241.1 [M+1] + .

[0291] E.4-bromo-2-ethyl-6-(3-fluoroazetidine-1-yl)-1H-pyrrolo[2,3-b]pyridine. 4-bromo-2-ethyl-1H-pyrrolo[2,3-b]pyridine 7-oxide;3-chlorobenzoic acid (0.500 g, 1.26 mmol) / acetonitrile (10 mL) was mixed with dimethyl sulfate (0.2 mL, 1.89 mmol) under nitrogen. The mixture was then stirred at 60°C for 12 hours. The reaction mixture was cooled to 25°C. N,N-diisopropylpropan-2-amine (1.0 mL, 5.03 mmol) and 3-fluoroazetidine hydrochloride (0.281 g, 2.51 mmol) were added. The mixture was warmed to 60°C and stirred for a further 4 hours. The reaction mixture was concentrated under vacuum. The residue was purified by silica gel chromatography (0-30% ethyl acetate / petroleum ether) to obtain the product 4-bromo-2-ethyl-6-(3-fluoroazetidine-1-yl)-1H-pyrrolo[2,3-b]pyridine (0.070 g, 0.23 mmol, 19% yield) as a pale yellow oily substance. 1 H NMR (400MHz, DMSO-d6)δ 11.45(s, 1H), 6.41(d, J=1.6 Hz, 1H), 5.92(s, 1H), 5.62 - 5.38(m, 1H), 4.34 - 4.16(m, 2H), 4.06 - 3.88(m, 2H), 2.66 - 2.60(m, 2H), 1.26 - 1.19(m, 3H). MS(ESI)m / z: 300.0 [M+1] + .

[0292] A mixture of F.4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-2-ethyl-6-(3-fluoroazetidine-1-yl)-1H-pyrrolo[2,3-b]pyridine (0.200 g, 0.67 mmol), 3-chloro-2-(tributylstannyl)-5-(trifluoromethyl)pyridine (intermediate M) (0.379 g, 0.80 mmol), tetrakis(triphenylphosphine)palladium (0) (0.078 g, 0.07 mmol), and copper iodide (0.025 g, 0.13 mmol) / dioxane (10 mL) was stirred at 100 °C for 12 hours under nitrogen. The reaction mixture was quenched with potassium fluoride solution and extracted with ethyl acetate (10 mL x 2). The organic layers were combined and concentrated under vacuum. The residue was purified by preparative TLC (30% ethyl acetate / petroleum ether) to obtain 4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-2-ethyl-6-(3-fluoroazetidine-1-yl)-1H-pyrrolo[2,3-b]pyridine (0.060 g, 0.15 mmol, 22% yield) as a yellow solid. MS(ESI)m / z: 399.1 [M+1] + .

[0293] G.tert-butyl(S)-5-amino-4-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-2-ethyl-6-(3-fluoroazetidine-1-yl)-1H-pyrrolo[2,3-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate. A mixture of 4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-2-ethyl-6-(3-fluoroazetidine-1-yl)-1H-pyrrolo[2,3-b]pyridine (0.060 g, 0.15 mmol), tert-butyl(S)-5-amino-4-(5-(bromomethyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (intermediate C) (0.075 g, 0.18 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.019 g, 0.15 mmol) / acetonitrile (3 mL) was stirred at 80°C for 6 hours. The reaction mixture was concentrated under reduced pressure. The residue was semi-preparative reverse-phase HPLC (25-55% acetonitrile / water + 0.225%). The solution was purified with formic acid for 7 minutes. The fraction of interest was freeze-dried to obtain the crude product tert-butyl(S)-5-amino-4-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-2-ethyl-6-(3-fluoroazetidine-1-yl)-1H-pyrrolo[2,3-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.020 g, 0.03 mmol, 18% yield) as a green solid. MS(ESI)m / z: 729.5 [M+1] + .

[0294] H.3-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-2-ethyl-6-(3-fluoroazetidine-1-yl)-1H-pyrrolo[2,3-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione formate. A mixture of tert-butyl(S)-5-amino-4-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-2-ethyl-6-(3-fluoroazetidine-1-yl)-1H-pyrrolo[2,3-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.015 g, 0.02 mmol) and 4-methylbenzenesulfonic acid (0.018 g, 0.10 mmol) / acetonitrile (1.5 mL) was stirred at 80°C for 2 hours. The reaction mixture was diluted with water (20 mL) and adjusted to pH 7 with sodium carbonate solid. The mixture was extracted with ethyl acetate (5 mL x 2). The organic layers were combined and concentrated under vacuum. The residue was purified by semi-preparative reverse-phase HPLC (22-52% acetonitrile / water + 0.225% formic acid, 7 minutes). The fraction of interest was lyophilized to obtain the product 3-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-2-ethyl-6-(3-fluoroazetidine-1-yl)-1H-pyrrolo[2,3-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione formate (0.002 g, 0.01 mmol, 17% yield, 95.5% purity) as a yellow solid. 1H NMR (400MHz, DMSO-d6)δ 10.97(s, 1H), 9.04(s, 1H), 8.58(s, 1H), 8.22(s, 1H), 7.71(d, J=8.0 Hz, 1H), 7.55(s, 1H), 7.47(d, J=7.6 Hz, 1H), 6.43 - 6.29 (m, 1H), 5.89 - 5.80 (m, 1H), 5.80 - 5.65 (m, 1H), 5.36 - 5.22 (m, 1H), 5.16 - 5.06 (m, 1H), 5.05 - 4.95 (m, 1H), 4.93 - 4.84 (m, 1H), 4.58 - 4.45 (m, 1H), 4.41 (d, J=17.6 Hz, 1H), 4.34 - 4.23 (m, 1H), 4.12 - 3.77 (m, 2H), 2.98 - 2.82 (m, 1H), 2.70 - 2.64 (m, 2H), 2.62 - 2.55 (m, 1H), 2.40 - 2.34 (m, 1H), 2.04 - 1.94 (m, 1H), 1.19 (t, J=7.6 Hz, 3H). MS(ESI)m / z: 655.1 [M+1] + .

[0295] Example 17: 3-(5-((4-(3-chloro-5-fluoropyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrrolo[2,3-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione [ka]

[0296] A. 4-(3-chloro-5-fluoropyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrrolo[2,3-b]pyridine. 4-chloro-6-(3-fluoroazetidine-1-yl)-1H-pyrrolo[2,3-b]pyridine (250 mg, 1.108 mmol), potassium acetate (326 mg, 3.32 mmol), B2pin2 (338 mg, 1.329 mmol), XPhos-Pd-G2 (65.3 mg, 0.083 mmol), and XPhos (39.6 mg, 0.083 mmol) were all placed in vials and placed under nitrogen. 1,4-dioxane (3.69 mL) was added, and the resulting suspension was heated at 80°C and stirred overnight. After the reaction continued overnight, the reaction mixture was cooled to room temperature, and PdCl2 (dppf) (81 mg, 0.111 mmol) and 2-bromo-3-chloro-5-fluoropyridine (256 mg, 1.219 mmol) were added to the reaction mixture, and the vial was quickly recapped. Potassium carbonate (2.0 M aqueous solution, 0.55 mL, 1.108 mmol) and 1,4-dioxane (0.5 mL) were added by syringe. The reaction mixture was degassed with nitrogen for 5 minutes. The reaction mixture was then heated to 80°C and stirred for 7 hours. At the end of the reaction, the reaction mixture was cooled to room temperature and diluted with DCM. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting crude residue was purified by silica gel chromatography (SiO2; ethyl acetate / hexane gradient) to obtain 4-(3-chloro-5-fluoropyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrrolo[2,3-b]pyridine (223 mg, 0.696 mmol, 63% yield) as an orange solid. MS(ESI)m / z: 321.0 [M+1] + .

[0297] B.3-(5-((4-(3-chloro-5-fluoropyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrrolo[2,3-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione. 4-(3-chloro-5-fluoropyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrrolo[2,3-b]pyridine (68 mg, 0.212 mmol), tert-butyl(S)-5-amino-4-(5-(bromomethyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (intermediate C) (122 mg, 0.297 mmol), and cesium carbonate (276 mg, 0.848 mmol) were placed in oven-dried vials and placed under nitrogen. DMF (1.06 mL) was added by syringe, and the reaction mixture was heated to 75°C with stirring overnight. After completion, the reaction mixture was cooled to room temperature and diluted with MeCN. The resulting suspension was filtered by Celite and rinsed with MeCN. The filtrate was concentrated under reduced pressure, then resuspended in DMF and DMSO, and filtered through a micron syringe filter. The obtained filtrate was purified by preparative reverse-phase HPLC (column: Xselect CSH C18, 30 mm x 100 mm, 5 μm particle size; eluent: water / MeCN w / 0.1% TFA; flow rate: 40.00 mL / min; column temperature: 25 °C). The pure fractions were combined and lyophilized to obtain 3-(5-((4-(3-chloro-5-fluoropyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrrolo[2,3-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (12.8 mg, 0.020 mmol, 14% yield) as a yellow solid. 1H NMR (500MHz, DMSO-d6)δ ppm 1.91 - 2.03(m, 1 H)2.32 - 2.41(m, 2 H)2.57 - 2.62(m, 1 H)2.83 - 2.96(m, 1 H)4.00 - 4.12(m, 2 H)4.25 - 4.47(m, 4) H)5.04 - 5.14(m, 1 H)5.42 - 5.61(m, 3 H)6.12(d, J=3.46 Hz, 1 H)6.38(s, 1 H)7.29 - 7.35(m, 1 H)7.47(d, J=7.87 Hz, 1 H)7.55(s, 1 H)7.67 - 7.73(m, 1H)8.26 - 8.32(m, 1H)8.73 - 8.76(m, 1H)10.97(s, 1H). MS(ESI)m / z: 577.7 [M+1] + .

[0298] Example 19: 3-(5-((7-(2-chloro-4-(trifluoromethyl)phenyl)-5-(3-fluoroazetidine-1-yl)-3H-imidazo[4,5-b]pyridine-3-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione [ka]

[0299] A. 2,6-Difluoro-4-iodo-3-nitropyridine. Nitric acid (11.4 mL, 268.21 mmol) was added at 0°C to a solution of 2,6-difluoro-4-iodopyridine (10,000 g, 41.50 mmol) / sulfuric acid (30.0 mL, 562.81 mmol). The mixture was then stirred under nitrogen at 25°C for 12 hours. The reaction mixture was slowly added to ice water (500 mL). The mixture was then adjusted to pH 7 with sodium carbonate solid and extracted with ethyl acetate (200 mL x 2). The organic layers were combined and concentrated under vacuum. The residue was purified by silica gel chromatography (0-1% ethyl acetate / petroleum ether) to obtain the product 2,6-difluoro-4-iodo-3-nitropyridine (8.444 g, 29.53 mmol, 71% yield) as a brown solid. 1H NMR (400MHz, CDCl3) δ 7.45 (d, J=3.2 Hz, 1H).

[0300] B. 6-Fluoro-4-iodo-3-nitropyridine-2-amine. Ammonium hydroxide (5.5 mL, 35.43 mmol) was slowly added at 0°C to a solution of 2,6-difluoro-4-iodo-3-nitropyridine (8.444 g, 29.53 mmol) / tetrahydrofuran (100 mL). The mixture was then stirred at 0°C for 2 hours. The reaction mixture was adjusted to pH 5 with 1 M phosphoric acid and extracted with ethyl acetate (30 mL x 2). The organic layers were combined and concentrated under vacuum. The residue was purified by silica gel chromatography (0-30% ethyl acetate / petroleum ether) to obtain the product 6-fluoro-4-iodo-3-nitropyridine-2-amine (7.330 g, 25.90 mmol, 88% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ 7.56 (s, 2H), 6.95 (dd, J=1.2, 2.8 Hz, 1H).

[0301] C.6-Fluoro-4-iodopyridine-2,3-diamine. A mixture of 6-fluoro-4-iodo-3-nitropyridine-2-amine (7.330 g, 25.90 mmol), iron (7.232 g, 129.51 mmol), and ammonium chloride (6.927 g, 129.51 mmol) / ethanol (100 mL) and water (20 mL) was stirred at 50°C for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (0-35% ethyl acetate / petroleum ether) to obtain the product 6-fluoro-4-iodopyridine-2,3-diamine (4.100 g, 16.20 mmol, 63% yield) as a brown solid. 1 H NMR (400MHz, DMSO-d6) δ 13.07 - 12.44 (m, 1H), 8.07 (s, 1H), 6.79 (s, 1H), 5.61 - 5.33 (m, 1H), 4.36 - 4.22 (m, 2H), 4.08 - 3.95 (m, 2H).

[0302] D. 5-Fluoro-7-iodo-3H-imidazo[4,5-b]pyridine. A mixture of 6-fluoro-4-iodopyridine-2,3-diamine (4.100 g, 16.20 mmol) / formic acid (12.0 mL, 318.05 mmol) was stirred at 80°C for 12 hours. The reaction mixture was diluted with water (50 mL) and adjusted to 7 with sodium carbonate solid. The mixture was then filtered, and the filtrate was dried under vacuum to obtain the product 5-fluoro-7-iodo-3H-imidazo[4,5-b]pyridine (3.700 g, 14.068 mmol, 86.816% yield) as an off-white solid. The filtrate was extracted with ethyl acetate (30 mL x 2). The organic layers were combined and dried over anhydrous sodium sulfate solids, filtered, and concentrated under reduced pressure to obtain the additional target product, 5-fluoro-7-iodo-3H-imidazo[4,5-b]pyridine (0.900 g, 3.42 mmol, 21% yield), as a brown solid. 1 H NMR (400MHz, DMSO-d6) δ 13.99 - 12.63 (m, 1H), 8.48 (s, 1H), 7.52 (d, J=1.2 Hz, 1H). MS(ESI)m / z: 263.9 [M+1] + .

[0303] E.5-(3-fluoroazetidine-1-yl)-7-iodo-3H-imidazo[4,5-b]pyridine. A mixture of 5-fluoro-7-iodo-3H-imidazo[4,5-b]pyridine (1,500 g, 5.70 mmol), 3-fluoroazetidine hydrochloride (0.763 g, 6.84 mmol), and N-ethyl-N-isopropylpropan-2-amine (2.0 mL, 11.41 mmol) / acetonitrile (15 mL) was stirred at 100°C for 3 days. The reaction mixture was divided into 3 batches. The reaction mixture was concentrated under reduced pressure. The residue was purified by semi-preparative reverse-phase HPLC (5-35% acetonitrile / water + 0.225% formic acid, 15 minutes). The collected fractions were then extracted with ethyl acetate (50 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate solids, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by semi-preparative reverse-phase HPLC (16-46% acetonitrile / water + 10 mM ammonium bicarbonate, 9 minutes). The fraction of interest was lyophilized to obtain the product 5-(3-fluoroazetidine-1-yl)-7-iodo-3H-imidazo[4,5-b]pyridine (0.070 g, 0.22 mmol, 4% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ 13.07 - 12.44 (m, 1H), 8.07 (s, 1H), 6.79 (s, 1H), 5.61 - 5.33 (m, 1H), 4.36 - 4.22 (m, 2H), 4.08 - 3.95 (m, 2H). MS(ESI)m / z: 319.0 [M+1] + .

[0304] F.tert-butyl(S)-5-amino-4-(5-((5-(3-fluoroazetidine-1-yl)-7-iodo-3H-imidazo[4,5-b]pyridine-3-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate. A mixture of 5-(3-fluoroazetidine-1-yl)-7-iodo-3H-imidazo[4,5-b]pyridine (0.070 g, 0.22 mmol), tert-butyl(S)-5-amino-4-(5-(chloromethyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (prepared similarly to intermediate C) (0.097 g, 0.26 mmol), and cesium carbonate (0.143 g, 0.44 mmol) / DMF (2 mL) was stirred at 50°C for 2 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 2). The organic layers were combined and concentrated under reduced pressure. The residue was purified by preparative TLC (80% ethyl acetate / petroleum ether) to obtain the product tert-butyl(S)-5-amino-4-(5-((5-(3-fluoroazetidine-1-yl)-7-iodo-3H-imidazo[4,5-b]pyridine-3-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.054 g, 0.08 mmol, 38% yield) as a white solid. 1 H NMR (400MHz, CDCl3)δ 7.85 - 7.79(m, 2H), 7.46 - 7.40(m, 1H), 7.37 - 7.30(m, 1H), 6.75(s, 1H), 6.37 - 6.21(m, 1H), 5.56 - 5.35 (m, 2H), 5.31 (s, 1H), 4.89 (dd, J=6.4, 8.8 Hz, 1H), 4.55 - 4.47 (m, 1H), 4.40 (d, J=17.6 Hz, 1H), 4.37 - 4.28 (m, 2H), 4.22 - 4.10(m, 2H), 2.43 - 2.07(m, 4H), 1.41(s, 9H). MS(ESI)m / z: 649.2 [M+1] + .

[0305] G.tert-butyl(S)-5-amino-4-(5-((7-(2-chloro-4-(trifluoromethyl)phenyl)-5-(3-fluoroazetidine-1-yl)-3H-imidazo[4,5-b]pyridine-3-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate. A mixture of tert-butyl(S)-5-amino-4-(5-((5-(3-fluoroazetidine-1-yl)-7-iodo-3H-imidazo[4,5-b]pyridine-3-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.050 g, 0.08 mmol), (2-chloro-4-(trifluoromethyl)phenyl)boronic acid (0.021 g, 0.09 mmol), tetrakis(triphenylphosphine)palladium (0) (0.009 g, 0.01 mmol), and 2M potassium carbonate (0.1 mL, 0.15 mmol) / dioxane (3 mL) was stirred at 100°C for 12 hours under nitrogen. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2). The organic layers were combined and concentrated under reduced pressure. The residue was purified by preparative TLC (60% ethyl acetate / petroleum ether) to obtain the product tert-butyl(S)-5-amino-4-(5-((7-(2-chloro-4-(trifluoromethyl)phenyl)-5-(3-fluoroazetidine-1-yl)-3H-imidazo[4,5-b]pyridine-3-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.020 g, 0.03 mmol, 37% yield) as a white solid. MS(ESI)m / z: 701.1 [M+1] + .

[0306] H.3-(5-((7-(2-chloro-4-(trifluoromethyl)phenyl)-5-(3-fluoroazetidine-1-yl)-3H-imidazo[4,5-b]pyridine-3-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione. To a solution of tert-butyl(S)-5-amino-4-(5-((7-(2-chloro-4-(trifluoromethyl)phenyl)-5-(3-fluoroazetidine-1-yl)-3H-imidazo[4,5-b]pyridine-3-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.020 g, 0.03 mmol) / dichloromethane (1 mL), TFA (0.3 mL, 4.04 mmol) was added at 25 °C. Next, the mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the product (S)-5-amino-4-(5-((7-(2-chloro-4-(trifluoromethyl)phenyl)-5-(3-fluoroazetidine-1-yl)-3H-imidazo[4,5-b]pyridine-3-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoic acid (0.018 g, 0.03 mmol, 97.8% yield) as a yellow oil, which was then used directly in the next step. A mixture of (S)-5-amino-4-(5-((7-(2-chloro-4-(trifluoromethyl)phenyl)-5-(3-fluoroazetidine-1-yl)-3H-imidazo[4,5-b]pyridine-3-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoic acid (0.018 g, 0.03 mmol), 4-dimethylaminopyridine (0.003 g, 0.03 mmol), di(1H-imidazole-1-yl)methanone (0.009 g, 0.06 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.1 mL, 0.08 mmol) / acetonitrile (1 mL) was stirred at 80°C for 2 hours. The reaction mixture was purified by semi-preparative reverse-phase HPLC (42-72% acetonitrile / water + 0.225% formic acid, 7 minutes).The fraction of interest was freeze-dried to obtain the product 3-(5-((7-(2-chloro-4-(trifluoromethyl)phenyl)-5-(3-fluoroazetidine-1-yl)-3H-imidazo[4,5-b]pyridine-3-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (0.004 g, 0.01 mmol, 23% yield, 98% purity) as a yellow solid. 1 H NMR (400MHz, DMSO-d6)δ 10.98(s, 1H), 8.27(s, 1H), 8.03(s, 1H), 7.89 - 7.81(m, 1H), 7.79 - 7.69(m, 2H), 7.68 - 7.64(m, 1H), 7.62 - 7.54 (m, 1H), 6.42 (s, 1H), 5.64 - 5.42 (m, 3H), 5.13 - 5.06 (m, 1H), 4.49 - 4.42 (m, 1H), 4.39 - 4.29 (m, 3H), 4.15 - 4.03(m, 3H), 2.89(dd, J=2.4, 5.6 Hz, 1H), 2.58(s, 1H), 2.40(d, J=1.6 Hz, 1H), 2.03 - 1.93(m, 1H). MS(ESI)m / z: 627.2 [M+1] + .

[0307] Example 21: 3-(5-((7-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-5-(3-fluoroazetidine-1-yl)-2-methyl-3H-imidazo[4,5-b]pyridine-3-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione [ka]

[0308] A. 2,6-Difluoro-4-iodo-3-nitropyridine. Nitric acid (20 mL, 479.37 mmol) was added at 0°C to a solution of 2,6-difluoro-4-iodopyridine (20,000 g, 82.99 mmol) / sulfuric acid (60 mL, 1126.5 mmol). The mixture was stirred at 25°C for 12 hours. The reaction mixture was slowly added to water (500 mL). The mixture was extracted with ethyl acetate (100 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate solids, filtered, and concentrated under vacuum to obtain 2,6-difluoro-4-iodo-3-nitropyridine (17,000 g, 59.45 mmol, 72% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ 7.45 (d, J=2.8 Hz, 1H).

[0309] B. 6-Fluoro-4-iodo-3-nitropyridine-2-amine. Ammonium hydroxide (9.70 mL, 62.94 mmol) was added at 0°C to a solution of 2,6-difluoro-4-iodo-3-nitropyridine (12.000 g, 41.96 mmol) / tetrahydrofuran (70 mL). The mixture was stirred at 0°C for 2 hours. The reaction mixture was adjusted to pH 7 with 1 M phosphoric acid and extracted with ethyl acetate (100 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate solids, filtered, and concentrated under reduced pressure to obtain the crude product 6-fluoro-4-iodo-3-nitropyridine-2-amine (9.000 g, 31.80 mmol, 76% yield) as a yellow solid, which was used directly in the next step. MS(ESI)m / z: 283.9 [M+1] + .

[0310] C.6-(3-fluoroazetidine-1-yl)-4-iodo-3-nitropyridine-2-amine. To a solution of 6-fluoro-4-iodo-3-nitropyridine-2-amine (12.000 g, 42.40 mmol) / acetonitrile (200 mL), 3-fluoroazetidine hydrochloride (5.680 g, 50.88 mmol) and N-ethyl-N-isopropylpropan-2-amine (14.74 mL, 84.81 mmol) were added. The mixture was stirred at 50°C for 1 hour. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was triturated with ethyl acetate (20 mL). The resulting precipitate was collected by filtration and dried under reduced pressure to obtain 6-(3-fluoroazetidine-1-yl)-4-iodo-3-nitropyridine-2-amine (11,000 g, 32.54 mmol, 77% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ 6.73(s, 2H), 5.54(s, 1H), 4.64 - 4.46(m, 1H), 3.51 - 3.42(m, 2H), 3.24 - 3.15(m, 2H). MS(ESI)m / z: 339.1 [M+1] + .

[0311] D. 6-(3-fluoroazetidine-1-yl)-4-iodopyridine-2,3-diamine. To a solution of 6-(3-fluoroazetidine-1-yl)-4-iodo-3-nitropyridine-2-amine (11,000 g, 32.54 mmol) in ethanol (15 mL) and water (5 mL), iron (14.540 g, 260.29 mmol) and ammonium chloride (17.240 g, 325.37 mmol) were added. The mixture was stirred at 50°C for 1 hour. The mixture was filtered and concentrated. It was purified by silica gel chromatography (0-80% ethyl acetate / petroleum ether) to obtain 6-(3-fluoroazetidine-1-yl)-4-iodopyridine-2,3-diamine (7,200 g, 23.37 mmol, 72% yield) as a brown solid. 1H NMR (400MHz, DMSO-d6) δ 5.94 (s, 1H), 5.65 (s, 2H), 5.48 - 5.29 (m, 1H), 4.07 - 3.98 (m, 4H), 3.79 - 3.70 (m, 2H).

[0312] E.5-(3-fluoroazetidine-1-yl)-7-iodo-2-methyl-3H-imidazo[4,5-b]pyridine. A mixture of 6-(3-fluoroazetidine-1-yl)-4-iodopyridine-2,3-diamine (4.000 g, 12.98 mmol), ethyl acetimide hydrochloride (4.810 g, 38.95 mmol), and 3A MS (1.000 g, 25.97 mmol) / ethanol (160 mL) was stirred at 100°C for 12 hours under nitrogen. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (0-96% ethyl acetate / petroleum ether) to obtain 5-(3-fluoroazetidine-1-yl)-7-iodo-2-methyl-3H-imidazo[4,5-b]pyridine (3,300 g, 9.94 mmol, 77% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3)δ 10.29 - 9.88(m, 1H), 6.64(s, 1H), 5.53 - 5.35(m, 1H), 4.36 - 4.27(m, 2H), 4.18 - 4.08(m, 2H), 2.60(s, 3H). MS(ESI)m / z: 333.0 [M+1] + .

[0313] F.tert-butyl(S)-5-amino-4-(5-((5-(3-fluoroazetidine-1-yl)-7-iodo-2-methyl-3H-imidazo[4,5-b]pyridine-3-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate. To a solution of 5-(3-fluoroazetidine-1-yl)-7-iodo-2-methyl-3H-imidazo[4,5-b]pyridine (1,000 g, 3.01 mmol) / acetonitrile (20 mL), tert-butyl(S)-5-amino-4-(5-(bromomethyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (intermediate C) (1,490 g, 3.61 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.05 mL, 6.02 mmol) were added. The mixture was stirred at 70°C for 12 hours. The mixture was divided into two batches. The mixture was concentrated under vacuum, and the residue was purified by semi-preparative reverse-phase HPLC (15-45% acetonitrile / water + 0.225% formic acid, 15 minutes). The target fraction was concentrated under vacuum and freeze-dried to obtain the product tert-butyl(S)-5-amino-4-(5-((5-(3-fluoroazetidine-1-yl)-7-iodo-2-methyl-3H-imidazo[4,5-b]pyridine-3-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.500 g, 0.75 mmol, 25% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6)δ 7.67 - 7.64(m, 1H), 7.54(s, 1H), 7.41(s, 1H), 7.33(d, J=8.4 Hz, 1H), 7.18(s, 1H), 6.77(s, 1H), 5.55 - 5.42(m, 3H), 4.71 - 4.69(m, 1H), 4.56 - 4.52(m, 1H), 4.43 - 4.24(m, 3H), 4.07 - 4.00(m, 2H), 2.43(s, 3H), 2.13(s, 3H), 1.94(d, J=10.4 Hz, 1H), 1.29(s, 9H). MS(ESI)m / z: 663.2 [M+1] + .

[0314] G.tert-butyl(S)-5-amino-4-(5-((7-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-5-(3-fluoroazetidine-1-yl)-2-methyl-3H-imidazo[4,5-b]pyridine-3-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate. tert-butyl(S)-5-amino-4-(5-((5-(3-fluoroazetidine-1-yl)-7-iodo-2-methyl-3H-imidazo[4,5-b]pyridine-3-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.110 g, 0.17 mmol) / N,N-dimethylacetamide (0.8 mL) is mixed with 3-chloro-2-(trib Chilstannyl)-5-(trifluoromethyl)pyridine (intermediate M) (0.391 g, 0.83 mmol) and methanesulfonate (2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (0.013 g, 0.02 mmol) were added. The mixture was stirred at 90°C under nitrogen for 12 hours. The mixture was divided into 11 batches. The mixture was quenched with saturated potassium fluoride aqueous solution (10 mL), diluted with water (5 mL), and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by semi-preparative reverse-phase HPLC (28-58% acetonitrile / water + 0.225% formic acid, 10 minutes). The target fraction was freeze-dried to obtain the product. The residue was re-purified by semi-preparative reverse-phase HPLC (42-72% acetonitrile / water + 0.225% formic acid, 9 minutes). The target fraction was concentrated under vacuum and freeze-dried to obtain the product tert-butyl(S)-5-amino-4-(5-((7-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-5-(3-fluoroazetidine-1-yl)-2-methyl-3H-imidazo[4,5-b]pyridine-3-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.015 g, 0.02 mmol, 13% yield) as a yellow oil. MS(ESI)m / z: 716.1 [M+1] +.

[0315] H.(S)-5-amino-4-(5-((7-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-5-(3-fluoroazetidine-1-yl)-2-methyl-3H-imidazo[4,5-b]pyridine-3-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoic acid. To a solution of tert-butyl(S)-5-amino-4-(5-((7-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-5-(3-fluoroazetidine-1-yl)-2-methyl-3H-imidazo[4,5-b]pyridine-3-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.015 g, 0.02 mmol) / dichloromethane (0.60 mL), TFA (0.3 mL, 0 mmol) was added. The mixture was stirred at 25°C for 1 hour. The mixture was concentrated under vacuum to obtain (S)-5-amino-4-(5-((7-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-5-(3-fluoroazetidine-1-yl)-2-methyl-3H-imidazo[4,5-b]pyridine-3-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoic acid (0.013 g, 0.02 mmol, 94% yield) as a yellow oil. MS(ESI)m / z: 660.3 [M+1] + .

[0316] I.3-(5-((7-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-5-(3-fluoroazetidine-1-yl)-2-methyl-3H-imidazo[4,5-b]pyridine-3-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione. (S)-5-amino-4-(5-((7-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-5-(3-fluoroazetidine-1-yl)-2-methyl-3H-imidazo[4,5-b]pyridine-3-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoic acid (0.013 g, 0.02 mmol) / acetonitrile (1 mL) was mixed with di(1H-imidazole-1-yl)methanone (0.006 g, 0.04 mmol) and dimethylaminopyridine (0.005 g, 0.04 mmol). The mixture was stirred under nitrogen at 80°C for 3 hours. The mixture was concentrated under vacuum, and the residue was purified by semi-preparative reverse-phase HPLC (18-48% acetonitrile / water + 0.225% formic acid, 10 minutes). The target fraction was concentrated under vacuum and freeze-dried to obtain 3-(5-((7-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-5-(3-fluoroazetidine-1-yl)-2-methyl-3H-imidazo[4,5-b]pyridine-3-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (0.005 g, 0.008 mmol, 41% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6)δ 10.97(s, 1H), 9.07(d, J=0.8 Hz, 1H), 8.64(d, J=1.2 Hz, 1H), 7.73(d, J=7.6 Hz, 1H), 7.48(s, 1H), 7.43(d, J=8.0 Hz, 1H), 6.42(s, 1H), 5.59 - 5.44(m, 3H), 5.09(dd, J=5.2, 13.2 Hz, 1H), 4.47 - 4.29(m, 4H), 4.11 - 4.03(m, 2H), 2.94 - 2.85(m, 1H), 2.61(s, 1H), 2.41(s, 3H), 2.35(dd, J=4.8, 13.6 Hz, 1H), 2.02 - 1.94(m, 1H). MS(ESI)m / z: 642.3[M+1] + .

[0317] Example 26: 3-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-indazole-1-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione [ka]

[0318] A. 6-Bromo-4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole. 6-Bromo-4-chloro-1H-indazole (1.852 g, 8 mmol) and tetrabutylammonium bromide (0.258 g, 0.800 mmol) were placed in a flask and DCM (48.0 mL) was added. The starting materials were dissolved, and the resulting solution was cooled to 0°C. Next, 50% potassium hydroxide (aqueous solution, 32.0 mL) was slowly added. After the addition, the resulting two-phase mixture was stirred for several minutes at 0°C. Then, 2-(trimethylsilyl)ethoxymethyl chloride (2.128 mL, 9.60 mmol) was added dropwise. The resulting solution was stirred overnight. After completion, the mixture was transferred to a separatory funnel. The organic layer was removed, and the aqueous layer was extracted twice more with DCM. The organic layers were washed together with water, and then with brine. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was removed under reduced pressure. The crude material was purified by silica gel chromatography (SiO2; dry load; ethyl acetate / hexane gradient) to obtain 6-bromo-4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (2.01 g, 1.478 mmol, 70% yield). MS(ESI)m / z: 361.0 [M+1] + .

[0319] B.3-(5-(((4-(2-chloro-4-(trifluoromethyl)phenyl)-6-cyclobutoxypyrimidine-2-yl)(methyl)amino)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione. 6-bromo-4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (1.25 g, 3.46 mmol), 3-fluoroazetidine hydrochloride (0.424 g, 3.80 mmol), PdCl2 (dppf) (0.126 g, 0.173 mmol), and tripotassium phosphate (2.200 g, 10.37 mmol) were placed in a vial. The vial was evacuated three times and refilled with nitrogen. 1,4-dioxane (6.91 mL) was added by syringe, and the mixture was degassed with nitrogen for 5 minutes. Next, the reaction mixture was heated to 85°C and stirred at that temperature for 2.5 days. After completion, the reaction mixture was cooled to room temperature, then diluted with DCM and filtered. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (SiO2; ethyl acetate / hexane gradient) to obtain 3-(5-(((4-(2-chloro-4-(trifluoromethyl)phenyl)-6-cyclobutoxypyrimidine-2-yl)(methyl)amino)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (916 mg, 2.57 mmol, 75% yield). MS(ESI)m / z: 356.0 [M+1] + .

[0320] C.6-(3-fluoroazetidine-1-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole. 4-chloro-6-(3-fluoroazetidine-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (470 mg, 1.321 mmol), potassium acetate (389 mg, 3.96 mmol), B2pin2 (419 mg, 1.651 mmol), Xphos (31.5 mg, 0.066 mmol), and Xphos-Pd-G2 (51.9 mg, 0.066 mmol) were all placed in vials and stored under nitrogen. 1,4-Dioxane (4.402 mL) was added, and the resulting suspension was degassed under nitrogen for 5 minutes with stirring. The solution was then heated to 50°C and stirred overnight. After completion, the reaction mixture was cooled to room temperature and diluted with DCM. The mixture was filtered through Celite, and the solvent was removed under reduced pressure. The crude residue was purified by silica gel chromatography (SiO2; ethyl acetate / hexane gradient) to obtain 6-(3-fluoroazetidine-1-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (377.5 mg, 0.844 mmol, 64% yield). MS(ESI)m / z: 448.2 [M+1] + .

[0321] D.4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole. PdCl2 (dppf) (61.7 mg, 0.084 mmol), K2CO3 (1266 μl, 2.53 mmol), 2-bromo-3-chloro-5-(trifluoromethyl)pyridine (264 mg, 1.012 mmol), and 6-(3-fluoroazetidine-1-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (377.5 mg, 0.844 mmol) were all placed in vials and stored under nitrogen. 1,4-Dioxane (3.8 mL) and water (0.42 mL) were added by syringe, and the resulting solution was degassed for 5 minutes. The reaction mixture was sealed and heated at 80°C for 5 hours. After completion, the reaction mixture was cooled to room temperature, and a biphasic mixture was formed. The aqueous layer was removed by pipette. The reaction mixture was diluted with DCM and filtered by Celite. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (SiO2; ethyl acetate / hexane gradient) to obtain 4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (291 mg, 0.580 mmol, 69% yield) as a yellow semi-solid. MS(ESI)m / z: 501.2 [M+1] + .

[0322] E. 4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-indazole. 4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (158 mg, 0.315 mmol) was placed in a vial and placed under nitrogen. Tetrahydrofuran (1577 μl) was added to dissolve the starting material. Tetrabutylammonium fluoride (3154 μl, 3.15 mmol) was added (solution / THF), and the reaction mixture was heated overnight at 50°C. After completion, the reaction mixture was cooled to room temperature and then quenched with 0.5 M potassium phosphate buffer (pH=7). The solution was extracted three times with ethyl acetate. The organic layers were combined, rinsed with brine, dried over anhydrous magnesium sulfate, and filtered. The crude material was purified by silica gel chromatography (SiO2, ethyl acetate / hexane gradient) to obtain 4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-indazole as a yellow solid (101 mg, 0.271 mmol, 86% yield). MS(ESI)m / z: 371.0 [M+1] + .

[0323] F.tert-butyl(S)-5-amino-4-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-indazole-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate. 4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-indazole (0.060 g, 0.162 mmol), tert-butyl(S)-5-amino-4-(5-(bromomethyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (intermediate C) (0.080 g, 0.194 mmol), and cesium carbonate (0.127 g, 0.388 mmol) were placed in a vial and placed under nitrogen. DMF (1.62 mL) was added, and the reaction mixture was stirred at 30°C for 4 hours. After completion, the reaction mixture was diluted with DCM and then filtered by Celite. The solvent was removed under reduced pressure. The crude substance was purified by silica gel chromatography (SiO2, methanol / dichloromethane gradient) to obtain tert-butyl(S)-5-amino-4-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-indazole-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (104.0 mg, 82% purity, 0.122 mmol, 75% yield). The isolated product contains the following 18% positional isomer, tert-butyl(S)-5-amino-4-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-2H-indazole-2-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate. MS(ESI)m / z: 701.2 [M+1] + .

[0324] G.3-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-indazole-1-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione. In a vial, tert-butyl(S)-5-amino-4-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-indazole-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (30 mg, 0.043 mmol) was dissolved in 0.5 mL of DCM. Then TFA (0.25 mL) was added dropwise, and the resulting solution was stirred at room temperature for 2 hours. Volatile substances were removed under reduced pressure. The crude substance was resuspended in toluene (0.5 mL), and the solvent was removed again under reduced pressure. The crude substance was placed under high vacuum for 1 hour. Next, the crude substance was dissolved in MeCN (0.86 mL). To this, 1,1'-carbonyldiimidazole (10.41 mg, 0.064 mmol) and 4-dimethylaminopyridine (1.046 mg, 8.56 μmol) were added. After complete dissolution of the solid, DIPEA (0.037 mL, 0.214 mmol) was added, and the vial was sealed. The reaction mixture was then heated overnight at 40°C with stirring. After completion, the reaction mixture was cooled and diluted with DMSO. The crude substance was filtered through a micron syringe filter and purified by preparative HPLC (Xselect CSH C18, 30 mm x 150 mm, 5 μm particle size; water / MeCN w / 0.1% formic acid; flow rate: 40 mL / min; column temperature: 25 °C). The pure fractions were combined and lyophilized to obtain 3-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-indazole-1-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (10.2 mg, 0.016 mmol, 38% yield) as a pale yellow solid. 1H NMR (400MHz, DMSO-d6)δ 10.90(s, 1H), 9.01(s, 1H), 8.58(d, J=1.8 Hz, 1H), 7.72(s, 1H), 7.63(d, J=7.8 Hz, 1H), 7.37(s, 1H), 7.31(d, J=7.7 Hz, 1H), 6.73(s, 1H), 6.62(d, J=1.5 Hz, 1H), 5.66(s, 2H), 5.57 - 5.34(m, 1H), 5.07 - 4.96(m, 1H), 4.41 - 4.31(m, 1H), 4.25 - 4.13(m, 3H), 3.98 - 3.86(m, 2H), 2.81(br dd, J=13.1, 4.8 Hz, 1H), 2.53(br d, J=2.0 Hz, 1H), 2.35 - 2.26(m, 1H), 1.96 - 1.86(m, 1H). MS(ESI)m / z: 627.2 [M+1] + .

[0325] Example 27: 5-Chloro-6-(2-(dimethylamino)-7-((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)nicotinonitrile [ka]

[0326] A.4-(2-amino-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-3-chlorobenzonitrile

[0327] To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-2-amine (0.200 g, 1.19 mmol) / dioxane (3 mL), (2-chloro-4-cyanophenyl)boronic acid (0.538 g, 2.97 mmol), potassium carbonate (0.491 g, 3.56 mmol, 2 M), and Xphos-Pd-G2 (0.093 g, 0.12 mmol) were added. The mixture was stirred at 100°C for 12 hours. The mixture was purified by semi-preparative reverse-phase HPLC (14%-44% acetonitrile / water + 0.1% TFA, 10 minutes). The solution was freeze-dried to obtain the product 4-(2-amino-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-3-chlorobenzonitrile (0.060 g, 0.22 mmol, 19% yield) as a yellow solid. MS(ESI)m / z: 269.8 [M+1] + .

[0328] B.4-(2-amino-7-((2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-3-chlorobenzonitrile

[0329] To a solution of 4-(2-amino-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-3-chlorobenzonitrile (0.040 g, 0.15 mmol) / tetrahydrofuran (10 mL), 3-(5-(bromomethyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (synthesis as described in WO2023015283) (0.100 g, 0.3 mmol) and cesium carbonate (0.145 g, 0.44 mmol) were added. The mixture was stirred at 90°C for 24 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by semi-preparative reverse-phase HPLC (20%~50% acetonitrile / water + 0.1% TFA, 10 minutes). The target fractions were combined and freeze-dried to obtain the product 4-(2-amino-7-((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-3-chlorobenzonitrile (0.020 g, 0.04 mmol, 26% yield) as a yellow solid. MS(ESI)m / z: 526.2 [M+1] + .

[0330] C.3-Chloro-4-(2-(dimethylamino)-7-((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)benzonitrile

[0331] 4-(2-amino-7-((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-3-chlorobenzonitrile (0.005 g, 0.01 mmol) / methanol (1.0 mL) and acetic acid (0.1 mL) were mixed with methyl aldehyde (0.1 mL, 2.40 mmol, 37% purity) and borane; 2-methylpyridine (0.005 g, 0.05 mmol). The mixture was stirred at 20°C for 12 hours. The mixture was purified by semi-preparative reverse-phase HPLC (38%~68% acetonitrile / water + 0.1% TFA, 10 minutes). The solution was freeze-dried to obtain 3-chloro-4-(2-(dimethylamino)-7-((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)benzonitrile (0.003 g, 0.01 mmol, 52% yield, 100% purity). 1 H NMR (400MHz, DMSO-d6)δ 10.98(s, 1H), 8.23(s, 1H), 8.55(s, 1H), 7.96(d, 1H), 7.77(dd, J=8.0, 16.0, Hz, 2H), 7.60(s, 1H), 7.52(d, J=7.6, Hz, 1H), 7.33(d, J=3.2, Hz, 1H), 6.16(d, J=3.6 Hz, 1H), 5.45(s, 2H), 5.12 - 5.08(m, 1H), 4.47 - 4.29(m, 2H), 3.18(s, 3H), 2.94 - 2.90(m, 1H), 2.61 - 2.59(m, 1H), 2.36 - 2.34(m, 1H), 2.00 - 1.97(m, 1H). MS(ESI)m / z: 554.2 [M+1] + .

[0332] Example 30: (3S)-3-(5-{[4-(2,4-difluorophenyl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl]methyl}-1-oxo-2,3-dihydro-1H-isoindole-2-yl)piperidine-2,6-dione [ka]

[0333] A.(S)-5-amino-4-(5-((4-(2,4-difluorophenyl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate. 2-(2,4-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(2) (55.5 mg, 0.231 mmol), tert-butyl(S)-5-amino-4-(5-((6-(3-fluoroazetidine-1-yl)-4-iodo-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (intermediate F), 1,4-dioxane (0.9 mL), water (0.100 mL), and sodium carbonate (49.0 mg, 0.463 mmol) were added to an 8 mL vial. The reaction mixture was purged with nitrogen gas for 10 minutes. To the reaction mixture, tetrakis(triphenylphosphine)palladium(0) (17.82 mg, 0.015 mmol) was added at room temperature, and the mixture was stirred at 100°C for 16 hours. The reaction mixture was diluted with ethyl acetate (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (FA method - column: Sunfire C18 (250 x 19) mm 5.0 μm, mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, flow rate: 15 mL / min, time: 0-25 min, gradient: 10-75% B). The target fraction was concentrated to obtain tert-butyl(S)-5-amino-4-(5-((4-(2,4-difluorophenyl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate 3 (60 mg, 0.093 mmol, 60% yield). MS(ESI, +ve)m / z: 635.2(M+1) + .

[0334] B.(S)-3-(5-((4-(2,4-difluorophenyl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione. In an 8 mL vial, tert-butyl(S)-5-amino-4-(5-((4-(2,4-difluorophenyl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (60 mg, 0.095 mmol) was dissolved in acetonitrile (1 mL), and p-toluenesulfonic acid (71.9 mg, 0.378 mmol) was added to the mixture at room temperature. The reaction mixture was then stirred at 60 °C for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (FA method - column: Sunfire C18 (250x19) mm 5.0 μm, mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, flow rate: 15 mL / min, time: 0-20 min, gradient: 10-65% B). The desired fraction was concentrated and lyophilized to obtain (S)-3-(5-((4-(2,4-difluorophenyl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (30 mg, 0.053 mmol, 56% yield). 1 H NMR (400MHz, DMSO-d6, 2 rotamers) δ: 10.98(s, 1H), 7.73-7.82(m, 2H), 7.70(d, J=7.8 Hz, 1H), 7.45-7.54(m, 2H), 7.42(d, J=7.9 Hz, 1H), 7.29(t, J=8.3 Hz, 1H), 6.45(s, 1H), 5.44-5.68(m, 3H), 5.10(dd, J=13.3, 5.1 Hz, 1H), 4.39-4.50(m, 3H), 4.12-4.33(m, 3H), 2.85-2.95(m, 1H), 2.55-2.63(m, 1H), 2.32-2.39(m, 1H), 1.93-2.03(m, 1H). MS(ESI,+ve)m / z: 561.0(M+1) + .

[0335] Example 32: (3S)-3-[5-({4-[5-ethoxy-3-(trifluoromethyl)pyridine-2-yl]-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl}methyl)-1-oxo-2,3-dihydro-1H-isoindole-2-yl]piperidine-2,6-dione [ka]

[0336] A. 2-Chloro-5-ethoxy-3-(trifluoromethyl)pyridine. 6-Chloro-5-(trifluoromethyl)pyridine-3-ol (2.0 g, 10.12 mmol) was dissolved in DMF (20 mL). Potassium carbonate (2.80 g, 20.25 mmol) and bromoethane (0.907 mL, 12.15 mmol) were added to this mixture. The resulting reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was treated with ice-cold water and extracted with ethyl acetate (2 x 75 mL). The organic layers were combined and washed with brine. The resulting organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 2-Chloro-5-ethoxy-3-(trifluoromethyl)pyridine (1.7 g, 7.08 mmol, 70% yield) as a brown liquid. MS (ESI, +ve ion) m / z: 226.0 (M+1) + .

[0337] B.tert-butyl(S)-5-amino-4-(5-((4-(5-ethoxy-3-(trifluoromethyl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate. Tert-butyl(S)-5-amino-4-(5-((6-(3-fluoroazetidine-1-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (intermediate G) (1009 mg, 1.556 mmol) was dissolved in 1,4-dioxane (15 mL) and water (1.667 mL) in a 40 mL screw-cap vial. To this mixture, 2-chloro-5-ethoxy-3-(trifluoromethyl)pyridine (270 mg, 1.197 mmol), potassium carbonate (331 mg, 2.394 mmol), and PdCl2(dppf)DCM adduct (98 mg, 0.120 mmol) were added. The resulting mixture was purged with nitrogen for 10 minutes, then stirred at 130°C for 2 hours. After completion, the reaction mixture was cooled to room temperature, extracted with ethyl acetate (2 x 50 mL), and washed with water and brine. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by RP column to obtain tert-butyl(S)-5-amino-4-(5-((4-(5-ethoxy-3-(trifluoromethyl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.260 g, 0.281 mmol, 24% yield) as a pale brown viscous solid. MS (ESI, +ve ion) m / z 712.0 (M+1) + .

[0338] C.(S)-3-(5-((4-(5-ethoxy-3-(trifluoromethyl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione. Tert-butyl(S)-5-amino-4-(5-((4-(5-ethoxy-3-(trifluoromethyl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.255 g, 0.358 mmol) was weighed into a 15 mL screw-cap vial. To this, acetonitrile (5 mL) was added, followed by p-toluenesulfonic acid (0.136 g, 0.717 mmol). The reaction mixture was stirred at 80°C for 4 hours. After completion, the reaction mixture was purified by reverse-phase preparative HPLC using the following conditions: column: YMC C18 phenyl (250 x 21) mm, 5 micron; diluent: THF: water: ACN (50:20:30); mobile phase A: 5 mM ammonium formate / water; mobile phase B: acetonitrile. (S)-3-(5-((4-(5-ethoxy-3-(trifluoromethyl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (7.5 mg, 0.011 mmol, 3% yield) was obtained as an off-white solid. 1H NMR (400MHz, DMSO-d6)δ 10.97(br s, 1H), 8.68(d, J=3.0 Hz, 1H), 7.87(d, J=3.0 Hz, 1H), 7.70(d, J=7.5 Hz, 1H), 7.59(s, 1H), 7.49(s, 1H), 7.45 - 7.38 (m, 1H), 6.32 (s, 1H), 5.66 - 5.43 (m, 3H), 5.09 (dd, J=5.0, 13.0 Hz, 1H), 4.49 - 4.36 (m, 3H), 4.35 - 4.27 (m, 3H), 4.23 - 4.09(m, 2H), 2.97 - 2.85 (m, 1H), 2.63 - 2.60 (m, 1H), 2.44 - 2.36 (m, 1H), 2.03 - 1.94 (m, 1H), 1.41 (t, J=7.0 Hz, 3H); MS (ESI, +ve ion) m / z: 638.2 (M+1) + .

[0339] Example 41: 4-(1-{[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]methyl}-5-fluoro-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-4-yl)-3-fluorobenzonitrile [ka]

[0340] A. tert-butyl(4S)-5-amino-4-(5-((4-(4-cyano-2-fluorophenyl)-5-fluoro-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate. To a solution of tert-butyl(S)-5-amino-4-(5-((5-fluoro-6-(3-fluoroazetidine-1-yl)-4-iodo-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (intermediate H) (0.080 g, 0.12 mmol) and 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (0.044 g, 0.18 mmol) / 1,4-dioxane (2 mL), 1.5 M potassium phosphate (0.2 mL, 0.36 mmol) and XPhos-Pd-G4 (0.010 g, 0.01 mmol) were added. The mixture was stirred under nitrogen at 55°C for 1 hour. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were dried together over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was then purified by preparative TLC (80% ethyl acetate / petroleum ether) to obtain the product tert-butyl(S)-5-amino-4-(5-((4-(4-cyano-2-fluorophenyl)-5-fluoro-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.070 g, 0.11 mmol, 88% yield) as a yellow oil. MS(ESI)m / z: 660.3 [M+1] + .

[0341] B. (4S)-5-amino-4-(5-((4-(4-cyano-2-fluorophenyl)-5-fluoro-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoic acid. To a solution of tert-butyl(4S)-5-amino-4-(5-((4-(4-cyano-2-fluorophenyl)-5-fluoro-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.070 g, 0.11 mmol) / dichloromethane (3 mL), TFA (0.6 mL, 7.84 mmol) was added. The mixture was stirred at 25°C for 1 hour. The mixture was diluted with water (8 mL) and extracted with ethyl acetate (8 mL x 3). The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (4S)-5-amino-4-(5-((4-(4-cyano-2-fluorophenyl)-5-fluoro-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoic acid (0.060 g, 0.10 mmol, 94% yield) as a yellow oil. MS(ESI)m / z: 604.2 [M+1] + .

[0342] C.4-(1-((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)methyl)-5-fluoro-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-4-yl)-3-fluorobenzonitrile. (4S)-5-amino-4-(5-((4-(4-cyano-2-fluorophenyl)-5-fluoro-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoic acid (0.060 g, 0.10 mmol) / acetonitrile (2 mL) was mixed with N-ethyl-N-isopropylpropan-2-amine (0.1 mL, 0.40 mmol). Next, (dimethylamino)pyridine (0.036 g, 0.30 mmol) and di(1H-imidazole-1-yl)methanone (0.048 g, 0.30 mmol) were added, and the mixture was stirred at 90°C for 12 hours. The mixture was concentrated. The residue was purified by semi-preparative reverse-phase HPLC (42-72% acetonitrile / water + 0.225% formic acid, 7 minutes). Next, the collected fraction was concentrated to remove most of the acetonitrile, and then freeze-dried to obtain the product 4-(1-((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)methyl)-5-fluoro-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-4-yl)-3-fluorobenzonitrile (0.028 g, 0.05 mmol, 40.5% yield, 98% purity) as an off-white solid. 1H NMR (400MHz, DMSO-d6)δ 11.01 - 10.97 (m, 1H), 8.15 - 8.12 (m, 1H), 7.93 - 7.86 (m, 2H), 7.76 (s, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.52(s, 1H), 7.43(d, J=7.6 Hz, 1H), 5.64 - 5.44(m, 3H), 5.09(dd, J=5.6, 13.2 Hz, 1H), 4.65 - 4.51(m, 2H), 4.45 - 4.25(m, 4H), 2.95 - 2.86 (m, 1H), 2.58 (d, J=18.0 Hz, 1H), 2.38 - 2.35(m, 1H), 2.00 - 1.96(m, 1H). MS(ESI)m / z: 586.2[M+1] + .

[0343] Example 44: 3-(5-{[4-(3-chloro-5-ethoxypyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl]methyl}-1-oxo-2,3-dihydro-1H-isoindole-2-yl)piperidine-2,6-dione [ka]

[0344] A. 3-Chloro-5-ethoxy-2-(trimethylstannyl)pyridine. To a solution of 2-bromo-3-chloro-5-ethoxypyridine (250 mg, 1.057 mmol) / toluene (5 mL), hexamethyltin (0.241 mL, 1.163 mmol) was added. The mixture was degassed for 30 seconds. Tetrakis(triphenylphosphine)palladium (0) (122 mg, 0.106 mmol) was added, and the mixture was heated at 100°C for 4 hours. The reaction mixture was filtered through a 0.45 micron filter, washed with DCM (5 mL), and the filtrate was concentrated under reduced pressure to obtain crude 3-chloro-5-ethoxy-2-(trimethylstannyl)pyridine. MS(ESI)m / z: 320.0 [M] + .

[0345] B.tert-butyl(S)-5-amino-4-(5-((4-(3-chloro-5-ethoxypyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate. To tert-butyl(S)-5-amino-4-(5-((6-(3-fluoroazetidine-1-yl)-4-iodo-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (intermediate F) (150 mg, 0.227 mmol) / dioxane (5 mL), 3-chloro-5-ethoxy-2-(trimethylstannyl)pyridine (145 mg, 0.453 mmol), copper(I) iodide (2.203 mg, 0.011 mmol), and lithium chloride (19.61 mg, 0.453 mmol) were added. The mixture was degassed for 30 seconds. Tetrakis(triphenylphosphine)palladium(0) (26.7 mg, 0.023 mmol) was added, and the mixture was heated overnight at 100°C. The reaction mixture was filtered through Celite, washed with DCM (10 mL), and concentrated under reduced pressure. The crude product was purified by preparative HPLC (formic acid), and the fraction was concentrated under reduced pressure to obtain tert-butyl(S)-5-amino-4-(5-((4-(3-chloro-5-ethoxypyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (58 mg, 0.081 mmol, 36% yield) as an off-white solid. MS(ESI) m / z: 678.2[M] + .

[0346] C.3-(5-((4-(3-chloro-5-ethoxypyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione. tert-butyl(S)-5-amino-4-(5-((4-(3-chloro-5-ethoxypyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (160 mg, 0.201 mmol) / acetonitrile (5 mL) was mixed with p-toluenesulfonic acid (156 mg, 0.803 mmol), and the reaction mixture was heated overnight at 70°C. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (0.1% formic acid), and the fraction was concentrated under reduced pressure. The concentrate was freeze-dried using (ACN:water) to obtain 3-(5-((4-(3-chloro-5-ethoxypyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (30.1 mg, 0.049 mmol, 25% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6)δ: 10.99(s, 1H), 8.44(d, J=2.0 Hz, 1H), 7.78(d, J=2.5 Hz, 1H), 7.76(s, 1H), 7.70(d, J=7.5 Hz, 1H), 7.49(s, 1H), 7.41(d, J=8.0 Hz, 1H), 6.55(s, 1H), 5.45-5.63(m, 3H), 5.06-5.14(m, 1H), 4.40-4.47(m, 3H), 4.12-4.25(m, 5H), 2.87-2.93(m, 1H), 2.61(br s, 1H), 2.38(br s, 1H), 1.96-2.01(m, 1H), 1.39(t, J=7.0 Hz, 3H). MS(ESI)m / z: 604.2[M] + .

[0347] Example 46: 2-(1-((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)methyl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-4-yl)-5-ethoxynicotinonitrile [ka]

[0348] A. 2-Chloro-5-ethoxynicotinonitrile. To a stirred solution of 2-chloro-5-hydroxynicotinonitrile (1) (500 mg, 3.24 mmol) / DMF (5 mL), cesium carbonate (3162 mg, 9.71 mmol) was added, followed by ethyl iodide (0.392 mL, 4.85 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC to identify new spots, and the mass of the target product was confirmed by ULC-MS. Water (30 mL) was added to the reaction mixture, and it was extracted with ethyl acetate (40 ml x 2). The collected organic layer was washed with brine (20 ml x 4). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 2-chloro-5-ethoxynicotinonitrile (550 mg, 1.837 mmol, 57% yield) as an off-white solid. MS(ESI, +ve)m / z: 183.0(M+1) + .

[0349] B. 5-Ethoxy-2-(trimethylstannyl)nicotinonitrile. 1,1,1,2,2,2-Hexamethyldistannan (1077 mg, 3.29 mmol) was added to a stirred solution of 2-chloro-5-ethoxynicotinonitrile (400 mg, 2.190 mmol) / toluene (8 mL). The reaction mixture was degassed with N2 for 10 minutes, and then tetrakis(triphenylphosphine)palladium (0) (506 mg, 0.438 mmol) was added at room temperature. The resulting reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was monitored by UPLC-MS to confirm the mass of the target product. The reaction mixture was filtered through a Celite layer and washed with ethyl acetate (30 mL x 3). The collected organic layer was concentrated under reduced pressure to obtain crude (1.2 gm) 5-ethoxy-2-(trimethylstannyl)nicotinonitrile as a brown liquid, which was used without purification. MS(ESI, +ve)m / z: 313.0(M+1) + .

[0350] C.tert-butyl(S)-5-amino-4-(5-((4-(3-cyano-5-ethoxypyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate. To a stirred solution of tert-butyl(S)-5-amino-4-(5-((6-(3-fluoroazetidine-1-yl)-4-iodo-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (intermediate F) (200 mg, 0.308 mmol) / dioxane (5 mL), 5-ethoxy-2-(trimethylstannyl)nicotinonitrile (432 mg, 1.388 mmol), followed by lithium chloride (26.1 mg, 0.617 mmol). The reaction mixture was degassed over N2 for 10 minutes. Then, tetrakis(triphenylphosphine)palladium(O) (35.6 mg, 0.031 mmol) and copper(I) iodide (11.75 mg, 0.062 mmol) were added at room temperature. The resulting reaction mixture was stirred at 100°C for 19 hours. The reaction mixture was treated with water (10 mL) and extracted with ethyl acetate (20 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (25 g SiO2, 30-400 nm mesh) using a gradient of 0-100% ethyl acetate / petroleum ether. The pure fraction was concentrated under reduced pressure. The compound was re-purified by preparative HPLC using the following method: (column - Xselect CSH C18 (250 x 19) mm 10.0 μm, mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, flow rate: 15 mL / min, time: 0-50 min, gradient: 10-90% B). The pure fraction was concentrated under reduced pressure to obtain tert-butyl(S)-5-amino-4-(5-((4-(3-cyano-5-ethoxypyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (50 mg, 0.072 mmol, 23% yield) as a yellow solid. MS(ESI, +ve)m / z: 699.2(M+1)+ .

[0351] D.2-(1-((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)methyl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-4-yl)-5-ethoxynicotinonitrile. tert-butyl(S)-5-amino-4-(5-((4-(3-cyano-5-ethoxypyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (45 mg, 0.067 mmol) / acetonitrile (3 mL) was stirred, and p-toluenesulfonic acid (46.4 mg, 0.269 mmol) was added at room temperature. The resulting reaction mixture was stirred at 65°C for 2 hours. The mixture was concentrated and purified by preparative HPLC using the following method: (Column: Atlantis T3 (250x19) mm 10.0 μm, Mobile phase A: 0.1% formic acid / water, Mobile phase B: acetonitrile, Flow rate: 15 mL / min, Time: 0-45 min, Gradient: 15-85% B). The pure fraction was concentrated under reduced pressure and lyophilized to obtain 2-(1-((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)methyl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-4-yl)-5-ethoxynicotinonitrile (15 mg, 0.025 mmol, 37% yield) as a yellow solid. 1H NMR (400MHz, DMSO-d6, 2 rotamers) δ: 10.98(s, 1H), 8.75(d, J=2.5 Hz, 1H), 8.17(d, J=3.0 Hz, 1H), 7.95(s, 1H), 7.69(d, J=8.0 Hz, 1H), 7.48(s, 1H), 7.41(d, J=8.0 Hz, 1H), 6.80(s, 1H), 5.47-5.65(m, 3H), 5.09(dd, J=13.3, 5.3 Hz, 1H), 4.39-4.51(m, 3H), 4.25-4.34(m, 3H), 4.13-4.24(m, 2H), 2.85-2.95( m, 1H), 2.57-2.62(m, 1H), 2.32-2.35(m, 1H), 1.94-2.02(m, 1H), 1.40(t, J=7.0 Hz, 3H). MS(ESI,+ve)m / z: 595.3(M+1) + .

[0352] Example 49: (3S)-3-[5-({4-[3-chloro-5-(difluoromethoxy)pyridine-2-yl]-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl}methyl)-1-oxo-2,3-dihydro-1H-isoindole-2-yl]piperidine-2,6-dione [ka]

[0353] A. 2-Bromo-3-chloro-5-(difluoromethoxy)pyridine. To a solution of 6-bromo-5-chloropyridine-3-ol (0.500 g, 2.40 mmol) / N,N-dimethylformamide (6 mL), sodium 2-chloro-2,2-difluoroacetate (0.731 g, 4.80 mmol) and potassium carbonate (0.430 g, 3.12 mmol) were added. The mixture was stirred at 80°C for 2 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic layers were dried together over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. It was purified by silica column chromatography (0-8% ethyl acetate / petroleum ether) to obtain 2-bromo-3-chloro-5-(difluoromethoxy)pyridine (0.350 g, 1.35 mmol, 57% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ 8.22 (d, J=2.8 Hz, 1H), 7.62 (d, J=2.8 Hz, 1H), 6.57 (t, J=71.6 Hz, 1H). MS(ESI)m / z: 259.9 [M+1] + .

[0354] B.tert-butyl(S)-5-amino-4-(5-((4-(3-chloro-5-(difluoromethoxy)pyridine-2-yl)-6-fluoro-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate. To a solution of 2-bromo-3-chloro-5-(difluoromethoxy)pyridine (0.100 g, 0.39 mmol) and tert-butyl(S)-5-amino-4-(5-((6-fluoro-4-(tributylstannyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (intermediate E) (0.322 g, 0.43 mmol) / N,N-dimethylacetamide (2 mL), PCy3-Pd-G3 (0.028 g, 0.04 mmol) was added. The mixture was stirred under nitrogen at 90°C for 12 hours. The mixture was quenched with aqueous potassium fluoride solution (8 mL), diluted with water (8 mL), and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by semi-preparative reverse-phase HPLC (43-73% acetonitrile / water + 0.225% formic acid, 10 minutes). The collected fraction was then concentrated to remove most of the acetonitrile, and subsequently lyophilized to obtain the product tert-butyl(S)-5-amino-4-(5-((4-(3-chloro-5-(difluoromethoxy)pyridine-2-yl)-6-fluoro-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.093 g, 0.14 mmol, 37% yield) as a colorless oil. MS(ESI)m / z: 645.4 [M+1] + .

[0355] C.tert-butyl(S)-5-amino-4-(5-((4-(3-chloro-5-(difluoromethoxy)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate. To a solution of tert-butyl(S)-5-amino-4-(5-((4-(3-chloro-5-(difluoromethoxy)pyridine-2-yl)-6-fluoro-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.093 g, 0.14 mmol) / acetonitrile (2 mL), 3-fluoroazetidine hydrochloride (0.019 g, 0.17 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.1 mL, 0.58 mmol) were added. The mixture was stirred at 60°C for 2 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain tert-butyl(S)-5-amino-4-(5-((4-(3-chloro-5-(difluoromethoxy)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.090 g, 0.13 mmol, 89% yield) as a yellow oil. MS(ESI)m / z: 700.4 [M+1] + .

[0356] D.(S)-3-(5-((4-(3-chloro-5-(difluoromethoxy)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione. To a solution of tert-butyl(S)-5-amino-4-(5-((4-(3-chloro-5-(difluoromethoxy)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.070 g, 0.10 mmol) / acetonitrile (1 mL), 4-methylbenzenesulfonic acid (0.069 g, 0.40 mmol) was added. The mixture was stirred at 60°C for 2 hours. The mixture was added to aqueous sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by semi-preparative reverse-phase HPLC (40-70% acetonitrile / water + 0.225% formic acid, 10 minutes). The collected fraction was then concentrated to remove most of the acetonitrile, and subsequently lyophilized to obtain the crude product. The crude product was separated by SFC separation (column: DAIEL CHIRALPAK OJ (250 mm x 30 mm, 10 μm), mobile phase: phase A CO2, phase B IPA (0.1% NH3H2O); gradient elution: IPA (0.1% NH3H2O) / CO2 40%-40%, flow rate: 150 mL / min; 9.8 min) to obtain one fraction. The fraction was concentrated under reduced pressure to obtain the residue. The obtained residue was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.The residue was redissolved in water (10 mL) and acetonitrile (5 mL), and then freeze-dried to obtain the product (S)-3-(5-((4-(3-chloro-5-(difluoromethoxy)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (0.008 g, 0.01 mmol, 12% yield, 99.8% purity, 99.1% ee) as a yellow oily substance. 1 H NMR (400MHz, DMSO-d6) δ=10.97(s, 1H), 8.66(d, J=2.4 Hz, 1H), 8.16(d, J=2.4 Hz, 1H), 7.75(s, 1H), 7.70 - 7.66(m, 1H), 7.49 - 7.30 (m, 3H), 6.57 (s, 1H), 5.63 - 5.46 (m, 3H), 5.09 (dd, J=5.6, 13.6 Hz, 1H), 4.49 - 4.40 (m, 3H), 4.32 - 4.27 (m, 1H), 4.22 - 4.13(m, 2H), 2.94 - 2.85(m, 1H), 2.61 - 2.60(m, 1H), 2.42 - 2.36(m, 1H), 2.00 - 1.94(m, 1H). MS(ESI)m / z: 626.0[M+1] + .

[0357] Example 60: 4-(6-(azetidine-1-yl)-1-((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)methyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-yl)-3-chlorobenzonitrile [ka]

[0358] A. 3-Bromo-6-fluoro-4-iodo-1H-pyrazolo[3,4-b]pyridine. A mixture of 6-fluoro-4-iodo-1H-pyrazolo[3,4-b]pyridine (intermediate A) (1,000 g, 3.80 mmol) and N-bromosuccinimide (1,353 g, 7.60 mmol) / DMF (10 mL) was stirred at 25°C for 12 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (20 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (0-18% ethyl acetate / petroleum ether) to obtain 3-bromo-6-fluoro-4-iodo-1H-pyrazolo[3,4-b]pyridine (1,300 g, 3.80 mmol, 100% yield) as a yellow oil, which was used directly in the next step. MS(ESI)m / z: 341.9 [M+1] + .

[0359] B. Product (S)-tert-butyl 5-amino-4-(5-((3-bromo-6-fluoro-4-iodo-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate. A mixture of 3-bromo-6-fluoro-4-iodo-1H-pyrazolo[3,4-b]pyridine (1.300 g, 3.80 mmol), (S)-tert-butyl 5-amino-4-(5-(bromomethyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (intermediate C) (1.567 g, 3.80 mmol), and cesium carbonate (2.471 g, 7.60 mmol) / DMF (20 mL) was stirred at 50°C for 2 hours. The reaction mixture was diluted with water (200 mL) and adjusted to pH 7 with 1 M phosphoric acid. The mixture was extracted with ethyl acetate (50 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to obtain (S)-tert-butyl 5-amino-4-(5-((3-bromo-6-fluoro-4-iodo-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.600 g, 0.89 mmol, 24% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6)δ 7.75(s, 1H), 7.66(d, J=7.6 Hz, 1H), 7.53(s, 1H), 7.44(s, 1H), 7.38(d, J=8.0 Hz, 1H), 7.16(s, 1H), 5.67(s, 2H), 4.69(dd, J=4.0, 10.4 Hz, 1H), 4.58 - 4.49(m, 1H), 4.47 - 4.37(m, 1H), 2.16 - 2.10(m, 3H), 1.98 - 1.90(m, 1H), 1.32 - 1.28(m, 9H). MS(ESI)m / z: 674.0 [M+1] + .

[0360] C.(S)-tert-butyl 5-amino-4-(5-((3-bromo-4-(2-chloro-4-cyanophenyl)-6-fluoro-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate. A mixture of (S)-tert-butylamino-4-(5-((3-bromo-6-fluoro-4-iodo-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.600 g, 0.89 mmol), 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (0.353 g, 1.34 mmol), [2-(2-aminophenyl)phenyl]-chloropalladium;dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphane (0.076 g, 0.09 mmol), and 2M potassium carbonate (0.9 mL, 1.78 mmol) / dioxane (10 mL) was stirred at 85°C for 24 hours under nitrogen. The reaction mixture was concentrated under vacuum and then purified by silica gel chromatography (0-70% ethyl acetate / petroleum ether) to obtain the product (S)-tert-butyl 5-amino-4-(5-((3-bromo-4-(2-chloro-4-cyanophenyl)-6-fluoro-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.200 g, 0.29 mmol, 33% yield) as a bright yellow solid. 1 H NMR (400MHz, DMSO-d6)δ 8.33(s, 1H), 8.05(d, J=8.0 Hz, 1H), 7.80 - 7.72(m, 1H), 7.69(d, J=7.6 Hz, 1H), 7.59 - 7.51(m, 2H), 7.46(d, J=7.6 Hz, 1H), 7.25(s, 1H), 7.16(s, 1H), 5.81 - 5.66(m, 2H), 4.70(dd, J=3.6, 10.4 Hz, 1H), 4.62 - 4.53(m, 1H), 4.48 - 4.40(m, 1H), 2.13(s, 3H), 1.98 - 1.85(m, 1H), 1.30(s, 9H). MS(ESI) m / z: 683.0 [M+1] + .

[0361] D.(S)-tert-butyl 5-amino-4-(5-((4-(2-chloro-4-cyanophenyl)-6-fluoro-3-methyl-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate. A mixture of (S)-tert-butyl 5-amino-4-(5-((3-bromo-4-(2-chloro-4-cyanophenyl)-6-fluoro-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.160 g, 0.23 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatrivolinan (0.018 g, 0.14 mmol), tetrakis(triphenylphosphine)palladium (0) (0.027 g, 0.02 mmol), and cesium carbonate (0.153 g, 0.47 mmol) / dioxane (5 mL) and water (0.5 mL) was stirred under nitrogen at 85°C for 24 hours. Reaction mixture preparative TLC (50% ethyl acetate / petroleum ether, R f The product was purified with (S)-tert-butyl 5-amino-4-(5-((4-(2-chloro-4-cyanophenyl)-6-fluoro-3-methyl-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.020 g, 0.03 mmol, 14% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6)δ 8.37 - 8.30(m, 1H), 8.07 - 7.99(m, 1H), 7.77(d, J=8.0 Hz, 1H), 7.67(d, J=7.6 Hz, 1H), 7.52(s, 2H), 7.42(d, J=8.0 Hz, 1H), 7.20 - 7.13(m, 1H), 7.06(s, 1H), 5.78 - 5.60(m, 2H), 4.69(dd, J=3.2, 10.0 Hz, 1H), 4.58 - 4.51(m, 1H), 4.47 - 4.39(m, 1H), 2.13(s, 3H), 2.02 - 1.87(m, 4H), 1.30(d, J=2.4Hz, 9H). MS(ESI)m / z: 617.3 [M+1]+ .

[0362] E.(S)-tert-butyl 5-amino-4-(5-((6-(azetidine-1-yl)-4-(2-chloro-4-cyanophenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate. A mixture of (S)-tert-butyl 5-amino-4-(5-((4-(2-chloro-4-cyanophenyl)-6-fluoro-3-methyl-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.030 g, 0.05 mmol), azetidine hydrochloride (0.007 g, 0.07 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.013 g, 0.10 mmol) / acetonitrile (2 mL) was stirred at 80°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product (S)-tert-butyl 5-amino-4-(5-((6-(azetidine-1-yl)-4-(2-chloro-4-cyanophenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.031 g, 0.05 mmol, 97% yield) as a yellow solid, which was used directly in the next step. MS(ESI)m / z: 645.3 [M+1] + .

[0363] F.(S)-5-amino-4-(5-((6-(azetidine-1-yl)-4-(2-chloro-4-cyanophenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoic acid. (S)-tert-butyl 5-amino-4-(5-((6-(azetidine-1-yl)-4-(2-chloro-4-cyanophenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.031 g, 0.05 mmol) / dichloromethane (1 mL) solution was to which TFA (0.3 mL, 3.89 mmol) was added at 25 °C. Next, the mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (10 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product (S)-5-amino-4-(5-((6-(azetidine-1-yl)-4-(2-chloro-4-cyanophenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoic acid (0.028 g, 0.05 mmol, 99% yield) as a pale yellow solid, which was used directly in the next step. MS(ESI)m / z: 598.2 [M+1] + .

[0364] G.4-(6-(azetidine-1-yl)-1-((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)methyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-yl)-3-chlorobenzonitrile. A mixture of (S)-5-amino-4-(5-((6-(azetidine-1-yl)-4-(2-chloro-4-cyanophenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoic acid (0.028 g, 0.05 mmol), carbonyldiimidazole (0.015 g, 0.09 mmol), 4-dimethylaminopyridine (0.006 g, 0.05 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.012 g, 0.09 mmol) / acetonitrile (1 mL) was stirred at 80°C for 12 hours. The reaction mixture was purified by semi-preparative reverse-phase HPLC (39-69% acetonitrile / water + 0.225% formic acid, 10 minutes). The fraction of interest was freeze-dried to obtain the product 4-(6-(azetidine-1-yl)-1-((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)methyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-yl)-3-chlorobenzonitrile (0.004 g, 0.01 mmol, 13% yield, 98% purity) as an off-white solid. 1 H NMR (400MHz, DMSO-d6)δ 11.10 - 10.81 (m, 1H), 8.32 - 8.20 (m, 1H), 8.02 - 7.88 (m, 1H), 7.74 - 7.60 (m, 2H), 7.51 (s, 1H), 7.42 (d, J=7.6 Hz, 1H), 6.33 - 6.06(m, 1H), 5.62 - 5.43(m, 2H), 5.09(dd, J=5.2, 13.2 Hz, 1H), 4.50 - 4.38(m, 1H), 4.37 - 4.25(m, 1H), 4.16 - 4.04(m, 4H), 2.96 - 2.84 (m, 1H), 2.64 - 2.56 (m, 1H), 2.44 - 2.32 (m, 4H), 2.04 - 1.93 (m, 1H), 1.81 (s, 2H). MS(ESI)m / z: 580.3 [M+1] + .

[0365] Example 61: (S)-3-(5-((4-(3-chloro-5-fluoropyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-4-fluoro-1-oxoisoindorin-2-yl)piperidine-2,6-dione [ka]

[0366] Example 109: (R)-3-(5-((4-(3-chloro-5-fluoropyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-4-fluoro-1-oxoisoindorin-2-yl)piperidine-2,6-dione [ka]

[0367] A. A mixture of tert-butyl(S)-5-amino-4-(4-fluoro-5-((6-fluoro-4-iodo-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate. 6-fluoro-4-iodo-1H-pyrazolo[3,4-b]pyridine (intermediate A) (1,000 g, 3.80 mmol), tert-butyl(S)-5-amino-4-(4-fluoro-5-(((methylsulfonyl)oxy)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (intermediate K) (2,535 g, 5.70 mmol), and cesium carbonate (2,471 g, 7.60 mmol) / DMF (20 mL) was stirred at 50°C for 2 hours. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (50 mL x 2). The organic layers were combined and concentrated under vacuum. The residue was purified by semi-preparative reverse-phase HPLC (50-80% acetonitrile / water + 0.225% formic acid, 17 minutes). The desired fraction was extracted with ethyl acetate (50 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate solid, filtered, and concentrated under vacuum to obtain tert-butyl(S)-5-amino-4-(4-fluoro-5-((6-fluoro-4-iodo-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (1.100 g, 1.80 mmol, 47% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3)δ 7.90(s, 1H), 7.56(d, J=7.6 Hz, 1H), 7.31(d, J=6.8 Hz, 1H), 7.28(s, 1H), 6.31(s, 1H), 5.72(s, 2H), 5.55(s, 1H), 4.93 - 4.86 (m, 1H), 4.67 - 4.61 (m, 1H), 4.54 - 4.46 (m, 1H), 2.41 - 2.22 (m, 3H), 2.17 - 2.10 (m, 1H), 1.42 (s, 9H). MS(ESI)m / z: 612.3 [M+1] + .

[0368] B.tert-butyl(S)-5-amino-4-(5-((4-(3-chloro-5-fluoropyridine-2-yl)-6-fluoro-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-4-fluoro-1-oxoisoindorin-2-yl)-5-oxopentanoate. A mixture of tert-butyl(S)-5-amino-4-(4-fluoro-5-((6-fluoro-4-iodo-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.250 g, 0.41 mmol), tributyl-(3-chloro-5-fluoro-2-pyridyl) stannan (prepared similarly to intermediate M) (0.206 g, 0.49 mmol), tetrakis(triphenylphosphine)palladium(0) (0.037 g, 0.04 mmol), and copper iodide (0.016 g, 0.08 mmol) / dioxane (5 mL) was stirred under nitrogen at 100 °C for 12 hours. The reaction mixture was quenched with aqueous potassium fluoride solution and extracted with ethyl acetate (10 mL x 2). The organic layers were combined and concentrated under vacuum. The resulting residue was further purified by preparative TLC (60% ethyl acetate / petroleum ether) to obtain the crude product tert-butyl(S)-5-amino-4-(5-((4-(3-chloro-5-fluoropyridine-2-yl)-6-fluoro-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-4-fluoro-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.280 g, 0.46 mmol) as a yellow oil, which was used directly in the next step. MS(ESI)m / z: 615.3 [M+1] + .

[0369] C.tert-butyl(S)-5-amino-4-(5-((4-(3-chloro-5-fluoropyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-4-fluoro-1-oxoisoindorin-2-yl)-5-oxopentanoate. A mixture of tert-butyl(S)-5-amino-4-(5-((4-(3-chloro-5-fluoropyridine-2-yl)-6-fluoro-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-4-fluoro-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.280 g, 0.46 mmol), 3-fluoroazetidine hydrochloride (0.061 g, 0.55 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.118 g, 0.91 mmol) / acetonitrile (5 mL) was stirred at 80°C for 3 hours. The reaction mixture was concentrated under vacuum. The residue was purified by preparative TLC (50% ethyl acetate / petroleum ether) to obtain the product tert-butyl(S)-5-amino-4-(5-((4-(3-chloro-5-fluoropyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-4-fluoro-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.170 g, 0.25 mmol, 56% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6)δ 8.78(d, J=2.4 Hz, 1H), 8.33(dd, J=2.4, 8.4 Hz, 1H), 7.74(s, 1H), 7.57(s, 1H), 7.51(d, J=7.6 Hz, 1H), 7.36(t, J=6.8 Hz, 1H), 7.20(s, 1H), 6.55(s, 1H), 5.68 - 5.43(m, 3H), 4.69(dd, J=4.0, 10.8 Hz, 1H), 4.64 - 4.54(m, 2H), 4.50 - 4.37(m, 2H), 4.24 - 4.10(m, 2H), 2.21 - 2.11(m, 3H), 2.06 - 1.99(m, 1H), 1.30(s, 9H). MS(ESI) m / z: 670.3 [M+1] + .

[0370] D.(S)-5-amino-4-(5-((4-(3-chloro-5-fluoropyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-4-fluoro-1-oxoisoindorin-2-yl)-5-oxopentanoic acid. To a solution of tert-butyl(S)-5-amino-4-(5-((4-(3-chloro-5-fluoropyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-4-fluoro-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.170 g, 0.25 mmol) / dichloromethane (2 mL), TFA (0.02 mL, 0.25 mmol) was added at 25°C. The mixture was then stirred at 25°C for 1 hour. The reaction mixture was diluted with water (20 mL) and adjusted to pH 6 with sodium sulfite solution. The mixture was then extracted with dichloromethane (10 mL x 2). The organic layers were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain (S)-5-amino-4-(5-((4-(3-chloro-5-fluoropyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-4-fluoro-1-oxoisoindorin-2-yl)-5-oxopentanoic acid (0.155 g, 0.25 mmol, 99.5% yield) as a white solid, which was then used directly in the next step.

[0371] E.3-(5-((4-(3-chloro-5-fluoropyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-4-fluoro-1-oxoisoindorin-2-yl)piperidine-2,6-dione. A mixture of (S)-5-amino-4-(5-((4-(3-chloro-5-fluoropyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-4-fluoro-1-oxoisoindorin-2-yl)-5-oxopentanoic acid (0.151 g, 0.25 mmol), N-ethyl-N-isopropylpropan-2-amine (0.1 mL, 0.76 mmol), 4-dimethylaminopyridine (0.031 g, 0.25 mmol), and carbonyldiimidazole (0.082 g, 0.50 mmol) / acetonitrile (3 mL) was stirred at 60°C for 4 hours. The reaction mixture was concentrated under vacuum. The residue was further purified by semi-preparative reverse-phase HPLC (42-62% acetonitrile / water + 0.225% formic acid, 7 minutes). The fraction of interest was lyophilized to obtain the product 3-(5-((4-(3-chloro-5-fluoropyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-4-fluoro-1-oxoisoindorin-2-yl)piperidine-2,6-dione (0.050 g, 0.08 mmol, 33% yield) as a white solid. MS(ESI)m / z: 596.4 [M+1] + .

[0372] F.(R)-3-(5-((4-(3-chloro-5-fluoropyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-4-fluoro-1-oxoisoindorin-2-yl)piperidine-2,6-dione. 3-(5-((4-(3-chloro-5-fluoropyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-4-fluoro-1-oxoisoindorin-2-yl)piperidine-2,6-dione (0.050g, 0.08mmol) was separated by SFC (column: DAIEL CHIRALPAK IC (250mm)). * Separation was performed using a 30mm, 10μm (30mm, 10μm) mobile phase (Phase A: CO2, Phase B: IPA+ACN(NEU)); gradient elution (IPA+ACN(NEU / CO2 70%~70%, flow rate: 80mL / min; 3.5 min, 43 min) to obtain two fractions. The fraction with the earlier elution peak was concentrated under reduced pressure to obtain the residue. The residue was redissolved in water (20 mL) and acetonitrile (5 mL), and then freeze-dried to obtain Example 61(S)-3-(5-((4-(3-chloro-5-fluoropyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-4-fluoro-1-oxoisoindorin-2-yl)piperidine-2,6-dione (0.017 g, 0.03 mmol, 33% yield, 99.5% purity, 100% ee%) as an off-white solid. 1H NMR (400MHz, DMSO-d6)δ 11.14 - 10.91(m, 1H), 8.78(d, J=2.4 Hz, 1H), 8.39 - 8.30(m, 1H), 7.74(s, 1H), 7.56(d, J=7.6 Hz, 1H), 7.38(t, J=6.8 Hz, 1H), 6.56(s, 1H), 5.67(s, 2H), 5.64 - 5.44(m, 1H), 5.11(dd, J=4.8, 13.2 Hz, 1H), 4.58(d, J=17.6 Hz, 1H), 4.51 - 4.38(m, 3H), 4.24 - 4.10(m, 2H), 2.97 - 2.85 (m, 1H), 2.63 - 2.56 (m, 1H), 2.40 (d, J=4.4 Hz, 1H), 2.03 - 1.95 (m, 1H). MS(ESI)m / z: 596.3 [M+1] + .

[0373] The fraction of the later elution peak was concentrated under vacuum. The residue was redissolved in water (20 mL) and acetonitrile (5 mL), and then lyophilized to obtain Example 109(R)-3-(5-((4-(3-chloro-5-fluoropyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-4-fluoro-1-oxoisoindorin-2-yl)piperidine-2,6-dione (0.022 g, 0.04 mmol, 43% yield, 98.5% purity, 98.3% ee%) as an off-white solid. 1H NMR (400MHz, DMSO-d6)δ 11.11 - 10.91(m, 1H), 8.78(d, J=2.4 Hz, 1H), 8.34(dd, J=2.4, 8.8 Hz, 1H), 7.74(s, 1H), 7.56(d, J=7.6 Hz, 1H), 7.38(t, J=7.2 Hz, 1H), 6.56(s, 1H), 5.71 - 5.46(m, 3H), 5.11(dd, J=4.8, 12.8 Hz, 1H), 4.62 - 4.54(m, 1H), 4.49 - 4.38(m, 3H), 4.23 - 4.11(m, 2H), 2.95 - 2.86 (m, 1H), 2.60 (s, 1H), 2.42 - 2.39 (m, 1H), 2.03 - 1.95 (m, 1H). MS(ESI)m / z: 596.3 [M+1] + .

[0374] Example 78: (3R)-3-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-5-fluoro-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione [ka]

[0375] A. tert-butyl(4S)-5-amino-4-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-5-fluoro-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate. To a solution of tert-butyl(S)-5-amino-4-(5-((5-fluoro-6-(3-fluoroazetidine-1-yl)-4-iodo-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (intermediate H) (0.200 g, 0.30 mmol) and 3-chloro-2-(tributylstannyl)-5-(trifluoromethyl)pyridine (intermediate M) (0.282 g, 0.60 mmol) / dioxane (2 mL), tetrakis(triphenylphosphine)palladium(O) (0.027 g, 0.03 mmol) and copper(I) iodide (0.006 g, 0.03 mmol) were added. The mixture was stirred under nitrogen at 90°C for 12 hours. The mixture was quenched with saturated potassium fluoride aqueous solution (10 mL) and stirred for 20 minutes; the mixture was then filtered, the filtrate was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were dried together over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then purified by preparative TLC (75% ethyl acetate / petroleum ether) to obtain the product tert-butyl(4S)-5-amino-4-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-5-fluoro-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.140 g, 0.19 mmol, 65% yield) as a yellow oil. 1H NMR (400MHz, CDCl3)δ 8.94(s, 1H), 8.15(d, J=2.0 Hz, 1H), 7.80(d, J=8.0 Hz, 1H), 7.59(s, 1H), 7.48(d, J=7.6 Hz, 1H), 7.39(s, 1H), 6.35(s, 1H), 5.65(s, 2H), 541 - 5.39(m, 2H), 4.89(dd, J=6.4, 8.8 Hz, 1H), 4.63 - 4.51(m, 2H), 4.47 - 4.38(m, 4H), 2.39 - 2.07(m, 4H), 1.41(s, 9H). MS(ESI)m / z: 720.2 [M+1] + .

[0376] B.(4S)-5-amino-4-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-5-fluoro-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoic acid. To a solution of tert-butyl(4S)-5-amino-4-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-5-fluoro-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.500 g, 0.69 mmol) / dichloromethane (6 mL), TFA (2 mL, 26.12 mmol) was added. The mixture was stirred at 25°C for 2 hours. The mixture was adjusted to pH 6 with aqueous sodium bicarbonate solution, diluted with water (10 mL), and extracted with ethyl acetate (15 mL x 3). The organic layers were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain (4S)-5-amino-4-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-5-fluoro-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoic acid (0.450 g, 0.68 mmol, 98% yield) as a yellow oil. This substance was used directly in the next step.

[0377] C.(3R)-3-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-5-fluoro-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione. (4S)-5-amino-4-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-5-fluoro-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoic acid (0.070 g, 0.11 mmol) / acetonitrile (2 mL) was mixed with N-ethyl-N-isopropylpropan-2-amine (0.1 mL, 0.32 mmol). Then di(1H-imidazole-1-yl)methanone (0.034 g, 0.21 mmol) and N,N-dimethylpyridine-2-amine (0.026 g, 0.21 mmol) were added, and the mixture was stirred under nitrogen at 60 °C for 12 hours. The residue was purified by semi-preparative reverse-phase HPLC (47-77% acetonitrile / water + 0.225% formic acid, 7 minutes). The desired fraction was concentrated under vacuum and then lyophilized to obtain the product. The product was separated by SFC separation (column: DAIEL CHIRALCEL OX (250 mm x 30 mm, 10 μm), mobile phase: phase A CO2, phase B IPA (0.05% DEA); gradient elution: IPA (0.05% DEA) / CO2 60%-60%, flow rate: 80 mL / min; 5 min, 40 min) to obtain two fractions. Fraction 2 was concentrated under vacuum to obtain the residue. The residue was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.The residue was redissolved in water (5 mL) and acetonitrile (5 mL), and then freeze-dried to obtain the product (3R)-3-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-5-fluoro-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (0.026 g, 0.04 mmol, 39% yield, 99.6% purity, 100% ee%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.98(s, 1H), 9.16(d, J=1.2 Hz, 1H), 8.77(d, J=1.2 Hz, 1H), 7.75 - 7.67(m, 2H), 7.52(s, 1H), 7.44(d, J=8.0 Hz, 1H), 5.67 - 5.42(m, 3H), 5.09(dd, J=4.8, 13.2 Hz, 1H), 4.68 - 4.52(m, 2H), 4.49 - 4.38(m, 1H), 4.37 - 4.23(m, 3H), 2.98 - 2.82(m, 1H), 2.63 - 2.55(m, 1H), 2.42 - 2.29(m, 1H), 2.03 - 1.94(m, 1H). MS(ESI)m / z: 646.3[M+1] + .

[0378] Example 87: (R)-3-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione [ka]

[0379] A.tert-butyl(S)-5-amino-4-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-6-fluoro-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate. To a solution of tert-butyl(S)-5-amino-4-(5-((6-fluoro-4-iodo-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (intermediate D) (0.250 g, 0.42 mmol) and 3-chloro-2-(tributylstannyl)-5-(trifluoromethyl)pyridine (intermediate M) (0.238 g, 0.51 mmol) / 1,4-dioxane (10 mL), tetrakis(triphenylphosphine)palladium (0.039 g, 0.04 mmol) and copper(I) iodide (0.016 g, 0.08 mmol) were added. The mixture was stirred under nitrogen at 100 °C for 12 hours. The reaction mixture was quenched with aqueous potassium fluoride solution and filtered. The filtrate was concentrated to obtain the residue. The residue was purified by preparative TLC (50% ethyl acetate / petroleum ether) to obtain tert-butyl(S)-5-amino-4-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-6-fluoro-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.180 g, 0.28 mmol, 66% yield) as a yellow oil. 1 H NMR (400MHz, DMSO-d6)δ 9.18(s, 1H), 8.80(d, J=1.2 Hz, 1H), 8.20(s, 1H), 7.67(d, J=8.0 Hz, 1H), 7.56 - 7.48(m, 2H), 7.44 - 7.38 (m, 2H), 7.16 (s, 1H), 5.77 (s, 2H), 4.69 (dd, J=4.0, 10.4 Hz, 1H), 4.59 - 4.36 (m, 2H), 2.17 - 2.07 (m, 3H), 1.97 - 1.88(m, 1H), 1.29(s, 9H). MS(ESI)m / z: 647.3 [M+1] + .

[0380] B.tert-butyl(S)-5-amino-4-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate. To a solution of tert-butyl(S)-5-amino-4-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-6-fluoro-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.180 g, 0.28 mmol) and 3-fluoroazetidine hydrochloride (0.037 g, 0.33 mmol) / acetonitrile (10 mL), N-ethyl-N-isopropylpropan-2-amine (0.2 mL, 0.83 mmol) was added. The reaction mixture was stirred at 80°C for 12 hours. The reaction mixture was adjusted to pH 6 with 1 M phosphoric acid solution and extracted with ethyl acetate (50 mL x 3). Next, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain tert-butyl(S)-5-amino-4-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.170 g, 0.24 mmol, 87% yield) as a yellow solid, and the obtained crude product was used directly in the next step. MS(ESI)m / z: 702.3 [M+1] + .

[0381] C.(S)-5-amino-4-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoic acid. To a solution of tert-butyl(S)-5-amino-4-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.170 g, 0.24 mmol) / dichloromethane (6 mL), 2,2,2-TFA (2.0 mL, 26.12 mmol) was added and the mixture was stirred at 25°C for 2 hours. The reaction mixture was adjusted to pH 6 with aqueous sodium bicarbonate solution and extracted with ethyl acetate (50 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain (S)-5-amino-4-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoic acid (0.140 g, 0.22 mmol, 90% yield) as a yellow solid.

[0382] D.(R)-3-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione. (S)-5-amino-4-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoic acid (0.140 g, 0.22 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.1 mL, 0.65 mmol) / acetonitrile (15 mL) were mixed with N,N'-carbonyldiimidazole (0.088 g, 0.54 mmol) and N,N-dimethylpyridine-4-amine (0.029 mg, 0.24 mmol). The reaction mixture was stirred at 80°C for 12 hours. The mixture was purified by semi-preparative reverse-phase HPLC (45-75% acetonitrile / water + 0.225% formic acid, 7 minutes). The desired fractions were combined and extracted with ethyl acetate (50 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by SFC separation (column: DAIEL CHIRALPAK IC (250 mm x 30 mm, 10 μm)), mobile phase: Phase A: carbon dioxide, Phase B: isophthalic acid + acetonitrile (0.05% DEA); gradient elution: isophthalic acid + acetonitrile (0.05% DEA) / carbon dioxide 60%-60%, flow rate: 80 mL / min; 5.7 min, 50 min) to obtain two fractions. Fraction 2 was concentrated under vacuum to obtain the residue. The residue was redissolved in water (10 mL) and acetonitrile (20 mL), and then freeze-dried to obtain the product (R)-3-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (0.029 g, 0.05 mmol, 21% yield, 99.4% purity, 100% ee%). 1H NMR (400MHz, DMSO-d6)δ 10.98(s, 1H), 9.12(s, 1H), 8.71(d, J=1.2 Hz, 1H), 7.79(s, 1H), 7.70(d, J=7.6 Hz, 1H), 7.50(s, 1H), 7.42(d, J=8.0 Hz, 1H), 6.62(s, 1H), 5.68 - 5.44(m, 3H), 5.09(dd, J=5.2, 13.1 Hz, 1H), 4.55 - 4.37(m, 3H), 4.33 - 4.26(m, 1H), 4.24 - 4.10(m, 2H), 2.96 - 2.82 (m, 1H), 2.65 - 2.54(m, 1H), 2.39 - 2.30(m, 1H), 2.03 - 1.91(m, 1H). MS(ESI)m / z: 628.2 [M+1] + .

[0383] Example 108: (3S)-3-[5-({4-[3-chloro-5-(oxetan-3-yl)pyridine-2-yl]-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl}methyl)-1-oxo-2,3-dihydro-1H-isoindole-2-yl]piperidine-2,6-dione [ka] [ka]

[0384] A. 2,3-Dichloro-5-(oxetan-3-yl)pyridine. 5-Bromo-2,3-dichloropyridine (2.000 g, 8.81 mmol), 3-bromooxetane (1570 g, 11.46 mmol), Ir[dF(CF3)ppy]2(dtbpy)(PF6) (0.099 g, 0.09 mmol), NiCl2dtbbpy (0.011 g, 0.09 mmol), tris(trimethylsilyl)silane (TTMSS 2.192 g, 8.81 mmol), and sodium carbonate (1869 g, 17.63 mmol) / acetonitrile (20 mL) were added to a 40 mL vial containing a stirring bar. The vial was placed under nitrogen and sealed. The reaction mixture was stirred, and while maintaining the reaction mixture temperature at 25°C with a cooling fan, it was irradiated with a 34W blue LED lamp (at a distance of 7 cm) for 14 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-70% ethyl acetate / petroleum ether). The residue was further purified by semi-preparative reverse-phase HPLC (25-55% acetonitrile / water + 0.225% formic acid, 10 minutes). The desired fractions were combined and extracted with ethyl acetate (50 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate solids, filtered, and concentrated under reduced pressure to obtain the product 2,3-dichloro-5-(oxetan-3-yl)pyridine (0.400 g, 1.96 mmol, 22% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3)δ 8.27(d, J=2.0 Hz, 1H), 7.98(d, J=2.0 Hz, 1H), 5.14(dd, J=6.4, 8.0 Hz, 2H), 4.69(t, J=6.4 Hz, 2H), 4.26 - 4.17(m, 1H). MS(ESI)m / z: 203.9 [M+1] + .

[0385] B.tert-butyl(S)-5-amino-4-(5-((4-(3-chloro-5-(oxetan-3-yl)pyridine-2-yl)-6-fluoro-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate. A mixture of 2,3-dichloro-5-(oxetan-3-yl)pyridine (0.200 g, 0.98 mmol), tert-butyl(S)-5-amino-4-(5-((6-fluoro-4-(tributylstannyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (intermediate E) (0.742 g, 0.98 mmol), and Cy3P-Pd-G3 (0.072 g, 0.10 mmol) / N,N-dimethylacetamide (5 mL) was stirred under nitrogen at 90°C for 72 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (20 mL x 2). The organic layers were combined and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-16% methyl alcohol / dichloromethane) to obtain the crude product. The crude product was further purified by semi-preparative reverse-phase HPLC (51-71% acetonitrile / water + 0.225% formic acid, 8 minutes). The fractions of interest were combined and extracted with ethyl acetate (20 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate solids, filtered, and concentrated under reduced pressure to obtain tert-butyl(S)-5-amino-4-(5-((4-(3-chloro-5-(oxetan-3-yl)pyridine-2-yl)-6-fluoro-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.110 g, 0.17 mmol, 18% yield) as a pale yellow solid, which was used directly in the next step. MS(ESI), m / z: 635.3 [M+1] + .

[0386] C.tert-butyl(S)-5-amino-4-(5-((4-(3-chloro-5-(oxetan-3-yl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate. A mixture of tert-butyl(S)-5-amino-4-(5-((4-(3-chloro-5-(oxetan-3-yl)pyridine-2-yl)-6-fluoro-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.110 g, 0.17 mmol), 3-fluoroazetidine hydrochloride (0.023 g, 0.21 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.1 mL, 0.35 mmol) / acetonitrile (3 mL) was stirred at 80°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product tert-butyl(S)-5-amino-4-(5-((4-(3-chloro-5-(oxetan-3-yl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.119 g, 0.17 mmol, 99% yield) as a pale yellow solid, which was then used directly in the next step. MS(ESI)m / z: 690.1 [M+1] + .

[0387] D.(S)-5-amino-4-(5-((4-(3-chloro-5-(oxetan-3-yl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoic acid. A mixture of tert-butyl(S)-5-amino-4-(5-((4-(3-chloro-5-(oxetan-3-yl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.109 g, 0.16 mmol) and trifluoroacetic acid (0.4 mL, 5.35 mmol) / dichloromethane (2 mL) was stirred at 25°C for 1 hour. The reaction mixture was adjusted to pH 7 with sodium carbonate solution and extracted with ethyl acetate (20 mL x 2). The organic layers were combined and dried over anhydrous sodium sulfate solid, filtered, and concentrated under reduced pressure to obtain the crude product (S)-5-amino-4-(5-((4-(3-chloro-5-(oxetan-3-yl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoic acid (0.100 g, 0.16 mmol, 99.9% yield) as a yellow solid, which was then used directly in the next step.

[0388] E.(3S)-3-[5-({4-[3-chloro-5-(oxetan-3-yl)pyridine-2-yl]-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl}methyl)-1-oxo-2,3-dihydro-1H-isoindole-2-yl]piperidine-2,6-dione. A mixture of (S)-5-amino-4-(5-((4-(3-chloro-5-(oxetan-3-yl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoic acid (0.100 g, 0.16 mmol), 4-dimethylaminopyridine (0.019 g, 0.16 mmol), carbonyldiimidazole (0.051 g, 0.32 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.061 g, 0.47 mmol) / acetonitrile (3 mL) was stirred at 80°C for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by semi-preparative reverse-phase HPLC (28-58% acetonitrile / water + 0.225% formic acid, 10 minutes). The fraction of interest was lyophilized to obtain the crude product. The crude product was purified by semi-preparative reverse-phase HPLC (28-58% acetonitrile / water + 10 mM ammonium bicarbonate, 10 minutes). The fraction of interest was lyophilized to obtain 3-(5-((4-(3-chloro-5-(oxetan-3-yl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (0.010 g, 0.02 mmol, 10% yield, 96.7% purity) as a white solid. MS(ESI)m / z: 616.3 [M+1] + .

[0389] 3-(5-((4-(3-chloro-5-(oxetan-3-yl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (0.010 g, 0.0200 mmol) was separated by SFC (column: REGIS(S,S)WHELK-O1 (250 mm x 25 mm, 10 μm), mobile phase: phase A CO2, phase B MeOH (0.1% NH3H2O); gradient elution: IPA / ACN (0.1% NH3H2O) / CO2 60%~60%, flow rate: 80 mL / min; 8.8 min, 70 min) to obtain two fractions. Fraction 1 was concentrated under reduced pressure. The residue was redissolved in water (20 mL) and acetonitrile (5 mL), and then freeze-dried to obtain the product (3S)-3-[5-({4-[3-chloro-5-(oxetan-3-yl)pyridine-2-yl]-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl}methyl)-1-oxo-2,3-dihydro-1H-isoindole-2-yl]piperidine-2,6-dione (0.004 g, 0.01 mmol, 39% yield, 99.2% purity, 92.3% ee%) as an off-white solid. 1 H NMR(400MHz, DMSO-d6)δ 11.09 - 10.86(m, 1H), 8.75 - 8.66(m, 1H), 8.25(d, J=1.6 Hz, 1H), 7.76(s, 1H), 7.69(d, J=7.6 Hz, 1H), 7.52 - 7.47(m, 1H), 7.44 - 7.38(m, 1H), 6.57(s, 1H), 5.66 - 5.44(m, 3H), 5.13(d, J=4.4 Hz, 1H), 4.98(dd, J=6.4, 8.4 Hz, 2H), 4.73(t, J=6.4 Hz, 2H), 4.46 - 4.41(m, 3H), 4.33 - 4.25 (m, 1H), 4.23 - 4.12 (m, 2H), 2.96 - 2.83 (m, 1H), 2.62 - 2.59 (m, 1H), 2.38 - 2.35 (m, 1H), 2.01 - 1.94 (m, 1H). MS(ESI)m / z: 616.3 [M+1] + .

[0390] Example 127: (R)-3-(5-((4-(3-chloro-5-(oxetan-3-yl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione [ka]

[0391] A. tert-butyl(S)-5-amino-4-(5-((4-(3-chloro-5-(oxetan-3-yl)pyridine-2-yl)-6-fluoro-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate. A mixture of 2,3-dichloro-5-(oxetan-3-yl)pyridine (synthesis described in Example 108) (0.200 g, 0.98 mmol), tert-butyl(S)-5-amino-4-(5-((6-fluoro-4-(tributylstannyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (intermediate E) (0.742 g, 0.98 mmol), and Cy3P-Pd-G3 (0.072 g, 0.10 mmol) / N,N-dimethylacetamide (10 mL) was stirred under nitrogen at 90°C for 72 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (20 mL x 2). The organic layers were combined and concentrated under vacuum. The residue was purified by silica gel chromatography (0-16% methanol / dichloromethane) to obtain the crude product. The crude product was further purified by semi-preparative reverse-phase HPLC (51-71% acetonitrile / water + 0.225% formic acid, 8 minutes). The fraction of interest was extracted with ethyl acetate (20 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the product tert-butyl(S)-5-amino-4-(5-((4-(3-chloro-5-(oxetan-3-yl)pyridine-2-yl)-6-fluoro-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.110 g, 0.17 mmol, 18% yield) as a pale yellow solid, which was used directly in the next step. MS(ESI)m / z: 635.3 [M+1] + .

[0392] B.tert-butyl(S)-5-amino-4-(5-((4-(3-chloro-5-(oxetan-3-yl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate. A mixture of tert-butyl(S)-5-amino-4-(5-((4-(3-chloro-5-(oxetan-3-yl)pyridine-2-yl)-6-fluoro-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.110 g, 0.17 mmol), 3-fluoroazetidine hydrochloride (0.023 g, 0.21 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.1 mL, 0.35 mmol) / acetonitrile (2 mL) was stirred at 80°C for 2 hours. The reaction mixture was concentrated under vacuum. The residue was purified by semi-preparative reverse-phase HPLC (36-66% acetonitrile / water + 10 mM ammonium bicarbonate, 8 minutes). The target fraction was freeze-dried to obtain the product tert-butyl(S)-5-amino-4-(5-((4-(3-chloro-5-(oxetan-3-yl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.090 g, 0.13 mmol, 75% yield) as a white solid, which was used directly in the next step. MS(ESI)m / z: 690.3 [M+1] + .

[0393] C.(S)-5-amino-4-(5-((4-(3-chloro-5-(oxetan-3-yl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoic acid. A mixture of tert-butyl(S)-5-amino-4-(5-((4-(3-chloro-5-(oxetan-3-yl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.09 g, 0.13 mmol) and TFA (0.5 mL, 6.53 mmol) / dichloromethane (2 mL) was stirred at 25°C for 1 hour. The reaction mixture was adjusted to pH 7 with sodium carbonate solution and extracted with ethyl acetate (20 mL x 2). The organic layers were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product (S)-5-amino-4-(5-((4-(3-chloro-5-(oxetan-3-yl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoic acid (0.082 g, 0.13 mmol, 99% yield) as a yellow solid, which was then used directly in the next step.

[0394] D.(R)-3-(5-((4-(3-chloro-5-(oxetan-3-yl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione. A mixture of (S)-5-amino-4-(5-((4-(3-chloro-5-(oxetan-3-yl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoic acid (0.082 g, 0.13 mmol), carbonyl diimidazole (0.042 g, 0.26 mmol), 4-dimethylaminopyridine (0.016 g, 0.13 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.050 g, 0.39 mmol) / acetonitrile (3 mL) was stirred at 60°C for 2 hours. The reaction mixture was concentrated under vacuum. The residue was purified by semi-preparative reverse-phase HPLC (28-58% acetonitrile / water + 0.225% formic acid, 7 minutes). The desired fraction was lyophilized to obtain the product. The product was further separated by SFC separation (column: REGIS(S,S)WHELK-O1 (250mm x 25mm, 10μm), mobile phase: phase A CO2, phase B isopropanol + acetonitrile (Neu); gradient elution: isopropanol + acetonitrile (Neu) / CO2 60-60%, flow rate: 80 mL / min; 10.8 min, 70 min) to obtain two fractions. Fraction 1 was concentrated under vacuum to obtain the residue. The residue was redissolved in water (20 mL) and acetonitrile (5 mL), and then freeze-dried to obtain product 1(R)-3-(5-((4-(3-chloro-5-(oxetan-3-yl)pyridine-2-yl)-6-(3-fluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (0.006 g, 0.01 mmol, 8% yield, 99.7% purity, 100% ee%) as an off-white solid. 1H NMR (400MHz, DMSO-d6)δ 10.97(s, 1H), 8.71(d, J=1.6 Hz, 1H), 8.25(d, J=1.6 Hz, 1H), 7.74(s, 1H), 7.69(d, J=8.0 Hz, 1H), 7.49(s, 1H), 7.41(d, J=8.0 Hz, 1H), 6.56(s, 1H), 5.69 - 5.44(m, 3H), 5.09(dd, J=5.2, 13.2 Hz, 1H), 4.98(dd, J=6.0, 8.4 Hz, 2H), 4.73(t, J=6.4 Hz, 2H), 4.52 - 4.37(m, 4H), 4.34 - 4.26 (m, 1H), 4.24 - 4.10 (m, 2H), 2.98 - 2.82 (m, 1H), 2.61 - 2.56 (m, 1H), 2.42 - 2.32 (m, 1H), 2.02 - 1.93 (m, 1H). MS(ESI)m / z: 616.3 [M+1] + .

[0395] Example 137: 6-(1-{[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]methyl}-6-[(propan-2-yl)amino]-1H-pyrazolo[3,4-b]pyridine-4-yl)-5-fluoropyridine-3-carbonitrile [ka]

[0396] A. 6-Fluoro-4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine. A mixture of 6-fluoro-4-iodo-1H-pyrazolo[3,4-b]pyridine (1,000 g, 3.80 mmol, intermediate A), 3,4-dihydro-2H-pyran (0.640 g, 7.60 mmol), and 4-methylbenzenesulfonic acid (0.065 g, 0.38 mmol) / dichloromethane (10 mL) was stirred at 25°C for 2 hours. The reaction mixture was diluted with water (20 mL) and adjusted to pH 7 with sodium carbonate solid. The mixture was then extracted with dichloromethane (10 mL x 2). The organic layers were dried together over anhydrous sodium sulfate solid, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-17% ethyl acetate / petroleum ether) to obtain 6-fluoro-4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine (1.040 g, 3.00 mmol, 79% yield). 1 H NMR (400MHz, CDCl3)δ 7.92(s, 1H), 7.26(d, J=1.2 Hz, 1H), 5.93(dd, J=2.4, 10.6 Hz, 1H), 4.18 - 4.03(m, 1H), 3.85 - 3.75(m, 1H), 2.67 - 2.53 (m, 1H), 2.23 - 2.09 (m, 1H), 2.02 - 1.89 (m, 1H), 1.83 - 1.73 (m, 2H), 1.62 - 1.47 (m, 1H).

[0397] B.6-Fluoro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridine. A mixture of 6-fluoro-4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine (1.040 g, 3.00 mmol), bis(pinacorato)diborone (1.141 g, 4.49 mmol), (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (0.245 g, 0.30 mmol), and potassium acetate (0.588 g, 5.99 mmol) / dioxane (2 mL) was stirred under nitrogen at 110 °C for 12 hours. The reaction mixture was purified by preparative TLC (0-30% ethyl acetate / petroleum ether) to obtain the product 6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridine (0.560 g, 1.61 mmol, 54% yield) as a brown oily substance. 1 H NMR (400MHz, CDCl3)δ 8.33(s, 1H), 7.19(d, J=1.2 Hz, 1H), 5.98(dd, J=2.4, 10.6 Hz, 1H), 4.14 - 4.11(m, 1H), 3.84 - 3.79 (m, 1H), 2.63 (ddt, J=4.4, 10.8, 12.8 Hz, 1H), 1.96 - 1.92 (m, 1H), 1.85 - 1.75 (m, 3H), 1.64 - 1.61 (m, 1H), 1.40 (s, 12H).

[0398] C. 5-chloro-6-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-yl)nicotinonitrile. A mixture of 6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridine (0.560 g, 1.61 mmol), 6-chloro-5-fluoropyridine-3-carbonitrile (0.202 g, 1.29 mmol), tetrakis(triphenylphosphine)palladium(0) (0.137 g, 0.16 mmol), and 2M potassium carbonate (1.6 mL, 3.23 mmol) / dioxane (20 mL) was stirred under nitrogen at 85°C for 12 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 2). The organic layers were combined and dried over anhydrous sodium sulfate solids, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (30% ethyl acetate / petroleum ether) to obtain 5-chloro-6-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-yl)nicotinonitrile (0.175 g, 0.51 mmol, 31.8% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3)δ 8.99 - 8.92(m, 1H), 8.49(s, 1H), 7.93(dd, J=1.6, 10.0 Hz, 1H), 7.43(d, J=1.2 Hz, 1H), 6.06(dd, J=2.4, 10.8 Hz, 1H), 4.15(td, J=2.0, 11.6 Hz, 1H), 3.84(dt, J=2.4, 11.6 Hz, 1H), 2.72 - 2.58(m, 1H), 2.25 - 2.12(m, 1H), 2.05 - 1.94(m, 1H), 1.85 - 1.78(m, 2H), 1.69 - 1.64(m, 1H). MS(ESI)m / z: 258.1 [M-84] + .

[0399] D. 5-Fluoro-6-(6-Fluoro-1H-Pyrazolo[3,4-b]pyridine-4-yl)nicotinonitrile. A mixture of 5-chloro-6-(6-Fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-yl)nicotinonitrile (0.175 g, 0.51 mmol) in 4M hydrogen chloride / dioxane (3.0 mL, 12.00 mmol) was stirred at 25°C for 2 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate solids, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (30% ethyl acetate / petroleum ether) to obtain 5-fluoro-6-(6-fluoro-1H-pyrazolo[3,4-b]pyridine-4-yl)nicotinonitrile (0.080 g, 0.31 mmol, 61% yield) as a pale yellow solid. MS(ESI)m / z: 258.1 [M+1] + .

[0400] E.tert-butyl(S)-5-amino-4-(5-((4-(5-cyano-3-fluoropyridine-2-yl)-6-fluoro-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate. A mixture of 5-fluoro-6-(6-fluoro-1H-pyrazolo[3,4-b]pyridine-4-yl)nicotinonitrile (0.080 g, 0.31 mmol), tert-butyl(S)-5-amino-4-(5-(bromomethyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.154 g, 0.37 mmol, intermediate C), and N-ethyl-N-isopropylpropan-2-amine (0.080 g, 0.62 mmol) / acetonitrile (2 mL) was stirred at 80°C for 12 hours. The reaction mixture was purified by semi-preparative reverse-phase HPLC (43-73% acetonitrile / water + 0.225% formic acid, 10 minutes). The collected fractions were then extracted with ethyl acetate (20 mL x 2). The organic layers were combined and dried over anhydrous sodium sulfate solid, filtered, and concentrated under reduced pressure to obtain the product: 1-tert-butyl(S)-5-amino-4-(5-((4-(5-cyano-3-fluoropyridine-2-yl)-6-fluoro-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.071 g, 0.12 mmol, 38.8% yield) was obtained as a pale yellow solid. 1 H NMR (400MHz, DMSO-d6)δ 9.18(s, 1H), 8.76(dd, J=1.6, 10.8 Hz, 1H), 8.47(s, 1H), 7.66(d, J=8.0 Hz, 1H), 7.52(s, 2H), 7.47(s, 1H), 7.38(d, J=8.0 Hz, 1H), 7.16(s, 1H), 5.78(s, 2H), 4.69(dd, J=4.0, 10.4 Hz, 1H), 4.60 - 4.48(m, 1H), 4.46 - 4.35(m, 1H), 2.18 - 2.08(m, 3H), 1.97 - 1.89(m, 1H), 1.29(s, 9H). MS(ESI)m / z: 588.2 [M+1] +The product 2tert-butyl(S)-5-amino-4-(5-((4-(5-cyano-3-fluoropyridine-2-yl)-6-fluoro-2H-pyrazolo[3,4-b]pyridine-2-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.052 g, 0.09 mmol, 28.5% yield) was obtained as a pale yellow solid. 1 H NMR (400MHz, DMSO-d6)δ 9.15(s, 1H), 8.99(s, 1H), 8.75(dd, J=1.6, 11.2 Hz, 1H), 7.69(d, J=7.6 Hz, 1H), 7.58(s, 1H), 7.54(s, 1H), 7.51 - 7.43 (m, 2H), 7.16 (s, 1H), 5.84 (s, 2H), 4.69 (dd, J=4.0, 10.4 Hz, 1H), 4.60 - 4.52 (m, 1H), 4.48 - 4.39 (m, 1H), 2.15 - 2.10 (m, 3H), 1.98 - 1.90(m, 1H), 1.30(s, 9H). MS(ESI)m / z: 588.2 [M+1] + .

[0401] F.tert-butyl(S)-5-amino-4-(5-((4-(5-cyano-3-fluoropyridine-2-yl)-6-(isopropylamino)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate. A mixture of tert-butyl(S)-5-amino-4-(5-((4-(5-cyano-3-fluoropyridine-2-yl)-6-fluoro-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.071 g, 0.12 mmol), propan-2-amine (0.014 g, 0.24 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.1 mL, 0.24 mmol) / acetonitrile (2 mL) was stirred at 80°C for 12 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (5 mL x 2). The organic layers were combined and dried over anhydrous sodium sulfate solid, filtered, and concentrated under reduced pressure to obtain the crude product tert-butyl(S)-5-amino-4-(5-((4-(5-cyano-3-fluoropyridine-2-yl)-6-(isopropylamino)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.075 g, 0.12 mmol, 99% yield) as a yellow solid. MS(ESI)m / z: 627.4 [M+1] + .

[0402] G.(S)-5-amino-4-(5-((4-(5-cyano-3-fluoropyridine-2-yl)-6-(isopropylamino)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoic acid. Trifluoroacetic acid (0.5 mL, 6.73 mmol) was added at 25°C to a solution of tert-butyl(S)-5-amino-4-(5-((4-(5-cyano-3-fluoropyridine-2-yl)-6-(isopropylamino)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.075 g, 0.12 mmol) / dichloromethane (2 mL). Next, the mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 2). The organic extracts were combined, dried over anhydrous sodium sulfate solids, filtered, and concentrated under reduced pressure to obtain the crude product (S)-5-amino-4-(5-((4-(5-cyano-3-fluoropyridine-2-yl)-6-(isopropylamino)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoic acid (0.068 g, 0.12 mmol, 99.6% yield) as a yellow solid. MS(ESI)m / z: 571.3 [M+1] + .

[0403] H.6-(1-{[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]methyl}6-[(propan-2-yl)amino]-1H-pyrazolo[3,4-b]pyridine-4-yl)-5-fluoropyridine-3-carbonitrile. A mixture of (S)-5-amino-4-(5-((4-(5-cyano-3-fluoropyridine-2-yl)-6-(isopropylamino)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoic acid (0.068 g, 0.12 mmol), 4-dimethylaminopyridine (0.015 g, 0.12 mmol), carbonyldiimidazole (0.039 g, 0.24 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.031 g, 0.24 mmol) / acetonitrile (2 mL) was stirred at 80°C for 2 hours. The reaction mixture was filtered, and the filtrate was purified by semi-preparative reverse-phase HPLC (36-66% acetonitrile / water + 0.225% formic acid, 10 minutes). The fraction of interest was freeze-dried to obtain 6-(1-{[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]methyl}6-[(propan-2-yl)amino]-1H-pyrazolo[3,4-b]pyridine-4-yl)-5-fluoropyridine-3-carbonitrile (0.016 g, 0.03 mmol, 23.9% yield, 96% purity) as a yellow solid. 1H NMR (400MHz, DMSO-d6)δ 11.09 - 10.80(m, 1H), 9.09(s, 1H), 8.63(dd, J=1.6, 11.2 Hz, 1H), 8.46(s, 1H), 7.98(s, 1H), 7.67(d, J=7.6 Hz, 1H), 7.50(s, 1H), 7.43 - 7.31(m, 2H), 6.97(s, 1H), 5.60(s, 2H), 5.08(dd, J=5.2, 13.2 Hz, 1H), 4.44 - 4.38(m, 1H), 4.33 - 4.24(m, 1H), 4.23 - 4.13(m, 1H), 2.94 - 2.84 (m, 1H), 2.59 (d, J=2.8 Hz, 1H), 2.44 - 2.35 (m, 1H), 2.02 - 1.92 (m, 1H), 1.21 (dd, J=2.0, 6.4 Hz, 6H). MS(ESI)m / z: 553.2 [M+1] + .

[0404] Example 140: (3S)-3-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-5-fluoro-6-((S)-3-hydroxy-3-methylpyrrolidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione [ka]

[0405] A.tert-butyl(S)-5-amino-4-(5-((6-((S)-3-hydroxy-3-methylpyrrolidine-1-yl)-4-iodo-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate. A mixture of tert-butyl(S)-5-amino-4-(5-((6-fluoro-4-iodo-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (intermediate C) (0.200 g, 0.34 mmol), (S)-3-methylpyrrolidine-3-ol (0.038 g, 0.37 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.2 mL, 1.01 mmol) / acetonitrile (10 mL) was stirred at 50°C for 12 hours. The reaction mixture was purified by semi-preparative reverse-phase HPLC (40-70% acetonitrile / water + 0.225% formic acid, 10 minutes). The fractions of interest were combined and extracted with ethyl acetate (30 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the product tert-butyl(S)-5-amino-4-(5-((6-((S)-3-hydroxy-3-methylpyrrolidine-1-yl)-4-iodo-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.190 g, 0.28 mmol, 84% yield) as a yellow solid. MS(ESI)m / z: 675.2 [M+1] + .

[0406] B.tert-butyl(S)-5-amino-4-(5-((5-fluoro-6-((S)-3-hydroxy-3-methylpyrrolidine-1-yl)-4-iodo-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate. To a solution of tert-butyl(S)-5-amino-4-(5-((6-((S)-3-hydroxy-3-methylpyrrolidine-1-yl)-4-iodo-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.190 g, 0.28 mmol) and silver carbonate (0.172 g, 0.62 mmol) / acetonitrile (2 mL), a solution of 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanbis(tetrafluoroborate) (0.110 g, 0.28 mmol) / water (1 mL) was added. The reaction mixture was divided into 7 batches and stirred at 0°C for 2 hours. The reaction mixture was filtered and concentrated to remove acetonitrile. The mixture was diluted with water and extracted with ethyl acetate (10 mL x 2). The organic layers were combined and concentrated under vacuum. The residue was purified by semi-preparative reverse-phase HPLC (50-80% acetonitrile / water + 0.225% formic acid, 7 minutes). The fractions of interest were combined and extracted with ethyl acetate (30 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain tert-butyl(S)-5-amino-4-(5-((5-fluoro-6-((S)-3-hydroxy-3-methylpyrrolidine-1-yl)-4-iodo-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.120 g, 0.17 mmol, 56% yield) as a white solid. 1H NMR(400MHz、CDCl3)δ 7.77(d、J=8.0 Hz、1H)、7.58(s、1H)、7.45(d、J=8.0 Hz、1H)、7.38(s、1H)、6.35(s、1H)、5.55(s、2H)、5.46(s、1H)、4.87(dd、J=6.0、8.8 Hz、1H)、4.43(q、J=17.2 Hz、2H)、3.98 - 3.83(m、2H)、3.77(dd、J=2.0、12.0 Hz、1H)、3.67 - 3.60(m、1H)、2.35 - 2.21(m、3H)、2.14 - 2.03(m、3H)、1.53(s、3H)、1.40(s、9H)。MS(ESI)m / z: 693.1 [M+1] + 。

[0407] C.tert-butyl(S)-5-amino-4-(5-((5-fluoro-6-((S)-3-hydroxy-3-methylpyrrolidine-1-yl)-4-(tributylstannyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate. A mixture of tert-butyl(S)-5-amino-4-(5-((5-fluoro-6-((S)-3-hydroxy-3-methylpyrrolidine-1-yl)-4-iodo-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.080 g, 0.12 mmol), 1,1,1,2,2,2-hexabutyldistannan (0.500 g, 0.86 mmol), tri-o-tolylphosphan (0.007 g, 0.02 mmol), triethylamine (0.1 mL, 0.29 mmol), and palladium(II) acetate (0.003 g, 0.01 mmol) / acetonitrile (2 mL) was stirred under nitrogen at 85°C for 4 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. This was purified by aluminum oxide chromatography (neutral aluminum oxide, 100% ethyl acetate) to obtain tert-butyl(S)-5-amino-4-(5-((5-fluoro-6-((S)-3-hydroxy-3-methylpyrrolidine-1-yl)-4-(tributylstannyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.070 g, 0.08 mmol, 71% yield) as a yellow oil. MS(ESI)m / z: 857.3 [M+1] + .

[0408] D.tert-butyl(4S)-5-amino-4-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-5-fluoro-6-((S)-3-hydroxy-3-methylpyrrolidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate. A mixture of tert-butyl(S)-5-amino-4-(5-((5-fluoro-6-((S)-3-hydroxy-3-methylpyrrolidine-1-yl)-4-(tributylstannyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.070 g, 0.08 mmol), 2-bromo-3-chloro-5-(trifluoromethyl)pyridine (0.043 g, 0.16 mmol), and PCy3-Pd-G3 (0.006 g, 0.01 mmol) / N,N-dimethylacetamide (1 mL) was stirred at 90°C for 30 hours. The reaction mixture was quenched with aqueous potassium fluoride solution and extracted with ethyl acetate (20 mL x 2). The organic layers were combined and concentrated under reduced pressure. The residue was purified by semi-preparative reverse-phase HPLC (25-55% acetonitrile / water + 0.225% formic acid, 10 minutes). The fraction of interest was lyophilized to obtain the product tert-butyl(4S)-5-amino-4-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-5-fluoro-6-((S)-3-hydroxy-3-methylpyrrolidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.020 g, 0.03 mmol, 33% yield) as a yellow solid. MS(ESI)m / z: 746.2 [M+1] + .

[0409] E.(3S)-3-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-5-fluoro-6-((S)-3-hydroxy-3-methylpyrrolidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione. A solution of tert-butyl(4S)-5-amino-4-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-5-fluoro-6-((S)-3-hydroxy-3-methylpyrrolidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)-5-oxopentanoate (0.018 g, 0.02 mmol) and 4-methylbenzenesulfonic acid (0.021 g, 0.12 mmol) / acetonitrile (2 mL) was stirred at 60°C for 20 hours. The reaction mixture was diluted with water (10 mL) and adjusted to pH 7 with sodium carbonate solid. The mixture was extracted with ethyl acetate (10 mL x 2). The organic layers were combined and concentrated under reduced pressure. The obtained residue was purified by semi-preparative reverse-phase HPLC (45-75% acetonitrile / water + 0.225% formic acid, 7 minutes). The fraction of interest was lyophilized to obtain (3S)-3-(5-((4-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-5-fluoro-6-((S)-3-hydroxy-3-methylpyrrolidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)methyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (0.006 g, 0.01 mmol, 34% yield, 96.9% purity, 99.9% ee%) as a yellow solid. 1H NMR (400MHz, DMSO-d6)δ 11.06 - 10.90(m, 1H), 9.15(s, 1H), 8.75(s, 1H), 7.70(d, J=8.0 Hz, 1H), 7.61(s, 1H), 7.50(s, 1H), 7.44(d, J=8.4 Hz, 1H), 5.61(s, 2H), 5.08(dd, J=5.2, 13.2 Hz, 1H), 4.87(s, 1H), 4.48 - 4.25(m, 2H), 3.86 - 3.75(m, 2H), 3.67 - 3.55(m, 2H), 2.92 - 2.84 (m, 1H), 2.61 (dd, J=2.4, 4.0 Hz, 1H), 2.40 - 2.35 (m, 1H), 2.02 - 1.94 (m, 1H), 1.93 - 1.85 (m, 2H), 1.36 (s, 3H). MS(ESI)m / z: 672.2 [M+1] + .

[0410] Each compound in Table 1 below (e.g., by example number) can be prepared according to the example cited in the “Procedure” column (e.g., synthesize Example 1 according to the procedure of Example 3). Those skilled in the art will understand the modifications required to synthesize the following compounds using the novel synthesis scheme described above.

[0411] Table 1 [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] Table 9 Table 10 Table 11 Table 12 Table 13 Table 14 Table 15 Table 16 Table 17 Table 18 Table 19 Table 20 Table 21 Table 22 Table 23 Table 24 Table 25 Table 26 Table 27 Table 28 Table 29 Table 30 Table 31 Table 32 Table 33 Table 34 Table 35 Table 36 Table 37 Table 38 Table 39 Table 40 Table 41 Table 42 Table 43 Table 44 Table 45 Table 46 Table 47 Table 48 Table 49 Table 50 Table 51 Table 52 Table 53 Table 54 Table 55 Table 56 Table 57 Table 58 Table 59 Table 60 Table 61 [Table 62] [Table 63] [Table 64] [Table 65] [Table 66] [Table 67] [Table 68] [Table 69] [Table 70] [Table 71] [Table 72] [Table 73] [Table 74] [Table 75]

[0412] Biological examples

[0413] B1. FAK-HiBiT degradation assay

[0414] To create JHH-4-FAK-HiBiT cells for FAK degradation assays, JHH-4 cells (Japanese Collection of Research Biosources Cell Bank, Japan) were transfected with a ribonucleoprotein reagent, and a HiBiT tag (Promega Corporation, Madison, WI) was introduced as a homozygous knock-in at the C-terminus of the natural genomic locus of the FAK gene using CRISPR-Cas9 editing. After CRISPR-Cas9 editing, single cells were grown to establish a clonal cell population. The clonal cell line, named JHH-4-FAK-HiBiT clone d01, was confirmed to contain the expected HiBiT-edited FAK gene by next-generation sequencing and selected for FAK degradation screening. The selected cells were cultured in complete DMEM medium (DMEM, 10% heat-inactivated FBS, non-essential amino acids) at 37°C and 5% CO2. Cells were transferred to a T75 flask every 3-4 days in 0.5 x 10⁶ cells. 6 The cells were subcultured by reseeding them.

[0415] Cells were dispensed into 384-well white plates (Corning #3570, NY) pre-spotted with compounds using an acoustic transfer system (Echo acoustic transfer system, Beckman Coulter Life Sciences, Carlsbad, CA). The compounds were arranged as a 10-point dose-response curve, starting from 1 μM and diluting 3-fold, and a DMSO control was also included. 25 μL of medium containing 2000 JHH-4-FAK-HiBiT clone d01 cells was dispensed into each well. The assay plates were incubated at 37°C in 5% CO2 for 2 hours. After incubation, 25 μL of Nano-Glo HiBiT lysis reagent working solution (Promega Corporation, Madison, WI) was added to each well, and the plates were incubated at room temperature in the dark for 10 minutes. After 10 minutes, luminescence was read using a PHERAstar luminometer (BMG Labtech, Cary, NC).

[0416] FAK-HiBiT decomposition at the half-maximal effective concentration (EC2) 50 To determine the value, a four-parameter logistic model (sigmoid dose-response model): (FIT=(A+((BA) / 1+((C / x)^D)))) was used. In the equation, C is the inflection point (EC 50 The curves are defined as follows: D is the Hill coefficient, and A and B are the lower and upper limits of the fit, respectively. The lower limit of the fit (value A) is referred to as Ymin. The upper limit Ymax was derived from the DMSO control. The curves were processed and evaluated using Dotmatics Atlas (Insightful Science, LLC, Boston, MA). The results are shown in Table 2 below.

[0417] CAL-51 Cell Proliferation Assay

[0418] CAL-51 cells were obtained from the Bristol Myers Squibb in-house cell bank (originally supplied by DSMZ-German Collection of Microorganisms and Cell Cultures GmbH in Germany) and cultured in RPMI Complete Medium (RPMI-1640, 10% fetal bovine serum, 1X antibiotic-antifungal agent, and 1X non-essential amino acids). Compounds were dispensed into 384-well plates using an acoustic dispenser (Beckman Coulter Life Sciences, Carlsbad, CA), with 14 different compounds in each plate in a double aliquot. For each compound, a 10-point dose-response was established from 10 μM to a 4-fold dilution. Assuming a final medium volume of 50 μL, the DMSO concentration was kept constant so that the final assay concentration in each well was 0.1%. Compound plates were sealed and frozen at -20°C until use.

[0419] In each assay batch, the compound plate was thawed and returned to room temperature, and cells were seeded in 350 cells / 50 μL of Complete RPMI medium per well. After incubation at 37°C and 5% CO2 for 120 hours, the cells were lysed with 25 μL of Cell-Titer-Glo reagent (Promega Corporation, Madison, WI), and the plates were shaken for 20 minutes in the dark according to the manufacturer's instructions. Total luminescence was read using a CLARIOstar Plus plate reader (BMG LabTech, Cary, NC). The total luminescence signal linearly correlated with the number of cells remaining in the well.

[0420] Luminescence data was processed plate by plate by subtracting the luminescence of the "blank" well containing only the reagent from all measurements and calculating the percentage (%) relative to the DMSO control value for each treated well. Next, to determine the maximum effective concentration (EC50) for cell proliferation inhibition, a four-parameter logistic model was fitted to the data of each compound normalized with DMSO: Sigmoid dose-response model: (FIT=(A+((BA) / 1+((C / x)^D)))). In the formula, C is the inflection point (EC50). 50 ) is the Hill coefficient, and A and B are the lower and upper limits of the fit, respectively. The lower limit of the fit (value A) was referred to as Ymin-calculated. For each compound, the minimum percentage (%) relative to the DMSO control observed at the tested concentration was classified as "Ymin-obs," recorded, and shown in the table. The sigmoid fit curves were processed and evaluated using Dotmatics Atlas (Insightful Science, LLC, Boston, MA). The results are shown in Table 2 below.

[0421] Table 2. FAK HiBiT degradation and CAL-51 cell proliferation [Table 76] [Table 77] [Table 78] [Table 79]

[0422] Although the present invention is described in detail with reference to the description and examples for clear understanding, this description and examples should not be construed as limiting the scope of the invention. All disclosures of patent and scientific documents cited herein are expressly incorporated herein by reference in their entirety.

Claims

1. Equation (I): 【Chemistry 1】 [In the formula: 【Chemistry 2】 It does not exist, or it may be a single bond; X is independently selected from C and N; Y is independently selected from C and N; YY is independently selected from C and N; Z is independently selected from C and N; ZZ is independently selected from C and N; R １ These are independently hydrogen, halogen, and -C １ -C ６ Selected from alkyl groups; R ２ is independently selected from hydrogen, halogen, -(=O), -C １ -C ６ alkyl, 3- to 6-membered cycloalkyl, and the alkyl or cycloalkyl may be substituted with -R ９ , -N(R ９ R １０ ), or -OR ９ ; R ３ They do not exist independently, or are selected from hydrogen and halogens; R ４ They do not exist independently, or hydrogen and -C １ -C ６ Selected from alkyl groups; R ５ They do not exist independently, or hydrogen, halogen, and -C １ -C ６ Selected from alkyl groups; R ６ The rings are independently selected from 5- to 12-membered aryl rings and 5- to 12-membered heteroaryl rings, wherein the aryl and heteroaryl rings have 1, 2, or 3 -R groups. ９ , -N(R ９ R １０ ), or -OR ９ It is also fine if it is replaced with; R ７ is hydrogen or halogen; R ８ These are independently -N(R ９ R １０ ) and 【Transformation 3】 A heterocycle is selected from those represented by , and the heterocycle has 1, 2, or 3 -R ９ , -N(R ９ R １０ ), or -OR ９ It is also fine if it is replaced with; R ９ These are independently hydrogen, halogen, and -OR １０ , -N(R １０ R １０ ), -C １ -C ６ Alkyl, -O-C １ -C ６ Selected from alkyl, -CN, 3- to 12-membered cycloalkyl, and 4- to 12-membered heterocycles; R ９ The alkyl, cycloalkyl, or heterocycle within each of these rings can be independently unsubstituted or have 1, 2, or 3 R rings. １０ Substituting with a substituent; In each case, R １０ These are independently hydrogen, -OH, and -C. １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, halogen, -O-(C) １ -C ６ Alkyl)-,-N(R １１ R １１ ), selected from 3-12 membered cycloalkyl groups, 4-12 membered heterocyclic groups, 5-12 membered aryl groups, and 5-12 membered heteroaryl rings; R １０ The alkyl, alkenyl, cycloalkyl, heterocyclic, aryl, or heteroaryl rings within each are independently unsubstituted or have 1, 2, or 3 R groups. １１ Substituting with substituents; and R １１ These are independently hydrogen, halogen, -OH, and -C １ -C ６ Selected from alkyl groups, and further each R ６ , R 9, and R １０ The heterocycle and heteroaryl ring within may contain one, two, or three heteroatoms independently selected from O, N, or S. The compounds represented by , or their pharmaceutically acceptable salts, solvates, hydrates, or tautomers, pharmaceutically acceptable salts of tautomers, any of the aforementioned stereoisomers, or mixtures thereof.

2. The 【Chemistry 4】 It is a single bond. The compound described in claim 1, or a pharmaceutically acceptable salt thereof, solvate, hydrate, or tautomer, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described above, or a mixture thereof.

3. The 【Transformation 5】 It does not exist. The compound described in claim 1, or a pharmaceutically acceptable salt thereof, solvate, hydrate, or tautomer, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described above, or a mixture thereof.

4. X is C, The compound described in claim 1, or a pharmaceutically acceptable salt thereof, solvate, hydrate, or tautomer, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described above, or a mixture thereof.

5. Y is N, The compound described in claim 1, or a pharmaceutically acceptable salt thereof, solvate, hydrate, or tautomer, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described above, or a mixture thereof.

6. Y is C, The compound described in claim 1, or a pharmaceutically acceptable salt thereof, solvate, hydrate, or tautomer, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described above, or a mixture thereof.

7. YY is N, The compound described in claim 1, or a pharmaceutically acceptable salt thereof, solvate, hydrate, or tautomer, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described above, or a mixture thereof.

8. YY is C, The compound described in claim 1, or a pharmaceutically acceptable salt thereof, solvate, hydrate, or tautomer, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described above, or a mixture thereof.

9. Z is N, The compound described in claim 1, or a pharmaceutically acceptable salt thereof, solvate, hydrate, or tautomer, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described above, or a mixture thereof.

10. Z is C, The compound described in claim 1, or a pharmaceutically acceptable salt thereof, solvate, hydrate, or tautomer, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described above, or a mixture thereof.

11. ZZ is N, The compound described in claim 1, or a pharmaceutically acceptable salt thereof, solvate, hydrate, or tautomer, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described above, or a mixture thereof.

12. ZZ is C. The compound described in claim 1, or a pharmaceutically acceptable salt thereof, solvate, hydrate, or tautomer, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described above, or a mixture thereof.

13. R １ That is hydrogen. The compound described in claim 1, or a pharmaceutically acceptable salt thereof, solvate, hydrate, or tautomer, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described above, or a mixture thereof.

14. R ２ That is hydrogen. The compound described in claim 1, or a pharmaceutically acceptable salt thereof, solvate, hydrate, or tautomer, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described above, or a mixture thereof.

15. R ３ That is hydrogen. The compound described in claim 1, or a pharmaceutically acceptable salt thereof, solvate, hydrate, or tautomer, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described above, or a mixture thereof.

16. R ４ It does not exist. The compound described in claim 1, or a pharmaceutically acceptable salt thereof, solvate, hydrate, or tautomer, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described above, or a mixture thereof.

17. R ４ That is hydrogen. The compound described in claim 1, or a pharmaceutically acceptable salt thereof, solvate, hydrate, or tautomer, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described above, or a mixture thereof.

18. R ４ ga-C １ -C ６ It is alkyl. The compound described in claim 1, or a pharmaceutically acceptable salt thereof, solvate, hydrate, or tautomer, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described above, or a mixture thereof.

19. R ４ ga-CH ３ That is, The compound described in claim 18, or a pharmaceutically acceptable salt thereof, solvate, hydrate, or tautomer, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described above, or a mixture thereof.

20. R ４ ga-CH ２ CH ３ That is, The compound described in claim 18, or a pharmaceutically acceptable salt thereof, solvate, hydrate, or tautomer, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described above, or a mixture thereof.

21. R ５ That is hydrogen. The compound described in claim 1, or a pharmaceutically acceptable salt thereof, solvate, hydrate, or tautomer, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described above, or a mixture thereof.

22. R ５ ga-C １ -C ６ It is alkyl. The compound described in claim 1, or a pharmaceutically acceptable salt thereof, solvate, hydrate, or tautomer, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described above, or a mixture thereof.

23. R ５ ga-CH ３ That is, The compound described in claim 22, or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described above, or a mixture thereof.

24. R ５ It is a halogen. The compound described in claim 1, or a pharmaceutically acceptable salt thereof, solvate, hydrate, or tautomer, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described above, or a mixture thereof.

25. Equation (Ia): 【Transformation 6】 [In the formula: R ５ These are independently hydrogen, halogen, and -C １ -C ６ Selected from alkyl groups; R ６ The rings are independently selected from a 5- to 12-membered aryl ring or a 5- to 12-membered heteroaryl ring, wherein the aryl and heteroaryl rings have 1, 2, or 3 -R groups. ９ , -N(R ９ R １０ ), or -OR ９ It is also fine if it is replaced with; R ７ is hydrogen or halogen; R ８ These are independently -N(R ９ R １０ ) and 【Transformation 7】 Selected from the heterocycles represented by, the heterocycle being optionally substituted with 1, 2 or 3 -R ９ , -N(R ９ R １０ ), or -OR ９ ; R ９ is independently selected from hydrogen, halogen, -C １ -C ６ alkyl, -OR １０ , -N(R １０ R １０ ), -CN, 3- to 12-membered cycloalkyl, or 4- to 12-membered heterocycle; R ９ The alkyl, cycloalkyl, or heterocycle within each ring can be independently unsubstituted or have 1, 2, or 3 R rings. １０ Substituting with a substituent; In each case, R １０ These are independently hydrogen, halogen, -OH, and -C. １ -C ６ Selected from alkyl groups, 3- to 12-membered cycloalkyl groups, and 4- to 12-membered heterocycles; R １０ The alkyl, cycloalkyl, and heterocycles within each are independently unsubstituted or have 1, 2, or 3 R groups. １１ Substituting with a substituent; R １１ These are independently hydrogen, halogen, -OH, and -C １ -C ６ Selected from alkyl groups, and further each R ６ , R 9, and R １０ The heterocycles and heteroaryl rings within may contain one, two, or three heteroatoms independently selected from O, N, or S. The compound described in claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, a pharmaceutically acceptable salt of a tautomer, any of the aforementioned stereoisomers, or a mixture thereof.

26. R ５ That is hydrogen. The compound described in claim 25, or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described herein, or a mixture thereof.

27. R ５ It is a halogen. The compound described in claim 25, or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described herein, or a mixture thereof.

28. R ５ is Cl or F, The compound described in claim 27, or a pharmaceutically acceptable salt thereof, solvate, hydrate, or tautomer, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described above, or a mixture thereof.

29. R ５ ga-C １ -C ６ It is alkyl. The compound described in claim 25, or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described herein, or a mixture thereof.

30. R ５ ga-CH ３ That is, The compound described in claim 29, or a pharmaceutically acceptable salt thereof, solvate, hydrate, or tautomer, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described above, or a mixture thereof.

31. R ６ is a 5- to 12-membered aryl ring, with 1, 2, or 3 -R ９ , -N(R ９ R １０ ), or -OR ９ It may be replaced with The compound described in claim 25, or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described herein, or a mixture thereof.

32. R ６ It is a 5- to 12-membered heteroaryl ring, with 1, 2, or 3 -R ９ , -N(R ９ R １０ ), or -OR ９ It may be replaced with The compound described in claim 25, or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described herein, or a mixture thereof.

33. R ７ That is hydrogen. The compound described in claim 25, or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described herein, or a mixture thereof.

34. R ７ It is a halogen. The compound described in claim 25, or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described herein, or a mixture thereof.

35. The halogen is F or Cl. The compound described in claim 34, or a pharmaceutically acceptable salt thereof, solvate, hydrate, or tautomer, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described above, or a mixture thereof.

36. R ８ -N(R) ９ R １０ ) and 【Transformation 8】 Selected from the heterocycles shown, The compound described in claim 25, or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described herein, or a mixture thereof.

37. R ８ ga-N(R ９ R １０ ) The compound described in claim 36, or a pharmaceutically acceptable salt thereof, solvate, hydrate, or tautomer, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described above, or a mixture thereof.

38. R ８ but 【Chemistry 9】 Selected from the heterocycles shown, The compound described in claim 36, or a pharmaceutically acceptable salt thereof, solvate, hydrate, or tautomer, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described above, or a mixture thereof.

39. R ９ That is hydrogen. The compound described in claim 25, or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described herein, or a mixture thereof.

40. R ９ It is a halogen. The compound described in claim 25, or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described herein, or a mixture thereof.

41. The halogen is selected from Cl and F. The compound described in claim 40, or a pharmaceutically acceptable salt thereof, solvate, hydrate, or tautomer, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described herein, or a mixture thereof.

42. The halogen is Cl. The compound described in claim 40, or a pharmaceutically acceptable salt thereof, solvate, hydrate, or tautomer, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described herein, or a mixture thereof.

43. The halogen is F. The compound described in claim 40, or a pharmaceutically acceptable salt thereof, solvate, hydrate, or tautomer, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described herein, or a mixture thereof.

44. R ９ ga-C １ -C ６ It is alkyl. The compound described in claim 25, or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described herein, or a mixture thereof.

45. -C １ -C ６ Alkyl is -CH ３ ien-CH ２ CH ３ , -CH(CH ３ ) ２ , and -C(CH ３ ) ３ Selected from, The compound described in claim 44, or a pharmaceutically acceptable salt thereof, solvate, hydrate, or tautomer, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described herein, or a mixture thereof.

46. R ９ ga- OR １０ , -N(R １０ R １０ ), -CN, a 3- to 12-membered cycloalkyl, or a 4- to 12-membered heterocycle; R ９ Each cycloalkyl or heterocycle within the molecule is independently unsubstituted, or contains 1, 2, or 3 R rings. １０ Substituting with a substituent, The compound described in claim 25, or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described herein, or a mixture thereof.

47. In each case, R １０ These independently form hydrogen, halogen, -OH, and -C. １ -C ６ Alkyl, -N(R) １１ R １１ ), selected from 3- to 12-membered cycloalkyl groups and 4- to 12-membered heterocycles; R １０ The alkyl, cycloalkyl, and heterocycles within the molecule are each independently unsubstituted, or have 1, 2, or 3 R rings. １１ Substituting with a substituent, The compound described in claim 25, or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described herein, or a mixture thereof.

48. R １１ These independently form hydrogen, halogen, -OH, or -C １ -C ６ It is alkyl. The compound described in claim 25, or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described herein, or a mixture thereof.

49. R ６ They became independent 【Chemistry 10】 Selected from, The compound described in claim 1, or a pharmaceutically acceptable salt thereof, solvate, hydrate, or tautomer, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described above, or a mixture thereof.

50. R ８ They became independent 【Chemistry 11】 Selected from, The compound described in claim 1, or a pharmaceutically acceptable salt thereof, solvate, hydrate, or tautomer, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described above, or a mixture thereof.

51. Formula (Ib): 【Chemistry 12】 [In the formula: R ６ teeth 【Chemistry 13】 and R ８ teeth 【Chemistry 14】 is] The compound described in claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, a pharmaceutically acceptable salt of a tautomer, any of the aforementioned stereoisomers, or a mixture thereof.

52. Formula (Ic): 【Chemistry 15】 [In the formula: X is either C or N; R ４ These are independently hydrogen or -C １ -C ６ Selected from alkyl groups; R ６ Independent 【Chemistry 16】 Selected from; and R ８ Independent 【Chemistry 17】 or -N(CH ３ CH ３ ) Selected from The compound described in claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, a pharmaceutically acceptable salt of a tautomer, any of the aforementioned stereoisomers, or a mixture thereof.

53. R ４ That is hydrogen. The compound described in claim 52, or a pharmaceutically acceptable salt thereof, solvate, hydrate, or tautomer, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described above, or a mixture thereof.

54. R ４ ga-C １ -C ６ It is alkyl. The compound described in claim 52, or a pharmaceutically acceptable salt thereof, solvate, hydrate, or tautomer, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described above, or a mixture thereof.

55. -C １ -C ６ Alkyl is -CH ３ That is, The compound described in claim 54, or a pharmaceutically acceptable salt thereof, solvate, hydrate, or tautomer, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described above, or a mixture thereof.

56. R ６ but [Chemistry 18] That is, The compound described in claim 52, or a pharmaceutically acceptable salt thereof, solvate, hydrate, or tautomer, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described above, or a mixture thereof.

57. R ６ but 【Chemistry 19】 That is, The compound described in claim 52, or a pharmaceutically acceptable salt thereof, solvate, hydrate, or tautomer, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described above, or a mixture thereof.

58. R ８ ga-N(CH ３ CH ３ ) The compound described in claim 52, or a pharmaceutically acceptable salt thereof, solvate, hydrate, or tautomer, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described above, or a mixture thereof.

59. R ８ but 【Chemistry 20】 That is, The compound described in claim 52, or a pharmaceutically acceptable salt thereof, solvate, hydrate, or tautomer, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described above, or a mixture thereof.

60. X is C, The compound described in claim 52, or a pharmaceutically acceptable salt thereof, solvate, hydrate, or tautomer, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described above, or a mixture thereof.

61. X is N, The compound described in claim 52, or a pharmaceutically acceptable salt thereof, solvate, hydrate, or tautomer, a pharmaceutically acceptable salt of a tautomer, any of the stereoisomers described above, or a mixture thereof.

62. Formula (Id): 【Chemistry 21】 [In the formula: R ４ These are independently hydrogen or -C １ -C ６ Selected from alkyl groups; R ６ Independent 【Chemistry 22】 Selected from; and R ８ Independent 【Chemistry 23】 [Selected from] The compound described in claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, a pharmaceutically acceptable salt of a tautomer, any of the aforementioned stereoisomers, or a mixture thereof.

63. Equation (Ie): 【Chemistry 24】 [In the formula: R ６ teeth 【Chemistry 25】 and R ８ Ha - N (CH ３ CH ３ ) The compound described in claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, a pharmaceutically acceptable salt of a tautomer, any of the aforementioned stereoisomers, or a mixture thereof.

64. below: 【Chemistry 26】 A compound selected from the above, or a pharmaceutically acceptable salt thereof, solvate, hydrate, or tautomer, a pharmaceutically acceptable salt of a tautomer, any of the aforementioned stereoisomers, or a mixture thereof.

65. A pharmaceutical composition comprising a compound according to any one of claims 1 to 64, or a pharmaceutically acceptable salt thereof, tautomer, isotopic molecular species, or stereoisomer thereof, for reducing the concentration of FAK protein.

66. A pharmaceutical composition for preventing or treating cancer, comprising a compound according to any one of claims 1 to 64, or a pharmaceutically acceptable salt thereof, tautomer, isotopic molecular species, or stereoisomer.

67. The cancer is selected from stomach cancer, lung cancer, pancreatic cancer, ovarian cancer, breast cancer, skin cancer, colon cancer, neuroblastoma, osteosarcoma, uterine cancer, rectal cancer, and kidney cancer. The pharmaceutical composition according to claim 66.

68. The cancer is selected from pancreatic ductal adenocarcinoma (PDAC), small cell lung cancer, non-small cell lung cancer (NSCLC), high-grade serous ovarian cancer, triple-negative breast cancer, serous uterine carcinoma, Ewing's sarcoma, melanoma, colon cancer, and clear cell renal cell carcinoma (ccRCC). The pharmaceutical composition according to claim 66.

69. A pharmaceutical product comprising a compound according to any one of claims 1 to 64, or a pharmaceutically acceptable salt thereof, tautomer, isotopic molecular species, or stereoisomer.

70. A pharmaceutical product according to claim 69 for treating cancer.

71. Use of a compound according to any one of claims 1 to 64, or a pharmaceutically acceptable salt thereof, tautomer, isotope, or stereoisomer, in the manufacture of a pharmaceutical for reducing FAK protein concentration.

72. Use of a compound according to any one of claims 1 to 64, or a pharmaceutically acceptable salt thereof, tautomer, isotopic species, or stereoisomer, in the manufacture of a pharmaceutical product for the prevention or treatment of cancer.

73. The cancer is selected from stomach cancer, lung cancer, pancreatic cancer, ovarian cancer, breast cancer, skin cancer, colon cancer, neuroblastoma, osteosarcoma, uterine cancer, rectal cancer, and kidney cancer. The use described in claim 72.

74. The cancer is selected from pancreatic ductal adenocarcinoma (PDAC), small cell lung cancer, non-small cell lung cancer (NSCLC), high-grade serous ovarian cancer, triple-negative breast cancer, serous uterine carcinoma, Ewing's sarcoma, melanoma, colon cancer, and clear cell renal cell carcinoma (ccRCC). The use described in claim 72.

75. A pharmaceutical product according to claim 69, which is used in combination with another secondary active agent or supportive therapy, A pharmaceutical product in which the other secondary active agent is a therapeutic antibody, hematopoietic growth factor, cytokine, anticancer agent, antibiotic, Cox-2 inhibitor, immunomodulator, immunosuppressant, corticosteroid, or a pharmacologically active variant or derivative thereof that specifically binds to a cancer antigen.

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