CDK inhibitors

Abstract

The present application provides CDK inhibitors. Specifically, the invention provides a compound which can be used for treating cancers and is represented by a structural formula (I) or pharmaceutically acceptable salts or stereoisomers thereof. # imgabs0 #

Description

[0001] This application is a divisional application of Chinese Patent Application (filing date: May 5, 2020; application number: 2020800490339).

[0002] Cross - Reference to Related Applications

[0003] This application claims the benefit of the priority of International Patent Application No. PCT / CN2019 / 085494, filed on May 5, 2019. The entire content of the foregoing application is incorporated herein by reference. Background Art

[0004] Cyclin-dependent kinases (CDKs) are a family of protein kinases that were initially discovered for their role in regulating the cell cycle. Since then, CDKs have been identified as playing a role in regulating many other biological functions such as transcription, mRNA processing, and the differentiation of nerve cells.

[0005] CDKs are relatively small proteins with a molecular weight between approximately 34 - 40 kDa. CDKs contain only 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 through binding to cyclins.

[0006] Like all kinases, the active site or ATP-binding site of CDK is a cleft between a small amino-terminal lobe and a larger carboxyl-terminal lobe. The structure of human CDK2 shows that CDK has a modified ATP-binding site that can be regulated by cyclin binding. Phosphorylation of Thr 161 on the T-loop by CDK-activating kinase (CAK) increases the activity of the complex. In the absence of cyclin, a flexible loop called the activation loop or T-loop blocks the cleft, and the positions of several key amino acid residues are not optimal for ATP binding. In the presence of cyclin, two α-helices change position to allow ATP binding. One of the helices, the L12 helix, which is just before the T-loop in the primary sequence, becomes a β-strand and helps to rearrange the T-loop so that it no longer blocks the active site. Another α-helix called the PSTAIRE helix rearranges and helps to change the positions of key amino acid residues in the active site.

[0007] Thus, only cyclin-CDK complexes possess active kinase activity, and most known cyclin-CDK complexes regulate the cell cycle progression. CDK is ubiquitous in all known eukaryotes, and the regulatory function of CDK in the cell cycle is evolutionarily conserved. For example, when the CDK gene in yeast cells is replaced by its human homolog, the yeast cells can proliferate normally. CDK exerts its regulatory function by phosphorylating its substrates at certain specific serine and threonine residues as well as at the consensus sequence of [S / T]PX[K / R], where S / T is the target Ser or Thr for phosphorylation, P is proline, X is any amino acid, K is lysine, and R is arginine.

[0008] In animal cells, there are at least nine different CDKs, four of which (CDK1, 2, 3, and 4) are directly involved in cell cycle regulation. In mammalian cells, CDK1 and its binding partners cyclin A2 and B1 can drive the cell cycle alone. Cyclin-CDK complexes in the early cell cycle stages can help activate cyclin-CDK complexes in the later stages.

[0009] The same CDK may form complexes with different cyclins to regulate different stages of the cell cycle. For example, CDK2 can form complexes with cyclin D or E to regulate the G1 phase; with cyclin A or E to regulate the S phase; and with cyclin A to regulate the G2 phase. Meanwhile, CDK4 and CDK6 can form complexes with cyclin D1, D2, and D3.

[0010] 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 exerts its function through the phosphorylation of the retinoblastoma protein (pRb). Once phosphorylated, pRb loses its inhibitory effect on the transcription of genes that promote entry into the S phase.

[0011] In contrast, specific inhibition of the CDK4 / 6 kinase activity by the endogenous protein regulator p16 INK4 or small molecule inhibitors results in hypophosphorylated pRb and cell arrest at the G1 restriction point. As a major mechanism for regulating the G1 restriction point, these kinase-regulated pathways are altered in a broad spectrum of human tumors, and thus inhibiting CDK4 / CDK6 in these tumors has therapeutic benefits by preventing cell division.

[0012] 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

[0013] This text describes compounds of formula (I), (II-A)-(II-J) and exemplified compounds (collectively referred to herein as "the compounds of the present invention") that inhibit the activity of cyclin-dependent kinases (CDKs), such as CDK2, CDK4, and / or CDK6, and their pharmaceutically acceptable salts or stereoisomers.

[0014] In one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof:

[0015]

[0016] wherein R 1 、R 2 、ring A, ring B, ring C and linker L are as defined herein.

[0017] In one embodiment, the compound or a pharmaceutically acceptable salt or stereoisomer thereof is selected from the exemplified compounds provided herein.

[0018] Also provided is a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt or stereoisomer thereof and a pharmaceutically acceptable carrier.

[0019] The present disclosure further provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of (1) a compound of the present invention or a pharmaceutically acceptable salt or stereoisomer thereof; or (2) a pharmaceutically acceptable composition comprising a compound of the present invention or a pharmaceutically acceptable salt or stereoisomer thereof and a pharmaceutically 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 myeloid leukemia, and acute myeloid leukemia.

[0020] In certain embodiments of the method of the present invention, cancer can be treated by inhibiting the activity of cyclin-dependent kinases (CDKs), such as CDK2, CDK4, and / or CDK6.

[0021] In certain embodiments of the methods of the present invention, the cancer is bladder cancer, breast cancer, colon cancer, kidney cancer, epidermal cancer, liver cancer, lung cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, nasal cancer, head and neck cancer, prostate cancer, or skin cancer; lymphoid hematopoietic tumors; myeloid hematopoietic tumors; follicular thyroid cancer; tumors of mesenchymal origin; central or peripheral nervous system tumors; melanoma; seminoma; teratoma; osteosarcoma; xeroderma pigmentosum; keratoacanthoma; follicular thyroid cancer; or Kaposi's sarcoma.

[0022] In certain embodiments of the methods of the present invention, the compounds of the present invention are administered together with any of a second therapeutic agent as described herein that also treats the same cancer.

[0023] The present disclosure also provides the use of the compounds of the present invention or pharmaceutically acceptable salts or stereoisomers thereof or pharmaceutical compositions comprising them in any of the methods of the present invention described above. In one embodiment, there is provided a compound of the present invention or a pharmaceutically acceptable salt or stereoisomer thereof or a pharmaceutical composition comprising them for any of the methods of the present invention described above. In another embodiment, there is provided the use of a compound of the present invention or a pharmaceutically acceptable salt or stereoisomer thereof or a pharmaceutical composition comprising them for the manufacture of a medicament for any of the methods of the present invention described. Detailed Description

[0024] 1. Overview

[0025] The present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof for a therapy such as cancer therapy.

[0026] The present invention also provides a pharmaceutical formulation comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent, or excipient.

[0027] The present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof that can be used to treat cancer. Specifically, those cancers can be any of the cancers described hereinbelow, such as colorectal cancer, breast cancer (including ER + HER2 - advanced or metastatic or recurrent breast cancer occurring in adult or postmenopausal women), lung cancer, particularly non-small cell lung cancer (NSCLC), prostate cancer, glioblastoma, mantle cell lymphoma (MCL), chronic myelogenous leukemia (CML), and acute myeloid leukemia (AML).

[0028] The present invention further provides a method for treating cancer in a mammal, said cancer being selected from the group consisting of: colorectal cancer, breast cancer (including ER + HER2 - advanced or metastatic or recurrent breast cancer occurring in adult or postmenopausal women), lung cancer, particularly non-small cell lung cancer (NSCLC), prostate cancer, glioblastoma, mantle cell lymphoma, chronic myeloid leukemia, and acute myeloid leukemia, said method comprising administering to a mammal in need of such treatment an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0029] In addition, the present invention provides the use of a compound of the present invention or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating cancer. Specifically, those cancers are selected from the group consisting of: colorectal cancer, breast cancer (including ER + HER2 - advanced or metastatic or recurrent breast cancer occurring in adult or postmenopausal women), lung cancer, particularly non-small cell lung cancer (NSCLC), prostate cancer, glioblastoma, mantle cell lymphoma, chronic myeloid leukemia, and acute myeloid leukemia.

[0030] Furthermore, the present invention provides a pharmaceutical formulation for therapy, said pharmaceutical formulation comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient. The present invention also provides a pharmaceutical composition for treating colorectal cancer, breast cancer (including ER + HER2 - advanced or metastatic or recurrent breast cancer occurring in adult or postmenopausal women), lung cancer, particularly non-small cell lung cancer (NSCLC), prostate cancer, glioblastoma, mantle cell lymphoma, chronic myeloid leukemia, and acute myeloid leukemia, said pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient.

[0031] The treatable disease indications and potential second therapeutic agents for combination therapy are described in further detail in the following sections.

[0032] It should be understood that any embodiment described herein, including those described only in one of the following sections or only in the examples, can be combined with any one or more other embodiments of the present invention, unless expressly disclaimed or otherwise inappropriate / inapplicable.

[0033] 2. Definitions

[0034] As used herein, the term "halo" or "halogen" means halogen and includes chlorine, fluorine, bromine, and iodine.

[0035] The term "alkyl", used alone or as part of a larger moiety, such as "alkoxy" or "haloalkyl", means a saturated aliphatic straight or branched chain monovalent hydrocarbon radical. Unless otherwise specified, alkyl generally has 1 to 4 carbon atoms, i.e., (C 1 -C 4 )alkyl. As used herein, "(C 1 -C 4 )alkyl" means a group having 1 to 4 carbon atoms arranged in a straight or branched chain. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0036] The term "alkenyl" means a branched or straight chain monovalent hydrocarbon radical containing at least one double bond. Alkenyl can be mono-unsaturated or poly-unsaturated and can exist in the E or Z configuration. Unless otherwise specified, alkenyl generally has 2 to 6 carbon atoms, i.e., (C 2 -C 6 )alkenyl. For example, "(C 2 -C 6 )alkenyl" means a group having 2 to 6 carbon atoms arranged in a straight or branched chain.

[0037] The term "alkynyl" means a branched or straight chain monovalent hydrocarbon radical containing at least one triple bond. Unless otherwise specified, alkynyl generally has 2 to 6 carbon atoms, i.e., (C 2 -C 6 )alkynyl. For example, "(C 2 -C 6 )alkynyl" means a group having 2 to 6 carbon atoms arranged in a straight or branched chain.

[0038] The term "alkoxy" means an alkyl group attached through an oxygen linking atom, represented by -O-alkyl. For example, "(C 1 -C 4 )alkoxy" includes methoxy, ethoxy, propoxy, and butoxy.

[0039] The terms "haloalkyl" and "haloalkoxy" mean an alkyl or alkoxy group optionally substituted with one or more halogen atoms. Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, etc.

[0040] The terms "hydroxyalkyl" and "hydroxyalkoxy" mean an alkyl or alkoxy group optionally substituted with one or more hydroxy groups.

[0041] As used herein, the term "cycloalkyl" includes saturated cyclic, bicyclic, tricyclic, or polycyclic hydrocarbon radicals having 3 to 14 carbons, said carbons containing a specified number of rings and carbon atoms (e.g., C 3 -C 14 monocyclic, C 4 -C14 Bicyclic, C 5 -C 14 Tricyclic or C 6 -C 14 Polycyclic cycloalkyl). In some embodiments, "cycloalkyl" is a monocyclic cycloalkyl. Examples of monocyclic cycloalkyls include cyclopentyl (C 5 ), cyclohexyl (C 5 ), cyclopropyl (C 3 ), cyclobutyl (C 4 ), cycloheptyl (C 7 ), and cyclooctyl (C 8 ). In some embodiments, "cycloalkyl" is a bicyclic cycloalkyl. Examples of bicyclic cycloalkyls include bicyclo[1.1.0]butane (C 4 ), bicyclo[1.1.1]pentane (C 5 ), spiro[2.2]pentane (C 5 ), bicyclo[2.1.0]pentane (C 5 ), bicyclo[2.1.1]hexane (C 6 ), bicyclo[3.3.3]undecane (C 11 ), decalin (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. Examples of tricyclic cycloalkyls include adamantane (C 12 ). Unless otherwise specified, "cycloalkyl" has three to six carbon atoms.

[0042] The term "aryl" as used alone or as part of a larger moiety in "aralkyl", "aralkoxy", or "aryloxyalkyl" means a carbocyclic aromatic ring. The term "aryl" may be used interchangeably with the terms "aromatic ring", "carbocyclic aromatic ring", "aryl", and "carbocyclic aromatic group". An aryl typically has six to fourteen ring atoms. Examples include phenyl, naphthyl, anthracenyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl, indenyl, etc. "Substituted aryl" is substituted at any one or more substitutable ring atoms, which are ring carbon atoms bonded to a hydrogen.

[0043] The term "heterocyclic group" or "heterocyclic moiety" means a monocyclic non-aromatic ring having 3 to 10 members with 1 to 4 ring heteroatoms or a polycyclic ring having 7 to 20 members and 1 to 4 ring heteroatoms, wherein 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); oxygen; and sulfur, including sulfoxide and sulfone. In one embodiment, the heterocyclic 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-ethylisoindol-5-yl, 2-methylisoindol-5-yl), indolyl, tetrahydrobenzo[f]oxazepinyl (such as 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-7-yl). The terms "heterocyclic", "heterocyclic group" or "heterocycle", whether saturated or partially unsaturated, also refer to optionally substituted rings. In some embodiments, the heterocyclic group is a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("3- to 14-membered heterocyclic group").

[0044] The terms "heteroaryl", "heteroaromatic", "heteroaryl ring", "heteroaryl group", "heteroaromatic ring", and "heteroaromatic moiety", used alone or as part of a larger moiety such as "heteroalkyl" or "heteroaryloxy", mean an aromatic ring group having five to fourteen ring atoms selected from carbon and at least one (usually 1 to 4, more usually 1 or 2) heteroatoms (e.g., oxygen, nitrogen, or sulfur). "Heteroaryl" includes monocyclic and polycyclic rings, wherein the monocyclic heteroaromatic ring is fused to one or more other carbocyclic aromatic rings or heteroaromatic rings. Thus, "5- to 14-membered heteroaryl" includes monocyclic, bicyclic, or tricyclic ring systems.

[0045] Examples of monocyclic 5- to 6-membered heteroaryls include furyl (e.g., 2-furyl, 3-furyl), 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., 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, pyridyl, and pyridazinyl. Examples of polycyclic aromatic heteroaryls include carbazolyl, benzimidazolyl, benzothienyl, benzofuryl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolinyl, indolyl, isoindolyl, acridinyl, or benzisoxazolyl. "Substituted heteroaryl" is substituted at any one or more substitutable ring atoms, which are ring carbon or ring nitrogen atoms bonded to a hydrogen.

[0046] The term "bridged bicyclic group" refers to a ring system comprising two rings that share at least three adjacent ring atoms.

[0047] As used herein, many moieties (e.g., alkyl, alkylene, cycloalkyl, aryl, heteroaryl, or heterocyclic group) are referred to as "substituted" or "optionally substituted". When a moiety is modified by one of these terms, unless otherwise specified, it means that any substitutable moiety known to those skilled in the art for the moiety can be substituted, which includes one or more substituents. In the case where there are more than one substituent, each substituent can be selected independently. Such alternative ways are well known in the art and / or taught by the present disclosure. Optional substituents can be any substituent suitable for attachment to the moiety.

[0048] In the absence of a specific listing of suitable substituents, exemplary substituents include, but are not limited to: (C 1 -C 5 ) alkyl, (C 1 -C 5 ) hydroxyalkyl, (C 1 -C 5 ) haloalkyl, (C 1 -C 5 ) alkoxy, (C 1 -C5 ) Haloalkoxy, halogen, hydroxy, cyano, amino, -CN, -NO 2 , -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 , NR 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 a 5- to 6-membered heteroaryl. Each R a1 and each R b1 is independently selected from -H and (C 1 -C 5 )alkyl, which is optionally substituted by hydroxy or (C 1 -C 3 )alkoxy; R c1 is -H, (C 1 -C 5 )haloalkyl or (C 1 -C 5 )alkyl, wherein (C 1 -C 5 )alkyl is optionally substituted by hydroxy or (C 1 -C3 ) substituted with an alkoxy group.

[0049] The compounds described herein may include one or more asymmetric centers and, thus, 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 a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers.

[0050] 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, crystallization of the compound as a chiral salt complex, or crystallization of the compound from a chiral solvent. Enantiomers and diastereomers can also be obtained from diastereomerically or enantiomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthesis methods. See, e.g., Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E.L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H., Tables of Resolving Agents and Optical Resolutions, p. 268 (E.L. Eliel, editor, Univ. of Notre Dame Press, Notre Dame, IN, 1972).

[0051] When a compound is represented by a name or structure indicating a single enantiomer, unless otherwise stated, the optical purity of the compound is at least 60%, 70%, 80%, 90%, 99%, or 99.9% (also referred to as "enantiomerically pure"). Optical purity is the weight of the named or depicted enantiomer in the mixture divided by the total weight of the two enantiomers in the mixture.

[0052] When the stereochemistry of a disclosed compound is named or depicted in a structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in diastereoisomers), it is to be understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers is included. It is further to be understood that the stereoisomeric purity of the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight. In such cases, the stereoisomeric purity is determined by dividing the total weight of the stereoisomers encompassed by the name or structure in the mixture by the total weight of all stereoisomers in the mixture.

[0053] When geometric isomers are named or depicted by a structure, it is to be understood that the geometric isomeric purity of the named or depicted geometric isomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% purity (by weight). The geometric isomeric purity is determined by dividing the weight of the geometric isomer named or depicted in the mixture by the total weight of the two geometric isomers in the mixture.

[0054] A racemic mixture means 50% of one enantiomer and 50% of the corresponding enantiomer. The present invention encompasses all enantiomerically pure, enantiomerically enriched, diastereomerically pure, diastereomerically enriched and racemic mixtures and diastereomeric mixtures of the compounds of the present invention.

[0055] The compounds described herein may also contain all atomic isotopes that occur in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0056] It will be recognized that, depending on the source of the chemical materials used in the synthesis, there will be some variation in the natural isotope abundances in the synthesized compounds. Thus, preparations of the compounds disclosed herein will inherently contain small amounts of deuterated isotopologues. Compared to the degree of stable isotope substitution of the compounds of the present invention, the concentrations of the naturally abundant stable hydrogen and carbon isotopes are small and insignificant despite this variation. See, for example, Wada, E et al., Seikagaku, 1994, 66:15; Gannes, LZ et al., Comp Biochem Physiol Mol Integr Physiol, 1998, 119:725.

[0057] The compounds described herein can exist in various tautomeric forms. The term "tautomer" or "tautomers" refers to two or more interconvertible compounds / substituents that are generated by at least one formal hydrogen atom migration and at least one valence change (e.g., single bond to double bond, triple bond to single bond, and vice versa). Exemplary tautomerizations include keto-enol, amide-imide, lactam-lactim, enamine-imine, and enamine-(different enamine) tautomerizations. The teachings of the present invention cover compounds in tautomeric forms that include forms not depicted structurally. All such isomeric forms of such compounds are expressly included. If the tautomer of a compound is aromatic, then the compound is aromatic. Similarly, if the tautomer of a compound is heteroaryl, then the compound is heteroaryl.

[0058] In some cases, tautomeric forms of the disclosed compounds exist, as shown by the tautomeric structures below:

[0059]

[0060] It should be understood that when the compounds herein are represented by structural formulas or designated by the chemical names herein, all other tautomeric forms that the compounds may exist in are covered by the structural formulas.

[0061] The compounds of the present invention can exist in free form for therapeutic use or, where appropriate, as pharmaceutically acceptable salt forms.

[0062] The term "pharmaceutically acceptable salts" refers to those salts which are within the scope of sound medical judgment suitable for contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc. and having 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 the Journal of Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable acid addition salts are salts having an amino group 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 formed by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphors, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptanoates, glycerophosphates, glucuronates, hemisulfates, heptanoates, hexanoates, hydroiodic acid, 2-hydroxyethanesulfonates, lactobionates, lactates, laurates, dodecylsulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, sodium p-toluenesulfonates, undecanoates, valerates, etc. Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1-4 alkyl) 4 - salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Additional pharmaceutically acceptable salts include ammonium, quaternary ammonium and amine cations formed with counterions (such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates and arylsulfonates) when appropriate.

[0063] Such pharmaceutically acceptable acid addition salts and common methods 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., edited in "Encyclopedia of Pharmaceutical Technology"; Swarbrick and Boylan, Volume 13, Marcel Dekker, Inc., New York, Basel, Hong Kong, China 1995, pp. 453-499; Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Sciences, 66(1):1977.

[0064] The terms "composition" and "formulation" are used interchangeably.

[0065] "Subject" is a mammal, preferably a human, but can 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.).

[0066] The terms "administer", "administering", or "administration" refer to methods of introducing a compound or its composition of the present invention into or onto a subject. These methods include, but are not limited to, intra-articular (in the joint), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, oral, topical, intrathecal, inhalation, transdermal, rectal, etc. Administration techniques that can be used with the agents and methods described herein are found, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current edition; Pergamon Press; and Remington's Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.

[0067] 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 the disease have developed or have been observed (i.e., therapeutic treatment). In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (i.e., prophylactic treatment) (e.g., based on a symptom history and / or based on exposure to a pathogen). Treatment may also be continued after symptom resolution, for example to delay or prevent recurrence.

[0068] The terms "condition", "disease" and "disorder" are used interchangeably.

[0069] Generally, the effective amount of a compound taught herein will vary depending on various 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 can still be routinely determined by one of ordinary skill in the art. A person of ordinary skill in the art can readily determine the effective amount of a compound taught by the present invention by conventional methods known in the art.

[0070] The term "effective amount" means an amount that, when administered to a subject, produces a beneficial or desired result, including a clinical result, such as an amount that inhibits, suppresses or alleviates the symptoms of the disorder being treated in the subject, compared to a control. For example, an effective amount may be administered in unit dosage forms (e.g., from 1 mg to about 50 g per day, e.g., from 1 mg to about 5 g per day).

[0071] A "therapeutically effective amount" is an effective amount for detectably killing or inhibiting the growth or spread of cancer cells; the size or number of tumors; or other measures of the level, stage, progression or severity of cancer. The precise 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, treatment in combination with other therapies, etc.

[0072] The general chemical terms used in the above formula have their ordinary meanings.

[0073] As used herein, "h" refers to one or more hours, "min" refers to one or more 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 dimethyl sulfoxide, "DMA" refers to dimethylacetamide, "THF" refers to tetrahydrofuran, "MtBE" 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 / kilogram, "po" refers to orally (by mouth), "qd" means administered once daily, "HPLC" means high performance liquid chromatography, "q2d" means a single dose every 2 days, "q2dx10" means a single dose every 2 days multiplied by 10 times, "VSMC" refers to vascular smooth muscle cells, and "XRD" refers to X-ray diffraction.

[0074] 3. Compound

[0075] In a first embodiment of the present invention, there is provided a compound represented by structural formula (I):

[0076]

[0077] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein

[0078] Ring A is

[0079]

[0080]

[0081] Ring B is a bond, a 3- to 10-membered heterocyclic group or a 5- to 10-membered heteroaryl group;

[0082] Ring C is a 5- to 6-membered heteroaryl group, a 5- to 10-membered heterocyclic group, a phenyl group, a 5- to 10-membered bridged bicyclic group, each of which is optionally substituted with one or two R 12 substituted;

[0083] Linker L is a bond, -(CH 2 ) q -, -(CH 2 ) q O-, -NR a (CH 2 ) q -, -C(O)-, -C(O)N(R a)-or -S(O) 2 -;

[0084] R a each instance of which is H or CH 3 ;

[0085] R 1 is H, deuterium, halogen, -OH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy;

[0086] R 2 each instance of which 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 SR 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 NR 7 R 8 、-(CH 2 ) n C(O)NR 7 R 8 、-(CH 2 ) n NR 7 C(O)R 6 、-(CH 2 ) n NR 7 S(O) m R 6 、C 3-8 cycloalkyl, 3 - to 10 - membered heterocyclic group, 6 - to 14 - membered aryl, 5 - to 14 - membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic group, aryl or heteroaryl represented by R 2 is each optionally substituted with one or more selected from deuterium, halogen, CN, -OH, C1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy and NR 7 R 8 are substituted; or

[0087] When ring B is a 3- to 10-membered heterocyclic group, two Rs attached to the same ring atom of ring B 2 may form a C 3-6 cycloalkyl or a 3- to 6-membered heterocyclic group, and the C 3-6 cycloalkyl or 3- to 6-membered heterocyclic group is optionally substituted by one or more groups selected from deuterium, halogen, CN, -OH, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy and NR 7 R 8 are substituted;

[0088] Each instance of R 3 is independently selected from H, deuterium, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl or a 3- to 10-membered heterocyclic group; wherein the C represented by R 3 alkyl, C 1-8 alkenyl, C 2-8 alkynyl, C 2-8 cycloalkyl or a 3- to 10-membered heterocyclic group is optionally substituted by one or more groups selected from deuterium, halogen, CN, -OH, C 3-8 alkyl and C 1-8 haloalkyl; 1-8

[0089] Each instance of R 4 is independently selected from 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 a 3- to 10-membered heterocyclic group; wherein the C represented by R 4 or in the group represented by R 4 alkyl, C 1-8 alkenyl, C 2-8 alkynyl, C 2-8 alkoxy, C 1-8 cycloalkyl or a 3- to 10-membered heterocyclic group is each optionally substituted by one or more groups selected from deuterium, halogen, -OH, C 3-8 alkyl and C 1-8 ​Substitution by an alkyl group and a C 1-8 haloalkyl group; or

[0090] Two Rs attached to the same ring atom of ring A 4 groups form a C 3-6 cycloalkyl group or a 3- to 6-membered heterocyclic group, each of which is optionally substituted by one or more groups selected from deuterium, halogen, CN, -OH, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy and NR 7 R 8 ;

[0091] Each instance of R 5 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 a 3- to 6-membered heterocyclic group;

[0092] Each instance of R 6 is independently H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, a 3- to 10-membered heterocyclic group, a 6- to 14-membered aryl group, a 5- to 14-membered heteroaryl group, wherein the C 6 represented by R 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, a 3- to 10-membered heterocyclic group, a 6- to 14-membered aryl group, a 5- to 14-membered heteroaryl group is each optionally substituted by one or more groups selected from halogen, CN, -OH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy and NR 7 R 8 ;

[0093] Each instance of R 7 and R 8 is independently H, C 1-4 alkyl or cyclopropyl;

[0094] Each instance of R 12 is H, deuterium, halogen, -OH, CN, NH 2 , C 1-8 alkyl, C 2-8 alkenyl, C2-8 alkynyl, C 1-8 alkoxy, C 3-8 cycloalkyl or a 3- to 10-membered heterocyclic group; wherein the C 12 represented by R 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 alkoxy, C 3-8 cycloalkyl or a 3- to 10-membered heterocyclic group is optionally substituted by one or more groups selected from halogen, CN, -OH, C 1-4 alkyl, C 1-4 haloalkyl and C 1-4 alkoxy;

[0095] q is 0, 1 or 2;

[0096] n is 0, 1, 2, 3, 4 or 5; and

[0097] m is 0, 1 or 2.

[0098] In a second embodiment of the present invention, there is provided a compound represented by formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ring C is and the remaining variables are as defined in the first embodiment.

[0099] In a third embodiment of the present invention, there is provided a compound of the first or second embodiment or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ring A is

[0100]

[0101]

[0102] wherein

[0103] Each instance of R 3 is H, deuterium, C 1-4 alkyl optionally substituted by -OH or C 3-6 cycloalkyl optionally substituted by -OH;

[0104] Each instance of R 4 is H, deuterium, halogen, C 1-4 alkyl optionally substituted by fluorine, C 2-4 alkenyl, C 3-6 cycloalkyl optionally substituted by methyl or a 3- to 6-membered heterocyclic group; or two R 4 groups attached to the same ring atom of ring A form C 3-6 cycloalkyl or a 3- to 6-membered heterocyclic group, each of which is optionally substituted by one or more groups selected from halogen, CN, -OH, C1-2 alkyl, C 1-2 alkoxy and NR 7 R 8 groups;

[0105] R 5 is H, deuterium, halogen, CN, -OH, C 1-4 alkyl, C 1-4 alkoxy or C 1-4 haloalkoxy, and the remaining variables are as defined in the first and / or second embodiments.

[0106] In the fourth embodiment of the present invention, the compound of structural formula (I) is represented by structural formulas (II-A)-(II-J):

[0107]

[0108]

[0109] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 12 is H, F, Cl, CH 3 or CF 3 ; and k is 0, 1 or 2, and the remaining variables are as defined in the first, second and / or third embodiments.

[0110] In the fifth embodiment of the present invention, the compound of structural formula (I), (II-A)-(II-J) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein L is a bond, -(CH 2 )-, -O(CH 2 )-, -C(=O)- or -S(O) 2 -, and the remaining variables are as defined in the first, second, third and / or fourth embodiments.

[0111] In the sixth embodiment of the present invention, the compound of structural formula (I), (II-A)-(II-J) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ring B is an optionally 4- to 10-membered heterocyclic group or a 5- to 6-membered monocyclic heteroaryl group substituted with one or two R 2 groups, and the remaining variables are as defined in the first, second, third, fourth and / or fifth embodiments.

[0112] In the seventh embodiment of the present invention, the compound of structural formula (I), (II-A)-(II-J) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein

[0113] R 2 each instance of is H, halogen, CN, -OH, C 1-4 alkyl, C 1-4 haloalkyl, C1-4 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 NR 7 R 8 、-(CH 2 ) n C(O)NR 7 R 8 、-(CH 2 ) n C(O)NHR 7 、-(CH 2 ) n NR 7 C(O)R 6 、-(CH 2 ) n NR 7 S(O) 2 R 6 、C 3-8 Cycloalkyl, 3- to 6-membered heterocyclic group, phenyl or 5- to 6-membered heteroaryl; or

[0114] Two Rs attached to the same ring atom of Ring B 2 form a 3- to 6-membered heterocyclic group (when Ring B is a 3- to 10-membered heterocyclic group), and the 3- to 6-membered heterocyclic group is optionally substituted with one or more groups selected from halogen, -OH, C 1-2 alkyl, C 1-2 haloalkyl, C 1-2 alkoxy, C 1-2 haloalkoxy and NR 7 R 8 ;

[0115] Each instance of R 6 is independently H, C 1-4 alkyl, C 3-6 cycloalkyl, 3- to 7-membered heterocyclic group, phenyl, 5- to 6-membered heteroaryl, wherein the C 6 represented by R 1-4 alkyl, C 3-6The cycloalkyl group, 3- to 7-membered heterocyclic group, phenyl group, 5- to 6-membered heteroaryl group are each optionally substituted by halogen, CN, -OH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or NR 7 R 8 ; and

[0116] n is 0, 1 or 2, and the remaining variables are as defined in the first, second, third, fourth, fifth and / or sixth embodiments.

[0117] In the eighth embodiment of the present invention, a compound of the structural formula (I), (II-A)-(II-J) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is H, F, Cl or CH 3 , and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth and / or seventh embodiments.

[0118] In the ninth embodiment of the present invention, a compound of the structural formula (I), (II-A)-(II-J) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ring B is

[0119]

[0120]

[0121] each of which is optionally substituted by one or two R 2 groups, and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh and / or eighth embodiments.

[0122] In the tenth embodiment of the present invention, a compound of the structural formula (I), (II-A)-(II-J) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each instance of R 2 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 NR 7 R 8 C 3-4 cycloalkyl or 3- to 6-membered heterocyclic group; and n is 0, 1 or 2; or when ring B is a 4- to 7-membered heterocyclic group, two R 2Form a 3- to 6-membered heterocyclic group, and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, and / or ninth embodiments.

[0123] In the eleventh embodiment of the present invention, a compound of structural formula (I), (II-A)-(II-J) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ring A is and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, and / or tenth embodiments.

[0124] In the twelfth embodiment of the present invention, a compound of structural formula (I), (II-A)-(II-J) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 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.

[0125] In the thirteenth embodiment of the present invention, a compound of structural formula (I), (II-A)-(II-J) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each instance of R 3 is H, C 1-3 alkyl optionally substituted with -OH or C 3-6 cycloalkyl optionally substituted with -OH; each instance of R 4 is H, halogen, C 1-3 alkyl, C 2-4 alkenyl, cyclopentyl, tetrahydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl; and each instance of R 5 is H, F, CN, methoxy, OCHF 2 , and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, and / or twelfth embodiments.

[0126] In the fourteenth embodiment of the present invention, a compound of structural formula (I), (II-A)-(II-J) or a pharmaceutically acceptable salt or stereoisomer thereof, 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.

[0127] In the fifteenth embodiment of the present invention, a compound of structural formula (I), (II-A)-(II-J) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ring B is

[0128]

[0129] Each of which is optionally substituted by one or two R 2 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.

[0130] In the sixteenth embodiment of the present invention, a compound of structural formula (I), (II-A)-(II-J) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2 each instance of is H, halogen, CN, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, NH 2 , N(CH 3 ) 2 , NH cyclopropyl, -(CH 2 ) n S(O) 2 C 1-3 alkyl, cyclopropyl, azetidinyl optionally substituted by F, oxetanyl, morpholinyl, piperidinyl, tetrahydro-2H-pyranyl, or when ring B is piperidinyl, two R 2 connected to the same ring atom of ring B form 2,5-pyrrolidinedionyl or 2-pyrrolidonyl; and 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.

[0131] In the seventeenth embodiment of the present invention, a compound of structural formula (I), (II-A)-(II-J) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ring A is and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, fourteenth, fifteenth, and / or sixteenth embodiments.

[0132] In the eighteenth embodiment of the present invention, a compound of structural formula (I), (II-A)-(II-J) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each instance of R 3 is H or C 1-3 alkyl; each instance of R 4 is H or C 1-3 alkyl; and R 5Each instance of 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.

[0133] In the nineteenth embodiment of the present invention, a compound of structural formula (I), (II-A)-(II-J) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is H, and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, fourteenth, fifteenth, sixteenth, seventeenth and / or eighteenth embodiments.

[0134] In the twentieth embodiment of the present invention, a compound of structural formula (I), (II-A)-(II-J) or a pharmaceutically acceptable salt or stereoisomer thereof, 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, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth and / or nineteenth embodiments.

[0135] In the twenty-first embodiment of the present invention, a compound of structural formula (I), (II-A)-(II-J) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ring B is each of which is optionally substituted by one or two R 2 groups, and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth and / or twentieth embodiments.

[0136] In the twenty-second embodiment of the present invention, a compound of structural formula (I), (II-A)-(II-J) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2 is H, halogen, CN, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, NH 2 , N(CH 3 ) 2 , NH cyclopropyl, and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth and / or twenty-first embodiments.

[0137] In one embodiment, the compound or a pharmaceutically acceptable salt or stereoisomer thereof is selected from the compounds of formula (I), (II-A)-(II-J) in the examples.

[0138] Another aspect of the present disclosure relates to the labeled compounds (radioactively labeled, fluorescently labeled, etc.) of the present invention, which can be used not only in imaging techniques, but also in in vitro and in vivo assays for localizing and quantifying CDK in tissue samples (including human), and for identifying CDK ligands by inhibiting the binding of the labeled compounds. Accordingly, the present disclosure encompasses such labeled compounds.

[0139] The present disclosure further encompasses isotopically labeled compounds of the present invention. An "isotopically labeled" or "radioactively labeled" compound of the present invention is a compound in which one or more atoms are replaced or substituted with an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring). Suitable radionuclides that can be incorporated into the compounds of the present invention include, but are not limited to 2 H (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 I. The radionuclide incorporated into the radioactively labeled compound of the present invention will depend on the specific application of the radioactively labeled compound.

[0140] The present invention may further encompass synthetic methods for incorporating radioactive isotopes into the compounds of the present invention. Synthetic methods for incorporating radioactive isotopes into organic compounds are well known in the art, and those of ordinary skill in the art will readily recognize methods suitable for the compounds of the present invention.

[0141] The labeled compounds of the present invention can be used in screening assays to identify / evaluate compounds. For example, a newly synthesized or identified labeled compound (i.e., a test compound) can be evaluated for its ability to bind to CDK by monitoring the change in its concentration upon contact with CDK by means of tracking the label. For example, the ability of a test compound (labeled) to reduce the binding of another compound that is known to bind to CDK (i.e., a standard compound) can be evaluated. Thus, the ability of a test compound to compete with a standard compound for binding to CDK is directly related to its binding affinity. Conversely, in some other screening assays, the standard compound is labeled and the test compound is unlabeled. Thus, the concentration of the labeled standard compound is monitored to evaluate the competition between the standard compound and the test compound, thereby determining the relative binding affinity of the test compound.

[0142] In one embodiment, the compound or a pharmaceutically acceptable salt or stereoisomer thereof, wherein one or more hydrogen atoms are replaced by deuterium.

[0143] 4. Treatable Diseases and Treatment Methods

[0144] Certain compounds of the present invention are selective inhibitors of CDK2, CDK4, and / or CDK6, and thus can be used to treat diseases or disorders characterized by abnormal cell proliferation, which can be inhibited by reducing the activity of CDK-cyclin complexes that include CDK2, CDK4, and / or CDK6.

[0145] In certain embodiments, the compounds of the present invention selectively inhibit CDK4 / 6 relative to CDK2, and the ratio of the IC 50 value of the latter (CDK2) to that of the former (CDK4 / 6) is at least about 10, 20, 50, 100, 200, 300, 400, 500, 800, 1,000, 2,000 or more.

[0146] In certain embodiments, the compounds of the present invention selectively inhibit CDK4 relative to CDK6, and the ratio of the IC 50 value of the latter (CDK6) to that of the former (CDK4) is at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 50 or more.

[0147] In certain embodiments, the compounds of the present invention selectively inhibit CDK4 relative to CDK2, and the ratio of the IC 50 value of the latter (CDK4) to that of the former (CDK2) is at least about 2, 5, 10, 15, 20, 40, 50, 60, 80, 100 or more.

[0148] In certain embodiments, the compounds of the present invention have a similar IC 50Values inhibit CDK2 / 4 / 6, such as IC 50 Values are within 10-fold, 5-fold, 3-fold or 2-fold. Such compounds of the invention can be used to treat cancers having cyclin D1 or E1 or E2 amplification or enhanced expression.

[0149] CDK2 is the catalytic subunit of the CDK-cyclin complex, and its activity is restricted to the G1-S phase of the cell cycle, during which the cell makes the proteins necessary for mitosis and replicates its DNA. CDK2 complexes with cyclin E or A. Cyclin E binds to CDK2 in the G1 phase, which is necessary for the G1 to S phase transition. On the other hand, binding of CDK2 to cyclin A is required to pass through the S phase.

[0150] Although CDK2 is almost dispensable in the cell cycle of normal functioning cells, it is crucial for the abnormal growth process of cancer cells. Overexpression of cyclin E occurs in many tumor cells, leading to the cells becoming dependent on CDK2 and cyclin E. Abnormal cyclin E activity has been observed in breast cancer, lung cancer, colorectal cancer, gastric cancer and bone cancer, as well as leukemia and lymphoma. Similarly, abnormal expression of cyclin A2 is associated with chromosomal instability and tumor proliferation, and inhibition leads to reduced tumor growth. Thus, CDK2 and its cyclin binding partners represent possible therapeutic targets for new cancer therapies. Preclinical models have shown preliminary success in restricting tumor growth and reduced side effects of current chemotherapeutic drugs have also been observed.

[0151] For example, Caldon et al. (Mol Cancer Ther 11(7):1488-1499, 2012) reported that cyclin E2 is included in several gene signatures that predict tamoxifen resistance or metastatic breast cancer disease progression, and high expression of CycE2 is characteristic of the luminal B and HER2 subtypes of breast cancer and strongly predicts shorter distant metastasis-free survival after endocrine therapy. Further, tamoxifen-resistant (MCF-7TAMR) breast cancer cells overexpress cyclin E2; and expression of cyclin E1 or E2 in T-47D breast cancer cells results in acute anti-estrogen resistance, indicating that cyclin E overexpression contributes to anti-estrogen resistance of tamoxifen-resistant cells. RNAi-mediated knockdown of cyclin E1, cyclin E2 or CDK2 inhibited the proliferation of tamoxifen-resistant cells. In addition, ectopic expression of cyclin E1 or E2 also reduces sensitivity to CDK4 inhibition, but not to CDK2 inhibition. In addition, CDK2 inhibition in E-cyclin overexpressing cells and tamoxifen-resistant cells restored sensitivity to tamoxifen or CDK4 inhibition.

[0152] These data indicate that cyclin E2 overexpression is a potential mechanism for resistance to endocrine therapy and CDK4 inhibition, and that CDK2 inhibitors can further overcome such resistance and can be beneficial as a component of combination therapy for endocrine-resistant diseases because the inhibitors effectively inhibit cyclin E1- and E2-overexpressing cells and enhance the efficacy of other therapies. Similarly, the subject compounds having strong inhibitory activity against both CDK2 and CDK4 are expected to be effective against cancer cells that are resistant and non-resistant to endocrine therapy or CDK4 inhibition.

[0153] Thus, in certain embodiments, the compounds of the invention can have strong inhibitory effects against both CDK2 and CDK4 (e.g., IC 50 values at levels independently <10 nM, <5 nM, <1 nM), and thus can be effective in treating tamoxifen-resistant or metastatic breast cancer such as tamoxifen-resistant or metastatic breast cancer having CycE overexpression.

[0154] The IC 50 values of the compounds of the invention against CDK2 / 4 / 6 can be measured using, for example, the methods described in Examples 1 to 3 (incorporated herein by reference).

[0155] Specifically, the compounds of the invention can be used to treat cancer. In other embodiments, the compounds of the invention can be used to treat chronic inflammatory diseases such as arthritis and cystic fibrosis.

[0156] Thus, in one aspect, the invention provides a method of treating cancer in a mammal, particularly the cancers described herein, the method comprising administering to a mammal in need of such treatment an effective amount of a compound of the invention.

[0157] In a related aspect, the invention relates to the use of a compound of the invention in the manufacture of a medicament for treating cancer, particularly the cancers described herein.

[0158] In another related aspect, a compound of the invention can be used in the manufacture of a medicament for treating cancer, particularly the cancers described herein.

[0159] In another related aspect, the invention provides a compound of the invention that can be used to treat cancer, particularly the cancers described herein.

[0160] According to any of the relevant aspects of the present invention described above, CDK4 and CDK6 can regulate their effects on the cell cycle, in part, through pRb phosphorylation. Thus, certain compounds of the present invention can inhibit pRb phosphorylation by inhibiting CDK4 / 6 activity in any cancer type and thereby inhibiting cell proliferation and / or tumor growth, where the cells are proliferating and contain a functional, intact Rb1 gene encoding pRb.

[0161] Thus, in certain embodiments, the compounds of the present invention can be used to treat pRb + cancers in a mammal such as: colorectal cancer, breast cancer, lung cancer, prostate cancer, chronic myelogenous leukemia, acute myelogenous 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). It is also contemplated that the compounds of the present invention can be used to treat rhabdomyosarcoma (Saab et al., Mol. Cancer Ther. 5(5):1299, 2006) and multiple myeloma (Baughn et al., Cancer Research 66(15):7661, 2006), including relapsed and refractory multiple myeloma in a mammal (e.g., human).

[0162] Meanwhile, Zhang et al. (Nature dx.doi.org / 10.1038 / nature25015, 2017) reported that inhibition of CDK4 / 6 in vivo may lead to reduced phosphorylation, thereby increasing the degradation of Cullin 3 SPOP E3 ligase (through APC / C Cdh1 ), which in turn leads to increased levels of PD-L1 on the surface of tumor cells and a reduction in the number of tumor infiltrating lymphocytes (TIL) in mouse tumors and primary human prostate cancer samples. In other words, inhibition of CDK4 / 6 in vivo increases the level of PD-L1 protein and contributes to increased resistance to immune checkpoint therapies targeting PD-1 (programmed cell death protein 1) and PD-L1 (PD-1 ligand). On the other hand, combining CDK4 / 6 inhibitor treatment with anti-PD-1 immunotherapy enhances tumor regression and significantly increases the overall survival rate in mouse tumor models.

[0163] Thus, in certain embodiments, the compounds of the invention can be used in combination with PD-1 / PD-L1 immune checkpoint inhibitors to enhance the therapeutic efficacy against human cancers.

[0164] PD-1 and PD-L1 inhibitors that can be used with the compounds of the invention are known in the art. PD-1 inhibitors include monoclonal antibodies or antigen-binding fragments thereof that are specific for PD-1. Exemplary PD-1 inhibitors include Pembrolizumab (Keytruda), Nivolumab (Opdivo), and Cemiplimab (Libtayo). PD-L1 inhibitors include monoclonal antibodies or antigen-binding fragments thereof that are specific for PD-L1. Exemplary PD-L1 inhibitors include Atezolizumab (Tecentriq), Avelumab (Bavencio), and Durvalumab (Imfinzi).

[0165] Additional immune checkpoint inhibitors that can be used with the compounds of the invention to enhance the therapeutic efficacy against human cancers include monoclonal antibodies or antigen-binding fragments thereof such as Ipilimumab (Yervoy) that are specific for CTLA-4.

[0166] Additional immune checkpoint inhibitors that can be used with the compounds of the invention to enhance the therapeutic efficacy against human cancers include bispecific monoclonal antibodies or antigen-binding fragments thereof that are specific for PD-1 and PD-L1 or combinations of monoclonal antibodies or antigen-binding fragments thereof that are specific for PD-1 and PD-L1 or PD-1 and CTLA-4, etc.

[0167] In certain embodiments, the compounds of the invention can be used in combination with a Tyr kinase inhibitor, such as a receptor Tyr kinase (RTK) inhibitor, to enhance the therapeutic efficacy against human cancers. Exemplary Tyr kinase inhibitors include ALK inhibitors (such as Crizotinib, Ceritinib, Alectinib, Brigatinib), Bcr-Abl inhibitors (such as Bosutinib, Dasatinib, Imatinib, Nilotinib, Ponatinib), BTK inhibitors (such as Ibrutinib), c-Met inhibitors (such as Crizotinib, Cabozantinib), EGFR inhibitors (such as Gefitinib, Erlotinib, Lapatinib, Vandetanib, Afatinib, Osimertinib), JAK inhibitors (such as Ruxolitinib, Tofacitinib), MEK1 / 2 inhibitors (such as Trametinib), PDGFR inhibitors (such as Axitinib, Gefitinib, Imatinib, Lenvatinib, Nintedanib, Pazopanib, Regorafenib, Sorafenib, Sunitinib), RET inhibitors (such as Vandetanib), Src family kinase inhibitors (such as Bosutinib, Dasatinib, Ponatinib, Vandetanib), and VEGFR family inhibitors (such as Axitinib, Lenvatinib, Nintedanib, Regorafenib, Pazopanib, Sorafenib, Sunitinib).

[0168] Additional suitable kinase inhibitors and treatable cancer indications that can be used in combination with the subject compounds are described in Bhullar et al., Molecular Cancer 17:48, 2018 (incorporated herein by reference).

[0169] Further additional RTK inhibitors include monoclonal antibodies and antigen-binding fragments thereof, including anti-EGFR mAbs such as cetuximab (effective in treating, for example, lung cancer, colorectal cancer, and head and neck cancer) and anti-HER2 mAbs such as trastuzumab (effective in treating, for example, breast cancer).

[0170] 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.

[0171] Cancers treatable 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, melanoma (including positive melanoma with 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.

[0172] In certain embodiments, treatable cancers include: bladder cancer, breast cancer, colon cancer, kidney cancer, epidermal cancer, liver cancer, lung cancer (including SCLC and NSCLC), esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, nasal cancer, head and neck cancer, prostate cancer or skin cancer; lymphoid hematopoietic tumors; myeloid hematopoietic tumors; follicular thyroid cancer; tumors of mesenchymal origin; central or peripheral nervous system tumors; melanoma; familial melanoma; seminoma; teratoma; osteosarcoma; xeroderma pigmentosum; keratoacanthoma; follicular thyroid cancer; Kaposi's sarcoma, squamous cell carcinoma, sarcoma; or tumors of mesenchymal origin.

[0173] In certain embodiments, the lymphoid hematopoietic tumors are leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, B cell lymphoma, T cell lymphoma, multiple myeloma, Hodgkin's lymphoma, Non-Hodgkin's lymphoma, hairy cell lymphoma or Burkett's lymphoma.

[0174] In certain embodiments, tumors of the central or peripheral nervous system are astrocytoma, neuroblastoma, glioma or schwannoma.

[0175] 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.

[0176] 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.

[0177] 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 invention and gemcitabine HCl.

[0178] In certain embodiments, the cancer is NSCLC, pancreatic cancer, ovarian cancer, or metastatic breast cancer, wherein the medicament comprising the compound of the invention further comprises gemcitabine HCl or is administered simultaneously with, separately from, or sequentially to gemcitabine HCl.

[0179] In certain embodiments, the compounds of the invention can be combined with other agents for the treatment of NSCLC, pancreatic cancer, ovarian cancer, and metastatic breast cancer. For example, the compounds of the invention can be combined with gemcitabine HCl simultaneously, separately, or sequentially for the treatment of NSCLC, pancreatic cancer, ovarian cancer, or metastatic breast cancer.

[0180] In certain embodiments, the cancer is selected from the group consisting of colorectal cancer, glioblastoma, acute myeloid leukemia, and lung cancer.

[0181] 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 with, separately from, or sequentially to temozolomide.

[0182] Breast cancer treatment

[0183] In certain embodiments, the compounds of the invention can be used for the treatment of breast cancer.

[0184] Breast cancer imposes a significant health burden globally, and in 2016 alone, breast cancer accounted for approximately 7% of all cancer-related deaths in the United States. Of all breast cancers, approximately 75% are diagnosed as hormone receptor-positive (HR + ) breast cancer, which expresses estrogen receptor (ER) and / or progesterone receptor (PgR) and generally relies on the ER signaling pathway for growth and survival. That is, HR + breast cancer utilizes the biological functions of the ER pathway to promote the growth, development, and progression of breast cancer. At the same time, the dependence of HR + breast cancer on ER signaling makes this breast cancer a therapeutic target 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).

[0185] Although endocrine therapy has filled the mainstay of HR + breast cancer treatment, due to the existence of alternative survival or "escape" pathways, the efficacy of endocrine therapy is limited by a high rate of pre-existing and treatment-acquired resistance. The ER pathway and many known escape pathways promote tumor growth through the cyclin D-CDK4 / 6-CDK4 inhibitor (INK4)-retinoblastoma (Rb) pathway. Thus, combinatorial targeting of ER and the cyclin D-CDK4 / 6-INK4-Rb pathway generally results in a more extensive inhibition of tumor growth and prevents the activation of escape pathways, thereby preventing the development of endocrine therapy resistance. See Sammons et al., Current Cancer Drug Targets 17:637-649, 2017.

[0186] 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 + ), progesterone receptor positive (PR + ), or ER + PR + ), HER2 / neu negative cancer, including HR + HER2 - , or ER + HER2 - , advanced or metastatic or recurrent breast cancer. In certain embodiments, the HR + HER2 - , or ER + HER2 - advanced or metastatic or recurrent breast cancer occurs in adult or postmenopausal women.

[0187] In certain embodiments, the compounds of the present invention are used alone or in combination with an aromatase inhibitor (which inhibits estrogen production) to treat HR-positive, HER2-negative advanced or metastatic or recurrent breast cancer. In certain embodiments, the aromatase inhibitor temporarily inactivates aromatase (such as anastrozole and letrozole ). In certain embodiments, the aromatase inhibitor permanently inactivates aromatase (such as exemestane ).

[0188] In certain embodiments, the compounds of the present invention are used in combination with a compound that interferes with the ability of estrogen to stimulate the growth of breast cancer cells, such as a selective estrogen receptor modulator (SERM), such as tamoxifen and toremifene The selective estrogen receptor modulators described above bind to estrogen receptors to prevent estrogen binding. Tamoxifen has been used to treat HR + breast cancer for over 30 years.

[0189] In certain embodiments, the compounds of the invention are used in combination with pure anti-estrogen agents such as fulvestrant that have no estrogen agonist activity.

[0190] In certain embodiments, HR-positive, HER2-negative advanced or metastatic or recurrent breast cancer occurs in postmenopausal women. In certain embodiments, HR-positive, HER2-negative advanced or metastatic or recurrent breast cancer progresses after receiving a therapy that alters the patient's hormones (e.g., estrogen and / or progesterone) or worsens after treatment with another hormonal therapy.

[0191] In certain embodiments, the compounds of the invention are used in patients who have undergone or are undergoing oophorectomy. In certain embodiments, oophorectomy is performed by ovariectomy or radiotherapy.

[0192] In certain embodiments, the compounds of the invention are used in combination with compounds that temporarily suppress ovarian function (e.g., estrogen and / or progesterone production). Such compounds include gonadotropin-releasing hormone (GnRH) agonists or luteinizing hormone-releasing hormone (LH-RH) agonists, including goserelin and leuprolide

[0193] In certain embodiments, the compounds of the invention are used in combination with 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, starfruit, milk thistle, niacinamide, ginkgo, piperine, isoniazid, and quercetin.

[0194] In certain embodiments, the compounds of the invention are used in combination with IGF-1 / IGF-2 inhibitors such as monoclonal antibodies or antigen-binding fragments thereof directed against IGF-1 / IGF-2. Exemplary antibodies include xentuzumab, a humanized IgG1 mAb.

[0195] In certain embodiments, the compounds of the invention are used in combination with compounds that inhibit PI3K. It is believed that inhibition of PI3K reduces the levels of cyclin D1 and other G1-S cyclins, abrogates pRb phosphorylation, and inhibits the activation of the S-phase transcriptional program. Representative PI3K inhibitors for use in combination with the compounds of the invention include idelalisib, copanlisib, duvelisib, taselisib, perifosine, buparlisib, alpelisib, umbralisib, copanlisib, dactolisib, and voxtalisib.

[0196] In certain embodiments, the mammal to be treated is a human such as an adult female with breast cancer (e.g., a postmenopausal or adult female with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic or recurrent breast cancer who has progressed on a therapy that alters the patient's hormones).

[0197] In addition, certain compounds of the invention exhibit the favorable property that they are able to cross the blood-brain barrier. Thus, such compounds are able to penetrate the brain and can therefore be used to treat primary and metastatic brain tumors in which cell proliferation occurs and which contain a functionally intact Rb1 gene. Such pRb + Examples of such brain tumors include glioblastoma, as well as medulloblastoma and astrocytoma (Lee et al., Science 235:1394, 1987).

[0198] Temozolomide is a cytotoxic DNA alkylating agent used to treat brain tumors including glioblastoma and astrocytoma (Friedman et al., Clin. Cancer Res. 6(7):2585-2597, 2000), and the brain tumors include brain metastases of melanoma, breast cancer, and NSCLC of non-small cell lung cancer (Siena et al., Annals of Oncology, doi:10.1093 / annonc / mdp343, 2009). The interaction of temozolomide with DNA results in chemical modification / damage (Marchesi et al., Pharmacol. Res. 56(4):275-287, 2007). Thus, in some embodiments, the compounds of the present invention can be combined with temozolomide for the treatment of primary and metastatic pRb such as glioblastoma and astrocytoma + brain tumors, such as where such metastases are derived from melanoma, breast cancer, or NSCLC.

[0199] 5. Pharmaceutical compositions

[0200] The present invention provides pharmaceutical compositions comprising any one of the compounds described herein or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients.

[0201] "Pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to substances that assist in formulating and / or administering an active agent to a subject and / or assist in the absorption of the subject, and such substances can be included in the compositions of the present disclosure without causing significant adverse toxicological effects to the subject. Non-limiting examples of pharmaceutically acceptable carriers and excipients include water, NaCl, saline solution, lactated Ringer's solution, common sucrose, common glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorants, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates (such as lactose, amylose, or starch), fatty acid esters, carboxymethyl cellulose, polyvinylpyrrolidone, and pigments, etc. Such formulations can be sterilized and, if desired, can be mixed with adjuvants that do not react harmfully with or interfere with the activity of the compounds provided herein, such as lubricants, preservatives, stabilizers, wetting agents, emulsifying agents, salts for affecting osmotic pressure, buffers, coloring substances, and / or aromatic substances, etc. Those of ordinary skill in the art will recognize that other pharmaceutical carriers and excipients are suitable for the disclosed compounds.

[0202] These compositions optionally further comprise one or more additional therapeutic agents. Alternatively, the compounds of the 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, farnesyl transferase inhibitors, bisphosphonates, thalidomide, cancer vaccines, hormone therapy, antibodies, radiation, etc.). For example, additional therapeutic agents for co-administration with the compounds of the invention or included in the pharmaceutical compositions can be one or more other anti-cancer agents.

[0203] As described herein, the compositions of the invention comprise the compounds of the invention and a pharmaceutically acceptable carrier, as used herein, the pharmaceutically acceptable carrier comprises any and all solvents, diluents or other vehicles, dispersion or suspension aids, surfactants, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, etc., suitable for the particular dosage form desired. Remington's Pharmaceutical Sciences, 5th Edition, E.W. Martin (Mack Publishing Co., Easton, Pa., 1975) discloses various carriers for formulating pharmaceutical compositions and known techniques for their preparation. Unless any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effects or otherwise interacting in a harmful manner with any other one or more components of the pharmaceutical composition, it is contemplated that it will be used within the scope of the present invention. Some examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; celluloses and their derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; ethylene glycol; such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol and phosphate buffer solutions and other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, and coloring agents, release agents, coating agents, sweetening agents, flavoring agents and perfuming agents, preservatives and antioxidants may also be present in the compositions.

[0204] 6. Formulations

[0205] The invention also encompasses a class of compositions that comprise the active compounds of the invention and one or more pharmaceutically acceptable carriers and / or diluents and / or adjuvants (collectively referred to herein as "carrier" materials) and, if desired, other active ingredients.

[0206] In certain embodiments, the present invention provides pharmaceutical formulations for treating cancer, particularly the cancers described herein, said pharmaceutical formulations comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0207] In certain embodiments, the present invention provides pharmaceutical formulations for treating cancer selected from the group consisting of colorectal cancer, mantle cell lymphoma, breast cancer (including ER in adult women or postmenopausal women) + HER2 - advanced or metastatic or recurrent breast cancer), glioblastoma, acute myeloid leukemia, and lung cancer, particularly NSCLC, said pharmaceutical formulations comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0208] In certain embodiments, the present invention provides pharmaceutical formulations for treating glioblastoma or astrocytoma, said pharmaceutical formulations comprising a compound of the present invention and temozolomide and a pharmaceutically acceptable carrier.

[0209] In certain embodiments, the present invention further provides a pharmaceutical formulation comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and temozolomide and a pharmaceutically acceptable carrier, diluent or excipient.

[0210] In certain embodiments, the present invention provides for treating NSCLC, pancreatic cancer, ovarian cancer or metastatic breast cancer (including ER in adult women or postmenopausal women) + HER2 - advanced or metastatic or recurrent breast cancer) pharmaceutical formulations, said pharmaceutical formulations comprising a compound of the present invention and gemcitabine HCl and a pharmaceutically acceptable carrier.

[0211] In certain embodiments, the present invention further provides a pharmaceutical formulation comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and gemcitabine HCl and a pharmaceutically acceptable carrier, diluent or excipient.

[0212] The active compounds of the present invention can be administered by any suitable route, preferably in the form of a pharmaceutical composition suitable for such route, and in a dose effective for the intended treatment. The compounds and compositions of the present invention can be administered, for example, orally, mucosally, topically, rectally, such as by inhalation spray, etc. to the lungs or parenterally including intravascular, intravenous, intraperitoneal, subcutaneous, intramuscular, intrasternal and infusion techniques in dosage unit formulations containing conventional pharmaceutically acceptable carriers, adjuvants and excipients.

[0213] The pharmaceutically active compounds of the present invention can be processed according to conventional pharmaceutical methods to produce medicaments for administration to patients including humans and other mammals.

[0214] For oral administration, the pharmaceutical composition can be in the form of, for example, tablets, capsules, suspensions or liquids. Preferably, the pharmaceutical composition is made into a dosage unit that contains a specific amount of the active ingredient.

[0215] Examples of such dosage units are tablets or capsules. For example, the appropriate daily dose for a human or other mammal can vary depending on the condition of the patient and other factors, but can again be determined using conventional methods.

[0216] The amount of the compound administered and the dosage regimen for treating a disease with the compounds and / or compositions of the present invention depend on a variety of 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 employed. Accordingly, the dosing regimen can vary widely, but can be routinely determined using standard methods. As previously mentioned, the daily dose can be administered in a single dose or can be divided into two, three, four or more doses.

[0217] For therapeutic purposes, the active compounds of the present invention are usually combined with one or more adjuvants, excipients or carriers suitable for the specified route of administration. If administered orally, these compounds can be combined with lactose, sucrose, starch powder, cellulose alkanoate esters, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, gum arabic, sodium alginate, polyvinylpyrrolidone and / or polyvinyl alcohol, and then compressed into tablets or encapsulated for convenient administration. Such capsules or tablets can contain controlled-release formulations, which can be provided in the form of a dispersion of the active compound in hydroxypropyl methylcellulose.

[0218] In the case of skin conditions, it is preferably to apply the topical preparation of the compounds of the present invention to the affected area two to four times a day. Formulations suitable for topical administration include liquid or semi-liquid formulations suitable for penetrating the skin (e.g., liniments, lotions, ointments, creams or pastes) and drops suitable for administration to the eye, ear or nose. For topical administration, based on the weight of the formulation, the active ingredient can comprise from 0.001% to 10% w / w, for example, 1% to 2%, although the active ingredient can comprise up to 10% w / w, but preferably does not exceed 5% w / w of the formulation, and more preferably is from 0.1% to 1%.

[0219] The compounds of the present invention can also be administered by transdermal devices. Preferably, transdermal administration will be accomplished using patches of the reservoir and porous membrane type or the solid matrix variety. In either case, the active agent is continuously delivered from the reservoir or microcapsules through the membrane into an active agent-permeable adhesive that contacts the skin or mucosa of the recipient. If 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 emulsions of the present invention can be constituted in a known manner from known ingredients.

[0220] While the phase can consist only of an emulsifier, it can include at least one emulsifier in admixture with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. It is also preferred to include oils and fats. The emulsifier, together or not together with the stabilizer, constitutes a so-called emulsifying wax, and the wax together with the oils and fats constitutes a so-called emulsifying ointment base that forms the oily disperse phase of the cream formulation. Emulsifiers and emulsion stabilizers suitable for the formulations of the present invention include Tween 60, Span 80, cetearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryl distearate alone or in admixture with waxes, or other materials well known in the art.

[0221] The selection of a suitable oil or fat for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils that might be used in pharmaceutical emulsion formulations is very low. Thus, the cream should preferably be a non-greasy, non-staining and washable product with a suitable consistency to avoid leakage from tubes or other containers. Straight-chain or branched-chain, mono- or di-alkyl esters such as diisoadipate, isocetyl stearate, propylene glycol dicaprylate, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or blends of branched-chain esters can be used. Depending on the desired properties, these can be used alone or in combination.

[0222] Alternatively, high melting point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils can be used.

[0223] Formulations suitable for topical administration to the eye also include eye drops in which the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent of the active ingredient.

[0224] The active ingredient is preferably present in such formulations at a concentration of from 0.5 to 20%, advantageously from 0.5 to 10% and especially about 1.5% w / w.

[0225] Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules using one or more of the carriers or diluents mentioned for formulations for oral administration or by using other suitable dispersing or wetting agents and suspending agents. The compounds may 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 buffering agents. Other adjuvants and modes of administration are well known in the pharmaceutical art. The active ingredient may also be administered by injection as a composition with a suitable carrier comprising saline, dextrose, or water or solubilized with a co-solvent (i.e., propylene glycol) or a micelle former (i.e., Tween 80), such as cyclodextrin (i.e., Captisol).

[0226] The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, a sterile, fixed oil is conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil including synthetic mono- or di-glycerides of fatty acids may be employed. In addition, fatty acids such as oleic acid have been found useful in the preparation of injectables.

[0227] For pulmonary administration, the pharmaceutical composition may be administered in the form of an aerosol or with an inhaler containing a dry powder aerosol.

[0228] Suppositories for rectal drug administration may be prepared by mixing the drug with suitable non-irritating excipients such as cocoa butter and polyethylene glycol, which are solid at ordinary temperature but liquid at rectal temperature and will thus melt in the rectum and release the drug.

[0229] The pharmaceutical composition may be subjected to conventional pharmaceutical operations such as sterilization and / or may contain conventional adjuvants such as preservatives, stabilizers, wetting agents, emulsifying agents, buffering agents, etc. Tablets and pills may additionally be prepared with enteric coatings. Such compositions may also include adjuvants such as wetting agents, sweetening agents, flavoring agents, and perfuming agents. The pharmaceutical composition of the present invention comprises a compound of the formula described herein or a pharmaceutically acceptable salt thereof; an additional agent selected from kinase inhibitors (small molecules, polypeptides, antibodies, etc.), immunosuppressants, anti-cancer agents, anti-viral agents, anti-inflammatory agents, anti-fungal agents, antibiotics, or anti-angiogenic compounds; and any pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0230] Alternative compositions of the invention include a compound of the formula described herein or a pharmaceutically acceptable salt thereof; and a pharmaceutically 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.), immunosuppressive agents, anti-cancer agents, antiviral agents, anti-inflammatory agents, anti-fungal agents, antibiotics or anti-angiogenic compounds.

[0231] The term "pharmaceutically acceptable carrier or adjuvant" refers to a carrier or adjuvant that can be administered to a patient together with a compound of the invention without destroying its pharmacological activity and is non-toxic when administered in a dose sufficient to deliver a therapeutically effective amount of the compound. Pharmaceutically acceptable carriers, adjuvants and vehicles that can be used in the pharmaceutical compositions of the invention include, but are not limited to: ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopheryl polyethylene glycol 1000 succinate, surfactants for pharmaceutical dosage forms such as Tween or other similar polymeric delivery matrices, serum proteins such as human serum albumin, buffering substances such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides 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, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polypropylene block polymers, polyethylene glycol and lanolin. Cyclodextrins such as α-, β- and γ-cyclodextrins or chemically modified derivatives such as hydroxyalkyl cyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrin, or other solubilizing derivatives can also be advantageously used to enhance the delivery of the compounds of the formula described herein.

[0232] The pharmaceutical compositions can be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions. In the case of tablets for oral use, carriers commonly used 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 administered orally, the active ingredient can be suspended or dissolved in the oil phase, mixed with an emulsifying agent and / or a suspending agent.

[0233] If desired, certain sweetening agents, flavoring agents and / or coloring agents can be added. The pharmaceutical compositions can include formulations utilizing liposome or microencapsulation techniques, various examples of which are known in the art.

[0234] The pharmaceutical composition can be administered by nasal aerosol or inhaler. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and can be prepared as a saline solution with benzyl alcohol or other suitable preservatives, absorption promoters for enhancing bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents, examples of which are also well known in the art.

[0235] 7. Therapeutic Kit

[0236] One aspect of the present invention relates to a kit for facilitating and effectively implementing the methods or uses according to the present invention. Generally, a pharmaceutical pack or kit includes one or more containers filled with one or more of the ingredients of the pharmaceutical composition of the present invention. Such kits are particularly suitable for delivering solid oral dosage forms such as tablets or capsules. Such kits preferably contain multiple unit doses and may also contain a card with doses oriented in the order of their intended use. If desired, a memory aid can be provided, for example, in the form of numbers, letters, or other markings or with a calendar insert, specifying the days in the treatment regimen on which the doses can be administered. Optionally associated with one or more such containers may be a notice in a form prescribed by a government agency that regulates the manufacture, use, or sale of pharmaceutical products, which reflects the agency's approval of the manufacture, use, or sale for human administration.

[0237] The following representative examples contain important additional information, illustration, and guidance that can be applied to the practice of the present invention in its various embodiments and their equivalents. These examples are intended to assist in illustrating the present invention and are not intended nor should they be construed as limiting the scope of the present invention. In fact, various modifications of the present invention and many additional embodiments thereof will become apparent to those skilled in the art upon reading this document, including the following examples and references to scientific and patent literature cited herein.

[0238] The contents of the cited references are incorporated herein by reference to assist in illustrating the prior art.

[0239] In addition, for the purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, inside front cover of the Handbook of Chemistry and Physics, 75th Edition. Additionally, general principles of organic chemistry and specific functional moieties and reactivity are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999 and "Organic Chemistry," Morrison and Boyd (3rd Edition), the entire contents of both of which are incorporated herein by reference.

[0240] 8. Synthetic Scheme

[0241] The compound of formula I can be prepared by those of ordinary skill in the art according to the techniques and procedures recognized in the art. More specifically, the compound of formula I can be prepared as described in the schemes, methods and examples below. Those skilled in the art will recognize that the individual steps in the following schemes can be varied to provide the compound of formula I. Reagents and starting materials are readily available to those of ordinary skill in the art. Unless otherwise specified, all substituents are as defined previously.

[0242] Examples

[0243] Biological Example 1. CDK4 / CyclinD1 Inhibition Assay

[0244] The CDK4 enzyme assay for IC 50 determination was performed as follows. The microfluidic kinase detection technology (Caliper) was used to monitor the phosphorylation of the peptide substrate by CDK4 / CyclinD1. The total reaction volume was 15 μL, which contained buffer A (100 mM HEPES (pH 7.5), 0.1% BSA, 0.01% Triton X-100, 1 mM DTT, 10 mM MgCl 2 , 10 μM sodium orthovanadate, 10 μM β-glycerophosphate), 200 μM ATP, 1 nM CDK4 / CyclinD1 (Thermofisher, PR8064A), 1 μM FL-34 (5-FAM-RRRFRPASPLRGPPK), and the test compound appropriately diluted in DMSO. All components were added to a 384-well plate (Corning, 4514) and incubated at room temperature for 3 hours. The reaction was terminated by adding 15 μL of the termination 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 aspirated into the microfluidic chip for separation and detection. The IC 50 value of the test compound was determined by fitting the inhibition curve using the 4-parameter sigmoidal dose-response model with Xlfit5 / GraphPad Prism 5 software.

[0245] Biological Example 2. CDK6 / CyclinD3 Inhibition Assay

[0246] The IC 50Measured CDK6 enzyme assay. The microfluidic kinase detection technology (Caliper) was used to monitor the phosphorylation of the peptide substrate by CDK6 / CyclinD3. The total reaction volume was 15 μL, which contained buffer A (100 mM HEPES (pH 7.5), 0.1% BSA, 0.01% Triton X-100, 1 mM DTT, 10 mM MgCl 2 , 10 μM sodium orthovanadate, 10 μM β-glycerophosphate), 300 μM ATP, 2 nM CDK6 / CyclinD3 (Carna, 04-107), 1 μM FL-34 (5-FAM-RRRFRPASPLRGPPK), and the test compound appropriately diluted in DMSO. All components were added to a 384-well plate (Corning, 4514) and incubated at room temperature for 3 hours. The reaction was terminated by adding 15 μL of termination 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 aspirated into the microfluidic chip for separation and detection. The IC 50 value of the test compound was determined by fitting the inhibition curve using the 4-parameter sigmoidal dose-response model with Xlfit5 / GraphPad Prism 5 software.

[0247] Biological Example 3. CDK2 / CyclinE1 Inhibition Assay

[0248] The CDK2 enzyme assay for IC 50 measurement was carried out as follows. The microfluidic kinase detection technology (Caliper) was used to monitor the phosphorylation of the peptide substrate by CDK2 / CyclinE1. The total reaction volume was 15 μL, which contained buffer A (100 mM HEPES (pH 7.5), 0.1% BSA, 0.01% Triton X-100, 1 mM DTT, 10 mM MgCl 2, 10 μM sodium orthovanadate, 10 μM β-glycerophosphate), 100 μM ATP, 5 nM CDK2 / Cyclin E1 (SignalChem, C29-18G), 5 μM FL-18 (5-FAM-QSPKKG-NH2), and the test compound appropriately diluted in DMSO. All components were added to a 384-well plate (Corning, 4514) and incubated at room temperature for 3 hours. The reaction was terminated by adding 15 μL of stop buffer (180 mM HEPES (pH 7.5), 20 mM EDTA, Coating-3 reagent (PerkinElmer, 760050)). The plate was loaded onto a Caliper EZ reader (EZ reader II, PerkinElmer, HD-4HYSG2772), and the reaction mixture containing the substrate and product was aspirated into a microfluidic chip for separation and detection. The IC 50 value of the test compound was determined by fitting the inhibition curve using Xlfit5 / GraphPad Prism 5 software with a 4-parameter sigmoidal dose-response model.

[0249] The IC 50 values of each example compound against CDK2, CDK4, and CDK6 are provided in the synthetic examples below. For values less than or equal to 10 nM; less than or equal to 100 nM; less than or equal to 1 μM; and greater than 1 μM, the IC 50 values are indicated as "A", "B", "C", and "D", respectively.

[0250] Biological Example 4. Antiproliferation Assay in T47D Cells

[0251] T47D is a human breast cancer cell line commonly used in biomedical research involving hormonal expression in cancer cells. T47D cells differ from other human breast cancer cells in that the progesterone receptor (PR) in T47D cells is not regulated by estradiol, a hormone that is abundant within the cells themselves. T47D cells have been used to study the effects of progesterone on breast cancer and the corresponding transcriptional regulation induced by introduced drugs. It has been noted that the cells are highly resistant to estrogens and anti-estrogens.

[0252] T47D breast cancer cells from the American Type Culture Collection (ATCC, HTB-133) were seeded at 3000 cells / well in a 96-well plate and incubated at 37 °C, 5% CO 2Incubate below in RPMI 1640 medium (Gibco, 31800105) containing 10% fetal bovine serum (FBS, Biowest, FB-1058). After overnight incubation, measure the baseline value of the samples from one plate using Cyquant reagent (Invitrogen, C35011) according to the manufacturer's recommendations. Incubate the cells with the detection reagent at 37 °C for 1 hour, then measure the fluorescence using Spectra Max M5 (Molecular Devices, HD-4HYSG3196) at 485 nm excitation and 535 nm emission. Other plates are added with compounds at ten-point dose concentrations from 10 μM to 0.51 nM in a 3-fold dilution scheme. On the 6th day after adding the compounds, add Cyquant reagent and measure the fluorescence using Spectra Max M5. Use Xlfit5 / GraphPad Prism 5 software to determine the IC 50 value of the anti-proliferative activity of the test compound from the viability readout curve with baseline subtracted.

[0253] Biological Example 5. Inhibition of phosphorylation of retinoblastoma protein (pRb) in T47D cells

[0254] T47D breast cancer cells from the American Type Culture Collection (ATCC, HTB-133) are seeded at 40,000 cells / well in a 96-well plate and incubated in RPMI 1640 medium (Gibco, 31800105) containing 10% fetal bovine serum (FBS, Biowest, FB-1058). Then the cells are incubated at 37 °C, 5% CO 2Adhere overnight. The next day, the compounds were titrated in a 3-fold dilution scheme, and the highest compound concentration tested was 10 μM. After incubation with the compounds for 24 hours, the cells were lysed in ice-cold lysis buffer containing a phosphatase inhibitor mixture and 1 mM PMSF. Then the cell lysates (50 μL / well) were transferred to an ELISA plate (pRb Ser807 / 811 ELISA kit, Cell Signaling, 13152 or pRb Ser780 ELISA kit, Cell Signaling, 13016)). The plate was incubated overnight at 4 °C with constant slow shaking. After incubation, the plate was washed as per the manufacturer's recommendations and then 100 μL of the reconstituted detection antibody was added to each well and incubated for 1 hour at 37 °C. After incubation, the plate was washed and then 100 μL of the reconstituted HRP-conjugated secondary antibody was added to each well and incubated for 30 minutes at 37 °C. After incubation, the plate was washed. Then, 100 μL of the TMB substrate was added to each well and incubated for 10 minutes at 37 °C or for 30 minutes at 25 °C. Finally, 100 μL of the stop solution was added to each well and gently mixed for a few seconds. The plate was read on an Envision plate reader (PerkinElmer, 2104 - 0010) using the 96-well luminescence mode. The IC 50 values were calculated using a 4-parameter sigmoidal dose-response model of Xlfit5 / GraphPad Prism 5 software.

[0255] The cell data obtained from Biological Examples 4 and 5 are listed in Table A below. For values less than or equal to 100 nM, the IC 50 values are indicated as "++++"; for values less than or equal to 500 nM, indicated as "+++"; for values less than or equal to 1 μM, indicated as "++"; and for values greater than 1 μM, indicated as "+".

[0256] Synthesis Examples

[0257] Device Description

[0258] 1H 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 describe the apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet), br (broad peak). 1

[0259] Analysis of low-resolution mass spectrometry (MS) was recorded on a Waters ACQUITY UPLC using a SQ detector with a Waters CORTECS C18+ column, 2.7 μm, 4.6×30 mm, and a gradient elution method.

[0260] Solvent A: Water containing 0.1% formic acid (FA)

[0261] Solvent B: Acetonitrile containing 0.1% FA

[0262] From 5% ACN to 95% ACN in 1.0 minute, held for 1.0 minute,

[0263] Total 2.5 minutes; flow rate: 1.8 mL / min; column temperature 40 °C.

[0264] Intermediate

[0265] Intermediate 1

[0266]

[0267] Step 1

[0268] At 25 °C, 2,4,6-Trimethylphenylsulfonyl azide (236 mg, 1.1 mmol) was added to a solution of 4-Benzyloxypyridine (185 mg, 998 μmol) in DCM (10 mL). The reaction mixture was stirred at 25 °C for 14 h. The mixture was concentrated under reduced pressure to afford the crude desired product as a colorless oil (400 mg, 99% yield). LC-MS: m / z 202 [M+H] + .

[0269] Step 2

[0270] To a solution of 4-Benzyloxypyridin-1-ium-1-amine (187 mg, 929 μmol) in DMF (10 mL) was added Cs 2 CO 3 (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 Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by column chromatography (eluting with PE / EA = 10 / 1) to afford the desired product as a yellow solid (90 mg, 35% yield). LC-MS: m / z 267 [M+H] + .

[0271] Step 3

[0272] In N 2 Under N, at -20 °C, butyllithium (43.3 mg, 675 μmol) was added dropwise to a solution of methyl(triphenyl)phosphonium bromide (241 mg, 675 μmol) in THF (10 ml). The reaction was stirred at -20 °C for 1 hour. 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 hours. The reaction mixture was quenched with MeOH (3 ml) and concentrated under reduced pressure. The residue was purified by preparative HPLC (eluting with PE:EA = 1 / 1) to give the crude desired product as a yellow solid (41.0 mg, 46% yield). LC-MS: m / z 265 [M+H] + .

[0273] Step 4

[0274] Pd / C (60 mg) was added to a solution of 5-benzyloxy-3-isopropenyl-pyrazolo[1,5-a]pyridine (600 mg, 2.3 mmol) in methanol (50 mL). The reaction mixture was stirred at 30 °C for 48 hours under H 2 . The reaction mixture was filtered and concentrated under reduced pressure to give the desired product as a yellow solid (380 mg, 95% yield). LC-MS: m / z 177 [M+H] + .

[0275] Step 5

[0276] In N 2 Under N, at 0 °C, Tf 2 O (1.1 g, 4.1 mmol) was added 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). The reaction mixture was stirred at 0 °C for 2 hours. The reaction mixture was washed with brine (15 mL) and dried over Na 2 SO 4 . The organic layer was filtered and the filtrate was concentrated to give the desired product as a colorless oil (1.1 g, 92% yield). LC-MS: m / z 309 [M+H] + .

[0277] Step 6

[0278] 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)Cl 2 (249 mg, 340 μmol) and KOAc (1.0 g, 10.2 mmol). The reaction mixture was stirred at 110 °C under N 2 for 2 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford the crude desired product as a dark solid (950 mg, 97% yield). LC-MS: m / z 287 [M+H] + .

[0279] Step 7

[0280] 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-fluoropyrimidine (665 mg, 4.0 mmol) in H 2 O (1 mL) and 1,4-dioxane (15 mL) was added Na 2 CO 3 (1.2 g, 10.0 mmol) and Pd(dppf)Cl 2 (242 mg, 332 μmol). The mixture was stirred at 110 °C under N 2 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 / EA with 0 - 50% EA) to give the desired product as a yellow solid (650 mg, 67% yield). LC-MS: m / z 291 [M+H] + .

[0281] Intermediate 2

[0282]

[0283] 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)Cl 2 (0.9 g, 1.2 mmol) and Na 2 CO3 (1.52 g, 14 mmol). The reaction mixture was stirred at 110 °C for 6 h under N 2 The mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (20 g silica gel column, PE with 0 - 50% EA) to afford the desired product as a yellow solid (2.1 g, 62% yield). LC-MS: m / z 273 [M+H] + .

[0284] Additional intermediates of the present invention were prepared by using the corresponding derivatives. The following table lists selected compounds and their corresponding characterization data.

[0285]

[0286] Intermediate 5

[0287]

[0288] 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-iodopyridine (269 mg, 1.1 mmol) in H 2 O (1 mL) and 1,4-dioxane (20 mL) was added Na 2 CO 3 (260 mg, 2.1 mmol) and Pd(dppf)Cl 2 (51.1 mg, 69.9 μmol). The reaction mixture was stirred at 110 °C for 6 h under N 2 The mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (20 g silica gel column, PE / EA with 0 - 50% EA) to afford the desired product as a yellow solid (140 mg, 69% yield). LC-MS: m / z 290 [M+H] + .

[0289] Intermediate 6

[0290]

[0291] Step 1

[0292] To a solution of 5-bromopyrazolo[1,5-a]pyridine (0.9 g, 4.6 mmol) in dry dioxane (40 mL) was added B 2 Pin 2 (1.8 g, 6.9 mmol), Pd(dppf)Cl 2(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 a 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 afford the desired product as a white solid (1.1 g, 75% yield). LC-MS: m / z 245 [M+H] + 。

[0293] Step 2

[0294] 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)Cl 2 (0.6 g, 0.8 mmol) and K 2 CO 3 (1.7 g, 12.0 mmol). Then 5 mL of H 2 O 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 / petroleum ether) to afford the desired product as a white solid (0.7 g, 66% yield). LC-MS: m / z 249 [M+H] + 。

[0295] Step 3

[0296] 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 afford the desired product as a white solid (680 mg, 84% yield). LC-MS: m / z 327 [M+H] + 。

[0297] Intermediate 7

[0298]

[0299] Step 1

[0300] To a solution of 5-bromo-3-iodopyrazolo[1,5-a]pyridine (1.0 g, 3.1 mmol) and cyclopent-1-en-1-ylboronic acid (0.4 g, 3.4 mmol) in dioxane (20 mL) and water (5 mL) was added cyclopentyl(diphenyl)phosphine dichloromethane dichloropalladium iron (0.8 g, 0.9 mmol) and tripotassium phosphate (2.0 g, 9.3 mmol). The reaction mixture was stirred at 100 °C for 5 h under N 2 atmosphere. The reaction mixture was extracted with EtOAc (3 × 10 mL). The organic phase was washed with brine (50 mL) and dried over anhydrous Na 2 SO 4 4, filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography to afford the desired product as a white solid (0.3 g, 38% yield). LC-MS: m / z 265.1 [M+H] + .

[0301] Step 2

[0302] To a solution of 5-bromo-3-(cyclopent-1-en-1-yl)pyrazolo[1,5-a]pyridine (270 mg, 1.0 mmol) in methanol (10 mL) was added PtO 2 (46.6 mg, 205.2 μmol). The mixture was stirred at 25 °C for 2 h under a hydrogen atmosphere. The mixture was filtered through a pad of Celite. The filtrate was concentrated to afford the desired product as a white solid (190 mg, 69% yield), which was used in the next step without further purification. LC-MS: m / z 267.1 [M+H] + .

[0303] Step 3

[0304] 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 was added cyclopentyl(diphenyl)phosphine dichloromethane dichloropalladium iron (57.9 mg, 79.2 μmol) and potassium acetate (233 mg, 2.4 mmol). The reaction mixture was stirred at 110 °C for 2 h. The mixture was filtered and concentrated in vacuo to afford 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] + .

[0305] Step 4

[0306] 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-fluoropyrimidine (134 mg, 807 μmol) in dioxane (5 mL) and water (1 mL) was added cyclopentyl(diphenyl)phosphine dichloropalladium(II) (49.2 mg, 67.2 μmol), potassium carbonate (278 mg, 2.0 mmol). The resulting mixture was stirred at 105 °C for 3 h under N 2 atmosphere. The reaction mixture was diluted with water (10 mL) and then extracted with EtOAc (3 × 10 mL). The combined organic phases were washed with brine (50 mL) and dried over anhydrous Na 2 SO 4 , filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography to afford the desired product as a white solid (40 mg, 19% yield). LC-MS: m / z 317.1 [M+H] + .

[0307] Intermediate 8

[0308]

[0309] Step 1

[0310] Under N 2 atmosphere, to a solution of 5-bromo-3-iodopyrazolo[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)Cl 2 (758 mg, 929 μmol), K 3 PO 4 (2.0 g, 9.3 mmol) and water (5 mL). Then the reaction mixture was 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 with 0 - 30% EtOAc) to afford the desired product as a brown solid (508 mg, 59% yield). LC-MS: m / z 279 [M+H] + .

[0311] Step 2

[0312] Under N 2Under an N atmosphere, cyclopentyl(diphenyl)phosphine dichloropalladium(II) (188 mg, 257 μmol) and potassium acetate (379 mg, 3.8 mmol) were added 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). The reaction mixture was then stirred at 110 °C for 8 h. The mixture was filtered and concentrated under reduced pressure to afford the crude desired product as a yellow oil, which was used in the next step without further purification. LC-MS: m / z 327 [M+H] + 。

[0313] Step 3

[0314] Under an N 2 atmosphere, cyclopentyl(diphenyl)phosphine dichloropalladium(II) (192 mg, 263 μmol), disodium carbonate (419 mg, 3.9 mmol) and water (1 mL) were added 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-fluoropyrimidine (242 mg, 1.5 mmol) in dioxane (15 mL). 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 with 0 - 30% EtOAc) to afford the desired product as an orange solid (360 mg, 82% yield). LC-MS: m / z 331.1 [M+H] + 。

[0315] Intermediate 9

[0316]

[0317] Step 1

[0318] Under an N 2 atmosphere at -78 °C, TMPMgCl-LiCl (1 M, 916 μL) was added to a solution of 5-(2-chloropyrimidin-4-yl)-3-isopropyl-pyrazolo[1,5-a]pyridine (100 mg, 366 μmol) in THF (8 mL). The reaction was stirred at -78 °C for 0.5 h. Then NBS (78.3 mg, 439 μmol) was added. The mixture was warmed to 25 °C and stirred for 1.5 h. The mixture was treated with NH4 The reaction mixture was quenched with an aqueous solution of Cl (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 of silica gel, 0 - 30% EtOAc / PE) to give the desired product as a yellow solid (45.0 mg, 34% yield). LC-MS: m / z 351.0 [M+H] + .

[0319] Step 2

[0320] A solution of 7-bromo-5-(2-chloropyrimidin-4-yl)-3-isopropyl-pyrazolo[1,5-a]pyridine (45.0 mg, 127 μmol), Pd(PPh 3 )(14.7 mg, 12.8 μmol) and Zn(CN) 4 (22.5 mg, 191 μmol) in NMP (5 mL) was irradiated in a microwave reactor at 110 °C for 0.5 h under N 2 . The mixture was concentrated under reduced pressure. The residue was purified by FCC (4 g of silica gel, 0 - 30% EtOAc / PE) to give the desired product as a yellow solid (15.0 mg, 39% yield). LC-MS: m / z 298.1 [M+H] 2 . + .

[0321] Intermediate 84

[0322]

[0323] Step 1

[0324] Under an N 2 atmosphere at 0 °C, 2-bromo-2-methyl-propane (4.1 g, 30.4 mmol) was added to a suspension of aluminum trichloride (2.7 g, 20.3 mmol) in DCM (10 mL). The reaction mixture was stirred at 0 °C for 10 minutes under an N 2 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). Then the mixture was extracted with DCM (3 × 50 mL), and the combined organic layers were dried over anhydrous Na 2 SO 4 , 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 as a yellow oil (1.2 g, 46% yield). LC-MS: m / z 253.1 [M+H] + .

[0325] Step 2

[0326] Under N 2 atmosphere, cyclopentyl(diphenyl)phosphine dichloropalladium(II) (173 mg, 237 μmol) and potassium acetate (232 mg, 2.4 mmol) were added 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). Then the mixture was stirred at 110 °C for 13 h under N 2 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.

[0327] Step 3

[0328] Under N 2 atmosphere, cyclopentyl(diphenyl)phosphine dichloropalladium(II) (72 mg, 99 μmol), disodium carbonate (174 mg, 1.6 mmol) and water (0.5 mL) were added 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). Then the reaction mixture was stirred at 110 °C for 5 h under N 2 atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography to give the desired product as a yellow solid (220 mg, 92% yield). LC-MS: m / z 287.1 [M+H] + .

[0329] Additional intermediates of the present invention were prepared by using the corresponding derivatives. The selected compounds and their corresponding characterization data are listed in the following table.

[0330]

[0331] Intermediate 10

[0332]

[0333] Step 1

[0334] At 0 °C, Cs 2 CO 3A solution of (500 mg, 1.5 mmol) in DMF (8 mL) was added to MeI (99 mg, 679 μmol). 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 phases were dried over anhydrous Na 2 SO 4 + . The filtrate was concentrated. The residue was purified by flash column chromatography (24 g silica gel column, 0 to 10% EA / DCM in 20 min) to afford the desired product (20.0 mg) as a pale purple solid. LC-MS: m / z 337.9 [M+H]

[0335] Step 2

[0336] 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)Cl 2 (90.0 mg, 100 μmol) and K 2 CO 3 (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 phases were dried over anhydrous Na 2 SO 4 and then filtered. The filtrate was concentrated. The residue was purified by flash column chromatography (24 g silica gel column, 0 to 70% EA / PE in 20 min) to afford the desired product (30.0 mg) as a yellow solid. LC-MS: m / z 252.1 [M+H] + .

[0337] Step 3

[0338] 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 PtO 2 (18.1 mg, 79.3 μmol), and the mixture was stirred at 25 °C for 2 h under a hydrogen atmosphere. The reaction mixture was filtered and then washed with methanol (5 mL). The filtrate was concentrated to afford 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] + .

[0339] Step 4

[0340] 5-Bromo-3-isopropyl-2-methyl-pyrazolo[3,4-c]pyridine (30.0 mg, 118 μmol), B 2 Pin 2 (46.0 mg, 181 μmol), Pd 2 (dba) 3 (22.0 mg, 24.0 μmol), KOAc (35.0 mg, 357 μmol) and tricyclohexylphosphine (14.0 mg, 0.05 mmol) in dioxane (2 mL) were 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 afford the crude desired product as a black solid (25.0 mg). LC-MS: m / z 220.1 [M+H] + 。

[0341] Step 5

[0342] (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)Cl 2 (9.0 mg, 12.3 μmol) and K 2 CO 3 (33.0 mg, 239 μmol) in dioxane (3 mL) and water (1.5 mL) were stirred at 100 °C for 16 h under N 2 atmosphere. The reaction mixture was quenched with water (50 mL) and then extracted with ethyl acetate (2 × 100 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (24 g, 0 to 90% EA / PE in 20 min) to afford the desired product as a yellow solid (30.0 mg). LC-MS: m / z 306.1 [M+H] + 。

[0343] Intermediate 11

[0344]

[0345] Step 1

[0346] Iron powder (2.6 g, 46.5 mmol), water (9 mL), and concentrated HCl (2 mL) were added to ethanol (50 mL) containing 4-amino-2,6-dichloro-3-nitropyridine (2.0 g, 9.6 mmol). The mixture was heated under reflux for 16 h. The mixture was cooled to room temperature and then 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 Na 2 SO 4 and evaporated to give the desired product as a yellow solid (1.9 g, 99% yield). LC-MS: m / z 177.9 [M+H] + .

[0347] Step 2

[0348] 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 with 0 - 50% EtOAc) to give the desired product as a yellow solid (1.3 g, 67% yield). LC-MS: m / z 201.9 [M+H] + .

[0349] Step 3

[0350] NaH (772 mg, 32.1 mmol) was added to a solution of 4,6-dichloro-2-methyl-1H-imidazo[4,5-c]pyridine (1.9 g) in anhydrous DMF (5 mL) at 0 °C. Then 2-iodopropane (3.3 g, 19.3 mmol) was added to the reaction mixture. The mixture was warmed 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 to 10% MeOH / DCM) to give the desired product as a yellow solid (487 mg, 31% yield). LC-MS: m / z 244 [M+H] + .

[0351] Step 4

[0352] 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, 5 mL in MeOH). The mixture was heated at 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 with 0 - 100% EtOAc) to afford the desired product as a white solid (140 mg, 71% yield). LC-MS: m / z 240 [M+H] + 。

[0353] Step 5

[0354] Under N 2 atmosphere, to a solution of 6-chloro-1-isopropyl-4-methoxy-2-methyl-1H-imidazo[4,5-c]pyridine (120 mg, 0.5 mmol) and Pin 2 B 2 (153 mg, 0.6 mmol) in anhydrous dioxane (8 mL) was added Pd 2 (dba) 3 (137 mg, 0.15 mmol), tricyclohexylphosphine (84.1 mg, 0.3 mmol), AcOK (147 mg, 1.5 mmol). 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 crude desired product as a brown oil, which was used in the next step without further purification. LC-MS: m / z 250 [M+H] + 。

[0355] Step 6

[0356] Under N 2 atmosphere, 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)Cl 2 (122 mg, 0.2 mmol), Na 2 CO 3(159 mg, 1.5 mmol). 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, petroleum ether / EtOAc with 0 - 50% EtOAc) to afford the desired product as a yellow solid (139 mg, 82% yield). LC-MS: m / z 336 [M+H] + 。

[0357] Additional intermediates of the present invention were prepared by using the corresponding derivatives. The selected compounds and their corresponding characterization data are listed in the following table.

[0358]

[0359] Intermediate 18

[0360]

[0361] Step 1

[0362] 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) was charged into a sealed tube. Then tris(dibenzylideneacetone)dipalladium(0) (194 mg, 212 μmol), tricyclohexylphosphine (119 mg, 425 μmol) and potassium acetate (208 mg, 2.1 mmol) were added under N 2 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 crude desired product, which was used in the next step without further purification. LC-MS: m / z 250 [M+H] + 。

[0363] Step 2

[0364] In N 2Under an atmosphere, cyclopentyl(diphenyl)phosphine dichloropalladium(II) (167 mg, 228 μmol), disodium carbonate (242 mg, 2.2 mmol) and water (2 mL) were added 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-iodopyridine (216 mg, 839 μmol) in dioxane (8 mL). Then the reaction mixture was 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, petroleum ether / EtOAc with 0 - 100% EtOAc) to give the desired product as a yellow solid (160 mg, 62% yield). LC-MS: (ESI) m / z 335 [M+H] + 。

[0365] Intermediate 19

[0366]

[0367] Step 1

[0368] CsF (510 mg, 3.4 mmol) was added to a mixture of 4,6-dichloro-1-isopropyl-imidazo[4,5-c]pyridine (250 mg, 1.1 mmol) in DMSO (10 mL), 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 Na 2 SO 4 and filtered. The filtrate was concentrated. The residue was purified by a flash column (80 g silica gel 200 - 300 mesh, PE / EA = 5 / 1 - 2 / 1) to give the desired product as an off-white solid (210 mg, 75% yield). LC-MS: (ESI) m / z 214.1 [M+H] + 。

[0369] Step 2

[0370] Potassium acetate (41.3 mg, 421 μmol) and cyclopentyl(diphenyl)phosphine dichloropalladium(II) (15.4 mg, 21.1 μmol) were added 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). The mixture was purged with N 2Degas and stir at 110 °C for 16 h. Filter the mixture through a Celite pad. Concentrate the filtrate under reduced pressure to the crude desired product as a black oil (50 mg), which is used directly in the next step. LC-MS: (ESI) m / z 224.2 [M+H] + 。

[0371] Step 3

[0372] 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-iodopyrimidine (53.9 mg, 224 μmol) in dioxane (3 mL) was added cyclopentyl(diphenyl)phosphine dichloropalladium(II) (24.6 mg, 33.6 μmol) and potassium acetate (66.0 mg, 672 μmol). The mixture was degassed and stirred at 110 °C for 16 h. Concentrate the mixture under reduced pressure. Purify the residue by flash chromatography eluting with 0 - 60% ethyl acetate / petroleum ether to afford the desired product as a white solid (30.0 mg, 46% yield). LC-MS: (ESI) m / z) 292.1 [M+H] 2 Degas and stir at 110 °C for 16 h. Concentrate the mixture under reduced pressure. Purify the residue by flash chromatography eluting with 0 - 60% ethyl acetate / petroleum ether to afford the desired product as a white solid (30.0 mg, 46% yield). LC-MS: (ESI) m / z) 292.1 [M+H] + 。

[0373] Additional intermediates of the invention were prepared by using the corresponding derivatives. The following table lists selected compounds and their corresponding characterization data.

[0374]

[0375] Intermediate 20

[0376]

[0377] Step 1

[0378] 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) was added cesium carbonate (16.1 g, 49.5 mmol). Stir the reaction mixture at 100 °C for 48 h. Then quench the reaction mixture with H 2 O (50 mL), and extract with EA (3 × 10 mL). Concentrate the organic layer under reduced pressure. Purify the residue by flash column chromatography (20 g silica gel column, 0 to 10% MeOH / DCM) to afford the desired product as a yellow solid (650 mg, 11% yield). LC-MS: m / z 286 [M+H] + 。

[0379] Step 2

[0380] 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 methoxide (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 / PE to afford the desired product as a pale yellow oil (600 mg, 94% yield). LC-MS: (ESI) m / z 282.2 [M+H] + 。

[0381] Step 3

[0382] 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 Pd 2 (dba) 3 (97.5 mg, 106 μmol), potassium acetate (209 mg, 2.1 mmol) and tricyclohexylphosphine (59.7 mg, 212 μmol). The resulting mixture was stirred at 110 °C for 6 h under a nitrogen atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford the crude desired product as a brown oil (200 mg, 96% yield), which was used in the next step without further purification. LC-MS: (ESI) m / z 292.2 [M+H] + 。

[0383] Step 4

[0384] In N 2Under an atmosphere, sodium carbonate (239 mg, 2.3 mmol) and cyclopentyl(diphenyl)phosphine dichloropalladium(II) (132 mg, 180 μmol) were added 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). 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 afford the desired product as a yellow solid (250 mg, 76% yield). LC-MS: m / z 378.1 [M+H] + 。

[0385] Additional intermediates of the present invention were prepared by using the corresponding derivatives. The following table lists selected compounds and their corresponding characterization data.

[0386]

[0387] Intermediate 22

[0388]

[0389] Step 1

[0390] At 0 °C, boron tribromide (618 mg, 2.4 mmol) was added 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). The mixture was stirred at 60 °C for 12 h. The mixture was quenched with an aqueous NaHCO 3 aqueous solution (10 mL), and extracted with DCM (2 × 10 mL). The organic layers were combined and dried over Na 2 SO 4 and filtered and concentrated to afford the desired crude product as a yellow solid (140 mg), which was used directly in the next step without further purification. LC-MS: m / z 290.1 [M+H] + 。

[0391] Step 2

[0392] At 0 °C, trimethylsilyl 2,2-difluoro-2-fluorosulfonyl-acetate (129 mg, 517 μmol) and 6-(2-chloropyrimidin-4-yl)-1-isopropyl-imidazo[4,5-c]pyridin-4-ol (0.1 g, 345 μmol) were added to CH 3To a solution in CN (5 mL), add NaH (16.5 mg, 690 μmol) and CsF (78.6 mg, 517 μmol). Stir the mixture at 0 °C for 1 hour. Quench the mixture with water (5 mL) and extract with EtOAc (2 × 10 mL). Combine the organic layers and dry over Na 2 SO 4 dry, filter and concentrate to obtain a residue, which is purified by flash column chromatography (SiO 2 , hexane / ethyl acetate 1:1) to obtain the desired product as a white solid (105 mg, 89% yield). LC-MS: m / z 340.1 [M+H] + .

[0393] Intermediate 23

[0394]

[0395] Step 1

[0396] 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), sequentially add 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-diphenylphosphoryl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphine (190 mg, 328 μmol), cesium carbonate (2.0 g, 6.1 mmol). Degas the mixture 5 times. Stir the mixture at 110 °C for 16 hours. Dilute the reaction mixture with water (100 mL) and extract with EA (3 × 30 mL). Dry the combined organic layers over Na 2 SO 2 SO 4 dry and filter. Concentrate the filtrate. Purify the residue by flash column to obtain the desired product as a yellow solid (611 mg, 92% yield). LC-MS: (ESI) m / z 517.3 [M+H] + .

[0397] Step 2

[0398] In an ice bath, HCl / EtOAc (2 M, 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). The mixture was stirred in the ice bath for 2 hours. The mixture was concentrated and dried in vacuo to give the desired product as a yellow solid (1220 mg, 91% yield). LC-MS: (ESI) m / z 417.2 [M+H] + 。

[0399] Intermediate 24

[0400]

[0401] Step 1

[0402] At 0 °C, K 2 CO 3 (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) were added to a solution of 2-bromo-6-fluorophenol (4.0 g, 21.1 mmol) in DMF (50 mL). The reaction mixture was stirred at 25 °C for 14 hours. The mixture was concentrated under reduced pressure and purified to give the product (4.5 g, 88% yield). LC-MS: m / z 245.0 [M+H] + 。

[0403] Step 2

[0404] Under N 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-Bu 3 SnH (3.6 g, 12.3 mmol) and AIBN (2.0 g, 2.3 mmol). The reaction mixture was stirred at 90 °C for 12 hours. The reaction mixture was quenched with water (50 mL) and extracted with DCM (2 × 50 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by column chromatography (eluting with PE / EA = 10 / 1) to give the desired product (1.4 g, 81% yield). LC-MS: m / z 167.1 [M+H] + 。

[0405] Step 3

[0406] Under N2 At 25 °C, NBS (1.8 g, 10.1 mmol) was added to a solution of 7-fluoro-3,3-dimethyl-2,3-dihydrobenzofuran (1.4 g, 8.4 mmol) in DMF (30 mL). 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 (eluting with PE:EA = 1 / 1) to give the desired product (450 mg, 22% yield). LC-MS: m / z 245.0 [M+H] + .

[0407] Step 4

[0408] Under N 2 atmosphere, Pd(dppf)Cl 2 B 2 (98.0 mg, 0.16 mmol) and KOAc (117 mg, 1.2 mmol) were added to a solution of 5-bromo-7-fluoro-3,3-dimethyl-2,3-dihydrobenzofuran (100 mg, 0.4 mmol) and Pin 2 (122 mg, 0.5 mmol) in anhydrous dioxane (10 mL). 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 crude desired 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] + .

[0409] Step 5

[0410] Under N 2 atmosphere, Pd(dppf)Cl 2 (98.0 mg, 0.16 mmol), Na 2 CO 3 (127 mg, 1.2 mmol) were added to a solution of the above 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). 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, petroleum ether / EtOAc with 0 - 50% EtOAc) to give the desired product (60.0 mg, 51% yield). LC-MS: m / z 279.1 [M+H] + .

[0411] Intermediate 25

[0412]

[0413] Step 1

[0414] At 25 °C, Boc 2 O (5.5 g, 43.2 mmol) was added 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). 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 × 100 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated. The residue was purified by flash column chromatography (24 g, 0 to 100% EtOAc / PE in 20 min) to afford the desired product as a yellow oil (4.7 g, 14.5 mmol). LC-MS: m / z 346.2 [M+Na] + .

[0415] Step 2

[0416] 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 Na 2 SO 4 and then filtered. The filtrate was concentrated. The residue was purified by flash column chromatography to afford the desired product as a colorless oil (2.7 g, 12.1 mmol). LC-MS: m / z 224.3 [M+H] + .

[0417] Step 3

[0418] 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 for 16 h under N 2 atmosphere. 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 Na 2 SO 4Dry and then filter. Concentrate the filtrate. Purify the residue by flash column chromatography (24 g, 0 to 20% MeOH / DCM in 20 minutes) to afford the desired product as a yellow oil (330 mg, 55% yield). LC-MS: m / z 266.2 [M+H] + .

[0419] Step 4

[0420] A mixture of tert-butyl 3-isopropyl-6,7-dihydro-4H-imidazo[4,5-c]pyridine-5-carboxylate (530 mg, 2.0 mmol), HCl (2 N, 2 mL) in ethyl acetate (2 mL) was stirred at 25 °C for 1 h. Quench the reaction mixture with water (50 mL) and then extract with EtOAc (2 × 100 mL). Dry the combined organic phases over anhydrous Na 2 SO 4 dry and then filter. Concentrate the filtrate. Purify the residue by flash column chromatography (24 g, 0 to 100% EtOAc / PE in 20 minutes) to afford the desired product as a yellow solid (300 mg, 90% yield). LC-MS: m / z 166.3 [M+H] + .

[0421] Step 5

[0422] 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 for 2 h under N 2 atmosphere. Quench the reaction mixture with water (50 mL) and then extract with EtOAc (2 × 100 mL). Dry the combined organic phases over anhydrous Na 2 SO 4 dry and then filter. Concentrate the filtrate. Purify the residue by flash column chromatography (24 g, 0 to 20% MeOH / DCM in 20 minutes) to afford the desired product as a colorless oil (66.0 mg). LC-MS: m / z 278.1 [M+H] + .

[0423] Additional intermediates of the present invention were prepared using the corresponding derivatives. The following table lists selected compounds and their corresponding characterization data.

[0424]

[0425] Intermediate 26

[0426]

[0427] Step 1

[0428] At 25 °C, cesium carbonate (32.1 g, 98.5 mmol), tris(dibenzylideneacetone)dipalladium(0) (4.5 g, 4.9 mmol) and (5-diphenylphosphino-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphine (2.8 g, 4.9 mmol) were added to a solution of 5-bromo-2-nitropyridine (10.0 g, 49.2 mmol) and tert-butyl 3-oxopiperazine-1-carboxylate (10.8 g, 54.1 mmol) in dioxane (30 mL). 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 using 0 - 15% MeOH / DCM elution within 20 min to give the desired product as a pale yellow solid (1.5 g, 9% yield). LC-MS: m / z 323.1 [M+H] + 。

[0429] Step 2

[0430] At 25 °C, iron powder (1.1 g, 19.8 mmol) and ammonium chloride (2.6 g, 49.6 mmol) were added to a stirred solution of tert-butyl 4-(6-nitro-3-pyridyl)-3-oxopiperazine-1-carboxylate (1.6 g, 4.9 mmol) in ethanol (20 mL). The reaction mixture was stirred at 80 °C for 2 h under a N 2 atmosphere. 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] + 。

[0431] Additional intermediates of the present invention were prepared by using the corresponding derivatives. The following table lists the selected compounds and their corresponding characterization data.

[0432]

[0433]

[0434]

[0435]

[0436] Intermediate 40

[0437]

[0438] Step 1

[0439] To a solution of 2-methylmorpholine (100 mg, 988 μmol) and 5-fluoro-2-nitropyridine (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 afford the desired product as a yellow solid (200 mg, 90% yield). LC-MS: m / z 224.1 [M+H] + 。

[0440] Step 2

[0441] 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 ammonium chloride (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 0 - 10% MeOH / DCM in 15 min to afford the desired product as a brown solid (150 mg, 86% yield). LC-MS: m / z 194.1 [M+H] + 。

[0442] Intermediate 115

[0443]

[0444] Step 1

[0445] To a solution of 5-bromo-2-nitropyridine (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-diphenylphosphino-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphine (570 mg, 985 μmol) and cesium carbonate (4.8 g, 14.8 mmol). The reaction mixture was then stirred at 110 °C under N 2 for 3 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography eluting with 1 - 100% ethyl acetate / petroleum ether to afford the desired product as a yellow solid (850 mg, 68% yield). LC-MS: m / z 251.1 [M+H] + 。

[0446] Step 2

[0447] To a solution of 1-isopropyl-4-(6-nitro-3-pyridinyl)piperazine (850 mg, 3.4 mmol) in methanol (30 mL) was added Pd / C (412 mg, 10%). The reaction mixture was then degassed 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 afford the desired product as a brown solid (620 mg, 82% yield). LC-MS: m / z 221.2 [M+H] 2 The reaction mixture was filtered and then washed with methanol (20 mL). The combined solvents were concentrated under reduced pressure to afford the desired product as a brown solid (620 mg, 82% yield). LC-MS: m / z 221.2 [M+H] + .

[0448] Additional intermediates of the present invention were prepared by using the corresponding derivatives. The following table lists selected compounds and their corresponding characterization data.

[0449]

[0450]

[0451]

[0452] Intermediate 56

[0453]

[0454] Step 1

[0455] To a mixture of piperidine-2,4-dione (2.1 g, 18.5 mmol) and N-methylmethylamine (3.4 g, 74.2 mmol) in DCM (36 mL) and THF (18 mL) was added CH 3 COOH (10 mL), and the resulting mixture was stirred at 25 °C for 3 h under a nitrogen atmosphere. Sodium triacetoxyborohydride (7.8 g, 37.1 mmol) was added to this mixture, and the resulting mixture was stirred at 25 °C for 12 h under a nitrogen atmosphere. The reaction was quenched with water (50 mL) and concentrated in vacuo to remove DCM and THF. The mixture was extracted with DCM (3 × 100 mL). The organic solution was washed with brine (20 mL). The organic phase was dried over Na 2 SO 4 dried, filtered and concentrated under reduced pressure to afford the desired product (2.6 g, 89% yield), which was used in the next step without any purification. LC-MS: m / z 141.2 [M+H] + .

[0456] Step 2

[0457] Sodium borohydride (539.0 mg, 14.2 mmol) was added to a mixture of 4-(dimethylamino)-2,3-dihydro-1H-pyridin-6-one (1.0 g, 7.1 mmol) in methanol (15 mL), and the resulting mixture was stirred at 25 °C for 12 h under a nitrogen atmosphere. The reaction was quenched with saturated aqueous NH 4 Cl (10 mL), and then concentrated in vacuo to remove MeOH. The aqueous solution was purified by elution through a reverse-phase column (C18, 40 g) using (MeCN / water (0.1% NH 4 OH) = 1 / 10) to give the desired product as a pale yellow solid (0.3 g, 32% yield). LC-MS: m / z 143.2 [M+H] + .

[0458] Step 3

[0459] (1S,2S)-N1,N2-Dimethylcyclohexane-1,2-diamine (162 mg, 1.1 mmol) and CuI (108 mg, 569 μmol) were added 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), and the resulting mixture was stirred at 110 °C for 12 h under a nitrogen atmosphere. The reaction was filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by elution through a reverse-phase column (C18, 20 g) using (MeCN / water (0.1% NH 4 OH) = 1 / 10) to give the desired product as a pale yellow solid (272 mg, 61% yield). LC-MS: m / z 235.2 [M+H] + .

[0460] Additional intermediates of the present invention were prepared using the corresponding derivatives. The following table lists selected compounds and their corresponding characterization data.

[0461]

[0462]

[0463] Intermediate 135

[0464]

[0465] Step 1

[0466] To a solution of piperidine-2,4-dione (5 g, 44.2 mmol) in methanol (20 mL) was added methylamine (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 afford the desired product as a brown solid. LC-MS: m / z 127.1 [M+1] + 。

[0467] Step 2

[0468] 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 H 2 Then the reaction mixture was stirred at 25 °C for 16 h. The mixture was filtered and concentrated in vacuo to afford the desired product as a black oil. LC-MS: m / z 129.1 [M+1] + 。

[0469] Step 3

[0470] To a solution of 4-(methylamino)piperidin-2-one (2.6 g, 20.5 mmol) in DCM (10 mL) was added N,N-diethylethylamine (4.1 g, 41.1 mmol) and tert-butyl dicarbonate (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, 0 - 10% MeOH / DCM) to afford the desired product as a yellow oil (2.9 g, 61% yield). LC-MS: m / z 229.2 [M+1] + 。

[0471] Step 4

[0472] To a solution of tert-butyl N-methyl-N-(2-oxo-4-piperidinyl)carbamate (2 g, 8.7 mmol) in dry dioxane (20 mL) was added 5-iodopyridin-2-amine (1.9 g, 8.7 mmol), copper(I) iodide (166.8 mg, 876 μmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (249 mg, 1.7 mmol) and tripotassium phosphate (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 to 10% MeOH / DCM) to afford the desired product as a black oil (1.7 g, 62% yield). LC-MS: m / z 321.2 [M+1] + 。

[0473] Additional intermediates of the present invention are prepared by using the corresponding derivatives. The following table lists selected compounds and their corresponding characterization data.

[0474]

[0475] Intermediate 61

[0476]

[0477] Step 1

[0478] In an ice bath, formic acid (610 mg, 13.2 mmol) and formaldehyde (540 mg, 17.9 mmol) were added to a mixture of 3-aminopyrrolidin-2-one (333 mg, 3.3 mmol) in water (8 mL). The resulting mixture was stirred at 100 °C for 1.5 hours. 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] + 。

[0479] Step 2

[0480] At 25 °C, (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) were added 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). The reaction mixture was stirred at 110 °C for 16 hours. 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 / PE to give the desired product (160 mg, 71% yield) as a yellow solid. LC-MS: m / z 221.1 [M+H] + 。

[0481] Additional intermediates of the present invention are prepared by using the corresponding derivatives. The following table lists selected compounds and their corresponding characterization data.

[0482]

[0483] Intermediate 62

[0484]

[0485] To a solution of 4-amino-1H-pyridin-2-one (4.0 g, 36.3 mmol) and tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (10.1 g, 36.3 mmol) in DMF (10 mL) at 25 °C was added NaH (835 mg, 34.8 mmol). The mixture was then 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 Na 2 SO 4 dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0 - 15% methanol / dichloromethane elution within 20 min to afford the desired product as a yellow solid (0.4 g, 5% yield). LC-MS: m / z 294.2 [M+H] + .

[0486] Intermediate 63

[0487]

[0488] Step 1

[0489] 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) were added (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (132 mg, 933 μmol), tripotassium phosphate (1.5 g, 7.0 mmol) and CuI (28.9 mg, 152 μmol). The reaction mixture was stirred at 110 °C for 5 h under N 2 atmosphere. The mixture was concentrated under reduced pressure to give a residue which was purified by flash column chromatography (80 g silica gel column) using 0 - 5% MeOH / DCM elution to afford the desired product as a brown solid (280 mg, 39% yield). LC-MS: m / z 306.2 [M+H] + .

[0490] Additional intermediates of the present invention were prepared by using the corresponding derivatives. The following table lists selected compounds and their corresponding characterization data.

[0491]

[0492]

[0493] Intermediate 68

[0494]

[0495] 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 for 2 h under N 2 atmosphere. 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 Na 2 SO 4 and then filtered. The filtrate was concentrated. The residue was purified by flash column chromatography (24 g, 0 to 20% MeOH / DCM in 20 min) to afford the desired product as a colorless oil (156 mg, 73% yield). LC-MS: (ESI) m / z 214.2 [M+H] + .

[0496] Additional intermediates of the present invention were prepared by using the corresponding derivatives. The selected compounds and their corresponding characterization data are listed in the following table.

[0497]

[0498] Intermediate 73

[0499]

[0500] Step 1

[0501] To a stirred solution of 5-methyl-2-nitropyridine (5.0 g, 36.2 mmol) was added 1-bromopyrrolidine-2,5-dione (6.7 g, 38.0 mmol) and azo-bis-isobutyronitrile (0.6 g, 3.6 mmol). The reaction mixture was stirred at 80 °C for 4 h under N 2 atmosphere. The mixture was filtered through Celite. The filtrate was concentrated and purified to afford the desired product as a pale yellow solid (4.8 g, 61% yield). LC-MS: m / z 216.9 [M+H] + .

[0502] Step 2

[0503] 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. 5-(Bromomethyl)-2-nitropyridine (1.0 g, 4.6 mmol) was added to the above mixture at 25 °C. Under N 2The resulting mixture was stirred at 25 °C for 4 h under an atmosphere. The mixture was poured into water (100 mL) and extracted with dichloromethane (5 × 200 mL). The combined organic phases were dried over Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified to afford the desired product as a white solid (100 mg, 7% yield). LC-MS: m / z 238 [M+H] + .

[0504] Step 3

[0505] To a stirred solution of 4-[(6-nitro-3-pyridinyl)methyl]morpholin-3-one (40.0 mg, 168 μmol) in ethanol (2 mL) at 25 °C was added NH 4 Cl (100 mg, 2.0 mmol) and iron powder (37.6 mg, 674 μmol). The reaction mixture was stirred at 80 °C for 12 h under an N 2 atmosphere. The mixture was filtered through a pad of diatomaceous earth. The filtrate was concentrated under reduced pressure to afford the desired product as a pale yellow solid (23.0 mg, 65% yield), which was used in the next step without further purification. LC-MS: m / z 208 [M+H] + .

[0506] Intermediate 74

[0507]

[0508] Step 1

[0509] 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 for 2 h under an N 2 atmosphere. The reaction mixture was quenched with water (100 mL) and then extracted with DCM (2 × 100 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 and then filtered. The filtrate was concentrated. The residue was purified by flash column chromatography (40 g, 0 to 100% EtOAc / PE in 20 min) to give the desired product as a yellow oil (3.5 g, 95% yield). LC-MS: m / z 253.1 [M+H] + .

[0510] Step 2

[0511] A mixture of 1-(6-chloro-2-methylpyridine-3-carbonyl)piperidin-4-one (760 mg, 3.0 mmol), tert-butyl carbamate (421 mg, 3.6 mmol), Pd 2 (dba) 3 (137 mg, 149 μmol), RuPhos (137 mg, 294 μmol) and Cs 2 CO 3 (1.5 g, 4.6 mmol) in dioxane (10 mL) was stirred at 100 °C for 2 h under a N 2 atmosphere. 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 Na 2 SO 4 and then filtered. The filtrate was concentrated. The residue was purified by flash column chromatography (12 g, 0 to 100% EtOAc / PE in 10 min) to afford the desired product as a yellow solid (430 mg, 36% yield). LC-MS: m / z 334.1 [M+H] + .

[0512] Step 3

[0513] A mixture of tert-butyl N-[6-methyl-5-(4-oxopiperidine-1-carbonyl)-2-pyridyl]carbamate (1.9 g, 5.9 mmol), cyclopropylamine (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 × 150 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 and then filtered. The filtrate was concentrated. The residue was purified by flash column chromatography (40 g, 0 to 100% EtOAc / PE in 25 min) to afford the desired product as a yellow solid (1.3 g, 30% yield). LC-MS: m / z 375.1 [M+H] + .

[0514] Step 4

[0515] 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 K 2 CO 3, and then filter. Concentrate the filtrate to obtain the desired product as a yellow solid (750 mg, 80% yield). LC-MS: m / z 275.1 [M+H] + .

[0516] Prepare additional intermediates of the present invention by using the corresponding derivatives.

[0517] The following table lists the selected compounds and their corresponding characterization data.

[0518]

[0519]

[0520] Intermediate 76

[0521]

[0522] Add anhydrous Na 2 CO 3 (4.6 g, 43.3 mmol) 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). Then stir the mixture at room temperature for 16 hours. Filter the mixture and concentrate the filtrate under reduced pressure. Dissolve the residue and 6-aminopyridine-3-carbaldehyde (1.3 g, 10.6 mmol) in DCM (20 mL). Then add sodium triacetoxyborohydride (6.0 g, 28.3 mmol) to the reaction mixture. Stir the reaction mixture at room temperature for 16 hours. Quench the mixture with 10 mL of MeOH. Dilute the mixture with EtOAc (200 mL). Then filter the mixture and concentrate the filtrate under reduced pressure. Purify the residue by flash column chromatography (40 g silica gel column, 0 to 20% MeOH (5% NH 4 OH) / DCM) to obtain the desired product (720 mg, 19% yield). LC-MS: m / z 233.1 [M+H] + .

[0523]

[0524] Intermediate 79

[0525]

[0526] Step 1

[0527] 1-((6-Bromopyridin-2-yl)methyl)-4-ethylpiperazine (300 mg, 1.1 mmol), bis(4-methoxybenzyl)amine (327 mg, 1.3 mmol), Pd 2 (dba) 3 (302 mg, 0.3 mmol), RuPhos (306 mg, 0.7 mmol) and Cs 2 CO 3 (718 mg, 2.2 mmol) in a mixture of dioxane (10 mL) was stirred at 110 °C for 4 h under N 2 protection. EtOAc (80 mL) was added to this 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 to 10% MeOH / DCM) to give the desired product as a pale yellow solid (409 mg, 84% yield). LC-MS: (ESI) m / z 461.3 [M+H] + 。

[0528] Step 2

[0529] 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 using 0-10% methanol / dichloromethane elution to give the desired product as a blank solid (50.0 mg, 80% yield). LC-MS: (ESI) m / z 221 [M+H] + 。

[0530] Intermediate 80

[0531]

[0532] 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) at 25 °C was added cesium carbonate (11.7 g, 36.1 mmol). The mixture was then 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 using 0-15% methanol / dichloromethane elution in 20 min to give the desired product as a brown solid (1.2 g, 35% yield). LC-MS: m / z 281.2 [M+H] + 。

[0533] Additional intermediates of the present invention are prepared by using the corresponding derivatives. The following table lists selected compounds and their corresponding characterization data.

[0534]

[0535] Synthesis Example 1

[0536]

[0537] In N 2 under, at 25 °C, 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 Pd 2 (dba) 3 (15.1 mg, 16.5 μmol), RuPhos (7.7 mg, 16.5 μmol) and cesium carbonate (161 mg, 494 μmol). The resulting mixture was stirred at 105 °C for 6 hours. 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 as a yellow solid (8.7 mg, 12% yield). LC-MS: m / z 429.2 [M+H] + .

[0538] CDK4 IC 50 : A; CDK6 IC 50 : B; CDK2 IC 50 : C.

[0539] Synthesis Example 16

[0540]

[0541] 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 under a nitrogen atmosphere at 110 °C for 4 hours. 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 Na 2 SO4 Drying. The mixture was concentrated under reduced pressure and purified by flash column chromatography (DCM / MeOH = 10:1) to afford the desired product as a yellow solid (23.8 mg, 39% yield). LC-MS: m / z 471.2 [M+H] + .

[0542] CDK4 IC 50 : A; CDK6 IC 50 : A; CDK2 IC 50 : B.

[0543] Synthesis Examples 160 and 161

[0544]

[0545] N-[5-[4-(Dimethylamino)-1-piperidinyl]-2-pyridinyl]-4-(3-isopropylpyrazolo[1,5-a]pyridin-5-yl)pyrimidin-2-amine (210 mg, 459.9 μmol) was subjected to chiral separation by SFC with mobile phase (hexane / EtOH / DEA = 60 / 40 / 0.1) (wavelength: UV 214 nm, column: CHIRALCEL OD-H 5.0 cm I.D. × 25 cm L, flow rate: 60 mL / min) to afford Synthesis Example 160 as a yellow solid (44.2 mg, 21% yield) (LC-MS: m / z 471.2 [M+H] + . ee value > 99%) and Synthesis Example 161 as a yellow solid (41.0 mg, 19% yield) (LC-MS: m / z 471.2 [M+H] + . ee value 97%).

[0546] Synthesis Example 160, CDK4 IC 50 : A; CDK6 IC 50 : B; CDK2 IC 50 : B.

[0547] Synthesis Example 161, CDK4 IC 50 : A; CDK6 IC 50 : A; CDK2 IC 50 : A.

[0548] Synthesis Example 10

[0549]

[0550] In N 2Under a nitrogen atmosphere, tris(dibenzylideneacetone)dipalladium(0) (9.45 mg, 10.3 μmol), dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphine (9.6 mg, 20.6 μmol), and cesium carbonate (100.8 mg, 309.5 μmol) were added 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). 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 as a pale yellow solid (9 mg, 20% yield). LC-MS: m / z 433.2 [M+H] + 。

[0551] CDK4 IC 50 : B; CDK6 IC 50 : C; CDK2 IC 50 : B。

[0552] Synthesis Example 175

[0553]

[0554] Under a nitrogen 2 atmosphere, 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) were added 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). The reaction mixture was then stirred at 110 °C for 3 h under a nitrogen 2 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% MeOH / DCM) to give the desired product as a yellow solid (25 mg, 37% yield). LC-MS: m / z 485.3 [M+H] + 。

[0555] CDK4 IC 50 : A; CDK6 IC 50 : A; CDK2 IC 50 : A。

[0556]

[0557]

[0558]

[0559]

[0560]

[0561]

[0562]

[0563]

[0564] Synthesis Example 29

[0565]

[0566] Step 1

[0567] 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-pyridin-3-yl)-3-oxo-piperazine-1-carboxylate (196 mg, 670 μmol) in dioxane (20 mL) at 25 °C was added tris(dibenzylideneacetone)dipalladium(0) (47.2 mg, 51.6 μmol), RuPhos (24.0 mg) and cesium carbonate (336 mg, 1.0 mmol). 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 / DCM in 20 min to afford the desired product as a pale yellow solid (240 mg, 85% yield). LC-MS: m / z 547.2 [M+H] + .

[0568] Step 2

[0569] To a solution of tert-butyl 4-[6-[[5-fluoro-4-(3-isopropylpyrazolo[1,5-a]pyridin-5-yl)pyrimidin-2-yl]amino]pyridin-3-yl]-3-oxo-piperazine-1-carboxylate (240 mg, 439 μmol) in DCM (2 mL) at 25 °C was added HCl (2 mL, 2N in EA). The mixture was then stirred for 2 h. The mixture was filtered and the residue was washed with Et 2 O (10 mL) to afford the desired product as a yellow solid (190 mg, 96% yield). LC-MS: m / z 447.2 [M+H] +。

[0570] CDK4 IC 50 : A; CDK6 IC 50 : B; CDK2 IC 50 : B。

[0571] Synthesis Example 204

[0572]

[0573] Step 1

[0574] To a solution of tert-butyl N-[1-(6-amino-3-pyridinyl)-2-oxo-4-piperidinyl]-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). The reaction mixture was stirred in a 15 mL sealed tube 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 to 10% MeOH / DCM) to afford the desired product as a yellow oil (544 mg, 78% yield). LC-MS: m / z 557.3 [M+H] + 。

[0575] Step 2

[0576] To a solution of tert-butyl N-[1-[6-[[4-(3-isopropylpyrazolo[1,5-a]pyridin-5-yl)pyrimidin-2-yl]amino]-3-pyridinyl]-2-oxo-4-piperidinyl]-N-methyl-carbamate (544 mg, 977.2 μmol) in DCM (10 mL) at 25 °C was added hydrochloric acid solution (2.0 M in ethyl acetate) (5 mL). The mixture was stirred at 25 °C for 2 h. The mixture was filtered and concentrated in vacuo to afford the desired product as a yellow solid (430 mg, 96% yield). LC-MS: m / z 457.3 [M+H] + 。

[0577] CDK4 IC 50 : A; CDK6 IC 50 : A; CDK2 IC 50 : A。

[0578] Synthesis Examples 205 and 206

[0579]

[0580] 1-[6-[[4-(3-Isopropylpyrazolo[1,5-a]pyridin-5-yl)pyrimidin-2-yl]amino]-3-pyridinyl]-4-(methylamino)piperidin-2-one (380 mg, 832 μmol) was subjected to chiral separation by an ID column with a mobile phase (MeOH / ACN / DEA = 50 / 50 / 0.1) (wavelength: UV 214 nm, column: CHIRALPAK ID-H 25 cm L 5.0 cm I.D., 10 μm, flow rate: 60 g / min) to obtain Synthesis Example 205 as a white solid (132 mg, 34% yield) (LC-MS: m / z 457.3 [M+H] + . ee value: >98%) and Synthesis Example 206 as a white solid (120 mg, 31% yield) (LC-MS: m / z 457.3 [M+H] + . ee value: >98%).

[0581] Synthesis Example 205, CDK4 IC 50 : A; CDK6 IC 50 : A; CDK2 IC 50 : A.

[0582] Synthesis Example 206, CDK4 IC 50 : A; CDK2 IC 50 : A.

[0583]

[0584]

[0585]

[0586]

[0587]

[0588]

[0589]

[0590] Synthesis Example 39

[0591]

[0592] Step 1

[0593] In N 2Under an atmosphere, 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) were added 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). The reaction was stirred at 110 °C for 8 hours. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with 0-35% MeOH / DCM) to give the desired product as a yellow solid (90.0 mg, 67% yield). LC-MS: m / z 292.2 [M+H] + 。

[0594] Step 2

[0595] Under an N 2 atmosphere, cesium carbonate (300 mg, 923 μmol), dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphine (28.7 mg, 61.5 μmol) and tris(dibenzylideneacetone)dipalladium(0) (28.1 mg, 30.7 μmol) were added to a solution of tert-butyl N-[1-(6-amino-3-pyridyl)-5-oxopyrrolidin-3-yl]carbamate (90.0 mg, 307 μmol) and 5-(2-chloropyrimidin-4-yl)-3-isopropylpyrazolo[1,5-a]pyridine (83.9 mg, 307 μmol) in dioxane (2 mL). The reaction was stirred at 110 °C for 8 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using 0-10% MeOH / DCM elution to give the desired product as a yellow solid (90.0 mg, 55% yield). LC-MS: m / z 529.3 [M+H] + 。

[0596] Step 3

[0597] To a solution of tert-butyl N-[1-[6-[[4-(3-isopropylpyrazolo[1,5-a]pyridin-5-yl)pyrimidin-2-yl]amino]-3-pyridinyl]-5-oxopyrrolidin-3-yl]carbamate (90.0 mg, 170 μmol) in DCM (10 mL) was added EA containing HCl (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 / DCM to afford the desired product as a yellow solid (70.0 mg, 95% yield). LC-MS: m / z 429.2 [M+H] + 。

[0598] Step 4

[0599] A solution of 4-amino-1-[6-[[4-(3-isopropylpyrazolo[1,5-a]pyridin-5-yl)pyrimidin-2-yl]amino]-3-pyridinyl]pyrrolidin-2-one (50.0 mg, 116 μmol) and formaldehyde (14.0 mg, 466 μmol) in DCM (5 mL) was 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 afford the desired product as a yellow solid (15.9 mg, 29% yield). LC-MS: m / z 457.2 [M+H] + 。

[0600] CDK4 IC 50 : A; CDK6 IC 50 : B; CDK2 IC 50 : B。

[0601] Synthesis Example 40

[0602]

[0603] Step 1

[0604] To a solution of 1-[6-[[4-(3-isopropylpyrazolo[1,5-a]pyridin-5-yl)pyrimidin-2-yl]amino]-3-pyridinyl]piperazin-2-one (80 mg, 186 μmol) and tert-butyl 3-oxoazetidine-1-carboxylate (63.9 mg, 373 μmol) in DCM (10 mL) were 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 treated with H2 Washed with O(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, 0 - 10% MeOH / DCM) to obtain the desired product as a yellow solid (72.0 mg, 66% yield). LC-MS: m / z 584.3 [M+H] + .

[0605] Step 2

[0606] A solution of tert-butyl 3-[4-[6-[[4-(3-isopropylpyrazolo[1,5-a]pyridin-5-yl)pyrimidin-2-yl]amino]-3-pyridinyl]-3-oxopiperazin-1-yl]azetidine-1-carboxylate (70.0 mg, 119 μmol) in HCl / 1,4-dioxane (1 N, 10 mL) was stirred at 25 °C for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography (20 g silica gel column, 0 - 10% MeOH / DCM) to obtain the desired product as a yellow solid (12.5 mg, 21% yield). LC-MS: m / z 484.2 [M+H] + .

[0607] CDK4 IC 50 : A; CDK6 IC 50 : B; CDK2 IC 50 : B.

[0608]

[0609] Synthesis Example 43

[0610]

[0611] A solution of 4-[6-[[5-fluoro-4-(3-isopropylpyrazolo[1,5-a]pyridin-5-yl)pyrimidin-2-yl]amino]-3-pyridinyl]-1,4-diazepan-5-one (40.0 mg, 86.8 μmol), azetidin-3-one (9.0 mg, 124 μmol) and NaBH 3 CN (20.0 mg, 300 μmol) in methanol (8 mL) was stirred at 25 °C for 16 hours. The mixture was filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC to obtain the desired product as a yellow solid (12.3 mg, 27% yield). LC-MS: m / z 517.3 [M+H] + .

[0612] CDK4 IC 50 : A; CDK6 IC 50: B; CDK2 IC 50 : B.

[0613]

[0614] Synthesis Example 49

[0615]

[0616] A solution of 4-[6-[[5-fluoro-4-(3-isopropylpyrazolo[1,5-a]pyridin-5-yl)pyrimidin-2-yl]amino]-3-pyridinyl]-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 toluene (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 as a yellow solid (2 mg, 9% yield). LC-MS: m / z 501.2 [M+H] + .

[0617] CDK4 IC 50 : A; CDK2 IC 50 : C.

[0618] Synthesis Example 50

[0619]

[0620] Methanesulfonyl chloride (7.3 mg, 64.2 μmol) was added to a stirred solution of 1-[6-[[5-fluoro-4-(3-isopropylpyrazolo[1,5-a]pyridin-5-yl)pyrimidin-2-yl]amino]-3-pyridinyl]-1,4-diazepan-2-one (22.0 mg, 47.7 μmol) and TEA (10 mg, 100 μmol) in DCM (5 mL). 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 as a yellow solid (5.0 mg, 17% yield). LC-MS: m / z 539.2 [M+H] + .

[0621] CDK4 IC 50 : A; CDK6 IC 50 : B; CDK2 IC 50 : B.

[0622]

[0623] Synthesis Example 52

[0624]

[0625] At 25 °C, 2-iodoethanol (13.4 mg, 78.3 μmol) was added to a solution of 5-[6-[[5-fluoro-4-(3-isopropylpyrazolo[1,5-a]pyridin-5-yl)pyrimidin-2-yl]amino]-3-pyridinyl]aza-4-one (30.0 mg, 65.2 μmol) and potassium carbonate (27.0 mg, 195 μmol) in acetonitrile (5 mL). 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 as a yellow solid (5.0 mg, 15% yield). LC-MS: m / z 505.3 [M+H] + 。

[0626] CDK4 IC 50 : A; CDK6 IC 50 : B; CDK2 IC 50 : B。

[0627]

[0628] Synthesis Example 55

[0629]

[0630] A solution of 4-(3-isopropylpyrazolo[1,5-a]pyridin-5-yl)-N-[1-(4-piperidinylmethyl)pyrazol-3-yl]pyrimidin-2-amine (20.0 mg, 48.0 μmol), glycolic 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 as a yellow solid (3.7 mg, 16% yield). LC-MS: (ESI) m / z 475.3 [M+H] + 。

[0631] CDK4 IC50 : B; CDK2 IC 50 : D。

[0632]

[0633] Synthesis Example 57

[0634]

[0635] 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-aminopyridin-3-yl)tetrahydropyran-3-one (54.8 mg, 285 μmol), tris(dibenzylideneacetone)dipalladium(0) (21.7 mg, 23.7 μmol), dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphine (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 a N 2 atmosphere. 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 Na 2 SO 4 and then filtered. The filtrate was concentrated. The residue was purified by preparative HPLC to give the desired product as a white solid (9.9 mg, 19% yield). LC-MS: (ESI) m / z 435.3 [M+H] + 。

[0636] CDK4 IC 50 : A; CDK6 IC 50 : C; CDK2 IC 50 : B。

[0637]

[0638]

[0639]

[0640]

[0641] Synthesis Example 58

[0642]

[0643] A mixture of 5-(6-chloro-3-fluoro-2-pyridinyl)-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), Pd 2 (dba) 3 (4.5 mg, 4.9 μmol), RuPhos (4.5 mg, 9.8 μmol) and Cs 2 CO 3 (64.1 mg, 196 μmol) in dioxane (4 mL) was stirred at 100 °C for 1 h under a N 2 atmosphere. The reaction mixture was quenched with water (50 mL) and extracted with EA (2 × 100 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the desired product as a yellow solid (3.0 mg, 6% yield). LC-MS: (ESI) m / z 490.1 [M+H] + .

[0644] CDK4 IC 50 : C; CDK6 IC 50 : D.

[0645] Synthesis Example 59

[0646]

[0647] Step 1

[0648] 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), Pd 2 (dba) 3 (10.0 mg, 10.0 μmol), RuPhos (10.0 mg, 19.0 μmol) and Cs 2 CO 3 (130 mg, 400 μmol) in dioxane (8 mL) was stirred at 100 °C for 1 h under a N 2 atmosphere. The reaction mixture was quenched with water (50 mL) and extracted with EA (2 × 100 mL). The combined organic phases were dried over anhydrous Na 2 SO 4Dry and then filter. Concentrate the filtrate under reduced pressure. Purify the residue by preparative HPLC to obtain the desired product (60 mg, 50%). LC-MS: (ESI) m / z 535.2 [M+H] + .

[0649] Step 2

[0650] Stir 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 (1 N, 10 mL) at 25 °C for 2 h. Concentrate the mixture under reduced pressure and purify the residue by flash column chromatography (20 g silica gel column, 0-10% MeOH / DCM) to obtain the desired product as a yellow solid (38.0 mg, 78% yield). LC-MS: m / z 435.2 [M+H] + .

[0651] CDK4 IC 50 : A; CDK6 IC 50 : B; CDK2 IC 50 : B.

[0652]

[0653]

[0654]

[0655] Synthesis Example 60

[0656]

[0657] Step 1

[0658] To a solution of 5-bromo-3-methoxypyrazin-2-amine (500 mg, 2.5 mmol) in EtOH (10 mL) at 25 °C, add 2-chloro-3-methylbutanal (443 mg, 3.68 mmol) dropwise. Stir the mixture at 80 °C for 2 h. Concentrate the mixture to obtain a residue. Purify the residue by silica gel column chromatography (PE:EtOAc = 10:1-5:1) to obtain the desired product as a yellow solid (25.0 mg, 4% yield). LC-MS: (ESI) m / z 270.0 [M+H] + .

[0659] Step 2

[0660] In N 2Under an atmosphere, at 25 °C, 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 B 2 Pin 2 (150 mg, 0.6 mmol), KOAc (27.0 mg, 0.3 mmol), and Pd(dppf)Cl 2 (15.0 mg, 0.02 mmol). The mixture was stirred at 110 °C for 3 hours. The mixture was filtered through Celite and concentrated to give the desired product as a yellow solid (30 mg), which was used in the next step without purification. LC-MS: (ESI) m / z 236.1 [M+H] + .

[0661] Step 3

[0662] Under an N 2 atmosphere, at 25 °C, 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 K 2 CO 3 (30.0 mg, 0.2 mmol) and Pd(dppf)Cl 2 (15.0 mg, 0.02 mmol). The mixture was stirred at 100 °C for 3 hours. The mixture was filtered through Celite and concentrated. The residue was purified by preparative HPLC to give the desired product as a yellow solid (5.1 mg, 9% yield). LC-MS: (ESI) m / z 506.3 [M+H] + .

[0663] CDK4 IC 50 : B; CDK6 IC 50 : C.

[0664] Synthesis Example 61

[0665]

[0666] 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) was added 4-(6-amino-3-pyridyl)morpholin-3-one (16.0 mg, 82.8 μmol), dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphine (12.0 mg, 25.7 μmol), tris(dibenzylideneacetone)dipalladium (11.0 mg, 12.0 μmol) and cesium carbonate (80.0 mg, 245 μmol), and the mixture was degassed with N 2 The resulting mixture was stirred at 100 °C for 12 h. The mixture was concentrated and purified by column (DCM / MeOH = 20 / 1 - 8 / 1) to afford the desired product (1 mg, 3% yield). LC-MS: m / z 449.1 [M+H] + .

[0667] CDK4 IC 50 : A; CDK6 IC 50 : B; CDK2 IC 50 : B.

[0668] Synthesis Example 287

[0669]

[0670] 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 Pd 2 (dba) 3 (47.1 mg, 51 μmol), RuPhos (47.9 mg, 102 μmol) and Cs 2 CO 3 (502.6 mg, 1.5 mmol). The mixture was stirred at 110 °C under N 2 for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0 - 10% MeOH / DCM to afford the desired product as a yellow solid (107.2 mg, 43% yield). LC-MS: m / z 476.2 [M+H] + .

[0671] CDK4 IC 50 : A; CDK6 IC 50 : B; CDK2 IC 50 : C.

[0672] Synthesis Example 301

[0673]

[0674] Step 1

[0675] To a solution of 6-(2-chloropyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methylimidazo[4,5-c]pyridine (150 mg, 490.6 μmol) and tert-butyl N-[1-(6-amino-3-pyridyl)-2-oxo-3-piperidinyl]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 μmol), 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 using 0 - 4% MeOH / DCM elution within 15 minutes to afford the desired product as a yellow solid (170 mg, 60% yield).

[0676] Step 2

[0677] To a solution of tert-butyl N-[1-[6-[[4-(4-fluoro-1-isopropyl-2-methylimidazo[4,5-c]pyridin-6-yl)pyrimidin-2-yl]amino]-3-pyridyl]-2-oxo-3-piperidinyl]carbamate (170 mg, 295.3 μmol) in DCM (5 mL) was added HCl (2 M, 738 μL). The reaction was stirred at 25 °C for 3 hours. The reaction was concentrated under reduced pressure to afford the desired product as a yellow solid (140 mg, 99% yield).

[0678] Step 3

[0679] To a solution of 3-amino-1-[6-[[4-(4-fluoro-1-isopropyl-2-methylimidazo[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 hour, sodium cyanoborohydride (31.7 mg, 504.7 μmol) was added to the above solution. The reaction was stirred at 25 °C for 2 hours. The reaction was concentrated under reduced pressure. The residue was purified by preparative HPLC to afford the desired product as a yellow solid (5.7 mg, 6% yield). LC-MS: m / z 504.3 [M + H] + 。

[0680] CDK4 IC50 : A; CDK6 IC 50 : A; CDK2 IC 50 : D。

[0681] Synthesis Examples 302 and 303

[0682]

[0683] 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: CO 2 / MeOH (0.1% DEA) = 70 / 30; flow rate: 2.0 mL / min) to obtain Synthesis Example 302 (50 mg, 29% yield) (LC-MS: m / z 504.3 [M+H] + . ee value: 94%) and Synthesis Example 303 (50 mg, 29% yield) as a white solid (LC-MS: m / z 504.3 [M+H] + . ee value: 94%).

[0684] Synthesis Example 302, CDK4 IC 50 : A; CDK2 IC 50 : D。

[0685] Synthesis Example 303, CDK4 IC 50 : A; CDK2 IC 50 : D。

[0686]

[0687]

[0688]

[0689]

[0690]

[0691]

[0692]

[0693] Synthesis Example 62

[0694]

[0695] 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'-diisopropoxy-1,1'-biphenyl (33.0 mg, 72.6 μmol) in dioxane (10 mL) was added Cs 2 CO 3 (355 mg, 1.1 mmol) and tris(dibenzylideneacetone)dipalladium (33.0 mg, 36.3 μmol). The resulting mixture was stirred at 110 °C for 4 h under a 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) eluting with (ACN: water (0.1% formic acid) = 1:10) to give the desired product as a white solid (9.8 mg, 5% yield). LC-MS: m / z 534.3 [M+H] + .

[0696] CDK4 IC 50 : A; CDK6 IC 50 : B; CDK2 IC 50 : D.

[0697] Synthesis Examples 62-1 and 62-2

[0698]

[0699] 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 (equipment: SFC 80, column: Daicel CHIRALPAK OJ-H 250 mm 20 mm I.D., 5 μm, mobile phase: CO 2 / MeOH (0.2% NH 4 OH) = 50 / 50, flow rate: 45 g / min, wavelength: UV214 nm, temperature: 35 °C) to give isomer 2: (2.3 mg, 29% yield), LC-MS: m / z 534.3 [M+H] + , retention time at room temperature = 12.72 min, ee > 99%; isomer 1: (1.6 mg, 20% yield), LC-MS: m / z 534.3 [M+H] +, Room temperature = 10.95 minutes, ee value > 99%.

[0700] Example 62-1, CDK4 IC 50 : A; CDK6 IC 50 : B; CDK2 IC 50 : D.

[0701] Example 62-2, CDK4 IC 50 : A; CDK6 IC 50 : B; CDK2 IC 50 : D.

[0702]

[0703]

[0704]

[0705]

[0706]

[0707]

[0708]

[0709]

[0710]

[0711] Synthesis Example 106

[0712]

[0713] Step 1

[0714] 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-pyridin-3-yl)piperazine-1-carboxylate (69.6 mg, 250 μmol), tris(dibenzylideneacetone)dipalladium(0) (19.0 mg, 20.8 μmol), (5-diphenylphosphoryl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphine (24.1 mg, 41.7 μmol) and cesium carbonate (203 mg, 625 μmol). The mixture was stirred at 110 °C for 16 h. 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 / DCM in 20 min) to afford the desired product as a white solid (92.0 mg, yield: 76%). LC-MS: m / z 578.2 [M+H] + 。

[0715] Step 2

[0716] 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]pyridin-3-yl]piperidine-1-carboxylate (92.0 mg, 159 μmol) in dry DCM (5 mL) was added hydrogen chloride (4 N 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 afford the desired product as a yellow solid (10.8 mg, 14% yield). LC-MS: m / z 478.2 [M+H] + 。

[0717] CDK4 IC 50 : A; CDK6 IC 50 : B; CDK2 IC 50 : D。

[0718]

[0719]

[0720]

[0721] Synthesis Example 121

[0722]

[0723] 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-pyridinyl]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. Then the reaction mixture was diluted with H 2 O (30 mL) and extracted with EA (3 × 10 mL). The organic layer was concentrated under reduced pressure. The residue was purified by preparative HPLC using 22%-24% acetonitrile / water (0.1% FA) elution in 6.0 min to afford the desired product as a yellow solid (2.7 mg, 4% yield). LC-MS: m / z 598.3 [M+H] + .

[0724] CDK4 IC 50 : A; CDK6 IC 50 : B; CDK2 IC 50 : D.

[0725]

[0726] Synthesis Example 127

[0727]

[0728] 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-pyridinyl]piperazin-2-one (0.2 g, 305 μmol) and TEA (92.6 mg, 915 μmol) in DCM (5 mL) at 0 °C was added methanesulfonyl chloride (52.4 mg, 457 μmol) dropwise. The mixture was stirred at 0 °C for 0.5 h. The mixture was concentrated and purified by preparative HPLC to afford the desired product as a yellow solid (7.8 mg, 4% yield). LC-MS: m / z 570.2 [M+H] + .

[0729] CDK4 IC 50 : A; CDK6 IC 50 : B; CDK2 IC 50 : C.

[0730] Synthesis Example 128

[0731]

[0732] 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-pyridinyl]piperazin-2-one (100 mg, 203 μmol) and acetaldehyde (17.9 mg, 406 μmol) in DCM (5 mL) was added NaB(OAc) 3 H (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 Na 2 SO 4 dried, filtered, concentrated, and purified by preparative HPLC to afford the desired product as a yellow solid (16.0 mg, 15% yield).

[0733] CDK4 IC 50 : A; CDK6 IC 50 : B; CDK2 IC 50 : D.

[0734]

[0735]

[0736]

[0737] Synthesis Example 138

[0738]

[0739] Step 1

[0740] 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-pyridinyl]piperazin-2-one (50.0 mg, 101 μmol). The reaction mixture was stirred at 25 °C for 1 h under N 2 atmosphere. Sodium cyanoborohydride (12.8 mg, 203 μmol) was added to the above mixture. The reaction mixture was stirred at 25 °C for 11 h under N 2 atmosphere. The mixture was concentrated and purified by flash column chromatography (4 g silica gel column) using DCM / MeOH elution with 0 - 6% MeOH to afford the desired product as a yellow solid (25.0 mg, 38% yield). LC-MS: m / z 647.3 [M+H]+ .

[0741] Step 2

[0742] To a stirred solution of tert-butyl 3-[4-[6-[[5-fluoro-4-(1-isopropyl-4-methoxy-2-methylimidazo[4,5-c]pyridin-6-yl)pyrimidin-2-yl]amino]-3-pyridinyl]-3-oxopiperazin-1-yl]azetidine-1-carboxylate (20.0 mg, 30.9 μmol) in DCM (3 mL) was added HCl (1 N in dioxane, 3 mL). The reaction mixture was stirred at 25 °C for 1 h under N 2 atmosphere. The mixture was concentrated and purified by preparative HPLC to afford the desired product as a yellow solid (1.8 mg, 11% yield). LC-MS: m / z 547.2 [M+H] + .

[0743] CDK4 IC 50 : A; CDK6 IC 50 : B; CDK2 IC 50 : C.

[0744]

[0745] Synthesis Example 140

[0746]

[0747] 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 were added N-[4-(1-isopropyl-4-methoxyimidazo[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 afford the desired product as a yellow solid (14.5 mg, 43% yield). LC-MS: (ESI) m / z 502.2 [M+H] + .

[0748] CDK4 IC 50 : A; CDK6 IC 50 : B; CDK2 IC 50 : D.

[0749]

[0750] Synthesis Example 143

[0751]

[0752] Step 1

[0753] A solution of 2-chloro-3-methyl-butanal (1.1 g, 9.1 mmol) and 5-bromo-pyrazin-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 × 25 mL). The combined organic phases were concentrated under reduced pressure. The residue was purified by FCC (20 g silica gel, 0 - 50% EtOAc / PE) to afford the desired product as a yellow solid (200 mg, 9% yield). LC-MS: (ESI) m / z 240.2 [M+H] + .

[0754] Step 2

[0755] 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), K 2 CO 3 (276 mg, 2.0 mmol) and Pd(dppf)Cl 2 (73.1 mg, 99.9 μmol) in dioxane (10 mL) and H 2 O (0.5 mL) was stirred at 110 °C for 16 h under N 2 . The mixture was concentrated under reduced pressure. The residue was purified by FCC (20 g silica gel, 0 - 10% MeOH / DCM) to afford the desired product as a dark solid (77.0 mg, 30% yield). LC-MS: (ESI) m / z 255.1 [M+H] + .

[0756] Step 3

[0757] 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), Cs 2 CO 3 (197 mg, 605 μmol), RuPhos (28.2 mg, 60.5 μmol) and Pd 2 (dba) 3A solution of (27.7 mg, 30.2 μmol) in dioxane (8 mL) was stirred at 110 °C for 16 h under N 2 + . The mixture was concentrated under reduced pressure. The residue was purified by FCC (12 g silica gel, 0 - 10% MeOH / DCM) to afford the desired product as a yellow solid (95.0 mg, 59% yield). LC-MS: (ESI) m / z 530.2 [M+H]

[0758] Step 4

[0759] To a solution of tert-butyl 4-[6-[[4-(3-isopropylimidazo[1,2-a]pyrazin-6-yl)pyrimidin-2-yl]amino]-3-pyridyl]-3-oxopiperazine-1-carboxylate (95.0 mg, 179 μmol) in DCM (8 mL) at 25 °C was added HCl (4 N, 180 μL). 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 afford the desired product as a yellow solid (19.4 mg, 25% yield). LC-MS: (ESI) m / z 430.2 [M+H] + .

[0760] CDK4 IC 50 : B; CDK2 IC 50 : D.

[0761] Comparative Synthesis Example 1

[0762] Compound 10 disclosed in CN109503573A was prepared. As shown in the following table, the activity of this compound in the CDK4 and CDK6 assays was very weak.

[0763]

[0764] Table A

[0765]

[0766]

[0767]

[0768]

[0769] IC 50 ≤100 nM: "++++"

[0770] 100 nM < IC 50 ≤500 nM: "+++"; 500 nM < IC 50≤1 μM: “++”

[0771] 1 μM < IC 50 : “+”

Claims

1. A compound represented by structural formula (I): or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ring A is Ring B is a bond, a 3- to 10-membered heterocyclic group, or a 5- to 10-membered heteroaryl; Ring C is a 5- to 6-membered heteroaryl group, a 5- to 10-membered heterocyclic group, a phenyl group, or a 5- to 10-membered bridged bicyclic group, each of which is optionally substituted by one or two R 12 substituents; The linker L is a bond, -(CH 2 ) q -, -(CH 2 ) q O-, -NR a (CH 2 ) q -, -C(O)-, -C(O)N(R a )-, or -S(O) 2 -; R a Each instance of is H or CH 3 ; R 1 is H, deuterium, a halogen, -OH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy; R 2 Each instance of 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 SR 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 NR 7 R 8 、-(CH 2 ) n C(O)NR 7 R 8 、-(CH 2 ) n NR 7 C(O)R 6 、-(CH 2 ) n NR 7 S(O) m R 6 、C 3-8 cycloalkyl, 3 - to 10 - membered heterocyclic group, 6 - to 14 - membered aryl group, 5 - to 14 - membered heteroaryl group, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic group, aryl or heteroaryl group represented by R 2 is each optionally substituted by one or more groups selected from deuterium, halogen, CN, -OH, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy and NR 7 R 8 ; or When ring B is a 3- to 10-membered heterocyclic group, two Rs attached to the same ring atom of ring B 2 may form a C 3-6 cycloalkyl group or a 3- to 6-membered heterocyclic group, and the C 3-6 cycloalkyl group or 3- to 6-membered heterocyclic group is optionally substituted by one or more groups selected from deuterium, halogen, CN, -OH, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy and NR 7 R 8 ; R 3 Each instance of is independently selected from H, deuterium, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl or a 3- to 10-membered heterocyclic group; wherein the C 3 represented by R 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl or a 3- to 10-membered heterocyclic group is optionally substituted by one or more groups selected from deuterium, halogen, CN, -OH, C 1-8 alkyl and C 1-8 haloalkyl; R 4 Each instance of is independently selected from 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 a 3- to 10-membered heterocyclic group; wherein the C 4 represented by R 4 or in the group represented by R 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 alkoxy, C 3-8 cycloalkyl or a 3- to 10-membered heterocyclic group is each optionally substituted by one or more groups selected from deuterium, halogen, -OH, C 1-8 alkyl and C 1-8 haloalkyl; or Two Rs attached to the same ring atom of ring A 4 groups form a C 3-6 cycloalkyl or 3- to 6-membered heterocyclic group, each of which is optionally substituted by one or more groups selected from deuterium, halogen, CN, -OH, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy and NR 7 R 8 ; and R 5 Each instance of which 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 a 3- to 6-membered heterocyclic group; R 6 Each instance of which is independently H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 14-membered aryl, 5- to 14-membered heteroaryl, wherein the C 6 represented by R 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 14-membered aryl, 5- to 14-membered heteroaryl is each optionally substituted by one or more groups selected from halogen, CN, -OH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy and NR 7 R 8 ; R 7 and R 8 each instance in is H, C 1-4 alkyl or cyclopropyl; R 12 Each instance of is H, deuterium, halogen, -OH, CN, NH 2 , C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 alkoxy, C 3-8 cycloalkyl or a 3- to 10-membered heterocyclic group; wherein the C 12 represented by R 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 alkoxy, C 3-8 cycloalkyl or a 3- to 10-membered heterocyclic group is optionally substituted by one or more groups selected from halogen, CN, -OH, C 1-4 alkyl, C 1-4 haloalkyl and C 1-4 alkoxy; q is 0, 1, or 2; n is 0, 1, 2, 3, 4, or 5; and m is 0, 1, or 2.

2. The compound or a pharmaceutically acceptable salt or stereoisomer thereof according to claim 1, wherein Ring C is 3. The compound or a pharmaceutically acceptable salt or stereoisomer thereof according to claim 1 or 2, wherein Ring A is wherein R 3 Each instance of which is H, deuterium, C 1-4 alkyl optionally substituted with -OH or C 3-6 cycloalkyl; R 4 Each instance of R is H, deuterium, a halogen, a C 1-4 alkyl group optionally substituted with fluorine, a C 2-4 alkenyl group, a C 3-6 cycloalkyl group or a 3- to 6-membered heterocyclic group; or two R 4 groups attached to the same ring atom of ring A form a C 3-6 cycloalkyl group or a 3- to 6-membered heterocyclic group, each of which is optionally substituted with one or more groups selected from halogen, CN, -OH, C 1-2 alkyl group, C 1-2 alkoxy group and NR 7 R 8 group; R 5 is H, deuterium, halogen, CN, -OH, C 1-4 alkyl, C 1-4 alkoxy or C 1-4 haloalkoxy.

4. The compound according to any one of claims 1 to 3, wherein the compound is represented by structural formulas (II-A)-(II-J): or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 12 is H, F, Cl, CH 3 or CF 3 ; and k is 0, 1 or 2.

5. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein L is a bond, -(CH 2 )-, -O(CH 2 )-, -C(=O)- or -S(O) 2 -.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ring B is a 4- to 10-membered heterocyclic group or a 5- to 6-membered monocyclic heteroaryl group optionally substituted with one or two R 2 groups.

7. The compound or a pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1 to 6, wherein R 2 Each instance of 1-4 is H, halogen, CN, -OH, C 1-4 alkyl, C 1-4 haloalkyl, C 2 hydroxyalkyl, -(CH n ) 6 OR 2 ) n C(O)R 6 ) 2 ) n C(O)OR 6 ) 2 ) n S(O) 2 R 6 ) 2 ) n NR 7 R 8 、 -(CH 2 ) n C(O)NR 7 R 8 、-(CH 2 ) n C(O)NHR 7 、-(CH 2 ) n NR 7 C(O)R 6 、-(CH 2 ) n NR 7 S(O) 2 R 6 、C 3-8 cycloalkyl, 3- to 6-membered heterocyclic group, phenyl or 5- to 6-membered heteroaryl; or Two Rs attached to the same ring atom of ring B 2 form a 3- to 6-membered heterocyclic group (when ring B is a 3- to 10-membered heterocyclic group), and the 3- to 6-membered heterocyclic group is optionally substituted by one or more groups selected from halogen, -OH, C 1-2 alkyl, C 1-2 haloalkyl, C 1-2 alkoxy, C 1-2 haloalkoxy, and NR 7 R 8 ; Each instance of R is independently H, C 6 alkyl, C 1-4 cycloalkyl, 3- to 7-membered heterocyclic group, phenyl, 5- to 6-membered heteroaryl, wherein the C 3-6 represented by R 6 alkyl, C 1-4 cycloalkyl, 3- to 7-membered heterocyclic group, phenyl, 5- to 6-membered heteroaryl is each optionally substituted by halogen, CN, -OH, C 3-6 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or NR 1-4 R 7 R 8 substituted; and n is 0, 1, or 2.

8. A compound or a pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1 to 7, wherein R 1 is H, F, Cl or CH 3 .

9. The compound or a pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1 to 8, wherein Ring B is The selected ground is substituted by one or two R 2 groups.

10. The compound or a pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1 to 9, wherein R 2 Each instance 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 NR 7 R 8 、C 3-4 cycloalkyl or a 3- to 6-membered heterocyclic group; and n is 0, 1 or 2; or When ring B is a 4- to 7-membered heterocyclic group, two Rs attached to the same ring atom of ring B 2 form a 3- to 6-membered heterocyclic group.

11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ring A is 12. A compound or a pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1 to 11, wherein R 1 is H or F.

13. The compound or a pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1 to 12, wherein R 3 Each instance of which is H, C 1-3 alkyl optionally substituted with -OH or C 3-6 cycloalkyl; R 4 each instance of which is H, halogen, C 1-3 alkyl, C 2-4 alkenyl, cyclopentyl, tetrahydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl; and R 5 Each instance of is H, F, CN, methoxy, OCHF 2 .

14. The compound or a pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1 to 13, wherein L is a bond.

15. The compound or a pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1 to 14, wherein Ring B is Each of which is optionally substituted by one or two R 2 groups.

16. The compound or a pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1 to 15, wherein R 2 each instance of which is H, halogen, CN, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, NH 2 , N(CH 3 ) 2 , NH-cyclopropyl, -(CH 2 ) n S(O) 2 C 1-3 alkyl, cyclopropyl, azetidinyl optionally substituted with F, oxetanyl, morpholinyl, piperidinyl, tetrahydro-2H-pyranyl, or When ring B is a piperidyl group, two Rs attached to the same ring atom of ring B 2 form a 2,5-pyrrolidinedionyl or a 2-pyrrolidonyl; and n is 0, 1, or 2.

17. A compound or a pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1 to 16, wherein ring A is 18. The compound or a pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1 to 17, wherein R 3 Each instance of which is H or C 1-3 alkyl; R 4 each instance of which is H or C 1-3 alkyl; and R 5 Each instance of which is H, F or OMe.

19. A compound or a pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1 to 18, wherein R 1 is H.

20. The compound or a pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1 to 19, wherein Ring C is unsubstituted.

21. The compound or a pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1 to 20, wherein ring B is each of which is optionally substituted with one or two R 2 groups.

22. The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2 each instance of is H, halogen, CN, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, NH 2 , N(CH 3 ) 2 , NH cyclopropyl.

23. The compound or a pharmaceutically acceptable salt or stereoisomer thereof according to claim 1, wherein the compound is a compound listed in the examples.

24. A pharmaceutical composition comprising an effective amount of the compound or a pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1 to 23 and a pharmaceutically acceptable carrier.

25. A method of treating cancer, the method comprising administering to a subject in need thereof an effective amount of the compound or a pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1 to 23, 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.

26. A method of treating cancer by inhibiting cyclin-dependent kinase (CDK), the method comprising administering to a subject in need thereof an effective amount of the compound according to any one of claims 1 to 23.

27. The method according to claim 26, wherein the cancer is bladder cancer, breast cancer, colon cancer, kidney cancer, epidermal cancer, liver cancer, lung cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, nasal cancer, head and neck cancer, prostate cancer or skin cancer; lymphoid hematopoietic tumors; myeloid hematopoietic tumors; follicular thyroid cancer; tumors of mesenchymal origin; central or peripheral nervous system tumors; melanoma; seminoma; teratoma; osteosarcoma; xeroderma pigmentosum; keratoacanthoma; follicular thyroid cancer; or Kaposi's sarcoma.

28. The method according to claim 27, wherein the lymphoid hematopoietic tumor is leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, multiple myeloma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma or Burkett's lymphoma.

29. The method according to claim 26, wherein the cancer is pRb + breast cancer or hormone receptor (HR)-positive (e.g., estrogen receptor-positive (ER + ), progesterone receptor-positive (PR + ), or ER + PR + ), HER2 / neu-negative cancer.

30. The method according to claim 29, wherein the cancer is advanced or metastatic or recurrent breast cancer.

31. The method according to claim 30, wherein the breast cancer occurs in adult or postmenopausal women.

32. The method according to any one of claims 29 to 31, further comprising administering a second agent selected from: aromatase inhibitors, selective estrogen receptor modulators (SERMs), pure antiestrogens without estrogen agonist activity, compounds that transiently inhibit ovarian function (e.g., estrogen and / or progesterone production) such as gonadotropin-releasing hormone (GnRH) agonists or luteinizing hormone-releasing hormone (LH-RH) agonists, compounds that inhibit CCYP3A4, or monoclonal antibodies or antigen-binding fragments thereof directed against IGF-1 / IGF-2.

33. The method according to any one of claims 25 to 32, further comprising administering 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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