CDK inhibitors

Abstract

The present invention provides compounds of structural formula (I), which are useful in the treatment of cancer: The present invention provides a compound represented by TIFF2022531687000157.tif35137, or a pharmaceutically acceptable salt or stereoisomer thereof.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to International Patent Application No. PCT / CN2019 / 085494, filed May 5, 2019. The entire contents of the aforementioned application are incorporated herein by reference. [Background technology]

[0002] Cyclin-dependent kinases (CDKs) are a family of protein kinases that were first discovered for their role in regulating the cell cycle. They have since been identified to play a role in regulating many other biological functions, including transcription, mRNA processing, and neuronal differentiation.

[0003] CDKs are relatively small proteins with molecular weights of approximately 34-40 kDa. They contain almost exclusively a kinase domain and are essentially inactive when not complexed with a class of regulatory proteins called cyclins. CDK levels remain relatively constant throughout the cell cycle, and most regulation is post-translational, most notably by binding to cyclins.

[0004] As in all kinases, the active site or ATP-binding site of CDKs is a cleft between a small amino-terminal lobe and a large carboxy-terminal lobe. The structure of human CDK2 reveals that CDKs have an altered ATP-binding site that can be regulated by cyclin binding. Phosphorylation by CDK-activating kinase (CAK) at Thr161 on the T-loop increases the complex activity. In the absence of cyclin, a flexible loop called the activation loop or T-loop blocks the cleft, making the position of several important amino acid residues suboptimal for ATP binding. In the presence of cyclin, two α-helices reposition to allow ATP binding. One of them, the L12 helix immediately preceding the T-loop in the primary sequence, becomes a β-strand and helps reposition the T-loop so that it no longer blocks the active site. The other α-helix, called the PSTAIRE helix, helps to reposition and reposition important amino acid residues in the active site.

[0005] Thus, only cyclin-CDK complexes have active kinase activity, and most of the known cyclin-CDK complexes regulate progression through the cell cycle. CDKs are ubiquitous in all known eukaryotes, and their regulatory function in the cell cycle is evolutionarily conserved. For example, yeast cells can grow normally when their CDK genes are replaced with homologous human genes. CDKs exert their regulatory function by phosphorylating substrates on certain serine and threonine residues, as well as on the consensus sequence [S / T]PX[K / R], where S / T is the phosphorylation target Ser or Thr, P is proline, X is any amino acid, K is lysine, and R is arginine.

[0006] In animal cells, there are at least nine different CDKs, four of which (CDK1, 2, 3, and 4) are directly involved in regulating the cell cycle. In mammalian cells, CDK1 and its binding partners cyclins A2 and B1 are the only ones that can drive the cell cycle. Cyclin-CDK complexes from early cell cycle stages serve to activate cyclin-CDK complexes at later stages.

[0007] The same CDK can form complexes with different cyclins to regulate different phases of the cell cycle. For example, CDK2 can form complexes with cyclins D or E to regulate the G1 phase, cyclins A or E to regulate the S phase, and cyclin A to regulate the G2 phase. Meanwhile, CDK4 and CDK6 can form complexes with cyclins D1, D2, and D3.

[0008] The highly homologous cyclin-dependent kinases (CDKs) CDK4 and CDK6 in combination with cyclin D are key regulators of the transition through the restriction point R between the G1 (growth) and S (DNA replication) phases of the cell cycle. CDK4 / 6 exert their effect through the phosphorylation of the retinoblastoma protein (pRb). Once phosphorylated, pRb loses its inhibitory effect on the transcription of genes that promote the entry into the S phase.

[0009] On the other hand, the endogenous protein modulator p16 INK4 Alternatively, specific inhibition of CDK4 / 6 kinase activity by small molecule inhibitors results in hypophosphorylated pRb and arrest of cells at the G1 restriction point. As the primary mechanism regulating the G1 restriction point, pathways regulated by these kinases are altered in a wide range of human tumors, and thus inhibition of CDK4 / CDK6 in these tumors has therapeutic utility by preventing cell division.

[0010] There remains a need to provide CDK4 / 6 inhibitors that can be used to treat cell proliferative disorders such as cancer. Summary of the Invention

[0011] Described herein are compounds of Formula (I), (II-A) through (II-J), and compounds of the Examples (collectively referred to herein as the "compounds of the invention"), and pharma- ceutically acceptable salts, or stereoisomers thereof, that inhibit the activity of cyclin-dependent kinases (CDKs), e.g., CDK2, CDK4, and / or CDK6.

[0012] In one aspect, the present invention provides a compound of formula (I), or a pharma- ceutically acceptable salt, or stereoisomer thereof: [ka] wherein R1, R2, ring A, ring B, ring C, and linker L are as defined herein.

[0013] In one embodiment, the compound, or a pharma- ceutically acceptable salt, or stereoisomer thereof, is selected from the example compounds provided herein.

[0014] Also provided is a pharmaceutical composition comprising a compound of the invention, or a pharma- ceutically acceptable salt, or stereoisomer thereof, and a pharma- ceutically acceptable carrier.

[0015] The present disclosure further provides a method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of (1) a compound of the present invention, or a pharma- ceutically acceptable salt, or stereoisomer thereof, or (2) a pharma- ceutically acceptable composition comprising a compound of the present invention, or a pharma- ceutically acceptable salt, or stereoisomer thereof, and a pharma- ceutically acceptable carrier. In certain embodiments, the cancer is selected from the group consisting of colorectal cancer, breast cancer (such as hormone receptor positive, HER2 / neu negative advanced or metastatic breast cancer in postmenopausal women), lung cancer, prostate cancer, glioblastoma, mantle cell lymphoma, chronic myelogenous leukemia, and acute myelogenous leukemia.

[0016] In certain embodiments of the methods of the invention, cancer can be treated by inhibiting the activity of a cyclin-dependent kinase (CDK), such as CDK2, CDK4, and / or CDK6.

[0017] In certain embodiments of the methods of the invention, the cancer is cancer of the bladder, breast, colon, kidney, epidermis, liver, lung, esophagus, gallbladder, ovary, pancreas, stomach, cervix, thyroid, nose, head and neck, prostate, or skin, hematopoietic tumors of the lymphoid system, hematopoietic tumors of the myeloid system, follicular thyroid carcinoma, tumors of mesenchymal origin, tumors of the central or peripheral nervous system, melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoma, follicular thyroid carcinoma, or Kaposi's sarcoma.

[0018] In certain embodiments of the methods of the invention, the compounds of the invention are administered in combination with any one of the second therapeutic agents described herein that also treats cancer.

[0019] The present disclosure also provides the use of the compound of the present invention, or its pharma- ceutically acceptable salt, or stereoisomer, or pharmaceutical composition comprising them, in any of the above-mentioned methods of the present invention.In one embodiment, the compound of the present invention, or its pharma- ceutically acceptable salt, or stereoisomer, or pharmaceutical composition comprising them, is provided for use in any of the above-mentioned methods of the present invention.In another embodiment, the use of the compound of the present invention, or its pharma- ceutically acceptable salt, or stereoisomer, or pharmaceutical composition comprising them, is provided for manufacturing a medicament for any of the described methods of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] 1. Overview The present invention provides a compound of the invention, or a pharma- ceutically acceptable salt thereof, for use in therapy, such as the treatment of cancer.

[0021] The present invention also provides a pharmaceutical formulation comprising a compound of the invention, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier, diluent, or excipient.

[0022] The present invention provides a compound of the present invention or a pharma- ceutically acceptable salt thereof for use in the treatment of cancer. In particular, these cancers include any of the cancers described below, such as colorectal cancer, breast cancer (ER in adult or postmenopausal women), + HER2 - The cancer may be advanced or metastatic or recurrent breast cancer), lung cancer, particularly non-small cell lung cancer (NSCLC), prostate cancer, glioblastoma, mantle cell lymphoma (MCL), chronic myeloid leukemia (CML) and acute myeloid leukemia (AML).

[0023] The present invention further relates to a method for the treatment of colorectal cancer, breast cancer (ER cancer in adult or postmenopausal women) in mammals. + HER2 - The present invention provides a method for treating a cancer selected from the group consisting of advanced or metastatic or recurrent breast cancer), lung cancer, particularly non-small cell lung cancer (NSCLC), prostate cancer, glioblastoma, mantle cell lymphoma (MCL), chronic myeloid leukemia and acute myeloid leukemia, comprising administering to a mammal in need of such treatment an effective amount of a compound of the present invention or a pharmacologic acceptable salt thereof.

[0024] Furthermore, the present invention provides the use of the compound of the present invention or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for the treatment of cancer. In particular, these cancers include colorectal cancer, breast cancer (ER in adult or postmenopausal women), and + HER2 - The cancer is selected from the group consisting of: advanced or metastatic or recurrent breast cancer), lung cancer, particularly non-small cell lung cancer (NSCLC), prostate cancer, glioblastoma, mantle cell lymphoma (MCL), chronic myeloid leukemia and acute myeloid leukemia.

[0025] Further, the present invention provides a pharmaceutical formulation for use in treatment, comprising the compound of the present invention or a pharma- ceutical acceptable salt thereof, and a pharma- ceutical acceptable carrier, diluent, or excipient. The present invention also provides a pharmaceutical formulation for use in treatment, comprising the compound of the present invention or a pharma- ceutical acceptable salt thereof, and a pharma- ceutical acceptable carrier, diluent, or excipient, for use in treatment of colorectal cancer, breast cancer (ER in adult women or postmenopausal women), and a pharma- ceutical acceptable salt thereof. + HER2 - The Company provides pharmaceutical formulations for the treatment of advanced or metastatic or recurrent breast cancer, lung cancer, particularly non-small cell lung cancer (NSCLC), prostate cancer, glioblastoma, mantle cell lymphoma (MCL), chronic myeloid leukemia and acute myeloid leukemia.

[0026] Treatable disease indications and potential second therapeutic agents useful in combination therapy are described in further detail in the following sections.

[0027] It is understood that any embodiment described herein, including those described in only one of the following sections or only in the examples, can be combined with any one or more additional embodiments of the present invention, unless expressly disclaimed or otherwise inappropriate / inapplicable.

[0028] 2.Definition The term "halo" or "halogen" as used herein means halogen and includes chloro, fluoro, bromo, and iodo.

[0029] The term "alkyl" used alone or as part of a larger moiety such as "alkoxy" or "haloalkyl" refers to a saturated aliphatic straight- or branched-chain monovalent hydrocarbon radical. Unless otherwise specified, an alkyl group typically has from 1 to 4 carbon atoms, i.e., a (C1-C4) alkyl. As used herein, a "(C1-C4) alkyl" group refers to a radical having from 1 to 4 carbon atoms in a straight- or branched-chain arrangement. Examples include methyl, ethyl, These include n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

[0030] The term "alkenyl" refers to a branched or straight-chain monovalent hydrocarbon radical containing at least one double bond. Alkenyl can be mono- or polyunsaturated and can exist in the E or Z configuration. Unless otherwise specified, an alkenyl group typically has from 2 to 6 carbon atoms, i.e., (C2-C6)alkenyl. For example, "(C2-C6)alkenyl" refers to a radical having from 2 to 6 carbon atoms in a straight or branched arrangement.

[0031] The term "alkynyl" refers to a branched or straight-chain monovalent hydrocarbon radical containing at least one triple bond. Unless otherwise specified, an alkynyl group typically has from 2 to 6 carbon atoms, i.e., (C2-C6)alkynyl. For example, "(C2-C6)alkynyl" refers to a radical having from 2 to 6 carbon atoms in a straight or branched arrangement.

[0032] The term "alkoxy" refers to an alkyl radical attached through an oxygen linking atom, represented by -O-alkyl. For example, "(C1-C4)alkoxy" includes methoxy, ethoxy, propoxy, and butoxy.

[0033] The terms "haloalkyl" and "haloalkoxy" mean alkyl or alkoxy, as the case may be, substituted with one or more halogen atoms. Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and the like.

[0034] The terms "hydroxyalkyl" and "hydroxyalkoxy" mean alkyl or alkoxy, as the case may be, substituted with one or more hydroxy groups.

[0035] As used herein, the term "cycloalkyl" refers to a saturated cyclic, bicyclic, tricyclic, or polycyclic hydrocarbon group having 3 to 14 carbons, including the indicated number of rings and carbon atoms (e.g., C3-C 14 Monocyclic, C4-C 14 Bicyclic, C5-C 14 Tricyclic, or C6-C 14 In some embodiments, "cycloalkyl" is a monocyclic cycloalkyl. Examples of monocyclic cycloalkyl groups include cyclopentyl (C5), cyclohexyl (C5), cyclopropyl (C3), cyclobutyl (C4), cycloheptyl (C7), and cyclooctyl (C8). In some embodiments, "cycloalkyl" is a bicyclic cycloalkyl. Examples of bicyclic cycloalkyl groups include bicyclo[1.1.0]butane (C4), bicyclo[1.1.1]pentane (C5), spiro[2.2]pentane (C5), bicyclo[2.1.0]pentane (C5), bicyclo[2.1.1]hexane (C6), bicyclo[3.3.3]undecane (C7), bicyclo[3.3.3]butane (C8), bicyclo[3.3.3]pentane (C9), bicyclo[3.3.3]pentane (C10), bicyclo[3.3.3]pentane (C11), bicyclo[3.3.3]pentane (C12), bicyclo[3.3.3]pentane (C13), bicyclo[3.3.3]pentane (C14), bicyclo[3.3.3]pentane (C15), bicyclo[3.3.3]pentane (C16), bicyclo[3.3.3]pentane (C17), bicyclo[3.3.3]pentane (C18), bicyclo[3.3.3]pentane (C19 ...8), bicyclo[3.3.3]pentane (C19), bicyclo[3.3.3]pentane (C19), bicyclo[3.3.3]pentane (C19), bicyclo[3.3.3]pentane (C20), bicyclo[3.3 11 ), decahydronaphthalene (C 10 ), bicyclo[4.3.2]undecane (C 11 ), spiro[5.5]undecane (C 11 ) and bicyclo[4.3.3]dodecane (C 12 In some embodiments, "cycloalkyl" is a tricyclic cycloalkyl. An example of a tricyclic cycloalkyl is adamantine (C 12 Unless otherwise specified, a "cycloalkyl" has 3 to 6 carbon atoms.

[0036] The term "aryl group" used alone or as part of a larger moiety, as in "aralkyl", "aralkoxy", or "aryloxyalkyl", means a carbocyclic aromatic ring. The term "aryl" may be used interchangeably with the terms "aryl ring", "carbocyclic aromatic ring", "aryl group" and "carbocyclic aromatic group". Aryl groups typically have 6 to 14 ring atoms. Examples include phenyl, naphthyl, anthracenyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl, indenyl, and the like. A "substituted aryl group" is a substituted ring atom that is bonded to a hydrogen atom at any one or more substitutable ring atoms.

[0037] The term "heterocyclyl group" or "heterocyclic group" means a 3-10 membered monocyclic non-aromatic ring having 1-4 ring heteroatoms, or a polycyclic ring having 7-20 members and 1-4 ring heteroatoms, where the polycyclic ring has one or more monocyclic non-aromatic heterocyclic rings fused to one or more aromatic or heteroaromatic rings. Each heteroatom is independently selected from nitrogen, quaternary nitrogen, nitrogen oxide (e.g., NO), air, and sulfur, including sulfoxides and sulfones. In one embodiment, the heterocyclyl group is a bicyclic ring having a monocyclic non-aromatic heterocyclic ring fused to a phenyl group. Exemplary polycyclic heterocyclic groups include tetrahydroisoquinolinyl (such as 1,2,3,4-tetrahydroisoquinolin-7-yl, 2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl, 1,2,3,4-tetrahydroisoquinolin-6-yl and 2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl), isoindolinyl (such as 2-ethylisoindolin-5-yl, 2-methylisoindolin-5-yl), indolinyl, tetrahydrobenzo[f]oxazepine (such as 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-7-yl). The terms "heterocycle", "heterocyclyl", or "heterocyclic" also refer to rings that are optionally substituted, whether saturated or partially unsaturated. In some embodiments, the heterocyclyl group is a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur (a "3- to 14-membered heterocyclyl").

[0038] The terms "heteroaryl", "heteroaromatic", "heteroaryl ring", "heteroaryl group", "heteroaromatic ring", and "heteroaromatic group", used alone or as part of a larger moiety, as in "heteroaralkyl" or "heteroarylalkoxy", refer to an aromatic ring group having 5 to 14 ring atoms selected from carbon and at least one (typically 1 to 4, more typically 1 or 2) heteroatoms (e.g., oxygen, nitrogen or sulfur). "Heteroaryl" includes monocyclic and polycyclic rings, where a monocyclic heteroaromatic ring is fused to one or more other carbocyclic aromatic or heteroaromatic rings. Thus, "5-14 membered heteroaryl" includes monocyclic, bicyclic, or tricyclic ring systems.

[0039] Examples of monocyclic 5- to 6-membered heteroaryl groups include furanyl (e.g., 2-furanyl, 3-furanyl), imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 2-oxadiazolyl, 5-oxadiazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrazolyl (e.g., 3-pyrazolyl, 4-pyrazolyl), pyrrolyl (e.g., Examples of such radicals include 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), triazolyl (e.g., 2-triazolyl, 5-triazolyl), tetrazolyl (e.g., tetrazolyl), thienyl (e.g., 2-thienyl, 3-thienyl), pyrimidinyl, pyridinyl and pyridazinyl. Examples of polycyclic aromatic heteroaryl groups include carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolinyl, indolyl, isoindolyl, acridinyl, or benzisoxazolyl. A "substituted heteroaryl group" is substituted at any one or more substitutable ring atoms that are ring carbon or ring nitrogen atoms bonded to a hydrogen.

[0040] The term "bridged bicyclic group" refers to a ring system containing two rings which share at least three adjacent ring atoms.

[0041] As used herein, many moieties (e.g., alkyl, alkylene, cycloalkyl, aryl, heteroaryl, or heterocyclyl) are referred to as being either "substituted" or "optionally substituted". When a moiety is modified by one of these terms, unless otherwise stated, it means that any part of the moiety known to those skilled in the art as available for substitution can be substituted, which includes one or more substituents. When more than one substituent is present, each substituent can be independently selected. Such means for substitution are well known in the art and / or taught by this disclosure. An optional substituent can be any substituent suitable for binding to a moiety.

[0042] If suitable substituents are not specifically recited, exemplary substituents include (C1-C5) alkyl, (C1-C5) hydroxyalkyl, (C1-C5) haloalkyl, (C1-C5) alkoxy, (C1-C5) haloalkoxy, halogen, hydroxyl, cyano, amino, -CN, -NO2, -OR c1 , -NR a1 R b1 , -S(O) i R a1 , -NR a1 S(O) i R b1 , -S(O) i NR a1 R b1 , -C(=O)OR a1 , -OC(=O)OR a1 , -C(=S)OR a1 , -O(C=S)R a1 , -C(=O)NR a1 R b1 , -NR a1 C(=O)R b1 , -C(=S)NR a1 R b1 , -C(=O)R a1 , -C(=S)R a1 , N.R. a1 C(=S)R b1 , -O(C=O)NR a1 R b1 , -NR a1(C=S)OR b1 , -O(C=S)NR a1 R b1 , -NR a1 (C=O)NR a1 R b1 , -NR a1 (C=S)NR a1 R b1 , phenyl, or 5-6 membered heteroaryl. a1 and each R b1 is independently selected from -H and (C1-C5)alkyl, optionally substituted with hydroxyl or (C1-C3)alkoxy. R c1 is -H, (C1-C5)haloalkyl or (C1-C5)alkyl, wherein the (C1-C5)alkyl is optionally substituted with hydroxyl or (C1-C3)alkoxy.

[0043] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers.

[0044] Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or stereoisomers by well-known methods such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compounds as chiral salt complexes, or crystallizing the compounds in chiral solvents. Enantiomers and diastereomers can also be obtained from diastereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods. See, e.g., Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, ELStereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SHTables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).

[0045] If a compound is designated by a name or structure indicating a single enantiomer, unless otherwise specified, the compound is at least 60%, 70%, 80%, 90%, 99% or 99.9% optically pure (also referred to as "enantiomerically pure"). Optical purity is the weight of the mixture of the named or depicted enantiomer divided by the total weight of the mixture of both enantiomers.

[0046] When the stereochemistry of a disclosed compound is named or depicted by a structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in the case of a diastereomeric pair), it is understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers is included. It is further understood that the stereoisomeric purity of the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight. Stereoisomeric purity in this case is determined by dividing the total weight of the mixture of stereoisomers included in the name or structure by the total weight of the mixture of all stereoisomers.

[0047] When a geometric isomer is depicted by name or structure, it is understood that the geometric isomer purity of the named or depicted isomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight. Geometric isomer purity is determined by dividing the weight of the named or depicted geometric isomer in the mixture by the total weight of all geometric isomers in the mixture.

[0048] A racemic mixture means 50% of one enantiomer and 50% of the corresponding enantiomer. The present invention includes all enantiomerically pure, enantiomerically enriched, diastereomerically pure, diastereomerically enriched, and racemic mixtures, as well as diastereomeric mixtures, of the compounds of the present invention.

[0049] The compounds described herein may also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0050] It will be recognized that, depending on the origin of the chemicals used in synthesis, some variation in natural isotope abundance will occur in the synthesized compound.Therefore, the preparation of the compounds disclosed herein will essentially contain a small amount of deuterated isotopologue.Despite this variation, the concentration of naturally abundant and stable hydrogen and carbon isotopes is low and insignificant compared to the degree of stable isotope substitution of the compounds of the present invention.See, for example, Wada, E et al., Seikagaku, 1994, 66:15; Gannes, LZ et al., Comp Biochem Physiol Mol Integr Physiol, 1998, 119:725.

[0051] The compounds described herein may exist in various tautomeric forms. The term "tautomer" or "tautomeric" refers to two or more interconvertible compounds / substituents resulting from at least one formal migration of a hydrogen atom and at least one change in valence (e.g., from a single bond to a double bond, from a triple bond to a single bond, or vice versa). Exemplary tautomerizations include keto to enol, amide to imide, lactam to lactim, enamine to imine, and enamine to (different enamine) tautomerizations. The teachings of the present invention encompass compounds in tautomeric forms, including forms not structurally depicted. All such isomeric forms of such compounds are expressly included. If a tautomer of a compound is aromatic, the compound is aromatic. Similarly, if a tautomer of a compound is heteroaryl, the compound is heteroaryl.

[0052] In certain instances, tautomeric forms of the disclosed compounds exist, such as the tautomeric structures shown below. [ka]

[0053] When a compound herein is represented by a structural formula or designated by a chemical name herein, it is understood that the structural formula also includes all other tautomeric forms that may exist for the compound.

[0054] The compounds of the present invention can exist in free form for therapy or, where appropriate, as a pharma- ceutically acceptable salt form.

[0055] The term "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and sub-animals without excessive toxicity, irritation, allergic reaction, etc., within the scope of sound medical judgment, and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art, for example, Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods known in the art, such as ion exchange. Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lanthanide ... Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N-butyl salts. + (C 1-4 Alkyl)4 -Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharma- ceutically acceptable salts include ammonium, quaternary ammonium, and amine cations, formed where appropriate using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0056] Such pharma- ceutically acceptable acid addition salts and the general methodology for preparing them are well known in the art. See, for example, Stahl et al., HANDBOOK OF PHARMACEUTICAL SALTS: PROPERTIES, SELECTION AND USE, (VCHA / Wiley-VCH, 2002); Bighley et al., in "Encyclopedia of Pharmaceutical Technology," Eds. Swarbrick and Boylan, Vol. 13, Marcel Dekker, Inc., New York, Basel, Hong Kong 1995, pp. 453-499; Berge et al., "Pharmaceutical Salts," Journal of Pharmaceutical Sciences, 66(1): 1977.

[0057] The terms "composition" and "formulation" are used interchangeably.

[0058] A "subject" is a mammal, preferably a human, but may also be an animal in need of veterinary treatment, such as companion animals (e.g., dogs, cats, etc.), farm animals (e.g., cows, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.).

[0059] The terms "administer", "administering" or "administration" refer to a method of introducing a compound of the invention or a composition thereof into or onto a subject. These methods include, but are not limited to, intra-articular (into a joint), intravenous, intramuscular, intratumor, intradermal, intraperitoneal, subcutaneous, oral, topical, intrathecal, inhalation, transdermal, rectal, and the like. Administration techniques that can be used with the agents and methods described herein can be found, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.

[0060] The terms "treatment", "treat" and "treating" refer to reversing, alleviating or inhibiting the progression of a disease as described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of a disease have occurred or been observed (i.e., treatment for treatment). In other embodiments, treatment may be administered in the absence of signs or symptoms of a disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., in view of a history of symptoms and / or exposure to a pathogen) (i.e., treatment for prevention). Treatment may also be continued after symptoms have resolved, e.g., to delay or prevent recurrence.

[0061] The terms "condition," "disease," and "disorder" are used interchangeably.

[0062] Generally, the effective amount of the compounds taught herein will vary depending on a variety of factors, such as the given drug or compound, the pharmaceutical formulation, the route of administration, the type of disease or disorder, the identity of the subject or host being treated, etc., but may nevertheless be routinely determined by one of ordinary skill in the art. Effective amounts of the compounds of the present teachings may be readily determined by one of ordinary skill in the art using routine methods known in the art.

[0063] The term "effective amount" refers to an amount that, when administered to a subject, produces beneficial or desired results, including clinical results, e.g., inhibiting, suppressing or reducing the symptoms of the condition being treated in the subject, e.g., compared to a control. For example, an effective amount can be administered in a unit dosage form (e.g., 1 mg to about 50 g per day, e.g., 1 mg to about 5 grams per day).

[0064] A "therapeutically effective amount" is an amount effective to detectably kill or inhibit the growth or spread of cancer cells; tumor size or number; or other measures of the level, stage, progression, or severity of the cancer. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease, the particular anti-cancer agent, its mode of administration, co-treatment with other therapies, etc.

[0065] General chemical terms used in the above formulae have their usual meanings.

[0066] As used herein, "h" refers to an hour or hours, "min" refers to minutes or minutes, "Cdk" or "CDK" refers to cyclin-dependent kinase, "pRb" refers to retinoblastoma protein, "MCL" refers to mantle cell lymphoma, "AML" refers to acute myeloid leukemia, "CML" refers to chronic myeloid leukemia, "Boc" refers to N-tert-butoxycarbonyl, "EA" refers to ethyl acetate, "DCM" refers to dichloromethane, "DMSO" refers to dimethylsulfoxide, "DMA" refers to dimethylacetamide, "THF" refers to tetrahydrofuran, and "M "tBE" refers to methyl tert-butyl ether, "TEA" refers to triethylamine, "FBS" refers to fetal bovine serum, "PBS" refers to phosphate buffered saline, "BSA" refers to bovine serum albumin, "RT" refers to room temperature, "mpk" means milligrams per kilogram, "po" refers to per os (oral), "qd" means once daily dose, "HPLC" means high pressure liquid chromatography, "q2d" means a single dose every 2 days, "q2dx10" means a single dose every 2 days x 10 doses, "VSMC" means vascular smooth muscle cells, and "XRD" refers to x-ray diffraction.

[0067] 3.Compound In a first embodiment of the present invention, a compound represented by structural formula (I) [ka] or a pharma- ceutically acceptable salt, or stereoisomer thereof, In the formula, ring A is [ka] and Ring B is a bond, a 3- to 10-membered heterocyclyl, or a 5- to 10-membered heteroaryl; Ring C is a 5- to 6-membered heteroaryl, a 5- to 10-membered heterocyclyl, a phenyl, or a 5- to 10-membered bridged bicyclic group, each of which is selected from the group consisting of one or two R12 and optionally substituted with The linker L is a bond, -(CH2) q -, -(CH2) q O-, -NR a (CH2) q -, -C(O)-, -C(O)N(R a )-,or -S(O)2-, R a each occurrence of is H or CH3, R1 is H, deuterium, halogen, -OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, or C 1-4 is haloalkoxy; Each occurrence of R2 is H, deuterium, halogen, -OH, CN, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, -(CH2) n OR6, -(CH2) n SR6, -(CH2) n C(O)R6, -(CH2) n C(O)OR6, -(CH2) n S(O) m R6, -(CH2) n NR7R8, -(CH2) n C(O)NR7R8, -(CH2) n NR7C(O)R6, -(CH2) n NR7S(O) m R6, C 3-8 cycloalkyl, 3- to 10-membered heterocyclyl, 6- to 14-membered aryl, and 5- to 14-membered heteroaryl, and the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl represented by R2 is independently selected from deuterium, halogen, CN, -OH, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8Optionally substituted with one or more groups selected from alkoxy, and NR7R8; When ring B is a 3- to 10-membered heterocyclyl, two R2s bonded to the same ring atom of ring B are deuterium, halogen, CN, -OH, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 haloalkoxy, and NR7R8, C 3-6 may form a cycloalkyl or a 3- to 6-membered heterocyclyl; Each occurrence of R3 is independently H, deuterium, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 cycloalkyl, or 3- to 10-membered heterocyclyl; C represented by R3 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl or 3-10 membered heterocyclyl is substituted with deuterium, halogen, CN, -OH, C 1-8 Alkyl, and C 1-8 haloalkyl; Each occurrence of R4 is independently H, deuterium, halogen, CN, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C(O)C 1-8 Alkyl, C 3-8 cycloalkyl, or C in the group represented by R4 or R4 is selected from 3-10 membered heterocyclyl 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C 3-8Cycloalkyl or 3-10 membered heterocyclyl is each independently selected from deuterium, halogen, -OH, C 1-8 Alkyl and C 1-8 haloalkyl; or Two R4 groups attached to the same ring atom of ring A are C 3-6 cycloalkyl or 3-6 membered heterocyclyl, each of which is selected from the group consisting of deuterium, halogen, CN, -OH, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Optionally substituted with one or more groups selected from haloalkoxy, and NR7R8; Each occurrence of R5 is H, deuterium, halogen, -OH, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C(O)C 1-4 alkyl, or 3-6 membered heterocyclyl; Each occurrence of R6 is independently selected from H, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, 6-14 membered aryl, 5-14 membered heteroaryl, represented by R 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 cycloalkyl, 3- to 10-membered heterocyclyl, The 6- to 14-membered aryl and the 5- to 14-membered heteroaryl are each selected from halogen, CN, -OH, and C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Optionally substituted with one or more groups selected from alkoxy, and NR7R8; Each occurrence of R7 and R8 is independently H, C 1-4 alkyl or cyclopropyl; R 12 Each occurrence of is H, deuterium, halogen, -OH, CN, NH2, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C 3-8 cycloalkyl, or 3- to 10-membered heterocyclyl; R 12 C represented by 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl or 3-10 membered heterocyclyl is substituted with halogen, CN, -OH, C 1-4 Alkyl, C 1-4 Haloalkyl, and C 1-4 Optionally substituted with one or more groups selected from alkoxy; q is 0, 1, or 2; n is 0, 1, 2, 3, 4, or 5; m is 0, 1, or 2.

[0068] In a second embodiment of the present invention, there is provided a compound represented by structural formula (I), or a pharma- ceutically acceptable salt, or stereoisomer thereof, wherein Ring C is [ka] and the remaining variables are as defined in the first embodiment.

[0069] In a third embodiment of the present invention, there is provided a compound of the first or second embodiment, or a pharma- ceutically acceptable salt, or stereoisomer thereof, wherein ring A is [ka] and During the ceremony, Each occurrence of R3 is C optionally substituted with H, deuterium, -OH. 1-4 C optionally substituted with alkyl or -OH 3-6 is cycloalkyl; Each occurrence of R4 is C optionally substituted with H, deuterium, halogen, fluoro. 1-4 Alkyl, C 2-4 C optionally substituted with alkenyl, methyl 3-6 cycloalkyl, or 3- to 6-membered heterocyclyl; or two R groups attached to the same ring atom of ring A are C 3-6 cycloalkyl or 3-6 membered heterocyclyl, each of which is selected from halogen, CN, -OH, C 1-2 Alkyl, C 1-2 optionally substituted with one or more groups selected from alkoxy, and NR7R8; R5 is H, deuterium, halogen, CN, -OH, C 1-4 Alkyl, C 1-4 Alkoxy, or C 1-4 and the remainder of the variables are as defined in the first and / or second embodiment.

[0070] In a fourth embodiment of the present invention, the compound of structural formula (I) is represented by structural formulas (II-A) to (II-J): [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof, wherein R 12 is H, F, Cl, CH3, or CF3, k is 0, 1, or 2, and the remainder of the variables are as defined in the first, second, and / or third embodiment.

[0071] In a fifth embodiment of the present invention, there is provided a compound represented by structural formula (I): Compounds of formula (II-A) through (II-J), or a pharma- ceutically acceptable salt, or stereoisomer thereof, are provided, wherein L is a bond, -(CH2)-, -O(CH2)-, -C(=O)-, or -S(O)2-, and the remainder of the variables are as defined in the first, second, third, and / or fourth embodiment.

[0072] In a sixth embodiment of the present invention, there is provided a compound represented by structural formula (I): Compounds of formula (II-A) through (II-J), or pharma- ceutically acceptable salts, or stereoisomers thereof, are provided, wherein ring B is a 4-10 membered heterocyclyl or a 5-6 membered monocyclic heteroaryl optionally substituted with one or two R2 groups, and the remainder of the variables are as defined in the first, second, third, fourth, and / or fifth embodiment.

[0073] In a seventh embodiment of the present invention, there is provided a compound represented by structural formula (I): Compounds of formula (II-A) to (II-J), or pharma- ceutically acceptable salts, or stereoisomers thereof, are provided, wherein: Each occurrence of R2 is H, halogen, CN, -OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -(CH2) n OR6, -(CH2) n C(O)R6, -(CH2) n C(O)OR6, -(CH2) n S(O)2R6, -(CH2) n NR7R8, -(CH2) n C(O)NR7R8, -(CH2) n C(O)NHR7, -(CH2) n NR7C(O)R6, -(CH2) n NR7S(O)2R6, C 3-8 cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl; or Two R2s bonded to the same ring atom of ring B are Halogen, -OH, C1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Alkoxy, C 1-2 haloalkoxy, and 3-6 heterocyclyl (when ring B is a 3-10 membered heterocyclyl) optionally substituted with one or more groups selected from NR7R8; Each occurrence of R6 is independently selected from H, C 1-4 Alkyl, C 3-6 cycloalkyl, 3- to 7-membered heterocyclyl, phenyl, 5- to 6-membered heteroaryl, represented by R 1-4 Alkyl, C 3-6 Cycloalkyl, 3- to 7-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl are each independently selected from halogen, CN, -OH, and C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 optionally substituted with alkoxy, or NR7R8; n is 0, 1, or 2, and the remainder of the variables are as defined in the first, second, third, fourth, fifth, and / or sixth embodiment.

[0074] In an eighth embodiment of the present invention, there is provided a compound represented by structural formula (I): Compounds of formula (II-A) through (II-J), or pharma- ceutically acceptable salts, or stereoisomers thereof, are provided, wherein R1 is H, F, Cl, or CH3, and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, and / or seventh embodiment.

[0075] In a ninth embodiment of the present invention, there is provided a compound represented by structural formula (I): The present invention provides compounds of formula (II-A) to (II-J), or pharma- ceutically acceptable salts, or stereoisomers thereof, wherein ring B is [ka] each of which is optionally substituted with one or two R groups, and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, and / or eighth embodiment.

[0076] In a tenth embodiment of the present invention, there is provided a compound represented by structural formula (I): Compounds of formula (II-A) through (II-J), or pharma- ceutically acceptable salts, or stereoisomers thereof, are provided, wherein each occurrence of R2 is H, halogen, CN, —OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -(CH2) n S(O)2C 1-4 Alkyl, -(CH2) n NR7R8, C 3-4 cycloalkyl, or 3-6 membered heterocyclyl; n is 0, 1, or 2; or, when Ring B is 4-7 membered heterocyclyl, two R2 attached to the same ring atom of Ring B form a 3-6 membered heterocyclyl, and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, and / or ninth embodiment.

[0077] In an eleventh embodiment of the present invention, there is provided a compound represented by structural formula (I): The present invention provides compounds of formula (II-A) to (II-J), or pharma- ceutically acceptable salts, or stereoisomers thereof, wherein ring A is [ka] and the remainder of the variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, and / or tenth embodiment.

[0078] In a twelfth embodiment of the present invention, there is provided a compound represented by structural formula (I): Compounds of formula (II-A) through (II-J), or pharma- ceutically acceptable salts, or stereoisomers thereof, are provided, wherein R1 is H or F, and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, and / or eleventh embodiments.

[0079] In a thirteenth embodiment of the present invention, there is provided a compound represented by structural formula (I): Compounds of formula (II-A) to (II-J), or pharma- ceutically acceptable salts, or stereoisomers thereof, are provided, wherein each occurrence of R is C optionally substituted with H, —OH, 1-3 C optionally substituted with alkyl or -OH 3-6 each occurrence of R is H, halogen, C 1-3 Alkyl, C 2-4 alkenyl, cyclopentyl, tetrahydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl; each occurrence of R5 is H, F, CN, methoxy, OCHF2, and the remainder of the variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, and / or twelfth embodiments.

[0080] In a fourteenth embodiment of the present invention, there is provided a compound represented by structural formula (I): Compounds (II-A) through (II-J), or pharma- ceutically acceptable salts, or stereoisomers thereof, are provided, wherein L is a bond, and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, and / or thirteenth embodiments.

[0081] In a fifteenth embodiment of the present invention, there is provided a compound represented by structural formula (I): The present invention provides compounds of formula (II-A) to (II-J), or pharma- ceutically acceptable salts, or stereoisomers thereof, wherein ring B is [ka] each of which is optionally substituted with one or two R groups, and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, and / or fourteenth embodiments.

[0082] In a sixteenth embodiment of the present invention, there is provided a compound represented by structural formula (I): Compounds of formula (II-A) through (II-J), or pharma- ceutically acceptable salts, or stereoisomers thereof, are provided, wherein each occurrence of R2 is H, halogen, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, NH2, N(CH3)2, NHcyclopropyl, -(CH2) n S(O)2C 1-3 or, when Ring B is piperidinyl, two R2 bonded to the same ring atom of Ring B form 2,5-pyrrolidinedionyl, or 2-pyrrolidonyl, where n is 0, 1, or 2, and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, and / or fifteenth embodiments.

[0083] In a seventeenth embodiment of the present invention, there is provided a compound represented by structural formula (I): The present invention provides compounds of formula (II-A) to (II-J), or pharma- ceutically acceptable salts, or stereoisomers thereof, wherein ring A is [ka] and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, and / or sixteenth embodiments.

[0084] In an eighteenth embodiment of the present invention, there is provided a compound represented by structural formula (I): Compounds of formula (II-A) through (II-J), or pharma- ceutically acceptable salts, or stereoisomers thereof, are provided, wherein each occurrence of R is H or C. 1-3 alkyl, and each occurrence of R4 is H or C 1-3 alkyl, each occurrence of R5 is H, F, or OMe, and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, and / or seventeenth embodiments.

[0085] In a nineteenth embodiment of the present invention, structural formula (I) is Compounds (II-A) through (II-J), or pharma- ceutically acceptable salts, or stereoisomers thereof, are provided, wherein R1 is H, and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, and / or eighteenth embodiments.

[0086] In a twentieth embodiment of the present invention, there is provided a compound represented by structural formula (I): (II-A) through (II-J), or a pharma- ceutically acceptable salt, or stereoisomer thereof, is provided, wherein Ring C is unsubstituted and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, and / or nineteenth embodiments.

[0087] In a twenty-first embodiment of the present invention, there is provided a compound represented by structural formula (I): The present invention provides compounds of formula (II-A) to (II-J), or pharma- ceutically acceptable salts, or stereoisomers thereof, wherein ring B is [ka] and each of which is optionally substituted with one or two R groups, and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, and / or twentieth embodiment.

[0088] In a twenty-second embodiment of the present invention, there is provided a compound of structural formula (I), (II-A) to (II-J), or a pharma- ceutically acceptable salt, or stereoisomer thereof, wherein R2 is H, halogen, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 hydroxyalkyl, NH, N(CH), NHcyclopropyl, and the remainder of the variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, and / or twenty-first embodiments.

[0089] In one embodiment, the compound or a pharma- ceutically acceptable salt, or stereoisomer thereof is selected from the compounds of Example Formulae (I), (II-A) to (II-J).

[0090] Another aspect of the disclosure relates to labeled compounds of the invention (radiolabeled, fluorescently labeled, etc.) that are useful not only in imaging techniques, but also in localizing and quantitating CDKs in tissue samples, including humans, both in vitro and in vivo, and in assays to identify CDK ligands by inhibiting binding of the labeled compounds. Thus, the disclosure includes such labeled compounds.

[0091] The present disclosure further includes isotopically labeled compounds of the present invention. An "isotopically" or "radiolabeled" compound is a compound of the present invention in which one or more atoms have been replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., of natural origin). Suitable radionuclides that can be incorporated into the compounds of the present invention include: 2H (also written as D for deuterium), 3 H (also written as T for tritium), 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 18 F, 35 S, 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I and 131 These include, but are not limited to, I. The radionuclide that is incorporated in the present radio-labeled compounds will depend on the particular application of that radio-labeled compound.

[0092] The present invention can further include synthetic methods for incorporating radioisotopes into the compounds of the present invention. Synthetic methods for incorporating radioisotopes into organic compounds are well known in the art, and one of ordinary skill in the art will readily recognize methods applicable to the compounds of the present invention.

[0093] The labeled compounds of the present invention can be used in screening assays to identify / evaluate compounds. For example, a labeled newly synthesized or identified compound (i.e., a test compound) can be evaluated for its ability to bind to CDK by monitoring its concentration fluctuation when contacting CDK through tracking of the label. For example, a test compound (labeled) can be evaluated for its ability to reduce the binding of another compound (i.e., a standard compound) known to bind to CDK. Thus, the ability of a test compound to compete with a standard compound for binding to CDK directly correlates with its binding affinity. Conversely, in some other screening assays, the standard compound is labeled and the test compound is not labeled. Thus, to evaluate the competition between the standard compound and the test compound, the concentration of the labeled standard compound is monitored to confirm the relative binding affinity of the test compound.

[0094] In one embodiment, a compound or a pharma- ceutically acceptable salt, or stereoisomer thereof is provided, wherein one or more hydrogen atoms are replaced with deuterium.

[0095] 4. Treatable diseases and treatment methods Certain compounds of the present invention are selective inhibitors of CDK2, CDK4, and / or CDK6 and are therefore useful for the treatment of diseases or disorders characterized by abnormal cell proliferation that can be inhibited by reducing the activity of CDK-cyclin complexes, including CDK2, CDK4, and / or CDK6.

[0096] In certain embodiments, the compounds of the invention selectively inhibit CDK4 / 6 over CDK2, with IC 50 The ratio of values ​​is at least about 10, 20, 50, 100, 200, 300, 400, 500, 800, 1,000, 2,000 or more.

[0097] In certain embodiments, the compounds of the invention selectively inhibit CDK4 over CDK6, with IC 50 The ratio of values ​​is at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 50 or more.

[0098] In certain embodiments, the compounds of the invention selectively inhibit CDK2 over CDK4, with IC 50 The ratio of values ​​is at least about 2, 5, 10, 15, 20, 40, 50, 60, 80, 100 or more.

[0099] In certain embodiments, the compounds of the present invention have similar IC 50 Values, e.g., within 10-fold, 5-fold, 3-fold, or 2-fold of IC 50 Such compounds of the invention are useful for treating cancers associated with amplified or enhanced expression of cyclin D1 or E1 or E2.

[0100] CDK2 is a catalytic subunit of the CDK-cyclin complex whose activity is restricted to the G1-S phase of the cell cycle, where cells make the proteins they need for mitosis and replicate their DNA. CDK2 forms a complex with cyclin E or A. Cyclin E binds to CDK2 in G1, which is required for the transition from G1 to S phase, whereas CDK2 binding to cyclin A is required for progression through S phase.

[0101] CDK2 is largely dispensable in the cell cycle of normally functioning cells, but is important for the abnormal proliferation process of cancer cells. Overexpression of cyclin E occurs in many tumor cells, causing the cells to become dependent on CDK2 and cyclin E. Aberrant cyclin E activity is observed in breast, lung, colorectal, gastric, and bone cancers, as well as in leukemias and lymphomas. Similarly, aberrant expression of cyclin A2 is associated with chromosomal instability and tumor growth, while inhibition leads to reduced tumor growth. Thus, CDK2 and its cyclin binding partners represent possible therapeutic targets for novel cancer therapeutics. Preclinical models have shown preliminary success in limiting tumor growth, and it has also been observed to reduce the side effects of current chemotherapeutic drugs.

[0102] For example, Caldon et al. (Mol Cancer Ther 11(7):1488-1499, 2012) reported that cyclin E2 is included in several gene signatures predicting disease progression in either tamoxifen-resistant or metastatic breast cancer, and that high expression of CycE2 is a hallmark of luminal B and HER2 subtypes of breast cancer and strongly predicts shorter distant metastasis-free survival after endocrine therapy. Furthermore, tamoxifen-resistant (MCF-7 TAMR) breast cancer cells overexpress cyclin E2, and expression of either cyclin E1 or E2 in T-47D breast cancer cells conferred acute anti-estrogen resistance, suggesting that overexpression of cyclin E contributes to the anti-estrogen resistance of tamoxifen-resistant cells. Proliferation of tamoxifen-resistant cells was inhibited by RNAi-mediated knockdown of cyclin E1, cyclin E2, or CDK2. In addition, ectopic expression of cyclins E1 or E2 also reduced sensitivity to CDK4, but not CDK2, inhibition of CDK2 in E-cyclin-overexpressing and tamoxifen-resistant cells restored sensitivity to tamoxifen or CDK4 inhibition.

[0103] These data indicate that overexpression of cyclin E2 is a potential mechanism of resistance to both endocrine therapy and CDK4 inhibition, and that CDK2 inhibitors can overcome such resistance and may be beneficial as components of combination therapy for endocrine-resistant disease, as they effectively inhibit cyclin E1 and E2 overexpressing cells and enhance the efficacy of other therapeutic agents. Similarly, subject compounds with potent inhibitory activity against both CDK2 and CDK4 are expected to be effective against cancer cells that are both non-resistant and resistant to endocrine therapy or CDK4 inhibition.

[0104] Thus, in certain embodiments, compounds of the invention may have potent inhibitory effects on both CDK2 and CDK4 (e.g., independently, <10 nM, <5 nM, IC at <1nM level 50 value), and is therefore effective in treating tamoxifen-resistant or metastatic breast cancer, such as tamoxifen-resistant or metastatic breast cancer with CycE overexpression.

[0105] IC of the compounds of the present invention against CDK2 / 4 / 6 50 The values ​​can be measured, for example, using the methods described in Examples 1-3, which are incorporated herein by reference.

[0106] In particular, the compounds of the present invention are useful in the treatment of cancer. In other embodiments, the compounds of the present invention are useful in the treatment of chronic inflammatory diseases, such as arthritis and cystic fibrosis.

[0107] Thus, in one aspect, the invention provides a method of treating cancer, particularly the cancers described herein, in a mammal, which method comprises administering to a mammal in need of such treatment an effective amount of a compound of the invention.

[0108] In a related aspect, the invention relates to the use of a compound of the invention in the manufacture of a medicament for the treatment of cancer, particularly the cancers described herein.

[0109] In another related aspect, the compounds of the invention can be used in the manufacture of a medicament for the treatment of cancer, particularly the cancers described herein.

[0110] In another related aspect, the invention provides a compound of the invention for use in the treatment of cancer, particularly the cancers described herein.

[0111] According to any of the above related aspects of the present invention, CDK4 and CDK6 can regulate their effects on cell cycle in part through pRb phosphorylation.Therefore, certain compounds of the present invention can inhibit pRb phosphorylation by inhibiting CDK4 / 6 activity, and thus inhibit cell proliferation and / or tumor proliferation, in any cancer type in which cells are proliferating and contain a functional and intact Rb1 gene encoding pRb.

[0112] Thus, in certain embodiments, the compounds of the present invention inhibit pRb in mammals. + The compounds of the present invention are also useful in the treatment of cancers such as colorectal cancer, breast cancer, lung cancer, prostate cancer, chronic myeloid leukemia, acute myeloid leukemia (Fry et al., Mol. Cancer Ther. 3(11):1427, 2004), mantle cell lymphoma (Marzec et al., Blood 108(5):1744, 2006), ovarian cancer (Kim et al., Cancer Research 54:605, 1994), pancreatic cancer (Schutte et al., Cancer Research 57:3126, 1997), malignant melanoma and metastatic malignant melanoma (Maelandsmo et al., British Journal of Cancer 73:909, 1996). The compounds of the present invention are also useful in the treatment of rhabdomyosarcoma (Saab et al., J. Med. 1999, 1999) in mammals (e.g., humans). al., Mol. Cancer. Ther. 5(5):1299, 2006), and multiple myeloma, including relapsed and refractory multiple myeloma (Baughn et al., Cancer Res. 66(15):7661, 2006).

[0113] On the other hand, Zhang et al. (Nature dx.doi.org / 10.1038 / nature25015, 2017) reported that inhibiting CDK4 / 6 in vivo reduced phosphorylation and thus (APC / C Cdh1 By Cullin 3 SPOP We reported that the degradation of E3 ligases can be increased, which leads to elevated PD-L1 levels on the tumor cell surface and reduced numbers of tumor-infiltrating lymphocytes (TILs) in mouse tumors and primary human prostate cancer specimens. In other words, in vivo inhibition of CDK4 / 6 increases PD-L1 protein levels and contributes to increased resistance to immune checkpoint therapy targeting PD-1 (programmed cell death protein 1) and PD-L1 (the ligand for PD-1). Meanwhile, combining CDK4 / 6 inhibitor treatment with anti-PD-1 immunotherapy promotes tumor regression and dramatically improves overall survival in mouse tumor models.

[0114] Thus, in certain embodiments, compounds of the invention may be used in combination with PD-1 / PD-L1 immune checkpoint inhibitors to enhance the treatment of human cancers.

[0115] PD-1 and PD-L1 inhibitors that can be used with the compounds of the present invention are known in the art. PD-1 inhibitors include monoclonal antibodies specific to PD-1 or antigen-binding fragments thereof. Exemplary PD-1 inhibitors include pembrolizumab (Keytruda), nivolumab (Opdivo), and cemiplimab (Libtayo). PD-L1 inhibitors include monoclonal antibodies specific to PD-L1 or antigen-binding fragments thereof. Exemplary PD-L1 inhibitors include atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi).

[0116] Additional immune checkpoint inhibitors that may be used together with the compounds of the present invention to enhance the therapeutic effect of human cancers include monoclonal antibodies or antigen-binding fragments thereof specific for CTLA-4, such as ipilimumab (Yervoy).

[0117] Additional immune checkpoint inhibitors that may be used in conjunction with the compounds of the present invention to enhance the therapeutic efficacy of human cancers include bispecific monoclonal antibodies or antigen-binding fragments thereof specific for PD-1 and PD-L1, or combinations of monoclonal antibodies or antigen-binding fragments thereof specific for PD-1 and PD-L1, or PD-1 and CTLA-4, etc.

[0118] In certain embodiments, the compounds of the present invention can be used in combination with Tyr kinase inhibitors, such as receptor Tyr kinase (RTK) inhibitors, to enhance the therapeutic effect of human cancer. Exemplary Tyr kinase inhibitors include ALK inhibitors (crizotinib, ceritinib, alectinib, brigatinib, etc.), Bcr-Abl inhibitors (bosutinib, dasatinib, imatinib, nilotinib, ponatinib, etc.), BTK inhibitors (ibrutinib, etc.), c-Met inhibitors (crizotinib, cabozantinib, etc.), EGFR inhibitors (gefitinib, erlotinib, lapatinib, vandetanib, afatinib, osimertinib, etc.), JAK inhibitors (ruxolitinib, tofacitinib, etc.), MEK inhibitors (ruxolitinib, tofacitinib, etc.), and ALK inhibitors (crizotinib, ceritinib, alectinib, brigatinib, etc.). These include 1 / 2 inhibitors (trametinib, etc.), PDGFR inhibitors (axitinib, gefitinib, imatinib, lenvatinib, nintedanib, pazopanib, regorafenib, sorafenib, sunitinib, etc.), RET inhibitors (vandetanib, etc.), Src family kinase inhibitors (bosutinib, dasatinib, ponatinib, vandetanib, etc.), and VEGFR family inhibitors (axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, sunitinib, etc.).

[0119] Additional suitable kinase inhibitors that can be used in combination with the subject compounds, as well as treatable cancer indications, are described in Bhullar et al., Molecular Cancer 17:48, 2018, incorporated herein by reference in its entirety.

[0120] Further additional RTK inhibitors include monoclonal antibodies and antigen-binding fragments thereof, including anti-EGFR mAbs such as cetuximab (e.g., effective in treating lung cancer, colorectal cancer, and head and neck cancer), and anti-HER2 mAbs such as trastuzumab (e.g., effective in treating breast cancer).

[0121] In certain embodiments, the compounds of the invention can be used in combination with antagonists of hormone receptor signaling, such as those previously described for the treatment of breast cancer.

[0122] Cancers that may be treated with the compounds of the invention include: non-Hodgkin's lymphoma; malignant mesothelioma; non-small cell lung cancer; cholangiocarcinoma; soft tissue sarcoma; glioblastoma; (recurrent) brain tumors; brain metastases secondary to hormone receptor positive breast cancer, non-small cell lung cancer, and melanoma (including melanoma with positive cyclin D1 expression); (recurrent or persistent) endometrial cancer; (recurrent or metastatic) head and neck squamous cell carcinoma (HNSCC); hepatocellular carcinoma; esophageal squamous cell carcinoma (SCC); esophageal adenocarcinoma (ADC); renal cell carcinoma, and urothelial carcinoma.

[0123] In certain embodiments, treatable cancers include: cancer of the bladder, breast, colon, kidney, epidermis, liver, lung (including SCLC and NSCLC), esophagus, gallbladder, ovary, pancreas, stomach, cervical, thyroid, nose, head and neck, prostate, or skin; hematopoietic tumors of the lymphoid system; hematopoietic tumors of the myeloid system; follicular thyroid cancer; tumors of mesenchymal origin; tumors of the central or peripheral nervous system; melanoma; familial melanoma; seminoma; teratocarcinoma; osteosarcoma; xeroderma pigmentosum; keratoma; follicular thyroid cancer; Kaposi's sarcoma, squamous cell carcinoma, sarcoma; or tumors of mesenchymal origin.

[0124] In certain embodiments, the hematopoietic tumor of the lymphatic system is leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, multiple myeloma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, or Burkitt's lymphoma.

[0125] In certain embodiments, the tumor of the central or peripheral nervous system is an astrocytoma, neuroblastoma, glioma, or schwannoma.

[0126] In certain embodiments, the cancer is small cell lung cancer, non-small cell lung cancer, pancreatic cancer, breast cancer, glioblastoma multiforme, T-cell ALL, and mantle cell lymphoma.

[0127] In certain embodiments, the cancer is selected from the group consisting of colorectal cancer, mantle cell lymphoma, breast cancer (including advanced or metastatic or recurrent breast cancer), pancreatic cancer, ovarian cancer, glioblastoma, acute myeloid leukemia, and lung cancer, particularly NSCLC.

[0128] In certain embodiments, the cancer is NSCLC, pancreatic cancer, ovarian cancer or metastatic breast cancer, and the treatment comprises administering to a mammal in need thereof a therapeutically effective combination of a compound of the present invention and gemcitabine hydrochloride HCl.

[0129] In certain embodiments, the cancer is NSCLC, pancreatic cancer, ovarian cancer or metastatic breast cancer, and the medicament comprising the compound of the present invention also comprises gemcitabine HCl or is administered simultaneously, separately or sequentially with gemcitabine HCl.

[0130] In certain embodiments, the compound of the present invention can be used in combination with other drugs for the treatment of NSCLC, pancreatic cancer, ovarian cancer and metastatic breast cancer.For example, the compound of the present invention can be used in simultaneous, separate or sequential combination with gemcitabine HCl in the treatment of NSCLC, pancreatic cancer, ovarian cancer or metastatic breast cancer.

[0131] In certain embodiments, the cancer is selected from the group consisting of colorectal cancer, glioblastoma, acute myeloid leukemia, and lung cancer.

[0132] In certain embodiments, the cancer is glioblastoma or astrocytoma and the treatment utilizes a therapeutically effective combination of a compound of the invention and temozolomide. The compound of the invention can be administered simultaneously, separately, or sequentially with temozolomide.

[0133] Breast Cancer Treatment In certain embodiments, the compounds of the present invention may be used to treat breast cancer.

[0134] Breast cancer represents a significant health burden worldwide, accounting for approximately 7% of all cancer-related deaths in the United States in 2016. Approximately 75% of all breast cancers are hormone receptor positive (HR + ) have been diagnosed with breast cancer that expresses estrogen receptors (ER) and / or progesterone receptors (PgR) and typically depends on the ER signaling pathway for growth and survival. + Breast cancer exploits the biological functions of the ER pathway to promote breast cancer growth, development, and progression. + Because breast cancers are dependent on ER signaling, such cancers are therapeutic targets for endocrine therapy agents that target the estrogen signaling pathway, such as aromatase inhibitors (AIs; including letrozole, anastrozole, and exemestane), selective ER modulators (tamoxifen), and selective ER downregulators (fulvestrant).

[0135] Endocrine therapy is HR +Although constituting the therapeutic backbone of breast cancer, the efficacy of endocrine therapy is limited by a high rate of both pre-existing de novo resistance and resistance acquired during treatment due to the presence of alternative survival or "escape" pathways. The ER pathway, and many of the known escape pathways, act through cyclin D-CDK4 / 6-inhibitors of the CDK4 (INK4)-retinoblastoma (Rb) pathway to promote tumor growth. Therefore, combined targeting of both the ER pathway and the cyclin D-CDK4 / 6-INK4-Rb pathway typically results in a more widespread inhibition of tumor growth and prevents the activation of escape pathways, thus preventing the development of endocrine therapy resistance. See Sammons et al., Current Cancer Drug Targets 17:637-649,2017.

[0136] Thus, in certain embodiments, the breast cancer is pRb+ breast cancer. In certain embodiments, the breast cancer is hormone receptor (HR) positive (e.g., estrogen receptor positive (ER) breast cancer). + ), progesterone receptor positive (PR + ), or ER + PR + ), HR + HER2 - or ER + HER2 - In certain embodiments, the cancer is a HER2 / neu negative cancer, including advanced or metastatic or recurrent breast cancer. + HER2 - or ER + HER2 - Advanced, metastatic or recurrent breast cancer occurs in adult women, or in postmenopausal women.

[0137] In certain embodiments, the compounds of the invention are used alone or in combination with aromatase inhibitors (which inhibit estrogen production) to treat HR positive, HER2 negative advanced or metastatic or recurrent breast cancer. In certain embodiments, the aromatase inhibitors temporarily inactivate aromatase (such as anastrozole (ARIMIDEX®) and letrozole (FEMARA®)). In certain embodiments, the aromatase inhibitors permanently inactivate aromatase (such as exemestane (AROMASIN®)).

[0138] In certain embodiments, the compounds of the invention are used with compounds that interfere with the ability of estrogen to stimulate the proliferation of breast cancer cells, such as selective estrogen receptor modulators (SERMs) that bind to the estrogen receptor and prevent estrogen binding, such as tamoxifen (NOLVADEX®) and toremifene (FARESTON®). Tamoxifen inhibits HR + It has been used to treat breast cancer for over 30 years.

[0139] In certain embodiments, the compounds of the invention are used in conjunction with a pure anti-estrogen that has no estrogen agonist activity, such as fulvestrant (FASLODEX®).

[0140] In certain embodiments, the HR positive, HER2 negative, advanced or metastatic or recurrent breast cancer is present in a postmenopausal woman. In certain embodiments, the HR positive, HER2 negative, advanced or metastatic or recurrent breast cancer progresses after undergoing treatment that alters the patient's hormones (e.g., estrogen and / or progesterone) or worsens after treatment with another hormone therapy.

[0141] In certain embodiments, the compounds of the present invention are used in patients who are undergoing or have been ovariectomized, hi certain embodiments, the ovariectomy is by oophorectomy or radiation therapy.

[0142] In certain embodiments, the compounds of the invention are used in conjunction with compounds that temporarily suppress ovarian function (e.g., estrogen and / or progesterone production). Such compounds include gonadotropin-releasing hormone (GnRH) or luteinizing hormone-releasing hormone (LH-RH) agonists, including goserelin (ZOLADEX®) and leuprolide (LUPRON®).

[0143] In certain embodiments, the compounds of the invention are compounds that inhibit CYP3A4, such as ritonavir, indinavir, nelfinavir, saquinavir, clarithromycin, telithromycin, chloramphenicol, ketoconazole, itraconazole, posaconazole, voriconazole, nefazodone, cobicistat, amiodarone, aprepitant, verapamil, diltiazem, erythromycin, fluconazole, miconazole, bergamottin, cimetidine, ciprofloxacin, cyclosporine, donedarone. , fluvoxamine, imatinib, valerian, buprenorphine, cafestol, cilostazol, fosaprepitant, gabapentin, lomitapide, orphenadrine, ranitidine, ranolazine, tacrolimus, ticagrelor, valproic acid, amlodipine, cannabidiol, dithiocarbamate, mifepristone, norfloxacin, delavirdine, gestodene, mibefradil, star fruit, milk thistle, niacinamide, ginkgo biloba, piperine, isoniazid, and quercetin.

[0144] In certain embodiments, the compounds of the invention are used in conjunction with inhibitors of IGF-1 / IGF-2, such as monoclonal antibodies against IGF-1 / IGF-2 or antigen-binding fragments thereof. An exemplary antibody is xentuzumab, a humanized IgG1 mAb.

[0145] In certain embodiments, the compounds of the present invention are used together with compounds that inhibit PI3K.Inhibition of PI3K is believed to reduce the level of cyclin D1 and other G1-S cyclins, abolish pRb phosphorylation, and inhibit the activation of S-phase transcription program.The representative PI3K inhibitors for use together with the compounds of the present invention include idelalisib, copanlisib, duvelisib, taselisib, perifosine, buparlisib, alpelisib, umbralisib, copanlisib, dactolisib, and voxtalisib.

[0146] In certain embodiments, the mammal being treated is a human, such as an adult female with breast cancer (e.g., a postmenopausal female or an adult female with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, advanced, metastatic or recurrent breast cancer that has progressed after undergoing treatment to alter the patient's hormones).

[0147] Moreover, certain compounds of the present invention exhibit the advantageous property that they can cross the blood-brain barrier. Thus, such compounds can penetrate the brain and are therefore useful for the treatment of primary and metastatic brain tumors whose cells are proliferating and contain a functional and intact Rb1 gene. + Examples of brain tumors include glioblastoma, as well as medulloblastoma and astrocytoma (Lee et al., Science 235:1394, 1987).

[0148] Temozolomide is a cytotoxic DNA alkylating agent used to treat brain tumors, including glioblastomas and astrocytomas (Friedman et al., Clin. Cancer Res. 6(7):2585-2597, 2000), including brain metastases from melanoma, breast cancer, and NSCLC (Siena et al., Annals of Oncology, doi:10.1093 / annonc / mdp343, 2009). Temozolomide interacts with DNA, causing chemical modification / damage (Marchesi et al., Pharmacol. Res. 56(4):275-287, 2007). Thus, in some embodiments, the compounds of the present invention inhibit primary and metastatic pRb tumors, such as glioblastomas and astrocytomas. + For the treatment of brain tumors, for example, where such metastases are from melanoma, breast cancer, or NSCLC, it can be used in combination with temozolomide.

[0149] 5. Pharmaceutical Compositions The present invention provides pharmaceutical compositions comprising any one of the compounds described herein, or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable carriers or excipients.

[0150] "Pharmaceutically acceptable excipient" and "Pharmaceutically acceptable carrier" refer to a substance that aids in the formulation and / or administration of an active agent to a subject and / or absorption by the subject, and means a substance that can be included in the composition of the present disclosure without causing harmful toxicological effects to the subject. Non-limiting examples of pharmaceutically acceptable carriers and excipients include water, NaCl, saline, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coating agents, sweeteners, flavoring agents, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and coloring agents. Such preparations can be sterilized and, if necessary, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring agents, and / or fragrances that do not adversely react with the compounds provided herein or interfere with their activity. Those skilled in the art will recognize that other pharmaceutical carriers and excipients are suitable for use with the disclosed compounds.

[0151] These compositions optionally further comprise one or more additional therapeutic agents. Alternatively, the compounds of the present invention can be administered to a patient in need thereof in combination with the administration of one or more other therapeutic regimens (e.g., Gleevec or other kinase inhibitors, interferon, bone marrow transplantation, farnesyltransferase inhibitors, bisphosphonates, thalidomide, cancer vaccines, hormone therapy, antibodies, radiation, etc.). For example, the additional therapeutic agent for combination with or inclusion in the pharmaceutical composition comprising the compounds of the present invention can be another one or more anti-cancer agents.

[0152] As described herein, the composition of the present invention, as used herein, comprises the compound of the present invention together with a pharma- ceutically acceptable carrier, including any and all solvents, diluents, or other vehicles, dispersing or suspending aids, surfactants, isotonicity agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, and the like, suitable for the particular dosage form desired. Remington's Pharmaceutical Sciences, Fifteenth Edition, EW Martin (Mack Publishing Co., Easton, Pa., 1975) discloses various carriers used in the formulation of pharmaceutical compositions and known techniques for their preparation. Except where any conventional carrier medium is incompatible with the compound of the present invention, for example, by producing undesirable biological effects or otherwise interacting in a deleterious manner with any other component of the pharmaceutical composition, its use is contemplated within the scope of the present invention. Some examples of materials that can serve as pharma- ceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives (e.g., sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate); powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffers, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening agents, flavoring and perfuming agents, preservatives, and antioxidants may also be present in the composition.

[0153] 6. Preparation The present invention also encompasses a class of compositions comprising the active compounds of the present invention in association with one or more pharma- ceutically acceptable carriers and / or diluents and / or adjuvants (collectively referred to herein as "carrier" materials), and optionally other active ingredients.

[0154] In certain embodiments, the present invention provides a pharmaceutical formulation for treating cancer, particularly the cancers described herein, comprising a compound of the present invention or a pharma- ceutically acceptable salt thereof, together with a pharma- ceutically acceptable carrier.

[0155] In certain embodiments, the present invention provides a method for the treatment of colorectal cancer, mantle cell lymphoma, breast cancer (ER in adult or postmenopausal women) comprising administering to the patient a compound of the present invention or a pharma- ceutical acceptable salt thereof, together with a pharma- ceutical acceptable carrier. + HER2 - The present invention provides a pharmaceutical formulation for treating cancer selected from the group consisting of advanced or metastatic or recurrent breast cancer, glioblastoma, acute myeloid leukemia and lung cancer, in particular NSCLC.

[0156] In certain embodiments, the present invention provides a pharmaceutical formulation for treating glioblastoma or astrocytoma comprising a compound of the present invention and temozolomide, together with a pharma- ceutically acceptable carrier.

[0157] In certain embodiments, the present invention also provides a pharmaceutical formulation comprising a compound of the present invention, or a pharma- ceutically acceptable salt thereof, and temozolomide, together with a pharma- ceutically acceptable carrier, diluent, or excipient.

[0158] In a specific embodiment, the present invention provides a method for the treatment of NSCLC, pancreatic cancer, ovarian cancer or metastatic breast cancer (including ER in adult or postmenopausal women) comprising administering the present invention and gemcitabine HCl together with a pharmacologic acceptable carrier. + HER2 - The present invention provides a pharmaceutical formulation for treating breast cancer (including advanced, metastatic or recurrent breast cancer).

[0159] In certain embodiments, the present invention also provides a pharmaceutical formulation comprising a compound of the present invention, or a pharma- ceutically acceptable salt thereof, and gemcitabine HCl, together with a pharma- ceutically acceptable carrier, diluent, or excipient.

[0160] The active compounds of the present invention are preferably administered by any suitable route in the form of a pharmaceutical composition adapted to such route, in a dosage effective for the intended treatment.The compounds and compositions of the present invention can be administered, for example, orally, mucosally, topically, rectally, pulmonary, such as by inhalation spray, or parenterally (including intravascular, intravenous, intraperitoneal, subcutaneous, intramuscular, intrasternal and infusion techniques) in dosage unit formulations containing conventional pharmaceutically acceptable carriers, adjuvants, and vehicles.

[0161] The pharma- ceutical active compounds of this invention can be processed in accordance with conventional methods of pharmacy to produce medicinal agents for administration to patients, including humans and other mammals.

[0162] For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient.

[0163] Examples of such dosage units are tablets or capsules. For example, a suitable daily dose for a human or other mammal may vary depending on the condition of the patient and other factors, but, again, can be determined using routine methods.

[0164] The amount and dosage schedule of the compound administered to treat medical conditions with the compound and / or composition of the present invention depends on various factors, including the age, weight, sex and medical condition of the subject, the type of disease, the severity of the disease, the route and frequency of administration, and the specific compound used.Thus, the dosage schedule can vary widely, but can be routinely determined by a physician using standard methods.As mentioned above, the daily dose can be administered in one dose or divided into two, three, four or more doses.

[0165] For therapeutic purposes, the active compound of the present invention is usually combined with one or more adjuvants, excipients or carriers suitable for the indicated administration route.When administered orally, the compound can be mixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acid, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphate and sulfate, gelatin, gum acacia, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol, and then tableted or encapsulated for convenient administration.Such capsules or tablets can contain sustained release formulations, such as can be provided with a dispersion of the active compound in hydroxypropylmethylcellulose.

[0166] For skin conditions, it may be preferable to apply a topical preparation of the compounds of the invention to the affected area two to four times a day. Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration into the skin (e.g., liniments, lotions, ointments, creams, or pastes) and drops suitable for administration to the eye, ear, or nose. For topical administration, the active ingredient may comprise 0.001% to 10% w / w, for example 1% to 2% by weight of the formulation, and may comprise 10% w / w, but is preferably 5% w / w or less, more preferably 0.1% to 1%.

[0167] The compounds of the present invention can also be administered by transdermal devices.Preferably, transdermal administration is accomplished using a patch, either of the reservoir and porous membrane type or of the solid matrix type.In either case, the active agent is continuously delivered from the reservoir or microcapsules through the membrane to the active agent permeable adhesive in contact with the skin or mucosa of the recipient.When the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the recipient.In the case of microcapsules, the encapsulating agent can also function as the membrane.The oil phase of the emulsion of the present invention can be composed of known ingredients in a known manner.

[0168] The phase may comprise only emulsifiers, but may also comprise a mixture of at least one emulsifier with fat or oil, or with both fat and oil.Preferably, a hydrophilic emulsifier is comprised together with a lipophilic emulsifier that acts as a stabilizer.It is also preferred to comprise both oil and fat.Together, the emulsifiers, with or without stabilizers, constitute the so-called emulsifying wax, which, together with oil and fat, constitute the so-called emulsifying ointment base that forms the oily dispersed phase of cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulations of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryl distearate alone or with wax, or other materials well known in the art.

[0169] The solubility of active compounds in most oils likely to be used in pharmaceutical emulsion formulations is very low, so the selection of suitable oils or fats for the formulation is based on achieving the desired appearance properties. Thus, the cream should preferably be a non-greasy, non-staining, washable product with a suitable consistency to avoid leakage from tubes or other containers. Linear or branched, mono- or dibasic alkyl esters, such as diisoadipate, isocetyl stearate, propylene glycol diesters of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate, or blends of branched esters may be used. These may also be used alone or in combination, depending on the properties required.

[0170] Alternatively, high melting point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils can be used.

[0171] Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient.

[0172] The active ingredient is preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% and especially about 1.5% w / w.

[0173] Preparations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions can be prepared from sterile powders or granules by using one or more of the carriers or diluents mentioned for use in preparations for oral administration, or by using other suitable dispersing or wetting agents and suspending agents. These compounds can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, tragacanth gum, and / or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical field. The active ingredient can also be administered by injection as a composition with suitable carriers including saline, dextrose, or water, or with cyclodextrin (i.e., Captisol), cosolvent solubilization (i.e., propylene glycol) or micelle solubilization (i.e., Tween 80).

[0174] Sterile injectable preparations may also be as sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example, solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland, fixed oil may be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0175] For pulmonary administration, the pharmaceutical composition can be administered in the form of an aerosol or using an inhaler that contains a dry powder aerosol.

[0176] Suppositories for rectal administration of drugs can be prepared by mixing the drug with a suitable non-irritating excipient such as cocoa butter and polyethylene glycol, which are solid at normal temperature but liquid at rectal temperature and therefore melt in the rectum to release the drug.

[0177] The pharmaceutical composition may be subjected to conventional pharmaceutical processes such as sterilization, and / or may contain conventional adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, buffers, etc. Tablets and pills may be further prepared with enteric coating. Such compositions may also contain auxiliary agents such as wetting agents, sweeteners, flavoring agents, and aromatic agents. The pharmaceutical composition of the present invention comprises a compound of the formula described herein or a pharma- ceutically acceptable salt thereof; an additional agent selected from a kinase inhibitor (such as a small molecule, polypeptide, antibody), an immunosuppressant, an anti-cancer agent, an anti-viral agent, an anti-inflammatory agent, an anti-fungal agent, an antibiotic, or an anti-vascular hyperproliferation compound; and any pharma- ceutically acceptable carrier, adjuvant, or vehicle.

[0178] Alternative compositions of the invention include a compound of the formula described herein or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier, adjuvant, or vehicle. Such compositions may optionally include one or more additional therapeutic agents, including, for example, kinase inhibitors (small molecules, polypeptides, antibodies, etc.), immunosuppressants, anti-cancer agents, anti-viral agents, anti-inflammatory agents, anti-fungal agents, antibiotics, or anti-vascular hyperproliferation compounds.

[0179] The term "pharmaceutically acceptable carrier or adjuvant" refers to a carrier or adjuvant that may be administered to a patient, together with a compound of the invention, which does not destroy its pharmacological activity and which is non-toxic when administered in a dosage sufficient to deliver a therapeutic amount of the compound. Pharmaceutically acceptable carriers, adjuvants, or vehicles that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as D-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms, such as Tween or other similar polymeric delivery matrices, serum albumin such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat. Cyclodextrins, such as u-, P-, and y-cyclodextrin, or chemically modified derivatives, such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-cyclodextrin, or other solubilizing derivatives, may also be advantageously used to enhance delivery of the compounds of the formulae described herein.

[0180] The pharmaceutical composition can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions.For oral tablets, commonly used carriers include lactose and corn starch.Lubricants such as magnesium stearate are also typically added.For oral administration in capsule form, useful diluents include lactose and dried corn starch.When aqueous suspensions and / or emulsions are orally administered, the active ingredient can be suspended or dissolved in an oily phase and combined with emulsifying and / or suspending agents.

[0181] If desired, certain sweetening, flavoring and / or coloring agents can be added.The pharmaceutical compositions may include formulations utilizing liposome or microencapsulation technology, various examples of which are known in the art.

[0182] Pharmaceutical compositions may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents, examples of which are well known in the art.

[0183] 7. Medical Kit One aspect of the present invention relates to a kit for conveniently and effectively carrying out the method or use according to the present invention. In general, a pharmaceutical pack or kit comprises one or more containers filled with one or more components of the pharmaceutical composition of the present invention. Such kits are particularly suitable for delivery of solid oral dosage forms such as tablets or capsules. Such kits preferably comprise several unit doses and may also comprise a card with the doses oriented in the order of their intended use. Optionally, a memory aid may be provided, for example in the form of numbers, letters, or other markings, or with a calendar insert designating the days of the treatment schedule on which the doses may be administered. Such containers may optionally be accompanied by a notice in a format prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, which reflects the approval by said agency of the manufacture, use, or sale for administration to humans.

[0184] The following representative examples contain important additional information, examples and guidance that can be adapted to the practice of the present invention in various embodiments and equivalents thereof. The following examples are intended to help illustrate the present invention, and are not intended to, and should not be interpreted as, limiting the scope of the present invention. Indeed, various modifications of the present invention, and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art upon review of this document, including the following examples and references to the scientific and patent literature cited herein.

[0185] The contents of the cited references are incorporated herein by reference to help describe the state of the art.

[0186] Further, for purposes of the present invention, chemical elements are defined as defined in the CAS edition, Handbook of Chemistry and Physics, vol. 75 thEd., inside cover. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "Organic Chemistry," Morrison & Boyd (3d Ed), the contents of both of which are incorporated herein by reference in their entireties.

[0187] 8.Synthetic Scheme Compounds of formula I can be prepared by those skilled in the art according to art-recognized techniques and procedures.More specifically, compounds of formula I can be prepared as described in the schemes, methods, and examples described below.It will be recognized by those skilled in the art that the individual steps of the following schemes can be modified to provide compounds of formula I.Reagents and starting materials are readily available to those skilled in the art.Unless otherwise specified, all substituents are as previously defined. EXAMPLES

[0188] Biological Example 1. CDK4 / Cyclin D1 Inhibition Assay I C 50The CDK4 enzyme assay for determination was carried out as follows. Microfluidic kinase detection technology (Caliper) was used to monitor the phosphorylation of peptide substrates by CDK4 / cyclin D1. The total reaction volume was 15 μL containing Buffer A (100 mM HEPES (pH 7.5), 0.1% BSA, 0.01% Triton X-100, 1 mM DTT, 10 mM MgCl2, 10 μM sodium orthovanadate, 10 μM beta-glycerophosphate), 200 μM ATP, 1 nM CDK4 / cyclin D1 (Thermofisher, PR8064A), 1 μM FL-34 (5-FAM-RRRFRPASPLRGPPK), and test compounds appropriately diluted in DMSO. All components were added to a 384-well plate (Corning, 4514) and incubated at room temperature for 3 h. The reaction was stopped by the addition of 15 μL of stop buffer (180 mM HEPES (pH 7.5), 20 mM EDTA, Coating-3 reagent (PerkinElmer, 760050)). The plate was then loaded onto a Caliper EZ Reader (EZ Reader II, PerkinElmer, HD-4HYSG2772) and the reaction mixture containing the substrate and product was introduced into the microfluidic chip for separation and detection. The IC of the test compounds was 50 Values ​​were determined by fitting inhibition curves with a four-parameter sigmoidal dose-response model using Xlfit5 / GraphPad Prism5 software.

[0189] Biological Example 2. Assay for inhibition of CDK6 / Cyclin D3 I C 50The CDK6 enzyme assay for determination was carried out as follows. Microfluidic kinase detection technology (Caliper) was used to monitor the phosphorylation of peptide substrates by CDK6 / cyclin D3. The total reaction volume was 15 μL containing Buffer A (100 mM HEPES (pH 7.5), 0.1% BSA, 0.01% Triton X-100, 1 mM DTT, 10 mM MgCl2, 10 μM sodium orthovanadate, 10 μM beta-glycerophosphate), 300 μM ATP, 2 nM CDK6 / cyclin D3 (Carna, 04-107), 1 μM FL-34 (5-FAM-RRRFRPASPLRGPPK), and test compounds appropriately diluted in DMSO. All components were added to a 384-well plate (Corning, 4514) and incubated at room temperature for 3 h. The reaction was stopped by the addition of 15 μL of stop buffer (180 mM HEPES (pH 7.5), 20 mM EDTA, Coating-3 reagent (PerkinElmer, 760050)). The plate was then loaded onto a Caliper EZ Reader (EZ Reader II, PerkinElmer, HD-4HYSG2772) and the reaction mixture containing the substrate and product was introduced into the microfluidic chip for separation and detection. The IC of the test compounds was 50 Values ​​were determined by fitting inhibition curves with a four-parameter sigmoidal dose-response model using Xlfit5 / GraphPad Prism5 software.

[0190] Biological Example 3. CDK2 / Cyclin E1 Inhibition Assay I C 50The CDK2 enzyme assay for determination was carried out as follows. Microfluidic kinase detection technology (Caliper) was used to monitor the phosphorylation of peptide substrates by CDK2 / cyclin E1. The total reaction volume was 15 μL containing Buffer A (100 mM HEPES (pH 7.5), 0.1% BSA, 0.01% Triton X-100, 1 mM DTT, 10 mM MgCl2, 10 μM sodium orthovanadate, 10 μM beta-glycerophosphate), 100 μM ATP, 5 nM CDK2 / cyclin E1 (SignalChem, C29-18G), 5 μM FL-18 (5-FAM-QSPKKG-NH2), and test compounds appropriately diluted in DMSO. All components were added to a 384-well plate (Corning, 4514) and incubated at room temperature for 3 h. The reaction was stopped by the addition of 15 μL of stop buffer (180 mM HEPES (pH 7.5), 20 mM EDTA, Coating-3 reagent (PerkinElmer, 760050)). The plate was loaded into a Caliper EZ Reader (EZ Reader II, PerkinElmer, HD-4HYSG2772) and the reaction mixture containing the substrate and product was introduced into the microfluidic chip for separation and detection. The IC of the test compounds was 50 Values ​​were determined by fitting inhibition curves with a four-parameter sigmoidal dose-response model using Xlfit5 / GraphPad Prism5 software.

[0191] IC of each example compound against CDK2, CDK4, and CDK6 50 Values ​​are provided in the synthesis examples below. IC 50 Values ​​are designated as "A," "B," "C," and "D" for values ​​below 10 nM, below 100 nM, below 1 μM, and above 1 μM, respectively.

[0192] Biological Example 4. Antiproliferative Assay in T47D Cells T47D is a human breast cancer cell line commonly used in biomedical research involving hormone expression in cancer cells. T47D cells differ from other human breast cancer cells in that the progesterone receptor (PR) is not regulated by estradiol, a hormone that is abundant within the cells themselves. T47D cells have been used to study the effect of progesterone on breast cancer and the corresponding transcriptional regulation caused by introduced drugs. The cells have been found to be highly resistant to estrogens and antiestrogens.

[0193] T47D breast cancer cells from American Type Culture Collection (ATCC, HTB-133) were seeded at 3000 cells / well in 96-well plates and incubated at 37°C, 5% CO2 in RPMI1640 medium (Gibco, 31800105) containing 10% fetal bovine serum (FBS, Biowest, FB-1058). After overnight incubation, baseline values ​​of samples from one plate were measured using Cyquant reagent (Invitrogen, C35011) according to the manufacturer's recommendations. After incubating cells with detection reagent for 1 h at 37°C, fluorescence was measured using Spectra Max M5 (Molecular Devices, HD-4HYSG3196) with excitation at 485 nm and emission at 535 nm. The other plate was loaded with compounds at 10-point dose concentrations ranging from 10 μM to 0.51 nM in a 3-fold dilution scheme. Cyquant reagent was added 6 days after compound addition, and fluorescence was measured using Spectra MaxM5. IC 50 Values ​​were determined from baseline-subtracted viability readout curves using Xlfit5 / GraphPad Prism5 software.

[0194] Biological Example 5. Inhibition of phosphorylation of retinoblastoma protein (pRb) in T47D cells T47D breast cancer cells from American Type Culture Collection (ATCC, HTB-133) were seeded at 40,000 cells / well in 96-well plates and incubated in RPMI1640 medium (Gibco, 31800105) containing 10% fetal bovine serum (FBS, Biowest, FB-1058). Cells were then allowed to attach overnight at 37°C, 5% CO2. The following day, compounds were titrated in a 3-fold dilution scheme, with the highest compound concentration tested being 10 μM. After 24 h of incubation with compounds, cells were lysed in ice-cold lysis buffer containing phosphatase inhibitor cocktail and 1 mM PMSF. Cell lysates (50 μL / well) were then transferred to ELISA plates (pRb Ser807 / 811 ELISA kit, Cell Signaling, 13152 or pRb Ser780 ELISA kit, Cell Signaling, 13016). The plates were incubated overnight at 4°C with constant slow shaking. After incubation, the plates were washed according to the manufacturer's recommendations, then 100 μL of reconstituted detection antibody was added to each well and incubated at 37°C for 1 hour. After incubation, the plates were washed, then 100 μL of reconstituted HRP-conjugated secondary antibody was added to each well and incubated at 37°C for 30 minutes. After incubation, the plates were washed. Then, 100 μL of TMB substrate was added to each well and incubated at 37°C for 10 minutes or at 25°C for 30 minutes. Finally, 100 μL of STOP solution was added to each well and mixed gently for a few seconds. The plates were read on an Envision plate reader (PerkinElmer, 2104-0010) using the 96-well luminescence mode. IC 50 Values ​​were calculated using a four-parameter sigmoidal dose-response model in Xlfit5 / GraphPad Prism5 software.

[0195] Cellular data from Biological Examples 4 and 5 are listed in Table A below. IC 50Values ​​are indicated as "++++" for values ​​below 100 nM, "+++" for values ​​below 500 nM, "++" for values ​​below 1 μM, and "+" for values ​​above 1 μM, respectively.

[0196] Synthesis Example Equipment Description 1 H NMR spectra were recorded on a Bruker Ascend 400 spectrometer. Chemical shifts are expressed in parts per million (ppm, δ units). Coupling constants are in Hertz (Hz). Splitting patterns indicate apparent multiplicity and are expressed as s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet), br (broad).

[0197] Analytical low resolution mass spectra (MS) were recorded on a Waters ACQUITY UPLC equipped with an SQ Detector using a Waters CORTECS C18+, 2.7 μm 4.6×30 mm, using gradient elution.

[0198] Solvent A: 0.1% formic acid (FA) in water Solvent B: 0.1% FA in acetonitrile 5% ACN to 95% ACN in 1.0 min, hold for 1.0 min; Total time: 2.5 min, flow rate: 1.8 mL / min, column temperature: 40°C.

[0199] Intermediates Intermediate 1 [ka]

[0200] Step 1 To a solution of 4-benzyloxypyridine (185 mg, 998 μmol) in DCM (10 mL) was added amino 2,4,6-trimethylbenzenesulfonate (236 mg, 1.1 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 14 h. The mixture was concentrated under reduced pressure to give the desired crude product (400 mg, 99% yield) as a colorless oil. LC-MS: m / z 202 [M+H] + .

[0201] Step 2 To a solution of 4-benzyloxypyridin-1-ium-1-amine (187 mg, 929 μmol) in DMF (10 mL) was added Cs2CO3 (192 mg, 1.4 mmol) and but-3-yn-2-one (94 mg, 1.4 mmol). The reaction mixture was stirred at 25° C. for 12 h. The reaction mixture was quenched with water (50 mL) and extracted with DCM (2×25 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (eluted with PE / EA=10 / 1) to give the desired product (90 mg, 35% yield) as a yellow solid. LC-MS: m / z 267 [M+H] + .

[0202] Step 3 To a solution of methyl(triphenyl)phosphonium bromide (241 mg, 675 μmol) in THF (10 ml) was added dropwise at −20° C. under N2. The reaction was stirred at −20° C. for 1 h. Then, a solution of 1-(5-benzyloxypyrazolo[1,5-a]pyridin-3-yl)ethanone (90 mg, 338 μmol) in THF (15 ml) was added dropwise at −20° C. The reaction mixture was stirred at 10° C. for 3 h. The reaction mixture was quenched with MeOH (3 ml) and concentrated under reduced pressure. The residue was purified by preparative HPLC (eluted with PE:EA=1 / 1) to give the desired crude product (41.0 mg, 46% yield) as a yellow solid. LC-MS: m / z 265 [M+H] + .

[0203] Step 4 To a solution of 5-benzyloxy-3-isopropenyl-pyrazolo[1,5-a]pyridine (600 mg, 2.3 mmol) in methanol (50 mL) was added Pd / C (60 mg). The reaction mixture was stirred under H2 at 30°C for 48 h. The reaction mixture was filtered and concentrated under reduced pressure to give the desired product (380 mg, 95% yield) as a yellow solid. LC-MS: m / z 177 [M+H] + .

[0204] Step 5 To a solution of 3-isopropylpyrazolo[1,5-a]pyridin-5-ol (650 mg, 3.7 mmol) and DIPEA (410 mg, 4.1 mmol) in DCM (15 mL) was added Tf2O (1.1 g, 4.1 mmol) under N2 at 0°C. The reaction mixture was stirred at 0°C for 2 h. The reaction mixture was washed with brine (15 mL) and dried over Na2SO4. The organic layer was filtered and the filtrate was concentrated to give the desired product (1.1 g, 92% yield) as a colorless oil. LC-MS: m / z 309 [M+H] + .

[0205] Step 6 To a solution of (3-isopropylpyrazolo[1,5-a]pyridin-5-yl)trifluoromethanesulfonate (1.1 g, 3.4 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5)-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.3 g, 5.1 mmol) in dioxane (10 mL) was added Pd(dppf)Cl2 (249 mg, 340 μmol) and KOAc (1.0 g, 10.2 mmol). The reaction mixture was stirred at 110 °C under N2 for 2 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the desired crude product (950 mg, 97% yield) as a dark solid. LC-MS: m / z 287 [M+H] + .

[0206] Step 7 To a solution of 3-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (950 mg, 3.3 mmol) and 2,4-dichloro-5-fluoro-pyrimidine (665 mg, 4.0 mmol) in H2O (1 mL) and 1,4-dioxane (15 mL) was added Na2CO3 (1.2 g, 10.0 mmol) and Pd(dppf)Cl2 (242 mg, 332 μmol). The mixture was stirred at 110 °C under N2 for 6 h. The mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (20 g silica gel column, EA 0-50% in PE / EA) to give the desired product (650 mg, 67% yield) as a yellow solid. LC-MS: m / z 291 [M+H] + .

[0207] Intermediate 2 [ka]

[0208] To a solution of 3-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (3.5 g, 12.2 mmol) and 2,4-dichloropyrimidine (2.7 g, 18.4 mmol) in water (3 mL) and 1,4-dioxane (60 mL) was added Pd(dppf)Cl2 (0.9 g, 1.2 mmol) and Na2CO3 (1.52 g, 14 mmol). The reaction mixture was stirred at 110 °C under N2 for 6 h. The mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (20 g silica gel column, PE with EA 0-50%) to give the desired product (2.1 g, 62% yield) as a yellow solid. LC-MS: m / z 273 [M+H] + .

[0209] Additional intermediates of the present invention were prepared by using the corresponding derivatives. Selected compounds and their corresponding property data are shown in the table below. [Table 1]

[0210] Intermediate 5 [ka]

[0211] To a solution of 3-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (200 mg, 698 μmol) and 2-chloro-5-fluoro-4-iodo-pyridine (269 mg, 1.1 mmol) in HO (1 mL) and 1,4-dioxane (20 mL) was added NaCO (260 mg, 2.1 mmol) and Pd(dppf)Cl (51.1 mg, 69.9 μmol). The reaction mixture was stirred at 110 °C under N for 6 h. The mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (20 g silica gel column, EA 0-50% with PE / EA) to give the desired product (140 mg, 69% yield) as a yellow solid. LC-MS: m / z 290 [M+H] + .

[0212] Intermediate 6 [ka]

[0213] Step 1 To a solution of 5-bromopyrazolo[1,5-a]pyridine (0.9 g, 4.6 mmol) in dry dioxane (40 mL) was added B2Pin2 (1.8 g, 6.9 mmol), Pd(dppf)Cl2 (0.7 g, 0.9 mmol) and potassium acetate (1.4 g, 13.9 mmol). The mixture was stirred at 110 °C for 8 h under nitrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (0-50% petroleum ether / EtOAc) to give the desired product (1.1 g, 75% yield) as a white solid. LC-MS: m / z 245 [M+H] + .

[0214] Step 2 To a solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (1.0 g, 4.0 mmol) in dioxane (45 mL) was added 2,4-dichloro-5-fluoropyrimidine (1.0 g, 6.0 mmol), Pd(dppf)Cl2 (0.6 g, 0.8 mmol) and K2CO3 (1.7 g, 12.0 mmol). Then, 5 mL of H2O was added. The mixture was stirred at 110 °C for 8 h. The mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (0-50% EtOAc in petroleum ether) to give the desired product (0.7 g, 66% yield) as a white solid. LC-MS: m / z 249 [M+H] + .

[0215] Step 3 To a solution of 5-(2-chloro-5-fluoropyrimidin-4-yl)pyrazolo[1,5-a]pyridine (610 mg, 2.5 mmol) in DCM (20 mL) was added NBS (482 mg, 2.7 mmol). The mixture was stirred at 25° C. for 4 h. The mixture was concentrated under reduced pressure and purified by silica gel chromatography (0-50% EtOAc / PE) to give the desired product (680 mg, 84% yield) as a white solid. LC-MS: m / z 327 [M+H] + .

[0216] Intermediate 7 [ka]

[0217] Step 1 To a solution of 5-bromo-3-iodo-pyrazolo[1,5-a]pyridine (1.0 g, 3.1 mmol) and cyclopenten-1-ylboronic acid (0.4 g, 3.4 mmol) in dioxane (20 mL) and water (5 mL), cyclopentyl(diphenyl)phosphane dichloromethane dichloropalladium iron (0.8 g, 0.9 mmol), potassium phosphate tribasic (2.0 g, 9.3 mmol) were added. The reaction mixture was stirred at 100 °C under N2 atmosphere for 5 h. The reaction mixture was extracted with EtOAc (3 x 10 mL). The organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography to give the desired product (0.3 g, 38% yield) as a white solid. LC-MS: m / z 265.1 [M+H] + .

[0218] Step 2 To a solution of 5-bromo-3-(cyclopenten-1-yl)pyrazolo[1,5-a]pyridine (270 mg, 1.0 mmol) in methanol (10 mL) was added PtO2 (46.6 mg, 205.2 μmol). The mixture was stirred under hydrogen atmosphere at 25° C. for 2 h. The mixture was filtered through a Celite pad. The filtrate was concentrated to give the desired product (190 mg, 69% yield) as a white solid, which was used directly in the next step without further purification. LC-MS: m / z 267.1 [M+H] + .

[0219] Step 3 To a stirred solution of 5-bromo-3-cyclopentyl-pyrazolo[1,5-a]pyridine (210 mg, 792 μmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5)-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (301 mg, 1.2 mmol) at 25° C., cyclopentyl(diphenyl)phosphanedichloropalladium iron (57.9 mg, 79.2 μmol) and potassium acetate (233 mg, 2.4 mmol) were added. The reaction mixture was stirred at 110° C. for 2 h. The mixture was filtered and concentrated in vacuo to give the desired product as a black solid, which was used directly in the next step without further purification. LC-MS: m / z 313.1 [M+H] + .

[0220] Step 4 To a mixture of 3-cyclopentyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (210 mg, 672 μmol) and 2,4-dichloro-5-fluoro-pyrimidine (134 mg, 807 μmol) in dioxane (5 mL) and water (1 mL), cyclopentyl(diphenyl)phosphane dichloropalladium iron (49.2 mg, 67.2 μmol), dipotassium carbonate (278 mg, 2.0 mmol) were added. The resulting mixture was stirred at 105° C. under N2 atmosphere for 3 h. The reaction mixture was diluted with water (10 mL) and then extracted with EtOAc (3×10 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography to give the desired product (40 mg, 19% yield) as a white solid. LC-MS: m / z 317.1 [M+H] + .

[0221] Intermediate 8 [ka]

[0222] Step 1 To a solution of 5-bromo-3-iodo-pyrazolo[1,5-a]pyridine (1.0 g, 3.1 mmol) and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (845.7 mg, 4.0 mmol) in anhydrous dioxane (20 mL) was added Pd(dppf)Cl2 (758 mg, 929 μmol), K3PO4 (2.0 g, 9.3 mmol) and water (5 mL) under N2 atmosphere. The reaction mixture was then stirred at 110 °C for 1 h. The mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (80 g silica gel column, petroleum ether / EtOAc 0-30% EtOAc) to give the desired product (508 mg, 59% yield) as a brown solid. LC-MS: m / z 279 [M+H] + .

[0223] Step 2 To a solution of 5-bromo-3-(3,6-dihydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyridine (360 mg, 1.3 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (425 mg, 1.7 mmol) in dioxane (15 mL) was added cyclopentyl(diphenyl)phosphanedichloropalladium iron (188 mg, 257 μmol), potassium acetate (379 mg, 3.8 mmol) under N2 atmosphere. The reaction mixture was then stirred at 110 °C for 8 h. The mixture was filtered and concentrated under reduced pressure to give the desired crude product as a yellow oil, which was used in the next step without further purification. LC-MS: m / z 327 [M+H] + .

[0224] Step 3 To a solution of 3-(3,6-dihydro-2H-pyran-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (430 mg, 1.3 mmol) and 2,4-dichloro-5-fluoro-pyrimidine (242 mg, 1.5 mmol) in dioxane (15 mL) was added cyclopentyl(diphenyl)phosphane dichloropalladium iron (192 mg, 263 μmol), disodium carbonate (419 mg, 3.9 mmol) and water (1 mL) under N2 atmosphere. The reaction mixture was then stirred at 110 °C for 3 h. The mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (40 g silica gel column, petroleum ether / EtOAC 0-30% EtOAC) to give the desired product (360 mg, 82% yield) as an orange solid. LC-MS: m / z 331.1 [M+H] + .

[0225] Intermediate 9 [ka]

[0226] Step 1 To a solution of 5-(2-chloropyrimidin-4-yl)-3-isopropyl-pyrazolo[1,5-a]pyridine (100 mg, 366 μmol) in THF (8 mL) was added TMPMgCl-LiCl (1M, 916 μL) at −78° C. under N2. The reaction was stirred at −78° C. for 0.5 h. NBS (78.3 mg, 439 μmol) was then added. The mixture was warmed to 25° C. and stirred for 1.5 h. The mixture was quenched with aqueous NH4Cl (10 mL) and extracted with EA (2×15 mL). The combined organic phases were concentrated under reduced pressure. The residue was purified by FCC (12 g silica gel, 0-30% EtOAc in PE) to give the desired product (45.0 mg, 34% yield) as a yellow solid. LC-MS: m / z 351.0 [M+H] + .

[0227] Step 2 A solution of 7-bromo-5-(2-chloropyrimidin-4-yl)-3-isopropyl-pyrazolo[1,5-a]pyridine (45.0 mg, 127 μmol), Pd(PPh3)4 (14.7 mg, 12.8 μmol) and Zn(CN)2 (22.5 mg, 191 μmol) in NMP (5 mL) was irradiated in a microwave reactor at 110 °C under N2 for 0.5 h. The mixture was concentrated under reduced pressure. The residue was purified by FCC (4 g silica gel, 0-30% EtOAc in PE) to give the desired product (15.0 mg, 39% yield) as a yellow solid. LC-MS: m / z 298.1 [M+H] + .

[0228] Intermediate 84 [ka]

[0229] Step 1 To a suspension of trichloroarmane (2.7 g, 20.3 mmol) in DCM (10 mL) was added 2-bromo-2-methyl-propane (4.1 g, 30.4 mmol) at 0 °C under N2 atmosphere. The reaction mixture was stirred at 0 °C for 10 min under N2 atmosphere. Then, 5-bromopyrazolo[1,5-a]pyridine (2 g, 10.1 mmol) was added to the reaction mixture. The reaction mixture was stirred at 0 °C for 3 h. The reaction mixture was quenched with ice water (50 mL). The mixture was then extracted with DCM (3 × 50 mL) and the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography to give the desired product 5-bromo-3-tert-butyl-pyrazolo[1,5-a]pyridine (1.2 g, 46% yield) as a yellow oil. LC-MS: m / z 253.1 [M+H] + .

[0230] Step 2 To a solution of 5-bromo-3-tert-butyl-pyrazolo[1,5-a]pyridine (200 mg, 790 μmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (300 mg, 1.2 mmol) in dioxane (8 mL) was added cyclopentyl(diphenyl)phosphanedichloropalladium iron (173 mg, 237 μmol) and potassium acetate (232 mg, 2.4 mmol) under N2 atmosphere. The mixture was then stirred at 110 °C for 13 h under N2 atmosphere. The mixture was filtered and concentrated under reduced pressure to give the desired product as a yellow oil, which was used in the next step without further purification.

[0231] Step 3 To a solution of (3-tert-butylpyrazolo[1,5-a]pyridin-5-yl)boronic acid (180 mg, 825 μmol) and 2,4-dichloropyrimidine (147 mg, 990 μmol) in dioxane (12 mL) was added cyclopentyl(diphenyl)phosphanedichloropalladium iron (72 mg, 99 μmol), disodium carbonate (174 mg, 1.6 mmol) and water (0.5 mL) under N2 atmosphere. The reaction mixture was then stirred at 110° C. for 5 h under N2 atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography to give the desired product (220 mg, 92% yield) as a yellow solid. LC-MS: m / z 287.1 [M+H] + .

[0232] Additional intermediates of the present invention were prepared by using the corresponding derivatives. Selected compounds and their corresponding property data are shown in the table below. [Table 2]

[0233] Intermediate 10 [ka]

[0234] Step 1 To a solution of 5-bromo-3-iodo-2H-pyrazolo[3,4-c]pyridine (200 mg, 617 μmol) and Cs2CO3 (500 mg, 1.5 mmol) in DMF (8 mL) was added MeI (99 mg, 679 μmol) at 0 °C. The reaction mixture was stirred at 25 °C for 1.5 h. The mixture was quenched with water (20 mL) and then extracted with ethyl acetate (2 × 50 mL). The combined organic phase was dried over anhydrous Na2SO4. The filtrate was concentrated. The residue was purified by flash column chromatography (24 g silica gel column, EA 0-10% in DCM in 20 min) to give the desired product (20.0 mg) as a light purple solid. LC-MS: m / z 337.9 [M+H] + .

[0235] Step 2 A solution of 5-bromo-3-iodo-2-methyl-pyrazolo[3,4-c]pyridine (167 mg, 494 μmol), potassium isopropenyltrifluoroborate (90.0 mg, 600 μmol), Pd(dppf)Cl2 (90.0 mg, 100 μmol) and K2CO3 (140 mg, 1 mmol) in dioxane (10 mL) was stirred at 80 °C for 72 h. The reaction mixture was quenched with water (50 mL) and then extracted with ethyl acetate (2 × 100 mL). The combined organic phase was dried over anhydrous Na2SO4 and then filtered. The filtrate was concentrated. The residue was purified by flash column chromatography (24 g silica gel column, EA 0-70% in PE in 20 min) to give the desired product (30.0 mg) as a yellow solid. LC-MS: m / z 252.1 [M+H] + .

[0236] Step 3 To a solution of 5-bromo-3-isopropenyl-2-methyl-pyrazolo[3,4-c]pyridine (40.0 mg, 158 μmol) in THF (12 mL) was added PtO2 (18.1 mg, 79.3 μmol) and the mixture was stirred under hydrogen atmosphere at 25° C. for 2 h. The reaction mixture was filtered and then washed with methanol (5 mL). The filtrate was concentrated to give the desired product (30.0 mg, 74% yield) as a white solid, which was used directly without further purification. LC-MS: m / z 254.1 [M+H] + .

[0237] Step 4 A solution of 5-bromo-3-isopropyl-2-methyl-pyrazolo[3,4-c]pyridine (30.0 mg, 118 μmol), B2Pin2 (46.0 mg, 181 μmol), Pd2(dba)3 (22.0 mg, 24.0 μmol), KOAc (35.0 mg, 357 μmol) and tricyclohexylphosphane (14.0 mg, 0.05 mmol) in dioxane (2 mL) was stirred at 120° C. for 1 h under microwave conditions. The reaction mixture was filtered and washed with DCM (5 mL). The filtrate was concentrated under reduced pressure to give the desired crude product (25.0 mg) as a black solid. LC-MS: m / z 220.1 [M+H] + .

[0238] Step 5 A solution of (3-isopropyl-2-methyl-pyrazolo[3,4-c]pyridin-5-yl)boronic acid (26.0 mg, 118 μmol), 2,4-dichloro-5-fluoro-pyrimidine (24.0 mg, 14 μmol), Pd(dppf)Cl2 (9.0 mg, 12.3 μmol) and K2CO3 (33.0 mg, 239 μmol) in dioxane (3 mL) and water (1.5 mL) was stirred at 100 °C for 16 h under N2 atmosphere. The reaction mixture was quenched with water (50 mL) and then extracted with ethyl acetate (2 × 100 mL). The combined organic phase was dried over anhydrous Na2SO4 and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (24 g, EA 0-90% in PE in 20 min) to give the desired product (30.0 mg) as a yellow solid. LC-MS: m / z 306.1 [M+H] + .

[0239] Intermediate 11 [ka]

[0240] Step 1 Iron powder (2.6 g, 46.5 mmol), water (9 mL), and concentrated HCl (2 mL) were added to 4-amino-2,6-dichloro-3-nitropyridine (2.0 g, 9.6 mmol) in ethanol (50 mL). The mixture was heated to reflux for 16 h. The mixture was cooled to room temperature, and then it was neutralized with sodium bicarbonate (saturated aqueous solution). The mixture was filtered and the residue was washed with ethyl acetate. The filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with water (30 mL). The organic layer was dried over Na2SO4 and evaporated to give the desired product (1.9 g, 99% yield) as a yellow solid. LC-MS: m / z 177.9 [M+H] + .

[0241] Step 2 A solution of 2,6-dichloropyridine-3,4-diamine (1.8 g, 8.4 mmol) in trimethyl orthoacetate (20 mL) was stirred at 140° C. for 5 h. The mixture was then concentrated under reduced pressure and the residue was dissolved in AcOH (20 mL). The mixture was then stirred at 120° C. for 5 h. The mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (40 g silica gel column, petroleum ether / EtOAc 0-50% EtOAc) to give the desired product (1.3 g, 67% yield) as a yellow solid. LC-MS: m / z 201.9 [M+H] + .

[0242] Step 3 To a solution of 4,6-dichloro-2-methyl-1H-imidazo[4,5-c]pyridine (1.9 g) in anhydrous DMF (5 mL) was added NaH (772 mg, 32.1 mmol) at 0° C. Then 2-iodopropane (3.3 g, 19.3 mmol) was added to the reaction mixture. The mixture was allowed to warm to room temperature and stirred for 13 h. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (80 g silica gel column, 0-10% MeOH in DCM) to give the desired product (487 mg, 31% yield) as a yellow solid. LC-MS: m / z 244 [M+H] + .

[0243] Step 4 To a solution of 4,6-dichloro-1-isopropyl-2-methyl-1H-imidazo[4,5-c]pyridine (200 mg, 0.8 mmol) in MeOH (5 mL) was added a solution of MeONa (5.4 N in MeOH, 5 mL). The mixture was heated to reflux (65° C.) for 10 h. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (40 g silica gel column, petroleum ether / EtOAc from 0% to 100% EtOAc) to give the desired product (140 mg, 71% yield) as a white solid. LC-MS: m / z 240 [M+H] + .

[0244] Step 5 To a solution of 6-chloro-1-isopropyl-4-methoxy-2-methyl-1H-imidazo[4,5-C]pyridine (120 mg, 0.5 mmol) and Pin2B2 (153 mg, 0.6 mmol) in anhydrous dioxane (8 mL) was added Pd2(dba)3 (137 mg, 0.15 mmol), tricyclohexylphosphine (84.1 mg, 0.3 mmol), AcOK (147 mg, 1.5 mmol) under N2 atmosphere. The mixture was then stirred at 110 °C (microwave) for 1.5 h. The mixture was filtered and concentrated under reduced pressure to give the desired crude product as a brown oil, which was used in the next step without further purification. LC-MS: m / z 250 [M+H] + .

[0245] Step 6 To a solution of (1-isopropyl-4-methoxy-2-methyl-1H-imidazo[4,5-c]pyridin-6-yl)boronic acid (300 mg) and 2,4-dichloro-5-fluoropyrimidine (83.5 mg, 0.5 mmol) in anhydrous dioxane / water (8 mL / 2 mL) was added Pd(dppf)Cl2 (122 mg, 0.2 mmol), Na2CO3 (159 mg, 1.5 mmol) under N2 atmosphere. The mixture was then stirred at 110 °C for 3 h. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (40 g silica gel column, 0% to 50% EtOAc in petroleum ether / EtOAc) to give the desired product (139 mg, 82% yield) as a yellow solid. LC-MS: m / z 336 [M+H] + .

[0246] Additional intermediates of the present invention were prepared by using the corresponding derivatives. Selected compounds and their corresponding property data are shown in the table below. [Table 3]

[0247] Intermediate 18 [ka]

[0248] Step 1 A sealed tube was charged with a solution of 6-chloro-1-isopropyl-4-methoxy-2-methyl-imidazo[4,5-c]pyridine (170 mg, 709 μmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (270 mg, 1.1 mmol) in dioxane (5 mL). Tris(dibenzylideneacetone)dipalladium(0) (194 mg, 212 μmol), tricyclohexylphosphane (119 mg, 425 μmol) and potassium acetate (208 mg, 2.1 mmol) were then added under N2 atmosphere. The reaction mixture was then stirred at 110 °C for 5 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the desired crude product, which was used in the next step without further purification. LC-MS: m / z 250 [M+H] + .

[0249] Step 2 To a solution of (1-isopropyl-4-methoxy-2-methyl-imidazo[4,5-c]pyridin-6-yl)boronic acid (190 mg, 762 μmol) and 2-chloro-5-fluoro-4-iodo-pyridine (216 mg, 839 μmol) in dioxane (8 mL), cyclopentyl(diphenyl)phosphanedichloropalladium iron (167 mg, 228 μmol), disodium carbonate (242 mg, 2.2 mmol) and water (2 mL) were added under N2 atmosphere. The reaction mixture was then stirred at 110 °C for 5 h. The mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (40 g silica gel column, 0 to 100% EtOAc in petroleum ether / EtOAc) to give the desired product (160 mg, 62% yield) as a yellow solid. LC-MS: (ESI) m / z 335 [M+H] + .

[0250] Intermediate 19 [ka]

[0251] Step 1 To a mixture of 4,6-dichloro-1-isopropyl-imidazo[4,5-c]pyridine (250 mg, 1.1 mmol) in DMSO (10 mL) was added CsF (510 mg, 3.4 mmol), and then the mixture was stirred at 140 °C for 1.5 h. The resulting mixture was poured into water (100 mL) and extracted with EA (3 × 30 mL). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated. The residue was purified by flash column (80 g, 200-300 mesh silica gel, PE / EA = 5 / 1-2 / 1) to give the desired product (210 mg, 75% yield) as a milky white solid. LC-MS: (ESI) m / z 214.1 [M+H].

[0252] Step 2 To a solution of 6-chloro-4-fluoro-1-isopropyl-imidazo[4,5-c]pyridine (30.0 mg, 140 μmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (35.6 mg, 140 μmol) in dioxane (5 mL) was added potassium acetate (41.3 mg, 421 μmol) and cyclopentyl(diphenyl)phosphanedichloropalladium iron (15.4 mg, 21.1 μmol). The mixture was degassed with N2 and stirred at 110° C. for 16 h. The mixture was filtered through a Celite pad. The filtrate was concentrated under reduced pressure to give the desired crude product (50 mg) as a black oil, which was used directly in the next step. LC-MS: (ESI) m / z 224.2 [M+H] + .

[0253] Step 3 To a solution of (4-fluoro-1-isopropyl-imidazo[4,5-c]pyridin-6-yl)boronic acid (50.0 mg, 224 μmol) and 2-chloro-4-iodo-pyrimidine (53.9 mg, 224 μmol) in dioxane (3 mL) was added cyclopentyl(diphenyl)phosphanedichloropalladium iron (24.6 mg, 33.6 μmol) and potassium acetate (66.0 mg, 672 μmol). The mixture was degassed with N2 and stirred at 110 °C for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 0-60% ethyl acetate in petroleum ether to give the desired product (30.0 mg, 46% yield) as a white solid. LC-MS: (ESI) m / z) 292.1 [M+H] + .

[0254] Additional intermediates of the present invention were prepared by using the corresponding derivatives. Selected compounds and their corresponding property data are shown in the table below. [Table 4]

[0255] Intermediate 20 [ka]

[0256] Step 1 To a solution of 4,6-dichloro-2-methyl-3H-imidazo[4,5-c]pyridine (4.0 g, 19.8 mmol) and 6-oxabicyclo[3.1.0]hexane (6.6 g, 79.1 mmol) in DMF (50 mL), cesium carbonate (16.1 g, 49.5 mmol) was added and the reaction mixture was stirred at 100 °C for 48 h. The reaction mixture was then quenched with H2O (50 mL) and extracted with EA (3 × 10 mL). The organic layer was concentrated under reduced pressure. The residue was purified by flash column chromatography (20 g silica gel column, DCM with MeOH 0-10%) to give the desired product (650 mg, 11% yield) as a yellow solid. LC-MS: m / z 286 [M+H]+ .

[0257] Step 2 To a solution of 2-(4,6-dichloro-2-methyl-imidazo[4,5-c]pyridin-1-yl)cyclopentanol (650 mg, 2.2 mmol) in methanol (10 mL) was added sodium methanolate (5.4 M, 841 μL) at 25 °C. The reaction mixture was stirred at 60 °C for 48 h. The mixture was quenched with water (20 mL) and then extracted with ethyl acetate (2 × 20 mL). The combined organic phases were dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 10-60% EA in PE to give the desired product (600 mg, 94% yield) as a pale yellow oil. LC-MS: (ESI) m / z 282.2 [M+H] + .

[0258] Step 3 To a mixture of 2-(6-chloro-4-methoxy-2-methyl-imidazo[4,5-c]pyridin-1-yl)cyclopentanol (200 mg, 709 μmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (270 mg, 1.1 mmol) in dioxane (8 mL) was added Pd2(dba)3 (97.5 mg, 106 μmol), potassium acetate (209 mg, 2.1 mmol) and tricyclohexylphosphane (59.7 mg, 212 μmol). The resulting mixture was stirred at 110 °C under nitrogen atmosphere for 6 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the desired crude product (200 mg, 96% yield) as a brown oil, which was used in the next step without further purification. LC-MS: (ESI) m / z 292.2 [M+H] + .

[0259] Step 4 To a solution of [1-(2-hydroxycyclopentyl)-4-methoxy-imidazo[4,5-c]pyridin-6-yl]boronic acid (250 mg, 902 μmol) and 2,4-dichloro-5-fluoro-pyrimidine (165 mg, 992 μmol) in dioxane (3 mL), disodium carbonate (239 mg, 2.3 mmol) and cyclopentyl(diphenyl)phosphane dichloropalladium iron (132 mg, 180 μmol) were added under N2 atmosphere. The reaction mixture was then stirred at 110 °C for 5 h. The mixture was concentrated under reduced pressure and the residue was purified to give the desired product (250 mg, 76% yield) as a yellow solid. LC-MS: m / z 378.1 [M+H] + .

[0260] Additional intermediates of the present invention were prepared by using the corresponding derivatives. Selected compounds and their corresponding property data are shown in the table below. [Table 5]

[0261] Intermediate 22 [ka]

[0262] Step 1 To a solution of 6-(2-chloropyrimidin-4-yl)-1-isopropyl-4-methoxy-imidazo[4,5-c]pyridine (150 mg, 493 μmol) in DCE (5 mL) was added tribromoborane (618 mg, 2.4 mmol) at 0° C. The mixture was stirred at 60° C. for 12 h. The mixture was quenched with aqueous NaHCO3 (10 mL) and extracted with DCM (2×10 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated to give the desired crude product (140 mg) as a yellow solid, which was used directly in the next step without further purification. LC-MS: m / z 290.1 ​​[M+H] + .

[0263] Step 2 To a solution of 6-(2-chloropyrimidin-4-yl)-1-isopropyl-imidazo[4,5-c]pyridin-4-ol (0.1 g, 345 μmol) and trimethylsilyl 2,2-difluoro-2-fluorosulfonyl-acetate (129 mg, 517 μmol) in CH3CN (5 mL) was added NaH (16.5 mg, 690 μmol) and CsF (78.6 mg, 517 μmol) at 0 °C. The mixture was stirred at 0 °C for 1 h. The mixture was quenched with water (5 mL) and extracted with EtOAc (2 × 10 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated to give a residue that was purified by flash column chromatography (SiO2, hexane / ethyl acetate 1:1) to give the desired product (105 mg, 89% yield) as a white solid. LC-MS: m / z 340.1 [M+H] + .

[0264] Intermediate 23 [ka]

[0265] Step 1 To a mixture of tert-butyl 2-chloro-7,8-dihydro-5H-1,6-naphthyridine-6-carboxylate (302 mg, 2.3 mmol) in dioxane (10 mL), 4-(1-isopropyl-4-methoxy-imidazo[4,5-c]pyridin-6-yl)pyrimidin-2-amine (322 mg, 1.1 mmol), tris(dibenzylideneacetone)dipalladium(0) (100 mg, 109 μmol), (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphane (190 mg, 328 μmol), and cesium carbonate (2.0 g, 6.1 mmol) were added in sequence. The mixture was degassed five times with N2. The mixture was stirred at 110 °C for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with EA (3×30 mL). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated. The residue was purified by flash column to give the desired product (611 mg, 92% yield) as a yellow solid. LC-MS: (ESI) m / z 517.3 [M+H] + .

[0266] Step 2 In an ice bath, HCl / EtOAc (2M, 7 mL) was added to tert-butyl 2-[[4-(1-isopropyl-4-methoxy-1H-imidazo[4,5-c]pyridin-6-yl)pyrimidin-2-yl]amino]-7,8-dihydro-5H-1,6-naphthyridine-6-carboxylate (152 mg, 280 μmol) and the mixture was stirred in an ice bath for 2 h. The mixture was concentrated and dried in vacuum to give the desired product (1220 mg, 91% yield) as a yellow solid. LC-MS: (ESI) m / z 417.2 [M+H] + .

[0267] Intermediate 24 [ka]

[0268] Step 1 To a solution of 2-bromo-6-fluorophenol (4.0 g, 21.1 mmol) in DMF (50 mL) was added K2CO3 (5.8 g, 42.2 mmol), TBAI (0.4 g, 1.1 mmol) and 3-chloro-2-methylprop-1-ene (2.8 g, 31.6 mmol) at 0 °C. The mixture was stirred at 25 °C for 14 h. The mixture was concentrated under reduced pressure and purified to give the desired product (4.5 g, 88% yield). LC-MS: m / z 245.0 [M+H] + .

[0269] Step 2 To a solution of 1-bromo-3-fluoro-2-((2-methylallyl)oxy)benzene (2.5 g, 10.2 mol) in toluene (50 mL) was added n-Bu3SnH (3.6 g, 12.3 mmol) and AIBN (2.0 g, 2.3 mmol) under N2. The reaction mixture was stirred at 90 °C for 12 h. The reaction mixture was quenched with water (50 mL) and extracted with DCM (2 x 50 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (eluted with PE / EA = 10 / 1) to give the desired product (1.4 g, 81% yield). LC-MS: m / z 167.1 [M+H] + .

[0270] Step 3 To a solution of 7-fluoro-3,3-dimethyl-2,3-dihydrobenzofuran (1.4 g, 8.4 mmol) in DMF (30 ml) was added NBS (1.8 g, 10.1 mmol) under N2 at 25°C. The reaction was stirred for 15 h. The reaction mixture was quenched with water (3 mL) and concentrated under reduced pressure. The residue was purified (eluted with PE:EA=1 / 1) to give the desired product (450 mg, 22% yield). LC-MS: m / z 245.0 [M+H] + .

[0271] Step 4 To a solution of 5-bromo-7-fluoro-3,3-dimethyl-2,3-dihydrobenzofuran (100 mg, 0.4 mmol) and Pin2B2 (122 mg, 0.5 mmol) in anhydrous dioxane (10 mL) was added Pd(dppf)Cl2 (98.0 mg, 0.16 mmol) and KOAc (117 mg, 1.2 mmol) under N2 atmosphere. The mixture was then stirred at 110 °C (microwave) for 1.5 h. The mixture was filtered and concentrated under reduced pressure to give the desired crude product (150 mg) as a brown oil, which was used in the next step without further purification. LC-MS: m / z 293.2 [M+H] + .

[0272] Step 5 To a solution of 2-(7-fluoro-3,3-dimethyl-2,3-dihydrobenzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (150 mg) and 2,4-dichloropyrimidine (61.0 mg, 0.4 mmol) in anhydrous dioxane / water (8 mL / 2 mL), Pd(dppf)Cl2 (98.0 mg, 0.16 mmol), Na2CO3 (127 mg, 1.2 mmol) were added under N2 atmosphere. The mixture was then stirred at 110 °C for 3 h. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (40 g silica gel column, 0% to 50% EtOAc in petroleum ether / EtOAc) to give the desired product (60.0 mg, 51% yield). LC-MS: m / z 279.1 [M+H] + .

[0273] Intermediate 25 [ka]

[0274] Step 1 To a mixture of 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine (2.3 g, 17.3 mmol) and DIPEA (4.4 g, 34 mmol) in methanol (30 mL) was added Boc2O (5.5 g, 43.2 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 18 h. The reaction mixture was quenched with water (50 mL) and then extracted with EtOAc (2 x 100 mL). The combined organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated. The residue was purified by flash column chromatography (24 g, 0-100% EtOAc in PE in 20 min) to give the desired product (4.7 g, 14.5 mmol) as a yellow oil. LC-MS: m / z 346.2 [M+Na] + .

[0275] Step 2 A mixture of di-tert-butyl 6,7-dihydro-4H-imidazo[4,5-c]pyridine-1,5-dicarboxylate (4.7 g, 14.5 mmol) and sodium hydroxide (1 M in water, 29.0 mL) in dioxane (36 mL) was stirred at 25° C. for 1 h. The reaction mixture was quenched with water (50 mL) and then extracted with EtOAc (2×100 mL). The combined organic phases were dried over anhydrous Na2SO4 and then filtered. The filtrate was concentrated. The residue was purified by flash column chromatography to give the desired product (2.7 g, 12.1 mmol) as a colorless oil. LC-MS: m / z 224.3 [M+H] + .

[0276] Step 3 A mixture of tert-butyl 1,4,6,7-tetrahydroimidazo[4,5-c]pyridine-5-carboxylate (500 mg, 2.2 mmol) and cesium carbonate (2.1 g, 6.7 mmol) in DMF (20 mL) was stirred at 25 °C under N2 atmosphere for 16 h. The reaction mixture was quenched with water (50 mL) and then extracted with EtOAc (2 x 100 mL). The combined organic phase was dried over anhydrous Na2SO4 and then filtered. The filtrate was concentrated. The residue was purified by flash column chromatography (24 g, 0-20% MeOH in DCM in 20 min) to give the desired product (330 mg, 55% yield) as a yellow oil. LC-MS: m / z 266.2 [M+H] + .

[0277] Step 4 A mixture of tert-butyl 3-isopropyl-6,7-dihydro-4H-imidazo[4,5-c]pyridine-5-carboxylate (530 mg, 2.0 mmol), HCl (2N, 2 mL) in ethyl acetate (2 mL) was stirred at 25° C. for 1 h. The reaction mixture was quenched with water (50 mL) and then extracted with EtOAc (2×100 mL). The combined organic phase was dried over anhydrous Na2SO4 and then filtered. The filtrate was concentrated. The residue was purified by flash column chromatography (24 g, 0-100% EtOAc in PE in 20 min) to give the desired product (300 mg, 90% yield) as a yellow solid. LC-MS: m / z 166.3 [M+H] + .

[0278] Step 5 A mixture of 3-isopropyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine (165 mg, 998 μmol) 2,4-dichloropyrimidine (178 mg, 1.2 mmol) and potassium carbonate (690 mg, 4.9 mmol) in methanol (10 mL) was stirred at 40 °C under N2 atmosphere for 2 h. The reaction mixture was quenched with water (50 mL) and then extracted with EtOAc (2 × 100 mL). The combined organic phase was dried over anhydrous Na2SO4 and then filtered. The filtrate was concentrated. The residue was purified by flash column chromatography (24 g, 0-20% MeOH in DCM in 20 min) to give the desired product (66.0 mg) as a colorless oil. LC-MS: m / z 278.1 [M+H] + .

[0279] Additional intermediates of the present invention were prepared by using the corresponding derivatives. Selected compounds and their corresponding property data are shown in the table below. [Table 6]

[0280] Intermediate 26 [ka]

[0281] Step 1 To a solution of 5-bromo-2-nitro-pyridine (10.0 g, 49.2 mmol) and tert-butyl 3-oxopiperazine-1-carboxylate (10.8 g, 54.1 mmol) in dioxane (30 mL) was added cesium carbonate (32.1 g, 98.5 mmol), tris(dibenzylideneacetone)dipalladium(0) (4.5 g, 4.9 mmol) and (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphane (2.8 g, 4.9 mmol) at 25 °C. The mixture was then stirred at 110 °C for 8 h. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-15% MeOH in DCM in 20 min to give the desired product (1.5 g, 9% yield) as a pale yellow solid. LC-MS: m / z 323.1 [M+H] + .

[0282] Step 2 To a stirred solution of tert-butyl 4-(6-nitro-3-pyridyl)-3-oxo-piperazine-1-carboxylate (1.6 g, 4.9 mmol) in ethanol (20 mL) was added iron powder (1.1 g, 19.8 mmol) and ammonia hydrochloride (2.6 g, 49.6 mmol) at 25° C. The reaction mixture was stirred at 80° C. under N2 atmosphere for 2 h. The mixture was filtered through a Celite pad. The filtrate was concentrated under reduced pressure to give the desired product, which was used directly in the next step without further purification. LC-MS: m / z 293.1 [M+H] + .

[0283] Additional intermediates of the present invention were prepared by using the corresponding derivatives. Selected compounds and their corresponding property data are shown in the table below. [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4]

[0284] Intermediate 40 [ka]

[0285] Step 1 To a solution of 2-methylmorpholine (100 mg, 988 μmol) and 5-fluoro-2-nitro-pyridine (140 mg, 988 μmol) in ethanol (15 mL) was added DIPEA (383 mg, 2.9 mmol). The mixture was stirred at 80° C. for 8 h. The reaction was concentrated under reduced pressure to give the desired product (200 mg, 90% yield) as a yellow solid. LC-MS: m / z 224.1 [M+H] + .

[0286] Step 2 To a solution of 2-methyl-4-(6-nitro-3-pyridyl)morpholine (200 mg, 895 μmol) in ethanol (15 mL) was added iron (250 mg, 4.4 mmol) and ammonia hydrochloride (239 mg, 4.4 mmol). The mixture was stirred at 80° C. for 8 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with MeOH / DCM 0-10% in 15 min to give the desired product (150 mg, 86% yield) as a brown solid. LC-MS: m / z 194.1 [M+H] + .

[0287] Intermediate 115 [ka]

[0288] Step 1 To a solution of 5-bromo-2-nitro-pyridine (1 g, 4.9 mmol) and 1-isopropylpiperazine (631.6 mg, 4.9 mmol) in dioxane (40 mL) was added tris(dibenzylideneacetone)dipalladium(0) (451.1 mg, 492 μmol), (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenylphosphane (570 mg, 985 μmol) and cesium carbonate (4.8 g, 14.8 mmol). The reaction mixture was then stirred at 110 °C under N2 for 3 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography eluting with 1-100% ethyl acetate in petroleum ether to give the desired product (850 mg, 68% yield) as a yellow solid. LC-MS: m / z 251.1 [M+H] + .

[0289] Step 2 To a solution of 1-isopropyl-4-(6-nitro-3-pyridyl)piperazine (850 mg, 3.4 mmol) in methanol (30 mL) was added Pd / C (412 mg, 10%). The reaction mixture was then degassed with H2 three times and stirred at 25°C for 3 h. The reaction mixture was filtered and then washed with methanol (20 mL). The combined solvents were concentrated under reduced pressure to give the desired product (620 mg, 82% yield) as a brown solid. LC-MS: m / z 221.2 [M+H] + .

[0290] Additional intermediates of the present invention were prepared by using the corresponding derivatives. Selected compounds and their corresponding property data are shown in the table below. [Table 8-1] [Table 8-2]

[0291] Intermediate 56 [ka]

[0292] Step 1 To a mixture of piperidine-2,4-dione (2.1 g, 18.5 mmol) and N-methylmethanamine (3.4 g, 74.2 mmol) in DCM (36 mL) and THF (18 mL) was added CH3COOH (10 mL) and the resulting mixture was stirred at 25 °C under nitrogen atmosphere for 3 h. To this mixture was added sodium triacetoxyborohydride (7.8 g, 37.1 mmol) and the resulting mixture was stirred at 25 °C under nitrogen atmosphere for 12 h. The reaction was quenched with water (50 mL) and concentrated in vacuo to remove DCM and THF. The mixture was extracted with DCM (3 x 100 mL). The organic solution was washed with brine (20 mL). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give the desired product (2.6 g, 89% yield), which was used in the next step without purification. LC-MS: m / z 141.2 [M+H] + .

[0293] Step 2 To a mixture of 4-(dimethylamino)-2,3-dihydro-1H-pyridin-6-one (1.0 g, 7.1 mmol) in methanol (15 mL) was added sodium borohydride (539.0 mg, 14.2 mmol), and the resulting mixture was stirred at 25 °C under nitrogen atmosphere for 12 h. The reaction was quenched with saturated aqueous NH4Cl (10 mL) and concentrated in vacuo to remove MeOH. The aqueous solution was purified by reverse phase column (C18, 40 g) eluted with (MeCN / water (0.1% NH4OH) = 1 / 10) to give the desired product (0.3 g, 32% yield) as a pale yellow solid. LC-MS: m / z 143.2 [M+H] + .

[0294] Step 3 To a mixture of 4-(dimethylamino)piperidin-2-one (270 mg, 1.9 mmol), 5-iodopyridin-2-amine (1.0 g, 4.7 mmol) and potassium phosphate (1.2 g, 5.7 mmol) in dioxane (26 mL), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (162 mg, 1.1 mmol) and CuI (108 mg, 569 μmol) were added and the resulting mixture was stirred at 110 °C under nitrogen atmosphere for 12 h. The reaction was filtered. The filtrate was concentrated in vacuum to give a residue. The residue was purified by reverse phase column (C18, 20 g) eluted with (MeCN / water (0.1% NH4OH) = 1 / 10) to give the desired product (272 mg, 61% yield) as a pale yellow solid. LC-MS: m / z 235.2 [M+H] + .

[0295] Additional intermediates of the present invention were prepared by using the corresponding derivatives. Selected compounds and their corresponding property data are shown in the table below. [Table 9-1] [Table 9-2]

[0296] Intermediate 135 [ka]

[0297] Step 1 To a solution of piperidine-2,4-dione (5 g, 44.2 mmol) in methanol (20 mL) was added methanamine (2.7 g, 88.4 mmol, 3.0 mL). The mixture was stirred at 25° C. for 16 h. The mixture was concentrated in vacuo to give the desired product as a brown solid. LC-MS: m / z 127.1 [M+1] + .

[0298] Step 2 To a solution of 4-(methylamino)-2,3-dihydro-1H-pyridin-6-one (2.6 g, 20.8 mmol) in methanol (20 mL) was added dioxoplatinum (474.1 mg, 2.0 mmol). The mixture was then degassed with H2. The reaction mixture was stirred at 25°C for 16 h. The mixture was filtered and concentrated in vacuo to give the desired product as a black oil. LC-MS: m / z 129.1 [M+1] + .

[0299] Step 3 To a solution of 4-(methylamino)piperidin-2-one (2.6 g, 20.5 mmol) in DCM (10 mL) was added N,N-diethylethanamine (4.1 g, 41.1 mmol) and tert-butoxycarbonyl tert-butyl carbonate (5.3 g, 24.6 mmol). The reaction mixture was stirred at 25 °C for 3 h. The mixture was concentrated under reduced pressure and purified by flash chromatography (40 g silica gel, MeOH 0-10% in DCM) to give the desired product (2.9 g, 61% yield) as a yellow oil. LC-MS: m / z 229.2 [M+1] + .

[0300] Step 4 To a solution of tert-butyl N-methyl-N-(2-oxo-4-piperidyl)carbamate (2 g, 8.7 mmol) in dry dioxane (20 mL) was added 5-iodopyridin-2-amine (1.9 g, 8.7 mmol), copper iodide (166.8 mg, 876 μmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (249 mg, 1.7 mmol) and potassium phosphate tribasic (5.5 g, 26.2 mmol). The reaction mixture was stirred at 105 °C for 16 h. The mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography (40 g silica gel, 0-10% MeOH in DCM) to give the desired product (1.7 g, 62% yield) as a black oil. LC-MS: m / z 321.2 [M+1] + .

[0301] Additional intermediates of the present invention were prepared by using the corresponding derivatives. Selected compounds and their corresponding property data are shown in the table below. [Table 10]

[0302] Intermediate 61 [ka]

[0303] Step 1 To a mixture of 3-aminopyrrolidin-2-one (333 mg, 3.3 mmol) in water (8 mL) in an ice bath, formic acid (610 mg, 13.2 mmol) and formaldehyde (540 mg, 17.9 mmol) were added and the resulting mixture was stirred at 100° C. for 1.5 h. The mixture was concentrated. The residue was purified by preparative HPLC and then lyophilized to give the desired product (162 mg) as a yellow oil. LC-MS: m / z 129.3 [M+H] + .

[0304] Step 2 To a solution of 3-(dimethylamino)pyrrolidin-2-one (130 mg, 1.0 mmol) and 5-iodopyridin-2-amine (267 mg, 1.2 mmol) in dioxane (3 mL) was added (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (43 mg, 304 μmol), CuI (28.9 mg, 152 μmol) and tripotassium phosphate (645 mg, 3.0 mmol) at 25 °C. The reaction mixture was stirred at 110 °C for 16 h. The mixture was quenched with water (20 mL) and then extracted with ethyl acetate (2 × 10 mL). The combined organic phases were dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 20-70% EA in PE to give the desired product (160 mg, 71% yield) as a yellow solid. LC-MS: m / z 221.1 [M+H] + .

[0305] Additional intermediates of the present invention were prepared by using the corresponding derivatives. Selected compounds and their corresponding property data are shown in the table below. [Table 11]

[0306] Intermediate 62 [ka]

[0307] To a solution of 4-amino-1H-pyridin-2-one (4.0 g, 36.3 mmol) and tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate (10.1 g, 36.3 mmol) in DMF (10 mL) was added NaH (835 mg, 34.8 mmol) at 25 °C. The mixture was stirred at 45 °C for 6 h. The reaction was quenched with water (200 mL) and then extracted with EA (3 × 100 mL). The organic solution was washed with brine (100 mL). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-15% methanol in dichloromethane in 20 min to give the desired product (0.4 g, 5% yield) as a yellow solid. LC-MS: m / z 294.2 [M+H] + .

[0308] Intermediate 63 [ka]

[0309] Step 1 To a stirred solution of tert-butyl 3-oxo-1,4-diazepane-1-carboxylate (500 mg, 2.3 mmol) and 5-iodopyridin-2-amine (564 mg, 2.5 mmol) in dioxane (10 mL) was added (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (132 mg, 933 μmol), potassium phosphate tripotassium (1.5 g, 7.0 mmol) and CuI (28.9 mg, 152 μmol). The reaction mixture was stirred at 110 °C under N2 atmosphere for 5 h. The mixture was concentrated under reduced pressure to give a residue which was purified by flash column chromatography (80 g silica gel column) eluting with 0-5% MeOH in DCM to give the desired product (280 mg, 39% yield) as a brown solid. LC-MS: m / z 306.2 [M+H] + .

[0310] Additional intermediates of the present invention were prepared by using the corresponding derivatives. Selected compounds and their corresponding property data are shown in the table below. [Table 12]

[0311] Intermediate 68 [ka]

[0312] A mixture of 3,3-difluoropyrrolidine (128.0 mg, 1.2 mmol), 3,3-difluoropyrrolidine (128 mg, 1.2 mmol) and NaBH(OAc)3 (633 mg, 3.0 mmol) in DCM (8 mL) was stirred at 25 °C under N2 atmosphere for 2 h. The reaction mixture was quenched with water (50 mL) and then extracted with EtOAc (2 x 100 mL). The combined organic phase was dried over anhydrous Na2SO4 and then filtered. The filtrate was concentrated. The residue was purified by flash column chromatography (24 g, 0-20% MeOH in DCM in 20 min) to give the desired product (156 mg, 73% yield) as a colorless oil. LC-MS: (ESI) m / z 214.2 [M+H] + .

[0313] Additional intermediates of the present invention were prepared by using the corresponding derivatives. Selected compounds and their corresponding property data are shown in the table below. [Table 13]

[0314] Intermediate 73 [ka]

[0315] Step 1 To a stirred solution of 5-methyl-2-nitro-pyridine (5.0 g, 36.2 mmol) was added 1-bromopyrrolidine-2,5-dione (6.7 g, 38.0 mmol) and azo-diisobutyronitrile (0.6 g, 3.6 mmol). The reaction mixture was stirred at 80° C. under N2 atmosphere for 4 h. The mixture was filtered through Celite. The filtrate was concentrated and purified to give the desired product (4.8 g, 61% yield) as a pale yellow solid. LC-MS: m / z 216.9 [M+H] + .

[0316] Step 2 A stirred mixture of morpholin-3-one (1.4 g, 13.8 mmol) and cesium carbonate (2.2 g, 6.9 mmol) in DMF (15 mL) was stirred at 25 °C for 12 h. To the above mixture, 5-(bromomethyl)-2-nitro-pyridine (1.0 g, 4.6 mmol) was added at 25 °C. The resulting mixture was stirred at 25 °C for 4 h under N2 atmosphere. The mixture was poured into water (100 mL) and extracted with dichloromethane (5 x 200 mL). The combined organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified to give the desired product (100 mg, 7% yield) as a white solid. LC-MS: m / z 238 [M+H] + .

[0317] Step 3 To a stirred solution of 4-[(6-nitro-3-pyridyl)methyl]morpholin-3-one (40.0 mg, 168 μmol) in ethanol (2 mL) was added NH4Cl (100 mg, 2.0 mmol) and iron powder (37.6 mg, 674 μmol) at 25 °C. The reaction mixture was stirred at 80 °C under N2 atmosphere for 12 h. The mixture was filtered through a Celite pad. The filtrate was concentrated under reduced pressure to give the desired product (23.0 mg, 65% yield) as a pale yellow solid, which was used directly in the next step without further purification. LC-MS: m / z 208 [M+H] + .

[0318] Intermediate 74 [ka]

[0319] Step 1 A mixture of 6-chloro-2-methyl-pyridine-3-carboxylic acid (2.0 g, 11.6 mmol), piperidin-4-one (1.4 g, 13.9 mmol), N-ethyl-N-isopropyl-propan-2-amine (3.8 g, 29.1 mmol) and HATU (5.3 g, 14.0 mmol) in DCM (25 mL) was stirred at room temperature under N2 atmosphere for 2 h. The reaction mixture was quenched with water (100 mL) and then extracted with DCM (2 x 100 mL). The combined organic phase was dried over anhydrous Na2SO4 and then filtered. The filtrate was concentrated. The residue was purified by flash column chromatography (40 g, 0-100% EtOAc in PE in 20 min) to give the desired product (3.5 g, 95% yield) as a yellow oil. LC-MS: m / z 253.1 [M+H] + .

[0320] Step 2 A mixture of 1-(6-chloro-2-methyl-pyridine-3-carbonyl)piperidin-4-one (760 mg, 3.0 mmol) tert-butyl carbamate (421 mg, 3.6 mmol), Pd2(dba)3 (137 mg, 149 μmol), RuPhos (137 mg, 294 μmol) and Cs2CO3 (1.5 g, 4.6 mmol) in dioxane (10 mL) was stirred at 100 °C for 2 h under N2 atmosphere. The reaction mixture was quenched with water (50 mL) and then extracted with EtOAc (2 × 100 mL). The combined organic phase was dried over anhydrous Na2SO4 and then filtered. The filtrate was concentrated. The residue was purified by flash column chromatography (12 g, 0-100% EtOAc in PE in 10 min) to give the desired product (430 mg, 36% yield) as a yellow solid. LC-MS: m / z 334.1 [M+H] + .

[0321] Step 3 A mixture of tert-butyl N-[6-methyl-5-(4-oxopiperidine-1-carbonyl)-2-pyridyl]carbamate (1.9 g, 5.9 mmol) cyclopropanamine (681 mg, 11.9 mmol) and NaBH(OAc)3 (3.8 g, 17.9 mmol) in DCM (100 mL) was stirred at 25 °C for 2 h. The reaction mixture was quenched with water (200 mL) and then extracted with DCM (3 x 150 mL). The combined organic phase was dried over anhydrous Na2SO4 and then filtered. The filtrate was concentrated. The residue was purified by flash column chromatography (40 g, 0-100% EtOAc in PE in 25 min) to give the desired product (1.3 g, 30% yield) as a yellow solid. LC-MS: m / z 375.1 [M+H] + .

[0322] Step 4 A mixture of tert-butyl N-[5-[4-(cyclopropylamino)piperidine-1-carbonyl]-6-methyl-2-pyridyl]carbamate (1.3 g, 3.4 mmol) in TFA (6 mL) was stirred at room temperature for 2 h. Anhydrous K2CO3 was added to the reaction mixture, which was then filtered. The filtrate was concentrated to give the desired product (750 mg, 80% yield) as a yellow solid. LC-MS: m / z 275.1 [M+H] + .

[0323] Additional intermediates of the present invention were prepared by using the corresponding derivatives.

[0324] Selected compounds and their corresponding characterization data are shown in the table below.

[0325] [Table 14-1] [Table 14-2]

[0326] Intermediate 76 [ka]

[0327] To a suspension of 1,2,3,4,6,7,8,8a-octahydropyrrolo[1,2-a]pyrazine (2.0 g, 15.8 mmol) oxalate in DCM / MeCN (5 / 1) was added anhydrous Na2CO3 (4.6 g, 43.3 mmol). The mixture was then stirred at room temperature for 16 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue and 6-aminopyridine-3-carbaldehyde (1.3 g, 10.6 mmol) were dissolved in DCM (20 mL). Sodium triacetoxyborohydride (6.0 g, 28.3 mmol) was then added to the reaction mixture. The reaction mixture was stirred at room temperature for 16 h. The mixture was quenched with 10 mL of MeOH. The mixture was then diluted with EtOAc (200 mL). The mixture was then filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (40 g silica gel column, 0-20% MeOH (5% NH4OH) in DCM) to give the desired product (720 mg, 19% yield). LC-MS: m / z 233.1 [M+H] + . [Table 15]

[0328] Intermediate 79 [ka]

[0329] Step 1 A mixture of 1-((6-bromopyridin-2-yl)methyl)-4-ethylpiperazine (300 mg, 1.1 mmol), bis(4-methoxybenzyl)amine (327 mg, 1.3 mmol), Pd2(dba)3 (302 mg, 0.3 mmol), RuPhos (306 mg, 0.7 mmol) and Cs2CO3 (718 mg, 2.2 mmol) in dioxane (10 mL) was stirred at 110 °C for 4 h under N2 protection. EtOAc (80 mL) was added to the mixture and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by flash column chromatography (4 g silica gel column, 0-10% MeOH in DCM) to give the desired product (409 mg, 84% yield) as a pale yellow solid. LC-MS: (ESI) m / z 461.3 [M+H] + .

[0330] Step 2 A mixture of 6-[(4-ethylpiperazin-1-yl)methyl]-N,N-bis[(4-methoxyphenyl)methyl]pyridin-2-amine (130 mg, 282 μmol) in 2,2,2-trifluoroacetic acid (2 mL) was stirred at 50° C. for 5 h. The mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography eluting with 0-10% dichloromethane in methyl alcohol to give the desired product (50.0 mg, 80% yield) as a blank solid. LC-MS: (ESI) m / z 221 [M+H] + .

[0331] Intermediate 80 [ka] To a solution of 1H-pyrazol-3-amine (1.0 g, 12.0 mmol) and tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (3.3 g, 12.0 mmol) in DMF (10 mL) was added cesium carbonate (11.7 g, 36.1 mmol) at 25 °C. The mixture was stirred at 25 °C for 3 h. The organic phase was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-15% methanol in dichloromethane in 20 min to give the desired product (1.2 g, 35% yield) as a brown solid. LC-MS: m / z 281.2 [M+H] + .

[0332] Additional intermediates of the present invention were prepared by using the corresponding derivatives. Selected compounds and their corresponding property data are shown in the table below.

[0333] [Table 16]

[0334] Synthesis Example 1 [ka] To a stirred solution of 1-(6-amino-3-pyridyl)hexahydropyrimidin-2-one (38.1 mg, 198 μmol) and 5-(2-chloropyrimidin-4-yl)-3-isopropyl-pyrazolo[1,5-a]pyridine (45.0 mg, 165 μmol) in anhydrous 1,4-dioxane (2 mL) was added Pd2(dba)3 (15.1 mg, 16.5 μmol), RuPhos (7.7 mg, 16.5 μmol) and cesium carbonate (161 mg, 494 μmol) under N2 at 25 °C. The resulting mixture was stirred at 105 °C for 6 h. The reaction was cooled to 25 °C. The mixture was filtered and the filtrate was concentrated. The residue was purified by preparative HPLC to give the desired product (8.7 mg, 12% yield) as a yellow solid. LC-MS: m / z 429.2 [M+H] + .

[0335] CDK4 IC 50 :A;CDK6 IC 50 :B;CDK2 IC 50 :C.

[0336] Synthesis Example 16 [ka]

[0337] To a mixture of 1-(6-amino-3-pyridyl)-4-(dimethylamino)piperidin-2-one (30 mg, 128 μmol) and 5-(2-chloropyrimidin-4-yl)-3-isopropyl-pyrazolo[1,5-a]pyridine (38.4 mg, 140.8 μmol) in dioxane (5 mL) was added cesium carbonate (125.1 mg, 384.1 μmol), tris(dibenzylideneacetone)dipalladium(0) (11.7 mg, 12.8 μmol) and RuPhos (11.9 mg, 25.6 μmol). The resulting mixture was stirred at 110° C. for 4 h under nitrogen atmosphere. The reaction mixture was extracted with EA (20 mL). The organic phase was washed with water (3×20 mL), brine (3×20 mL) and dried over Na2SO4. The mixture was concentrated under reduced pressure and purified by flash column chromatography (DCM / MeOH=10:1) to give the desired product (23.8 mg, 39% yield) as a yellow solid. LC-MS: m / z 471.2 [M+H] + .

[0338] CDK4 IC 50 :A;CDK6 IC 50 :A;CDK2 IC 50 :B.

[0339] Synthesis Examples 160 and 161 [ka]

[0340] N-[5-[4-(dimethylamino)-1-piperidyl]-2-pyridyl]-4-(3-isopropylpyrazolo[1,5-a]pyridin-5-yl)pyrimidin-2-amine (210 mg, 459.9 μmol) was separated by chiral separation using SFC (hexane / EtOH / DEA=60 / 40 / 0.1) with a mobile phase (wavelength: UV214 nm, column: CHIRALCEL OD-H5.0 cm ID×25 cm L, flow rate: 60 mL / min) to obtain Synthesis Example 160 (44.2 mg, 21% yield) as a yellow solid (LC-MS: m / z 471.2 [M+H] + , ee value >99%), Synthesis Example 161 (41.0 mg, 19% yield) was obtained as a yellow solid (LC-MS: m / z 471.2 [M+H] + , ee value 97%).

[0341] Synthesis Example 160, CDK4 IC 50 :A;CDK6 IC 50 :B;CDK2 IC 50 :B.

[0342] Synthesis example 161, CDK4 IC 50 :A;CDK6 IC 50 :A;CDK2 IC 50 :A.

[0343] Synthesis Example 10 [ka]

[0344] To a solution of 1-methylsulfonylpiperidin-4-amine (20.2 mg, 113.5 μmol) and 5-(2-chloro-5-fluoro-pyrimidin-4-yl)-3-isopropyl-pyrazolo[1,5-a]pyridine (30 mg, 103.2 μmol) in anhydrous dioxane (8 mL), tris(dibenzylideneacetone)dipalladium(0) (9.45 mg, 10.3 μmol), dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (9.6 mg, 20.6 μmol) and cesium carbonate (100.8 mg, 309.5 μmol) were added under N2 atmosphere. The reaction mixture was then stirred at 110° C. for 5 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography to give the desired product (9 mg, 20% yield) as a pale yellow solid. LC-MS: m / z 433.2 [M+H] + .

[0345] CDK4 IC 50 :B;CDK6 IC 50 :C;CDK2 IC 50 :B.

[0346] Synthesis Example 175 [ka]

[0347] To a solution of 3-tert-butyl-5-(2-chloropyrimidin-4-yl)pyrazolo[1,5-a]pyridine (40 mg, 139.4 μmol) and 1-(6-amino-3-pyridyl)-4-(dimethylamino)piperidin-2-one (32.6 mg, 139.4 μmol) in anhydrous dioxane (8 mL) was added tris(dibenzylideneacetone)dipalladium(0) (12.7 mg, 13.95 μmol), RuPhos (13 mg, 27.9 μmol) and cesium carbonate (136.3 mg, 418.4 μmol) under N2 atmosphere. The reaction mixture was then stirred at 110° C. for 3 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (40 g silica gel column, 0-10% DCM in MeOH) to give the desired product (25 mg, 37% yield) as a yellow solid. LC-MS: m / z 485.3 [M+H] + .

[0348] CDK4 IC 50 :A;CDK6 IC 50 :A;CDK2 IC 50 :A. [Table 17-1] [Table 17-2] [Table 17-3] [Table 17-4] [Table 17-5] [Table 17-6] [Table 17-7]

[0349] Synthesis Example 29 [ka]

[0350] Step 1 To a solution of 5-(2-chloro-5-fluoro-pyrimidin-4-yl)-3-isopropyl-pyrazolo[1,5-a]pyridine (150 mg, 515 μmol) and tert-butyl 4-(6-amino-3-pyridyl)-3-oxo-piperazine-1-carboxylate (196 mg, 670 μmol) in dioxane (20 mL) was added tris(dibenzylideneacetone)dipalladium(0) (47.2 mg, 51.6 μmol), RuPhos (24.0 mg) and cesium carbonate (336 mg, 1.0 mmol) at 25 °C. The mixture was then stirred at 110 °C for 2 h. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-15% MeOH in DCM in 20 min to give the desired product (240 mg, 85% yield) as a pale yellow solid. LC-MS: m / z 547.2 [M+H] + .

[0351] Step 2 To a solution of tert-butyl 4-[6-[[5-fluoro-4-(3-isopropylpyrazolo[1,5-a]pyridin-5-yl)pyri-midin-2-yl]amino]-3-pyridyl]-3-oxo-piperazine-1-carboxylate (240 mg, 439 μmol) in DCM (2 mL) was added HCl (2 mL, 2N in EA) at 25° C. The mixture was stirred for 2 h. The mixture was filtered and the residue was washed with Et2O (10 mL) to give the desired product (190 mg, 96% yield) as a yellow solid. LC-MS: m / z 447.2 [M+H] + .

[0352] CDK4 IC 50 :A;CDK6 IC 50 :B;CDK2 IC 50:B.

[0353] Synthesis Example 204 [ka]

[0354] Step 1 To a solution of tert-butyl N-[1-(6-amino-3-pyridyl)-2-oxo-4-piperidyl]-N-methyl-carbamate (399.4 mg, 1.2 mmol) in dioxane (30 mL) was added 5-(2-chloropyrimidin-4-yl)-3-isopropyl-pyrazolo[1,5-a]pyridine (340 mg, 1.2 mmol), tris(dibenzylideneacetone)dipalladium(0) (114.1 mg, 124.6 μmol), RuPhos (116.3 mg, 249.3 μmol) and cesium carbonate (812.3 mg, 2.4 mmol). In a 15 mL sealed tube, the reaction mixture was stirred at 110° C. for 16 h. The mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography (12 g silica gel, 0-10% MeOH in DCM) to give the desired product (544 mg, 78% yield) as a yellow oil. LC-MS: m / z 557.3 [M+H] + .

[0355] Step 2 To a solution of tert-butyl N-[1-[6-[[4-(3-isopropylpyrazolo[1,5-a]pyridin-5-yl)pyrimidin-2-yl]amino]-3-pyridyl]-2-oxo-4-piperidyl]-N-methyl-carbamate (544 mg, 977.2 μmol) in DCM (10 mL) was added hydrogen chloride solution (2.0 M in ethyl acetate) (5 mL) at 25° C. The mixture was stirred at 25° C. for 2 h. The mixture was filtered and concentrated in vacuo to give the desired product (430 mg, 96% yield) as a yellow solid. LC-MS: m / z 457.3 [M+H] + .

[0356] CDK4 IC 50 :A;CDK6 IC 50 :A;CDK2 IC50 :A.

[0357] Synthesis Examples 205 and 206 [ka]

[0358] 1-[6-[[4-(3-isopropylpyrazolo[1,5-a]pyridin-5-yl)pyrimidin-2-yl]amino]-3-pyridyl]-4-(methylamino)piperidin-2-one (380 mg, 832 μmol) was subjected to chiral separation using an ID column (MeOH / ACN / DEA=50 / 50 / 0.1) with a mobile phase (wavelength: UV214 nm, column: CHIRALPAK ID-H25 cm L5.0 cm ID10 μm, flow rate: 60 g / min) to obtain Synthesis Example 205 (132 mg, 34% yield) as a white solid (LC-MS: m / z 457.3 [M+H] + , ee value:>98%). Synthesis Example 206 (120 mg, yield 31%) was obtained as a white solid (LC-MS: m / z 457.3 [M+H] + , ee value:>98%).

[0359] Synthesis example 205, CDK4 IC 50 :A;CDK6 IC 50 :A;CDK2 IC 50 :A.

[0360] Synthesis example 206, CDK4 IC 50 :A;CDK2 IC 50 :A. [Table 18-1] [Table 18-2] [Table 18-3] [Table 18-4] [Table 18-5] [Table 18-6] [Table 18-7]

[0361] Synthesis Example 39 [ka]

[0362] Step 1 To a solution of 5-iodopyridin-2-amine (100 mg, 454 μmol) and tert-butyl N-(5-oxopyrrolidin-3-yl)carbamate (91.1 mg, 454 μmol) in dioxane (5 mL) was added CuI (8.6 mg, 45.4 μmol), tripotassium phosphate (289 mg, 1.3 mmol) and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (12.9 mg, 90.9 μmol) under N2 atmosphere. The reaction was stirred at 110 °C for 8 h. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (eluted with 0-35% MeOH in DCM) to give the desired product (90.0 mg, 67% yield) as a yellow solid. LC-MS: m / z 292.2 [M+H] + .

[0363] Step 2 To a solution of tert-butyl N-[1-(6-amino-3-pyridyl)-5-oxo-pyrrolidin-3-yl]carbamate (90.0 mg, 307 μmol) and 5-(2-chloropyrimidin-4-yl)-3-isopropyl-pyrazolo[1,5-a]pyridine (83.9 mg, 307 μmol) in dioxane (2 mL) was added cesium carbonate (300 mg, 923 μmol), dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (28.7 mg, 61.5 μmol) and tris(dibenzylideneacetone)dipalladium(0) (28.1 mg, 30.7 μmol) under N2 atmosphere. The reaction was stirred at 110° C. for 8 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with 0-10% MeOH in DCM to give the desired product (90.0 mg, 55% yield) as a yellow solid. LC-MS: m / z 529.3 [M+H] + .

[0364] Step 3 To a solution of tert-butyl N-[1-[6-[[4-(3-isopropylpyrazolo[1,5-a]pyridin-5-yl)pyrimidin-2-yl]amino]-3-pyridyl]-5-oxo-pyrrolidin-3-yl]carbamate (90.0 mg, 170 μmol) in DCM (10 mL) was added HCl in EA (4N, 0.1 mL). The reaction was stirred at 25° C. for 2 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with 0-10% MeOH in DCM to give the desired product (70.0 mg, 95% yield) as a yellow solid. LC-MS: m / z 429.2 [M+H] + .

[0365] Step 4 4-Amino-1-[6-[[4-(3-isopropylpyrazolo[1,5-a]pyridin-5-yl)pyrimidin-2-yl]amino]-3-pyridyl]pyrrolidin-2-one (50.0 mg, 116 μmol) and formaldehyde (14.0 mg, 466 μmol) in DCM (5 mL) were stirred at 25° C. for 0.5 h. Then NaBH(OAc)3 (74.1 mg, 350 μmol) was added to the above solution. The mixture was stirred at 25° C. for 8 h. The reaction was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the desired product (15.9 mg, 29% yield) as a yellow solid. LC-MS: m / z 457.2 [M+H] + .

[0366] CDK4 IC 50 :A;CDK6 IC 50 :B;CDK2 IC 50 :B.

[0367] Synthesis Example 40 [ka]

[0368] Step 1 To a solution of 1-[6-[[4-(3-isopropylpyrazolo[1,5-a]pyridin-5-yl)pyrimidin-2-yl]amino]-3-pyridyl]piperazin-2-one (80 mg, 186 μmol) and tert-butyl 3-oxoazetidine-1-carboxylate (63.9 mg, 373 μmol) in DCM (10 mL) was added sodium triacetoxyborohydride (118 mg, 560 μmol) and acetic acid (16.8 mg, 280 μmol). The reaction mixture was stirred at 15 °C for 12 h. The reaction mixture was washed with H2O (5 ml) and brine (5 mL). The organic layer was concentrated and the residue was purified by flash column chromatography (12 g silica gel column, MeOH 0-10% in DCM) to give the desired product (72.0 mg, 66% yield) as a yellow solid. LC-MS: m / z 584.3 [M+H] + .

[0369] Step 2 A solution of tert-butyl 3-[4-[6-[[4-(3-isopropylpyrazolo[1,5-a]pyridin-5-yl)pyrimidin-2-yl]amino]-3-pyridyl]-3-oxo-piperazin-1-yl]azetidine-1-carboxylate (70.0 mg, 119 μmol) in HCl / 1,4-dioxane (1N, 10 mL) was stirred at 25° C. for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (20 g silica gel column, MeOH 0-10% in DCM) to give the desired product (12.5 mg, 21% yield) as a yellow solid. LC-MS: m / z 484.2 [M+H] + .

[0370] CDK4 IC 50 :A;CDK6 IC 50 :B;CDK2 IC 50 :B. [Table 19]

[0371] Synthesis Example 43 [ka]

[0372] A solution of 4-[6-[[5-fluoro-4-(3-isopropylpyrazolo[1,5-a]pyridin-5-yl)pyrimidin-2-yl]amino]-3-pyridyl]-1,4-diazepan-5-one (40.0 mg, 86.8 μmol), oxetan-3-one (9.0 mg, 124 μmol) and NaBH3CN (20.0 mg, 300 μmol) in methanol (8 mL) was stirred at 25° C. for 16 h. The mixture was filtered and the filtrate was concentrated. The residue was purified by preparative HPLC to give the desired product (12.3 mg, 27% yield) as a yellow solid. LC-MS: m / z 517.3 [M+H] + .

[0373] CDK4 IC 50:A;CDK6 IC 50 :B;CDK2 IC 50 :B. [Table 20]

[0374] Synthesis Example 49 [ka]

[0375] A solution of 4-[6-[[5-fluoro-4-(3-isopropylpyrazolo[1,5-a]pyridin-5-yl)pyrimidin-2-yl]amino]-3-pyridyl]-1,4-diazepan-5-one (20 mg, 43.4 μmol), bromocyclopropane (4.7 mg, 39.0 μmol) and silver carbonate (7.2 mg, 43.4 μmol) in methylbenzene (5 mL) was stirred at 70° C. for 5 h. The mixture was diluted with water (15 mL) and extracted with DCM (2×20 mL). The combined organic phases were concentrated under reduced pressure. The residue was purified by preparative HPLC to give the desired product (2 mg, 9% yield) as a yellow solid. LC-MS: m / z 501.2 [M+H] + .

[0376] CDK4 IC 50 :A;CDK2 IC 50 :C.

[0377] Synthesis Example 50 [ka]

[0378] To a stirred solution of 1-[6-[[5-fluoro-4-(3-isopropylpyrazolo[1,5-a]pyridin-5-yl)pyrimidin-2-yl]amino]-3-pyridyl]-1,4-diazepan-2-one (22.0 mg, 47.7 μmol) and TEA (10 mg, 100 μmol) in DCM (5 mL) was added methylsulfonyl chloride (7.3 mg, 64.2 μmol). The reaction mixture was stirred at 20° C. for 16 h. The reaction mixture was quenched with water (3 mL) and then extracted with ethyl acetate (2×5 mL). The combined organic phases were dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the desired product (5.0 mg, 17% yield) as a yellow solid. LC-MS: m / z 539.2 [M+H] + .

[0379] CDK4 IC 50 :A;CDK6 IC 50 :B;CDK2 IC 50 :B. [Table 21]

[0380] Synthesis Example 52 [ka]

[0381] To a solution of 5-[6-[[5-fluoro-4-(3-isopropylpyrazolo[1,5-a]pyridin-5-yl)pyrimidin-2-yl]amino]-3-pyridyl]azepan-4-one (30.0 mg, 65.2 μmol) and dipotassium carbonate (27.0 mg, 195 μmol) in acetonitrile (5 mL) was added 2-iodoethanol (13.4 mg, 78.3 μmol) at 25° C. The reaction mixture was stirred at 50° C. for 16 h. The mixture was quenched with water (20 mL) and then extracted with ethyl acetate (2×10 mL). The combined organic phases were dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the desired product (5.0 mg, 15% yield) as a yellow solid. LC-MS: m / z 505.3 [M+H] + .

[0382] CDK4 IC 50 :A;CDK6 IC 50 :B;CDK2 IC 50 :B. [Table 22]

[0383] Synthesis Example 55 [ka]

[0384] A solution of 4-(3-isopropylpyrazolo[1,5-a]pyridin-5-yl)-N-[1-(4-piperidylmethyl)pyrazol-3-yl]pyrimidin-2-amine (20.0 mg, 48.0 μmol), 2-hydroxyacetic acid (5.4 mg, 72.0 μmol), 4-methylmorpholine (4.8 mg, 48.0 μmol), EDCI (13.8 mg, 71.9 μmol) and HOBT (9.7 mg, 72.0 μmol) in DCM (4 mL) was stirred at 20° C. for 5 h. The mixture was diluted with water (15 mL) and extracted with DCM (2×20 mL). The combined organic phases were concentrated under reduced pressure. The residue was purified to give the desired product (3.7 mg, 16% yield) as a yellow solid. LC-MS: (ESI) m / z 475.3 [M+H] + .

[0385] CDK4 IC 50 :B;CDK2 IC 50 :D. [Table 23]

[0386] Synthesis Example 57 [ka]

[0387] A mixture of 5-(2-chloropyrimidin-4-yl)-3-isopropyl-6,7-dihydro-4H-imidazo[4,5-c]pyridine (66.0 mg, 237 μmol), 4-(6-amino-3-pyridyl)tetrahydropyran-3-one (54.8 mg, 285 μmol), tris(dibenzylideneacetone)dipalladium(0) (21.7 mg, 23.7 μmol), dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (22.1 mg, 47.5 μmol) and cesium carbonate (232 mg, 712 μmol) in dioxane (6.5 mL) was stirred at 110° C. for 6 h under N2 atmosphere. The reaction mixture was quenched with water (50 mL) and then extracted with EtOAc (2×100 mL). The combined organic phase was dried over anhydrous Na2SO4 and then filtered. The filtrate was concentrated. The residue was purified by preparative HPLC to give the desired product (9.9 mg, 19% yield) as a white solid. LC-MS: (ESI) m / z 435.3 [M+H] + .

[0388] CDK4 IC 50 :A;CDK6 IC 50 :C;CDK2 IC 50 :B. [Table 24-1] [Table 24-2] [Table 24-3]

[0389] Synthesis Example 58 [ka]

[0390] A mixture of 5-(6-chloro-3-fluoro-2-pyridyl)-3-isopropyl-2-methyl-pyrazolo[3,4-c]pyridine (30.0 mg, 98.4 μmol), 5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-amine (26.0 mg, 118 μmol), Pd2(dba)3 (4.5 mg, 4.9 μmol), RuPhos (4.5 mg, 9.8 μmol) and Cs2CO3 (64.1 mg, 196 μmol) in dioxane (4 mL) was stirred at 100° C. for 1 h under N2 atmosphere. The reaction mixture was quenched with water (50 mL) and extracted with EA (2×100 mL). The combined organic phase was dried over anhydrous Na2SO4 and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the desired product (3.0 mg, 6% yield) as a yellow solid. LC-MS: (ESI) m / z 490.1 [M+H] + .

[0391] CDK4 IC 50 :C;CDK6 IC 50 :D.

[0392] Synthesis Example 59 [ka]

[0393] Step 1 A mixture of 2-chloro-4-(7-fluoro-3,3-dimethyl-2,3-dihydrobenzofuran-5-yl)pyrimidine (50.0 mg, 180 μmol), tert-butyl 4-(6-aminopyridin-3-yl)-3-oxopiperazine-1-carboxylate (26.0 mg, 216 μmol), Pd2(dba)3 (10.0 mg, 10.0 μmol), RuPhos (10.0 mg, 19.0 μmol) and Cs2CO3 (130 mg, 400 μmol) in dioxane (8 mL) was stirred at 100° C. for 1 h under N2 atmosphere. The reaction mixture was quenched with water (50 mL) and extracted with EA (2×100 mL). The combined organic phase was dried over anhydrous Na2SO4 and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the desired product (60 mg, 50%). LC-MS: (ESI) m / z 535.2 [M+H] + .

[0394] Step 2 A solution of tert-butyl 4-(6-((4-(7-fluoro-3,3-dimethyl-2,3-dihydrobenzofuran-5-yl)pyrimidin-2-yl)amino)pyridin-3-yl)-3-oxopiperazine-1-carboxylate (60.0 mg, 112 μmol) in HCl / 1,4-dioxane (1N, 10 mL) was stirred at 25° C. for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (20 g silica gel column, MeOH 0-10% in DCM) to give the desired product (38.0 mg, 78% yield) as a yellow solid. LC-MS: m / z 435.2 [M+H] + .

[0395] CDK4 IC 50 :A;CDK6 IC 50 :B;CDK2 IC 50 :B. [Table 25-1] [Table 25-2]

[0396] Synthesis Example 60 [ka]

[0397] Step 1 To a solution of 5-bromo-3-methoxypyrazin-2-amine (500 mg, 2.5 mmol) in EtOH (10 mL) was added 2-chloro-3-methylbutanal (443 mg, 3.68 mmol) dropwise at 25° C. The mixture was stirred at 80° C. for 2 h. The mixture was concentrated to give a residue. The residue was purified by silica gel column chromatography (PE:EtOAc=10:1-5:1) to give the desired product (25.0 mg, 4% yield) as a yellow solid. LC-MS: (ESI) m / z 270.0 [M+H] + .

[0398] Step 2 To a solution of 6-bromo-3-isopropyl-8-methoxyimidazo[1,2-a]pyrazine (25.0 mg, 0.09 mmol) in dioxane (5 mL) was added B2Pin2 (150 mg, 0.6 mmol), KOAc (27.0 mg, 0.3 mmol) and Pd(DPPF)Cl2 (15.0 mg, 0.02 mmol) at 25 °C under N2 atmosphere. The mixture was stirred at 110 °C for 3 h. The mixture was filtered through diatomaceous earth and concentrated to give the desired product (30 mg) as a yellow solid, which was used in the next step without purification. LC-MS: (ESI) m / z 236.1 [M+H] + .

[0399] Step 3 To a solution of (3-isopropyl-8-methoxyimidazo[1,2-a]pyrazin-6-yl)boronic acid (25.0 mg, 0.1 mmol) and 4-chloro-N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoropyrimidin-2-amine (37.0 mg, 0.2 mmol) in dioxane (4 mL) and water (1 mL) was added K2CO3 (30.0 mg, 0.2 mmol) and Pd(dppf)Cl2 (15.0 mg, 0.02 mmol) at 25 °C under N2 atmosphere. The mixture was stirred at 100 °C for 3 h. The mixture was filtered through Celite and concentrated. The residue was purified by preparative HPLC to give the desired product (5.1 mg, 9% yield) as a yellow solid. LC-MS: (ESI) m / z 506.3 [M+H] + .

[0400] CDK4 IC 50 :B;CDK6 IC 50 :C.

[0401] Synthesis Example 61 [ka]

[0402] To a mixture of 6-(2-chloropyrimidin-4-yl)-4-fluoro-1-isopropyl-imidazo[4,5-c]pyridine (22.0 mg, 75.4 μmol) in 1,4-dioxane (5 mL), 4-(6-amino-3-pyridyl)morpholin-3-one (16.0 mg, 82.8 μmol), dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (12.0 mg, 25.7 μmol), tris(dibenzylideneacetone)dipalladium (11.0 mg, 12.0 μmol) and cesium carbonate (80.0 mg, 245 μmol) were added, and the mixture was degassed with N2. The resulting mixture was stirred at 100° C. for 12 hours. The mixture was concentrated and purified by column (DCM / MeOH=20 / 1-8 / 1) to give the desired product (1 mg, 3% yield). LC-MS: m / z 449.1 [M+H] + .

[0403] CDK4 IC 50 :A;CDK6 IC 50 :B;CDK2 IC 50 :B.

[0404] Synthesis Example 287 [ka]

[0405] To a solution of 5-(4-isopropylpiperazin-1-yl)pyridin-2-amine (124.6 mg, 565 μmol) and 6-(2-chloropyrimidin-4-yl)-4-fluoro-1-isopropyl-imidazo[4,5-c]pyridine (150 mg, 514 μmol) in dioxane (15 mL) was added Pd2(dba)3 (47.1 mg, 51 μmol), RuPhos (47.9 mg, 102 μmol) and Cs2CO3 (502.6 mg, 1.5 mmol). The mixture was stirred at 110 °C under N2 for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-10% MeOH in DCM to give the desired product (107.2 mg, 43% yield) as a yellow solid. LC-MS: m / z 476.2 [M+H] + .

[0406] CDK4 IC 50 :A;CDK6 IC 50 :B;CDK2 IC 50 :C.

[0407] Synthesis Example 301 [ka]

[0408] Step 1 To a solution of 6-(2-chloropyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-imidazo[4,5-c]pyridine (150 mg, 490.6 μmol) and tert-butyl N-[1-(6-amino-3-pyridyl)-2-oxo-3-piperidyl]carbamate (150.3 mg, 490.6 μmol) in dioxane (5 mL) was added cesium carbonate (479.5 mg, 1.4 mmol), RuPhos (45.7 mg, 98.1 umol) and tris(dibenzylideneacetone)dipalladium(0) (44.9 mg, 49.0 μmol). The reaction was stirred at 110° C. for 8 hours. The reaction was purified by column chromatography eluting with 0-4% MeOH in DCM in 15 min to give the desired product (170 mg, 60% yield) as a yellow solid.

[0409] Step 2 To a solution of tert-butyl N-[1-[6-[[4-(4-fluoro-1-isopropyl-2-methyl-imidazo[4,5-c]pyridin-6-yl)pyrimidin-2-yl]amino]-3-pyridyl]-2-oxo-3-piperidyl]carbamate (170 mg, 295.3 μmol) in DCM (5 mL) was added HCl (2M, 738 μL). The reaction was stirred at 25° C. for 3 h. The reaction was concentrated under reduced pressure to give the desired product (140 mg, 99% yield) as a yellow solid.

[0410] Step 3 To a solution of 3-amino-1-[6-[[4-(4-fluoro-1-isopropyl-2-methyl-imidazo[4,5-c]pyridin-6-yl)pyrimidin-2-yl]amino]-3-pyridyl]piperidin-2-one (80 mg, 168.2 μmol) in THF (5 mL) was added formaldehyde (50.5 mg, 1.6 mmol). After 1 h, sodium cyanoborohydride (31.7 mg, 504.7 μmol) was added to the above solution. The reaction was stirred at 25° C. for 2 h. The reaction was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the desired product (5.7 mg, 6% yield) as a yellow solid. LC-MS: m / z 504.3 [M+H] + .

[0411] CDK4 IC 50 :A;CDK6 IC 50 :A;CDK2 IC 50 :D.

[0412] Synthesis Examples 302 and 303 [ka]

[0413] 3-(Dimethylamino)-1-[6-[[4-(4-fluoro-1-isopropyl-2-methyl-imidazo[4,5-c]pyridin-6-yl)pyrimidin-2-yl]amino]-3-pyridyl]piperidin-2-one (170 mg, 337.6 μmol) was separated by SFC (column: Daicel CHIRALPAK OD_3, 3×150 mm, 3 μm; mobile phase: A / B: CO2 / MeOH (0.1% DEA)=70 / 30; flow rate: 2.0 mL / min) to give Synthesis Example 302 (50 mg, 29% yield) (LC-MS: m / z 504.3 [M+H] + , ee value: 94%) and Synthesis Example 303 (50 mg, yield 29%) (LC-MS: m / z 504.3 [M + H] + , ee value: 94%) was obtained as a white solid.

[0414] Synthesis example 302, CDK4 IC 50 :A;CDK2 IC 50 :D.

[0415] Synthesis Example 303, CDK4 IC 50 :A;CDK2 IC 50 :D. [Table 26-1] [Table 26-2] [Table 26-3] [Table 26-4] [Table 26-5] [Table 26-6]

[0416] Synthesis Example 62 [ka]

[0417] To a mixture of 1-(6-amino-3-pyridyl)-4-(dimethylamino)piperidin-2-one (85.0 mg, 363 μmol), 6-(2-chloro-5-fluoro-pyrimidin-4-yl)-1-isopropyl-4-methoxy-2-methyl-imidazo[4,5-c]pyridine (122 mg, 363 μmol) and 2-dicyclohexylphosphino-2',6'-di-ipropoxy-1,1'-biphenyl (33.0 mg, 72.6 μmol) in dioxane (10 mL) was added Cs2CO3 (355 mg, 1.1 mmol) and tris(dibenzylideneacetone)dipalladium (33.0 mg, 36.3 μmol) and the resulting mixture was stirred at 110° C. for 4 hours under nitrogen atmosphere. The reaction was filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase column (C18, 20 g) eluted with (ACN:water (0.1% formic acid)=1:10) to give the desired product (9.8 mg, 5% yield) as a white solid. LC-MS: m / z 534.3 [M+H] + .

[0418] CDK4 IC 50 :A;CDK6 IC 50 :B;CDK2 IC 50 :D.

[0419] Synthesis Examples 62-1 and 62-2 [ka]

[0420] 4-(Dimethylamino)-1-[6-[[5-fluoro-4-(1-isopropyl-4-methoxy-2-methyl-imidazo[4,5-c]pyridin-6-yl)pyrimidin-2-yl]amino]-3-pyridyl]piperidin-2-one (7.9 mg, 14.8 μmol) was purified by chiral-HPLC (instrument: SFC 80, column: Daicel CHIRALPAK OJ-H250mm 20 mm ID, 5 μm, mobile phase: CO2 / MeOH (0.2% NH4OH) = 50 / 50, flow rate: 45 g / min, wavelength: UV214 nm, temperature: 35 °C) to give isomer 2: (2.3 mg, yield 29%) (LC-MS: m / z 534.3 [M+H] + , RT = 12.72 min, ee value > 99%), Isomer 1: (1.6 mg, 20% yield) (LC-MS: m / z 534.3 [M + H] + , RT=10.95 min, ee value >99%) was obtained.

[0421] Example 62-1, CDK4 IC 50 :A;CDK6 IC 50 :B;CDK2 IC 50 :D.

[0422] Example 62-2, CDK4 IC 50 :A;CDK6 IC 50 :B;CDK2 IC 50 :D. [Table 27-1] [Table 27-2] [Table 27-3] [Table 27-4] [Table 27-5] [Table 27-6] [Table 27-7]

[0423] Synthesis Example 106 [ka]

[0424] Step 1 To a solution of 6-(2-chloro-5-fluoro-pyrimidin-4-yl)-1-isopropyl-4-methoxy-2-methyl-imidazo[4,5-c]pyridine (70.0 mg, 208 μmol) in dry dioxane (10 mL) was added tert-butyl 4-(6-amino-3-pyridyl)piperazine-1-carboxylate (69.6 mg, 250 μmol), tris(dibenzylideneacetone)dipalladium(0) (19.0 mg, 20.8 μmol), (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenylphosphane (24.1 mg, 41.7 μmol) and cesium carbonate (203 mg, 625 μmol). The mixture was stirred at 110° C. for 16 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (4 g silica gel, 0-15% MeOH in DCM in 20 min) to give the desired product (92.0 mg, yield: 76%) as a white solid. LC-MS: m / z 578.2 [M+H] + .

[0425] Step 2 To a solution of tert-butyl 4-[6-[[5-fluoro-4-(1-isopropyl-4-methoxy-2-methyl-imidazo[4,5-c]pyridin-6-yl)pyrimidin-2-yl]amino]-3-pyridyl]piperazine-1-carboxylate (92.0 mg, 159 μmol) in dry DCM (5 mL) was added hydrogen chloride (4N in 1,4-dioxane) (5 mL). The reaction mixture was stirred at 25° C. for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the desired product (10.8 mg, 14% yield) as a yellow solid. LC-MS: m / z 478.2 [M+H] + .

[0426] CDK4 IC 50 :A;CDK6 IC 50 :B;CDK2 IC 50 :D. [Table 28-1] [Table 28-2]

[0427] Synthesis Example 121 [ka]

[0428] To a solution of 1-[6-[[5-fluoro-4-(1-isopropyl-4-methoxy-2-methyl-imidazo[4,5-c]pyridin-6-yl)pyrimidin-2-yl]amino]-3-pyridyl]piperazin-2-one (50.0 mg, 101 μmol) and 1-methylsulfonylethylene (21.6 mg, 203 μmol) in DMF (5 mL) was added DIPEA (30.9 mg, 305 μmol). The reaction mixture was stirred at 25 °C for 48 h. The reaction mixture was then diluted with H2O (30 ml) and extracted with EA (3 × 10 mL). The organic layer was concentrated under reduced pressure. The residue was purified by preparative HPLC eluting with acetonitrile in water (0.1% FA) 22% to 24% in 6.0 min to give the desired product (2.7 mg, 4% yield) as a yellow solid. LC-MS: m / z 598.3 [M+H] + .

[0429] CDK4 IC 50 :A;CDK6 IC 50 :B;CDK2 IC 50 :D. [Table 29]

[0430] Synthesis Example 127 [ka]

[0431] To a solution of 1-[6-[[5-fluoro-4-(1-isopropyl-4-methoxy-2-methyl-imidazo[4,5-c]pyridin-6-yl)pyrimidin-2-yl]amino]-3-pyridyl]piperazin-2-one (0.2 g, 305 μmol) and TEA (92.6 mg, 915 μmol) in DCM (5 mL) was added methylsulfonyl chloride (52.4 mg, 457 μmol) dropwise at 0° C. The mixture was stirred at 0° C. for 0.5 h. The mixture was concentrated and purified by preparative HPLC to give the desired product (7.8 mg, 4% yield) as a yellow solid. LC-MS: m / z 570.2 [M+H] + .

[0432] CDK4 IC 50 :A;CDK6 IC 50 :B;CDK2 IC 50 :C.

[0433] Synthesis Example 128 [ka]

[0434] To a solution of 1-[6-[[5-fluoro-4-(1-isopropyl-4-methoxy-2-methyl-imidazo[4,5-c]pyridin-6-yl)pyrimidin-2-yl]amino]-3-pyridyl]piperazin-2-one (100 mg, 203 μmol) and acetaldehyde (17.9 mg, 406 μmol) in DCM (5 mL) was added NaB(OAc)3H (129 mg, 610 μmol). The mixture was stirred at 25° C. for 1 h. The mixture was diluted with water (10 mL) and extracted with DCM (2×10 mL). The organic layers were combined, dried over Na2SO4, filtered, concentrated, and purified by preparative HPLC to give the desired product (16.0 mg, 15% yield) as a yellow solid.

[0435] CDK4 IC 50 :A;CDK6 IC 50 :B;CDK2 IC 50 :D. [Table 30-1] [Table 30-2]

[0436] Synthesis Example 138 [ka]

[0437] Step 1 To a stirred solution of tert-butyl 3-oxoazetidine-1-carboxylate (26.1 mg, 152 μmol) in methanol (5 mL) was added 1-[6-[[5-fluoro-4-(1-isopropyl-4-)methoxy-2-methyl-imidazo[4,5-c]pyridin-6-yl)pyrimidin-2-yl]amino]-3-pyridyl]piperazin-2-one (50.0 mg, 101 μmol). The reaction mixture was stirred at 25° C. for 1 h under N2 atmosphere. To the above mixture was added sodium cyanoborohydride (12.8 mg, 203 μmol). The reaction mixture was stirred at 25° C. for 11 h under N2 atmosphere. The mixture was concentrated and purified by flash column chromatography (4 g silica gel column), eluting with DCM / MeOH with 0-6% MeOH to give the desired product (25.0 mg, 38% yield) as a yellow solid. LC-MS: m / z 647.3 [M+H] + .

[0438] Step 2 To a stirred solution of tert-butyl 3-[4-[6-[[5-fluoro-4-(1-isopropyl-4-methoxy-2-methyl-imidazo]4,5-c]pyridin-6-yl)pyrimidin-2-yl]amino]-3-pyridyl]-3-oxo-piperazin-1-yl]azetidine-1-carboxylate (20.0 mg, 30.9 μmol) in DCM (3 mL) was added HCl (1N in dioxane, 3 mL). The reaction mixture was stirred at 25° C. under N2 atmosphere for 1 h. The mixture was concentrated and purified by preparative HPLC to give the desired product (1.8 mg, 11% yield) as a yellow solid. LC-MS: m / z 547.2 [M+H] + .

[0439] CDK4 IC 50 :A;CDK6 IC 50 :B;CDK2 IC 50 :C. [Table 31]

[0440] Synthesis Example 140 [ka]

[0441] To a mixture of 2-(dimethylamino)acetic acid (6.9 mg, 67.2 μmol) in DCM (6 mL) was added DIPEA (82.3 mg, 636 μmol). The mixture was stirred at 20° C. for 10 min. To the above mixture was added N-[4-(1-isopropyl-4-methoxy-imidazo[4,5-c]pyridin-6-yl)pyrimidin-2-yl]-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine (28.0 mg, 67.2 μmol) and HATU (25.7 mg, 67.3 μmol). The mixture was stirred at 20° C. for 12 h. The mixture was quenched with water (1 mL) and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the desired product (14.5 mg, 43% yield) as a yellow solid. LC-MS: (ESI) m / z 502.2 [M+H] + .

[0442] CDK4 IC 50 :A;CDK6 IC 50 :B;CDK2 IC 50 :D. [Table 32]

[0443] Synthesis Example 143 [ka]

[0444] Step 1 A solution of 2-chloro-3-methyl-butanal (1.1 g, 9.1 mmol) and 5-bromopyrazin-2-amine (1.6 g, 9.1 mmol) in ethylene glycol (10 mL) was stirred at 120 °C for 16 h. The mixture was diluted with water (25 mL) and extracted with EtOAc (2 x 25 mL). The combined organic phases were concentrated under reduced pressure. The residue was purified by FCC (20 g silica gel, 0-50% EtOAc in PE) to give the desired product (200 mg, 9% yield) as a yellow solid. LC-MS: (ESI) m / z 240.2 [M+H] + .

[0445] Step 2 A solution of 6-bromo-3-isopropyl-imidazo[1,2-a]pyrazine (480 mg, 999 μmol), (2-aminopyrimidin-4-yl)boronic acid (138 mg, 999.5 μmol), K2CO3 (276 mg, 2.0 mmol) and Pd(DPPF)Cl2 (73.1 mg, 99.9 μmol) in dioxane (10 mL) and H2O (0.5 mL) was stirred at 110 °C under N2 for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by FCC (20 g silica gel, MeOH 0-10% in DCM) to give the desired product (77.0 mg, 30% yield) as a dark solid. LC-MS: (ESI) m / z 255.1 [M+H] + .

[0446] Step 3 A solution of 4-(3-isopropylimidazo[1,2-a]pyrazin-6-yl)pyrimidin-2-amine (77.0 mg, 302 μmol), tert-butyl 4-(6-chloro-3-pyridyl)-3-oxo-piperazine-1-carboxylate (94.4 mg, 302 μmol), Cs2CO3 (197 mg, 605 μmol), RuPhos (28.2 mg, 60.5 μmol) and Pd2(dba)3 (27.7 mg, 30.2 μmol) in dioxane (8 mL) was stirred at 110 °C under N2 for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by FCC (12 g silica gel, MeOH 0-10% in DCM) to give the desired product (95.0 mg, 59% yield) as a yellow solid. LC-MS: (ESI) m / z 530.2 [M+H] + .

[0447] Step 4 To a solution of tert-butyl 4-[6-[[4-(3-isopropylimidazo[1,2-a]pyrazin-6-yl)pyrimidin-2-yl]amino]-3-pyridyl]-3-oxo-piperazine-1-carboxylate (95.0 mg, 179 μmol) in DCM (8 mL) was added HCl (4N, 180 μL) at 25° C. The reaction was stirred at 25° C. for 4 h. The mixture was concentrated under reduced pressure. The residue was purified by preparative reverse phase HPLC to give the desired product (19.4 mg, 25% yield) as a yellow solid. LC-MS: (ESI) m / z 430.2 [M+H] + .

[0448] CDK4 IC 50 :B;CDK2 IC 50 :D.

[0449] Comparative synthesis example 1 Compound 10, disclosed in CN109503573A, was prepared. As shown in the table below, this compound exhibits very weak activity in the CDK4 and CDK6 assays. [Table 33] [Table 34-1]

Table 34-2

Table 34-3

Claims

1. Compound represented by structural formula (II-A) 【Chemistry 1】 (Wherein, ring A is 【Chemistry 2】 and Ring B is 【Chemistry 3】 each optionally containing one or two R ２ may be substituted with The linker L is a bond, R １ is H, R ２ Each occurrence of is H, deuterium, halogen, -OH, CN, C １－８ Alkyl, C ２－８ Alkenyl, C ２－８ Alkynyl, C １－８ Alkoxy, -(CH ２ ) ｎ OR ６ , -(CH ２ ) ｎ S.R. ６ , -(CH ２ ) ｎ C(O)R ６ , -(CH ２ ) ｎ C(O)OR ６ , -(CH ２ ) ｎ S (O) ｍ R ６ , -(CH ２ ) ｎ N.R. ７ R ８ , -(CH ２ ) ｎ C(O)NR ７ R ８ , -(CH ２ ) ｎ N.R. ７ C(O)R ６ , -(CH ２ ) ｎ N.R. ７ S (O) ｍ R ６ , C ３－８ cycloalkyl, 3- to 10-membered heterocyclyl, 6- to 14-membered aryl, or 5- to 14-membered heteroaryl; R ２ The alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl represented by the formula (I) is independently selected from deuterium, halogen, CN, —OH, C １－８ Alkyl, C １－８ Haloalkyl, C １－８ Alkoxy, and NR ７ R ８ and optionally substituted with one or more groups selected from R ３ Each occurrence of １－４ Alkyl, or C ３－６ cycloalkyl, wherein said C １－４ Alkyl or C ３－６ The cycloalkyl may be optionally substituted by -OH; R ４ Each occurrence of is H, deuterium, halogen, C １－４ Alkyl, C ２－４ Alkenyl, C ３－６ cycloalkyl, or 3- to 6-membered heterocyclyl, １－４ The alkyl may be optionally substituted with fluoro, ３－６ The cycloalkyl may be optionally substituted with methyl or Two R's bonded to the same ring atom of ring A ４ The group is C ３－６ cycloalkyl or 3-6 membered heterocyclyl, each of which is optionally halogen, CN, —OH, C １－２ Alkyl, C １－２ Alkoxy, and NR ７ R ８ and optionally substituted with one or more groups selected from R ５ Each occurrence of is H, deuterium, halogen, CN, -OH, C １－４ Alkyl, C １－４ Alkoxy, or C １－４ is haloalkoxy; R ６ Each occurrence of １－８ Alkyl, C ２－８ Alkenyl, C ２－８ Alkynyl, C ３－８ cycloalkyl, 3- to 10-membered heterocyclyl, 6- to 14-membered aryl, or 5- to 14-membered heteroaryl; R ６ The C represented by １－８ Alkyl, C ２－８ Alkenyl, C ２－８ Alkynyl, C ３－８ Cycloalkyl, 3- to 10-membered heterocyclyl, 6- to 14-membered aryl, or 5- to 14-membered heteroaryl are each independently selected from halogen, CN, —OH, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, and NR ７ R ８ and optionally substituted with one or more groups selected from R ７ and R ８ Each occurrence of １－４ alkyl or cyclopropyl; R １２ Each occurrence of ３ , or C.F. ３ and k is 0, 1, or 2; n is 0, 1, 2, 3, 4, or 5; m is 0, 1, or 2), or a pharma- ceutically acceptable salt, or stereoisomer thereof.

2. R ２ Each occurrence of is H, halogen, CN, -OH, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, -(CH ２ ) ｎ OR ６ , -(CH ２ ) ｎ C(O)R ６ , -(CH ２ ) ｎ C(O)OR ６ , -(CH ２ ) ｎ S (O) ２ R ６ , -(CH ２ ) ｎ N.R. ７ R ８ , -(CH ２ ) ｎ C(O)NR ７ R ８ , -(CH ２ ) ｎ C(O)NHR ７ , -(CH ２ ) ｎ N.R. ７ C(O)R ６ , -(CH ２ ) ｎ N.R. ７ S (O) ２ R ６ , C ３－８ cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl; R ６ Each occurrence of １－４ Alkyl, C ３－６ Cycloalkyl, 3-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; R ６ C represented by １－４ Alkyl, C ３－６ Cycloalkyl, 3- to 7-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl are each independently selected from halogen, CN, —OH, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, or NR ７ R ８ and optionally substituted with 2. The compound of claim 1, or a pharma- ceutically acceptable salt, or stereoisomer thereof, wherein n is 0, 1, or 2.

3. R ２ Each occurrence of is H, halogen, CN, -OH, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, -(CH ２ ) ｎ S (O) ２ C １－４ Alkyl, -(CH ２ ) ｎ N.R. ７ R ８ , C ３－４ 3. The compound of claim 1 or 2, or a pharma- ceutically acceptable salt, or stereoisomer thereof, wherein n is 0, 1, or 2; cycloalkyl, or 3- to 6-membered heterocyclyl;

4. R ３ Each occurrence of １－３ C optionally substituted with alkyl or -OH ３－６ is cycloalkyl, R ４ Each occurrence of １－３ Alkyl, C ２－４ alkenyl, cyclopentyl, tetrahydro-2H-pyranyl, or 3,6-dihydro-2H-pyranyl; R ５ Each occurrence of is H, F, CN, methoxy, or OCHF. ２ 4. The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt or stereoisomer thereof,

5. R ２ Each occurrence of is H, halogen, CN, C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Hydroxyalkyl, NH ２ , N(CH ３ ) ２ , NHcyclopropyl, -(CH ２ ) ｎ S (O) ２ C １－３ alkyl, cyclopropyl, azetidinyl optionally substituted with F, oxetanyl, morpholinyl, piperidinyl, tetrahydro-2H-pyranyl; 5. The compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt, or stereoisomer thereof, wherein n is 0, 1, or 2.

6. R ３ Each occurrence of １－３ is alkyl, R ４ Each occurrence of １－３ is alkyl, R ５ 6. The compound of any one of claims 1 to 5, or a pharma- ceutically acceptable salt, or stereoisomer thereof, wherein each occurrence of is H, F, or OMe.

7. The compound according to any one of claims 1 to 6, or a pharma- ceutically acceptable salt, or stereoisomer thereof, wherein k is 0.

8. Ring B 【Chemistry 4】 each of which contains one or two R ２ 8. The compound of claim 1, or a pharma- ceutically acceptable salt, or stereoisomer thereof, optionally substituted with a group.

9. R ２ Each occurrence of is H, halogen, CN, C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Hydroxyalkyl, NH ２ , N(CH ３ ) ２ or NHcyclopropyl, or a pharma- ceutically acceptable salt, or stereoisomer thereof.

10. The compound is the following compound: 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】 【Table 1-6】 【Table 1-7】 【Table 1-8】 【Table 1-9】 【Table 1-10】 【Table 1-11】 【Table 1-12】 【Table 1-13】 【Table 1-14】 【Table 1-15】 【Table 1-16】 2. The compound of claim 1, or a pharma- ceutically acceptable salt or stereoisomer thereof.

11. The compound has the following structure: 【Chemistry 5】 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof.

12. The compound has the following structure: 【Chemistry 6】 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof.

13. The compound has the following structure: 【Chemistry 7】 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof.

14. The compound has the following structure: 【Chemistry 8】 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof.

15. The compound has the following structure: 【Chemistry 9】 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof.

16. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 15, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

17. 17. The pharmaceutical composition of claim 16 for treating cancer, wherein the cancer is selected from the group consisting of colorectal cancer, breast cancer, lung cancer, prostate cancer, glioblastoma, mantle cell lymphoma, chronic myeloid leukemia and acute myeloid leukemia.

18. 17. The pharmaceutical composition according to claim 16 for treating cancer by inhibiting cyclin dependent kinases (CDKs).

19. 19. The pharmaceutical composition of claim 18, wherein the cancer is cancer of the bladder, breast, colon, kidney, epidermis, liver, lung, esophagus, gallbladder, ovary, pancreas, stomach, cervix, thyroid, nose, head and neck, prostate, or skin, hematopoietic tumors of the lymphoid system, hematopoietic tumors of the myeloid system, follicular thyroid carcinoma, tumors of mesenchymal origin, tumors of the central or peripheral nervous system, melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, or Kaposi's sarcoma.

20. 20. The pharmaceutical composition of claim 19, wherein the lymphatic hematopoietic tumor is leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, multiple myeloma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, or Burkitt's lymphoma.

21. The cancer is ＋ Breast cancer, or hormone receptor (HR) positive (e.g., estrogen receptor positive (ER) ＋ ), progesterone receptor positive (PR ＋ ), or E.R. ＋ PR ＋ ), HER2 / neu negative breast cancer.

22. 22. The pharmaceutical composition of claim 21, wherein the cancer is advanced or metastatic or recurrent breast cancer.

23. 23. The pharmaceutical composition of claim 22, wherein the breast cancer is in an adult or postmenopausal woman.

24. 24. The pharmaceutical composition of any one of claims 19 to 23, for use with a second agent selected from an aromatase inhibitor, a selective estrogen receptor modulator (SERM), a pure anti-estrogen with no estrogen agonist activity, a compound that temporarily suppresses ovarian function (e.g. estrogen and / or progesterone production), such as a gonadotropin releasing hormone (GnRH) agonist or a luteinizing hormone releasing hormone (LH-RH) agonist, a compound that inhibits CCYP3A4, or a monoclonal antibody against IGF-1 / IGF-2 or an antigen-binding fragment thereof.

25. 25. The pharmaceutical composition according to any one of claims 17 to 24, for use with an immune checkpoint inhibitor (such as a PD-1 inhibitor, a PD-L1 inhibitor, or a CTLA-4 inhibitor), a receptor Tyr kinase inhibitor, and / or an antagonist of a hormone receptor (such as an estrogen receptor).

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